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Park PG, Choi S, Ahn YH, Kim SH, Kim C, Kim HJ, Kang HG. Single-cell transcriptomics in a child with coenzyme Q10 nephropathy: potential of single-cell RNA sequencing in pediatric kidney disease. Pediatr Nephrol 2025; 40:1653-1662. [PMID: 39805995 PMCID: PMC11946986 DOI: 10.1007/s00467-024-06611-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/07/2024] [Accepted: 11/07/2024] [Indexed: 01/16/2025]
Abstract
BACKGROUND Coenzyme Q10 (CoQ10) nephropathy is a well-known cause of hereditary steroid-resistant nephrotic syndrome, primarily impacting podocytes. This study aimed to elucidate variations in individual cell-level gene expression in CoQ10 nephropathy using single-cell transcriptomics. METHODS We conducted single-cell sequencing of a kidney biopsy specimen from a 5-year-old boy diagnosed with a CoQ10 nephropathy caused by a compound heterozygous COQ2 mutation complicated with immune complex-mediated glomerulonephritis. The analysis focused on the proportion of cell types, differentially expressed genes in each cell type, and changes in gene expression related to mitochondrial function and oxidative phosphorylation (OXPHOS). RESULTS Our findings revealed a uniform downregulation of mitochondrial gene expression across various cell types in the context of these mutations. Notably, there was a specific decrease in mitochondrial gene expression across all cell types. The study also highlighted an altered immune cell population proportion attributed to the COQ2 gene mutation. Pathway analysis indicated a downregulation in OXPHOS and an upregulation of various synthesis pathways, particularly in podocytes. CONCLUSIONS This study improves our understanding of CoQ10 nephropathy's pathogenesis and highlights the potential applications of single-cell sequencing in pediatric hereditary kidney diseases.
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Affiliation(s)
- Peong Gang Park
- Department of Pediatrics, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sowon Choi
- Departments of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Yo Han Ahn
- Departments of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seong Heon Kim
- Departments of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Chaeyoon Kim
- Departments of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Hyun Je Kim
- Departments of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea.
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Interdisciplinary Program in Artificial Intelligence (IPAI), Seoul National University, Seoul, Republic of Korea.
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Hee Gyung Kang
- Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Departments of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
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Avila AC, Martinefski MR, Teves S, Rojas AM, Tripodi VP. A high-dose coenzyme Q 10-emulgel for chronic oral therapy of deficient patients with secondary dysphagia. J Pharm Sci 2025; 114:103794. [PMID: 40221093 DOI: 10.1016/j.xphs.2025.103794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/14/2025]
Abstract
Coenzyme Q10 (CoQ10) is the major endogenously fat-soluble antioxidant synthesized in the mitochondrion inner membrane as the electron carrier in the respiratory chain. In CoQ10-deficient patients, early high-oral doses (5-50 mg/kg/day) can constrain renal dysfunction and neurological signs. CoQ10, a typical class IV drug, with low bulk density, was dissolved at high-dose (1 g) in the oil phase (20:80 O/W) of a novel emulgel of small serving size (25 g) for its chronic administration in deficient patients with secondary dysphagia, as an alternative to maintain therapy adherence. The novelty is that CoQ10 remained dissolved in 5 g of oil phase (MCT and coconut oils) per 25 g of alginate-emulgel. This was physically stable for 9 months at 25 °C as a "weak gel" type network, with high zeta potential (‒80 mV) being then the oil droplet size (5.0 μm) successfully maintained. The emulgel showed pseudoplastic behavior and four times lower viscosities than those of a contrast fluid used for swallow studies in dysphagic patients. Chemical stability of CoQ10 was 100 % for 12 months. Emulgel administration (25 g/day) for 2 weeks increased CoQ10 plasma concentration in 3.9 times. The number of doses for high CoQ10 therapy can then be reduced, without swallowing discomfort.
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Affiliation(s)
- Ailin Camila Avila
- Departamento de Industrias-ITAPROQ, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Int. Güiraldes 2620, Ciudad Universitaria, C1428BGA Buenos Aires, Argentina; Fellow
| | - Manuela R Martinefski
- Departamento de Química Analítica y Fisicoquímica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 954, C1113AAD Buenos Aires, Argentina; Member of CONICET
| | - Sergio Teves
- Departamento de Microbiología, Inmunología, Biotecnología y Genética, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 954, C1113AAD Buenos Aires, Argentina
| | - Ana M Rojas
- Departamento de Industrias-ITAPROQ, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Int. Güiraldes 2620, Ciudad Universitaria, C1428BGA Buenos Aires, Argentina; Member of CONICET.
| | - Valeria P Tripodi
- Departamento de Tecnología Farmacéutica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 954, C1113AAD Buenos Aires, Argentina; Member of CONICET
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Magro G, Laterza V, Tosto F. Leigh Syndrome: A Comprehensive Review of the Disease and Present and Future Treatments. Biomedicines 2025; 13:733. [PMID: 40149709 PMCID: PMC11940177 DOI: 10.3390/biomedicines13030733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/11/2025] [Accepted: 03/14/2025] [Indexed: 03/29/2025] Open
Abstract
Leigh syndrome (LS) is a severe neurodegenerative condition with an early onset, typically during early childhood or infancy. The disorder exhibits substantial clinical and genetic diversity. From a clinical standpoint, Leigh syndrome showcases a broad range of irregularities, ranging from severe neurological issues to minimal or no discernible abnormalities. The central nervous system is most affected, resulting in psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also experience involvement of the peripheral nervous system, such as polyneuropathy or myopathy, as well as non-neurological anomalies, such as diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). Mutations associated with Leigh syndrome impact genes in both the mitochondrial and nuclear genomes. Presently, LS remains without a cure and shows limited response to various treatments, although certain case reports suggest potential improvement with supplements. Ongoing preclinical studies are actively exploring new treatment approaches. This review comprehensively outlines the genetic underpinnings of LS, its current treatment methods, and preclinical investigations, with a particular focus on treatment.
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Affiliation(s)
- Giuseppe Magro
- Department of Neuroscience, “Giovanni Paolo II” Hospital, 88100 Lamezia Terme, Italy
| | - Vincenzo Laterza
- Department of Medical and Surgical Sciences, Institute of Neurology, Magna Graecia University, 88100 Catanzaro, Italy
| | - Federico Tosto
- Department of Neuroscience, “Giovanni Paolo II” Hospital, 88100 Lamezia Terme, Italy
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Fernández-Ayala DJM, Jiménez-Gancedo S, Guerra I, Hernández-Camacho JD, Neto M, Scialo F, Astillero-López V, Cortés-Rodríguez AB, Santos-Ocaña C, Rodríguez-Aguilera JC, Casares F, Sanz A, López-Lluch G, Navas P. Modelling the human coenzyme Q deficiency in Drosophila melanogaster. Free Radic Biol Med 2025; 230:95-111. [PMID: 39864756 DOI: 10.1016/j.freeradbiomed.2024.12.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 12/15/2024] [Accepted: 12/29/2024] [Indexed: 01/28/2025]
Abstract
The interference of the expression of each of the genes involved in the synthesis of coenzyme Q (CoQ) in Drosophila melanogaster can help to understand the pathophysiology of CoQ-dependent mitochondrial diseases in humans. We have knocked-down all genes involved in the CoQ biosynthesis pathway at different temperatures to induce depletion of CoQ at different levels throughout the body and in a tissue-specific manner. The efficiency of the knockdowns was quantified by Q-RTPCR and determination of CoQ levels by HPLC-UV + ECD. We performed mitochondria purification and quantified respiratory chain activity, both mitochondrial hydrogen peroxide and superoxide production, resistance to mechanical stress and determination of life expectancy. Finally, we evaluated the effect of CoQ10 supplementation as phenotype rescue therapy. D. melanogaster presents 3 isoforms of CoQ: CoQ8, CoQ9 and CoQ10. The level of depletion depended on the efficiency of the RNAi used and is specific for each gene. The interference of some genes interrupted fly development in embryogenesis (pdss2) or during metamorphosis (pdss1, coq3, coq5, coq8 and coq10), while in other cases viable adults can be obtained (coq2, coq6 and coq7). The knockdown of coq7 accumulated intermediates of the CoQ biosynthesis pathway at all stages of development, altered electron transfer with poor assembly of mitochondrial complexes, and deregulated mitochondrial hydrogen peroxide and superoxide production. Coq7 mutant flies showed partial lethality in metamorphosis, bang sensitivity and reduced life span of surviving animals. CoQ10 supplementation rescued the coq7-mutant phenotypes. Knock-down in the imaginal disc generated gene-specific eye deformities that can be mitigated by CoQ10 supplementation. Our results indicate that interference of the CoQ biosynthesis pathway in D. melanogaster shows a great diversity of phenotypes depending on the target gene, mirroring the heterogeneity of CoQ deficiency syndrome in humans and point to why mutations in certain genes are rarely found in patients.
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Affiliation(s)
- Daniel J M Fernández-Ayala
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain; CIBERER, U729, Instituto de Salud Carlos III, Madrid, Spain.
| | - Sandra Jiménez-Gancedo
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
| | - Ignacio Guerra
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
| | - Juan D Hernández-Camacho
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain; CIBERER, U729, Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Neto
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
| | - Filippo Scialo
- School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ, Glasgow, UK
| | | | | | - Carlos Santos-Ocaña
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain; CIBERER, U729, Instituto de Salud Carlos III, Madrid, Spain
| | - Juan Carlos Rodríguez-Aguilera
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain; CIBERER, U729, Instituto de Salud Carlos III, Madrid, Spain
| | - Fernando Casares
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
| | - Alberto Sanz
- School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ, Glasgow, UK
| | - Guillermo López-Lluch
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain; CIBERER, U729, Instituto de Salud Carlos III, Madrid, Spain
| | - Plácido Navas
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain; CIBERER, U729, Instituto de Salud Carlos III, Madrid, Spain.
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Wahedi A, Sudhakar S, Lam A, Ciancio JIR, Mills P, Gissen P, Gardham A, Kapadia J, Hassell J, Heales S, Rahman S. Clinical Features, Biochemistry, Imaging, and Treatment Response in a Single-Center Cohort With Coenzyme Q 10 Biosynthesis Disorders. Neurol Genet 2024; 10:e200209. [PMID: 39601013 PMCID: PMC11595325 DOI: 10.1212/nxg.0000000000200209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 09/09/2024] [Indexed: 11/29/2024]
Abstract
Background and Objectives Disorders of coenzyme Q10 (CoQ10) biosynthesis comprise a group of 11 clinically and genetically heterogeneous rare primary mitochondrial diseases. We sought to delineate clinical, biochemical, and neuroimaging features of these disorders, together with outcomes after oral CoQ10 supplementation and the utility of peripheral blood mononuclear cell (PBMNC) CoQ10 levels in monitoring therapy. Methods This was a retrospective cohort study, registered as an audit at a specialist pediatric hospital (Registration Number: 3318) of 14 patients with genetically confirmed CoQ10 biosynthesis deficiency, including 13 previously unreported cases. Results We show that oral doses of CoQ10 up to 70 mg/kg/d were needed to ameliorate neurologic features. Additional idebenone was required to control seizures in some cases, and 3 children with neonatal-onset neurologic disease died in early childhood despite receiving high-dose oral CoQ10 from birth. We also demonstrate that early diagnosis and treatment of CoQ10 deficiency with oral supplementation (30 mg/kg/d) can reverse renal manifestations and can completely prevent kidney disease over 10 years of follow-up. PBMNC CoQ10 levels increased after oral CoQ10 supplementation, demonstrating absorption of exogenous CoQ10 into the bloodstream. Discussion An early genome-wide diagnostic approach is needed for expeditious diagnosis of CoQ10 biosynthesis disorder because our study demonstrates that there are no pathognomonic blood, muscle, or imaging biomarkers of these diseases. Our findings indicate that earlier diagnosis and treatment with high-dose CoQ10 is key in halting progression of kidney disease or preventing it altogether. This study uses serial PBMNC CoQ10 levels to monitor therapy. Patients with genetically confirmed CoQ10 biosynthesis disorder should receive high-dose oral CoQ10 as soon as possible after presentation, regardless of genetic cause, to prevent disease progression, but parents of children with neonatal or infantile neurologic presentations should be counseled about the poor prognosis.
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Affiliation(s)
- Azizia Wahedi
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Sniya Sudhakar
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Amanda Lam
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Jose Ignacio Rodriguez Ciancio
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Philippa Mills
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Paul Gissen
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Alice Gardham
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Jogesh Kapadia
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Jane Hassell
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Simon Heales
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Shamima Rahman
- From the Mitochondrial Research Group (A.W., S.R.), Genetics and Genomic Medicine Department, UCL Great Ormond Street Institute of Child Health, London; Medical Sciences Division (A.W.), University of Oxford; Department of Radiology (S.S.), Great Ormond Street Hospital for Children; Neurometabolic Unit (A.L., S.H.), National Hospital for Neurology and Neurosurgery; Department of Chemical Pathology, Great Ormond Street Hospital for Children; Neuromuscular Diseases (A.L.), Queen Square, UCL Institute of Neurology; Inborn Errors of Metabolism Section (J.I.R.C., P.M., S.H.), Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health; National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre (P.G.), University College London; Metabolic Department (P.G., S.R.), Great Ormond Street Hospital for Children; North West Thames Regional Genetic Service (A.G.), North West London Hospitals; Neonatal Intensive Care Unit (J.K.), Luton and Dunstable University Hospital; and Department of Paediatric Neurology (J.H.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
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Hernández‐Camacho JD, Vicente‐García C, Ardila‐García L, Padilla‐Campos A, López‐Lluch G, Santos‐Ocaña C, Zammit PS, Carvajal JJ, Navas P, Fernández‐Ayala DJ. Prenatal and progressive coenzyme Q 10 administration to mitigate muscle dysfunction in mitochondrial disease. J Cachexia Sarcopenia Muscle 2024; 15:2402-2416. [PMID: 39354863 PMCID: PMC11634497 DOI: 10.1002/jcsm.13574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 07/22/2024] [Accepted: 07/29/2024] [Indexed: 10/03/2024] Open
Abstract
BACKGROUND ADCK genes encode aarF domain-containing mitochondrial kinases involved in coenzyme Q (CoQ) biosynthesis and regulation. Haploinsufficiency of ADCK2 in humans leads to adult-onset physical incapacity with reduced mitochondrial CoQ levels in skeletal muscle, resulting in mitochondrial myopathy and alterations in fatty acid β-oxidation. The sole current treatment for CoQ deficiencies is oral administration of CoQ10, which causes only partial recovery with postnatal treatment, underscoring the importance of early diagnosis for successful intervention. METHODS We used Adck2 heterozygous mice to examine the influence of this gene on muscle structure, function and regeneration throughout development, growth and ageing. This investigation involved techniques including immunohistochemistry, analysis of CoQ levels, mitochondrial respiratory content, muscle transcriptome analysis and functional tests. RESULTS We demonstrated that Adck2 heterozygous mice exhibit defects from embryonic development, particularly in skeletal muscle (1102 genes deregulated). Adck2 heterozygous embryos were 7% smaller in size and displayed signs of delayed development. Prenatal administration of CoQ10 could mitigate these embryonic defects. Heterozygous Adck2 mice also showed a decrease in myogenic cell differentiation, with more severe consequences in 'aged' mice (41.63% smaller) (P < 0.01). Consequently, heterozygous Adck2 mice displayed accelerated muscle wasting associated with ageing in muscle structure (P < 0.05), muscle function (less grip strength capacity) (P < 0.001) and muscle mitochondrial respiration (P < 0.001). Furthermore, progressive CoQ10 administration conferred protective effects on mitochondrial function (P < 0.0001) and skeletal muscle (P < 0.05). CONCLUSIONS Our work uncovered novel aspects of CoQ deficiencies, revealing defects during embryonic development in mammals for the first time. Additionally, we identified the gradual establishment and progression of the deleterious Adck2 mouse phenotype. Importantly, CoQ10 supplementation demonstrated a protective effect when initiated during development.
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Affiliation(s)
- Juan Diego Hernández‐Camacho
- Centro Andaluz de Biología del Desarrollo—CSICUniversidad Pablo de OlavideSevilleSpain
- CIBERERInstituto de Salud Carlos IIIMadridSpain
| | | | - Lorena Ardila‐García
- Centro Andaluz de Biología del Desarrollo—CSICUniversidad Pablo de OlavideSevilleSpain
| | - Ana Padilla‐Campos
- Centro Andaluz de Biología del Desarrollo—CSICUniversidad Pablo de OlavideSevilleSpain
| | - Guillermo López‐Lluch
- Centro Andaluz de Biología del Desarrollo—CSICUniversidad Pablo de OlavideSevilleSpain
- CIBERERInstituto de Salud Carlos IIIMadridSpain
| | - Carlos Santos‐Ocaña
- Centro Andaluz de Biología del Desarrollo—CSICUniversidad Pablo de OlavideSevilleSpain
- CIBERERInstituto de Salud Carlos IIIMadridSpain
| | - Peter S. Zammit
- Randall Centre for Cell and Molecular BiophysicsKing's College LondonLondonUK
| | - Jaime J. Carvajal
- Centro Andaluz de Biología del Desarrollo—CSICUniversidad Pablo de OlavideSevilleSpain
| | - Plácido Navas
- Centro Andaluz de Biología del Desarrollo—CSICUniversidad Pablo de OlavideSevilleSpain
- CIBERERInstituto de Salud Carlos IIIMadridSpain
| | - Daniel J.M. Fernández‐Ayala
- Centro Andaluz de Biología del Desarrollo—CSICUniversidad Pablo de OlavideSevilleSpain
- CIBERERInstituto de Salud Carlos IIIMadridSpain
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7
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Pan P, Zhou N, Sun Y, Chen Z, Han J, Zhou W. The Spectrum of clinical manifestations in newborns with the COQ4 mutation: case series and literature review. Front Pediatr 2024; 12:1410133. [PMID: 39398416 PMCID: PMC11466766 DOI: 10.3389/fped.2024.1410133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 09/12/2024] [Indexed: 10/15/2024] Open
Abstract
Background Coenzyme Q10 (CoQ10) plays an important role in the electron transport chain within the human mitochondrial respiratory chain. The manifestations of this deficiency exhibit a diverse range. This study investigates the clinical manifestations of primary coenzyme Q10 deficiency in neonates with the COQ4 mutation to improve the diagnosis of the disease and the prognosis through targeted treatment. Methods We report 4 patients with primary coenzyme Q10 deficiency by COQ4 variants in neonates. A comprehensive literature search and review for original articles and case reports with COQ4 mutation published from January 1989 to November 2023 was performed through Pubmed. We review clinical manifestations, diagnostic approaches, and treatment monitoring in these and 20 previously reported patients. Results Within the cohort of four cases examined, three females and one male were identified from two distinct families. Specifically, case 1 and 2 consisted of monoamniotic twins. Cases 3 and 4 were siblings. A comprehensive review of 20 cases involving neonatal-onset COQ4 mutation was conducted. Half of the cases are Chinese. There was no statistically significant difference in the mortality between Chinese (9/12, 75%) and other regions (11/12, 91.7%) (P = 0.27). The survival time for the 24 cases was 60.0 ± 98.0 days (95% confidence interval CI: 0-252.0 days). The incidence of prenatal abnormalities in preterm infants was significantly higher than that in full-term infants (66.7% vs. 16.7%, P = 0.02). Hyperlactatemia was one of the most common manifestations, accounting for 75% of cases (18/24). Twenty of the 24 cases were diagnosed by whole exome sequencing. Only 9 patients received exogenous coenzyme Q10 treatment, and all the 4 surviving patients received coenzyme Q10 supplementation. Conclusion The prognosis of COQ4 mutation in the neonatal period indicates a low survival rate and an poor prognosis. This may be due to the incomplete understanding of the mechanism of how COQ4 gene defects lead to coenzyme Q10 deficiency and why CoQ10 supplementation does not respond well to treatment. To improve the diagnostic rate, in addition to genetic testing, mitochondrial functional verification should be prioritized in southern China, where the incidence is relatively high. It will facilitate more in-depth mechanistic studies.
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Affiliation(s)
- Pianpian Pan
- Nenoatal Intensive Care Unit, Guangzhou Wowen and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Na Zhou
- Heart Center, Guangzhou Wowen and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Yi Sun
- Nenoatal Intensive Care Unit, Guangzhou Wowen and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Zhengrong Chen
- Pathology Department, Guangzhou Wowen and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jin Han
- Prenatal Diagnostic Center, Guangzhou Wowen and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wei Zhou
- Nenoatal Intensive Care Unit, Guangzhou Wowen and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
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8
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Caparali EB, De Gregorio V, Barua M. Genetic Causes of Nephrotic Syndrome and Focal and Segmental Glomerulosclerosis. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:309-316. [PMID: 39084756 DOI: 10.1053/j.akdh.2024.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 03/29/2024] [Accepted: 04/01/2024] [Indexed: 08/02/2024]
Abstract
The field of nephrology has a long-standing interest in deciphering the genetic basis of nephrotic syndrome (NS), motivated by the mechanistic insights it provides in chronic kidney disease. The initial era of genetic studies solidified NS and the focal segmental glomerulosclerosis lesion as podocyte disorders. The likelihood of identifying a single gene (called monogenic) cause is higher if certain factors are present such as positive family history. Obtaining a monogenic diagnosis enables reproductive counseling and screening of family members. Now, with a new era of genomic studies facilitated by technological advances and the emergence of large genetically characterized cohorts, more insights are apparent. This includes the phenotypic breadth associated with disease genes, as evidenced in Alport syndrome and congenital NS of the Finnish type. Moreover, the underlying genetic architecture is more complex than previously appreciated, as shown by genome-wide association studies, suggesting that variants in multiple genes collectively influence risk. Achieving molecularly informed diagnoses also holds substantial potential for personalizing medicine, including the development of targeted therapeutics. Illustrative examples include coenzyme Q10 for ADCK4-associated NS and inaxaplin, a small molecule that inhibits apolipoprotein L1 channel activity, though larger studies are required to confirm benefit.
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Affiliation(s)
- Emine Bilge Caparali
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Vanessa De Gregorio
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Moumita Barua
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
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9
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Lopriore P, Vista M, Tessa A, Giuntini M, Caldarazzo Ienco E, Mancuso M, Siciliano G, Santorelli FM, Orsucci D. Primary Coenzyme Q10 Deficiency-Related Ataxias. J Clin Med 2024; 13:2391. [PMID: 38673663 PMCID: PMC11050807 DOI: 10.3390/jcm13082391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
Cerebellar ataxia is a neurological syndrome characterized by the imbalance (e.g., truncal ataxia, gait ataxia) and incoordination of limbs while executing a task (dysmetria), caused by the dysfunction of the cerebellum or its connections. It is frequently associated with other signs of cerebellar dysfunction, including abnormal eye movements, dysmetria, kinetic tremor, dysarthria, and/or dysphagia. Among the so-termed mitochondrial ataxias, variants in genes encoding steps of the coenzyme Q10 biosynthetic pathway represent a common cause of autosomal recessive primary coenzyme Q10 deficiencies (PCoQD)s. PCoQD is a potentially treatable condition; therefore, a correct and timely diagnosis is essential. After a brief presentation of the illustrative case of an Italian woman with this condition (due to a novel homozygous nonsense mutation in COQ8A), this article will review ataxias due to PCoQD.
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Affiliation(s)
- Piervito Lopriore
- Unit of Neurology, San Luca Hospital, Via Lippi-Francesconi, 55100 Lucca, Italy; (P.L.); (M.V.); (M.G.); (E.C.I.)
- Neurological Institute, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.M.); (G.S.)
| | - Marco Vista
- Unit of Neurology, San Luca Hospital, Via Lippi-Francesconi, 55100 Lucca, Italy; (P.L.); (M.V.); (M.G.); (E.C.I.)
| | - Alessandra Tessa
- Molecular Medicine, IRCCS Stella Maris Foundation, 56122 Pisa, Italy; (A.T.); (F.M.S.)
| | - Martina Giuntini
- Unit of Neurology, San Luca Hospital, Via Lippi-Francesconi, 55100 Lucca, Italy; (P.L.); (M.V.); (M.G.); (E.C.I.)
| | - Elena Caldarazzo Ienco
- Unit of Neurology, San Luca Hospital, Via Lippi-Francesconi, 55100 Lucca, Italy; (P.L.); (M.V.); (M.G.); (E.C.I.)
| | - Michelangelo Mancuso
- Neurological Institute, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.M.); (G.S.)
| | - Gabriele Siciliano
- Neurological Institute, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.M.); (G.S.)
| | | | - Daniele Orsucci
- Unit of Neurology, San Luca Hospital, Via Lippi-Francesconi, 55100 Lucca, Italy; (P.L.); (M.V.); (M.G.); (E.C.I.)
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10
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Esson G, Logan I, Wood K, Browning AC, Sayer JA. Diverse retinal-kidney phenotypes associated with NPHP1 homozygous whole-gene deletions in patients with kidney failure. JOURNAL OF RARE DISEASES (BERLIN, GERMANY) 2024; 3:7. [PMID: 38433745 PMCID: PMC10904492 DOI: 10.1007/s44162-024-00031-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/19/2024] [Indexed: 03/05/2024]
Abstract
A precise diagnosis in medicine allows appropriate disease-specific management. Kidney failure of unknown aetiology remains a frequent diagnostic label within the haemodialysis unit and kidney transplant clinic, accounting for 15-20% of these patients. Approximately 10% of such cases may have an underlying monogenic cause of kidney failure. Modern genetic approaches can provide a precise diagnosis for patients and their families. A search for extra-renal disease manifestations is also important as this may point to a specific genetic diagnosis. Here, we present two patients where molecular genetic testing was performed because of kidney failure of unknown aetiology and associated retinal phenotypes. The first patient reached kidney failure at 16 years of age but only presented with a retinal phenotype at 59 years of age and was found to have evidence of rod-cone dystrophy. The second patient presented with childhood kidney failure at the age of 15 years and developed visual difficulties and photophobia at the age of 32 years and was diagnosed with cone dystrophy. In both cases, genetic tests were performed which revealed a homozygous whole-gene deletion of NPHP1-encoding nephrocystin-1, providing the unifying diagnosis of Senior-Løken syndrome type 1. We conclude that reviewing kidney and extra-renal phenotypes together with targeted genetic testing was informative in these cases of kidney failure of unknown aetiology and associated retinal phenotypes. The involvement of an interdisciplinary team is advisable when managing such patients and allows referral to other relevant specialities. The long time lag and lack of diagnostic clarity and clinical evaluation in our cases should encourage genetic investigations for every young patient with unexplained kidney failure. For these and similar patients, a more timely genetic diagnosis would allow for improved management, a risk assessment of kidney disease in relatives, and the earlier identification of extra-renal disease manifestations. Supplementary Information The online version contains supplementary material available at 10.1007/s44162-024-00031-4.
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Affiliation(s)
- Gavin Esson
- Renal Services, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Ian Logan
- Renal Services, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Katrina Wood
- Histopathology Department, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, NE1 4LP UK
| | - Andrew C. Browning
- Ophthalmology Department, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, NE1 4LP UK
| | - John A. Sayer
- Renal Services, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle Upon Tyne, NE1 3BZ UK
- NIHR Newcastle Biomedical Research Centre, Newcastle Upon Tyne, UK
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11
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Wang Y, Yang J, Zhang Y, Zhou J. Focus on Mitochondrial Respiratory Chain: Potential Therapeutic Target for Chronic Renal Failure. Int J Mol Sci 2024; 25:949. [PMID: 38256023 PMCID: PMC10815764 DOI: 10.3390/ijms25020949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/26/2023] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
The function of the respiratory chain is closely associated with kidney function, and the dysfunction of the respiratory chain is a primary pathophysiological change in chronic kidney failure. The incidence of chronic kidney failure caused by defects in respiratory-chain-related genes has frequently been overlooked. Correcting abnormal metabolic reprogramming, rescuing the "toxic respiratory chain", and targeting the clearance of mitochondrial reactive oxygen species are potential therapies for treating chronic kidney failure. These treatments have shown promising results in slowing fibrosis and inflammation progression and improving kidney function in various animal models of chronic kidney failure and patients with chronic kidney disease (CKD). The mitochondrial respiratory chain is a key target worthy of attention in the treatment of chronic kidney failure. This review integrated research related to the mitochondrial respiratory chain and chronic kidney failure, primarily elucidating the pathological status of the mitochondrial respiratory chain in chronic kidney failure and potential therapeutic drugs. It provided new ideas for the treatment of kidney failure and promoted the development of drugs targeting the mitochondrial respiratory chain.
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Affiliation(s)
| | | | | | - Jianhua Zhou
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China; (Y.W.); (J.Y.); (Y.Z.)
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12
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Diaz-Vegas A, Madsen S, Cooke KC, Carroll L, Khor JXY, Turner N, Lim XY, Astore MA, Morris JC, Don AS, Garfield A, Zarini S, Zemski Berry KA, Ryan AP, Bergman BC, Brozinick JT, James DE, Burchfield JG. Mitochondrial electron transport chain, ceramide, and coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle. eLife 2023; 12:RP87340. [PMID: 38149844 PMCID: PMC10752590 DOI: 10.7554/elife.87340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023] Open
Abstract
Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.
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Affiliation(s)
- Alexis Diaz-Vegas
- Charles Perkins Centre, School of life and Environmental Sciences, University of SydneySydneyAustralia
| | - Søren Madsen
- Charles Perkins Centre, School of life and Environmental Sciences, University of SydneySydneyAustralia
| | - Kristen C Cooke
- Charles Perkins Centre, School of life and Environmental Sciences, University of SydneySydneyAustralia
| | - Luke Carroll
- Charles Perkins Centre, School of life and Environmental Sciences, University of SydneySydneyAustralia
| | - Jasmine XY Khor
- Charles Perkins Centre, School of life and Environmental Sciences, University of SydneySydneyAustralia
- Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of SydneySydneyAustralia
| | - Nigel Turner
- Cellular Bioenergetics Laboratory, Victor Chang Cardiac Research InstituteSydneyAustralia
| | - Xin Y Lim
- Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of SydneySydneyAustralia
| | - Miro A Astore
- Center for Computational Biology and Center for Computational Mathematics, Flatiron InstituteNew YorkUnited States
| | | | - Anthony S Don
- Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of SydneySydneyAustralia
| | - Amanda Garfield
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Simona Zarini
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Karin A Zemski Berry
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Andrew P Ryan
- Lilly Research Laboratories, Division of Eli Lilly and CompanyIndianapolisUnited States
| | - Bryan C Bergman
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Joseph T Brozinick
- Lilly Research Laboratories, Division of Eli Lilly and CompanyIndianapolisUnited States
| | - David E James
- Charles Perkins Centre, School of life and Environmental Sciences, University of SydneySydneyAustralia
- Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of SydneySydneyAustralia
| | - James G Burchfield
- Charles Perkins Centre, School of life and Environmental Sciences, University of SydneySydneyAustralia
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13
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Hsu CJ, Lee WT. Epilepsy and Coenzyme Q10 deficiency with COQ4 variants. Epilepsy Behav 2023; 149:109498. [PMID: 37948995 DOI: 10.1016/j.yebeh.2023.109498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 10/14/2023] [Accepted: 10/17/2023] [Indexed: 11/12/2023]
Abstract
Coenzyme Q10 (CoQ10) is one of the essential substances for mitochondrial energy synthesis and extra-mitochondrial vital function. Primary CoQ10 deficiency is a rare disease resulting from interruption of CoQ10 biosynthetic pathway and biallelic COQ4 variants are one of the genetic etiologies recognized in this hereditary disorder. The clinical heterogenicity is broad with wide onset age from prenatal period to adulthood. The typical manifestations include early pharmacoresistant seizure, severe cognition and/or developmental delay, dystonia, ataxia, and spasticity. Patients may also have multisystemic involvements such as cardiomyopathy, lactic acidosis or gastro-esophageal regurgitation disease. Oral CoQ10 supplement is the major therapeutic medication currently. Among those patients, c.370G > A variant is the most common pathogenic variant detected, especially in Asian population. This phenomenon also suggests that this specific allele may be the founder variants in Asia. In this article, we report two siblings with infantile onset seizures, developmental delay, cardiomyopathy, and diffuse brain atrophy. Genetic analysis of both two cases revealed homozygous COQ4 c.370G > A (p.Gly124Ser) variants. We also review the clinical manifestations of primary CoQ10 deficiency patients and possible treatment categories, which are still under survey. As oral CoQ10 supplement may improve or stabilize disease severity, early precise diagnosis of primary CoQ10 deficiency and early treatment are the most important issues. This review article helps to further understand clinical spectrum and treatment categories of primary CoQ10 deficiency with COQ4 variant.
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Affiliation(s)
- Chia-Jui Hsu
- Department of Pediatrics, National Taiwan University Hsin-Chu Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
| | - Wang-Tso Lee
- Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Pediatric Neurology, National Taiwan University Children's Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan.
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14
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Stallworth JY, Blair DR, Slavotinek A, Moore AT, Duncan JL, de Alba Campomanes AG. Retinopathy and optic atrophy in a case of COQ2-related primary coenzyme Q 10 deficiency. Ophthalmic Genet 2023; 44:486-490. [PMID: 36420660 PMCID: PMC10205914 DOI: 10.1080/13816810.2022.2141792] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 09/08/2022] [Accepted: 10/22/2022] [Indexed: 11/25/2022]
Abstract
PURPOSE To describe a case of primary coenzyme Q10 deficiency in a child manifesting as early-onset renal failure, retinal dystrophy, and optic atrophy leading to progressive vision loss. METHODS Clinical presentation and workup including visual fields, electroretinogram, and optical coherence tomography are presented. Genetic testing was performed. RESULTS An eight-year-old female with nephropathy requiring renal transplantation subsequently developed progressive cone-rod dystrophy and optic atrophy. The patient had negative results on a targeted next-generation sequencing retinal dystrophy panel but whole-exome sequencing revealed two variants in COQ2 (likely biallelic), consistent with a diagnosis of primary coenzyme Q10 deficiency. CONCLUSIONS Primary coenzyme Q10 deficiency is a rare disorder with variable systemic and ocular findings; there is also genetic heterogeneity. Genetic testing aids in the diagnosis of this condition, and variants in the COQ2 and PDSS1 genes appear to have the strongest association with ocular manifestations. Oral supplementation of coenzyme Q10 may slow progression of disease. This case highlights the utility of whole-exome sequencing in the diagnosis of a rare syndromic form of ocular disease and reports a novel phenotypic association for this condition.
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Affiliation(s)
| | - David R Blair
- Department of Pediatrics, University of California, San Francisco, CA, USA
| | - Anne Slavotinek
- Department of Pediatrics, University of California, San Francisco, CA, USA
| | - Anthony T Moore
- Department of Ophthalmology, University of California, San Francisco, CA, USA
| | - Jacque L Duncan
- Department of Ophthalmology, University of California, San Francisco, CA, USA
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15
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Diaz-Vegas A, Madsen S, Cooke KC, Carroll L, Khor JXY, Turner N, Lim XY, Astore MA, Morris J, Don A, Garfield A, Zarini S, Zemski Berry KA, Ryan A, Bergman BC, Brozinick JT, James DE, Burchfield JG. Mitochondrial electron transport chain, ceramide and Coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.10.532020. [PMID: 36945619 PMCID: PMC10028964 DOI: 10.1101/2023.03.10.532020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, deficiency of coenzyme Q (CoQ), mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells results in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (under chow and high fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial Ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.
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Affiliation(s)
- Alexis Diaz-Vegas
- Charles Perkins Centre, School of life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - Soren Madsen
- Charles Perkins Centre, School of life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - Kristen C. Cooke
- Charles Perkins Centre, School of life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - Luke Carroll
- Charles Perkins Centre, School of life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - Jasmine X. Y. Khor
- Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Nigel Turner
- Cellular Bioenergetics Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
| | - Xin Ying Lim
- Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Miro A. Astore
- Center for Computational Biology and Center for Computational Mathematics, Flatiron Institute, New York, NY 10010, USA
| | - Jonathan Morris
- School of Chemistry, UNSW Sydney, Sydney, 2052, NSW, Australia
| | - Anthony Don
- Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - Amanda Garfield
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Simona Zarini
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Karin A. Zemski Berry
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Andrew Ryan
- Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, IN, USA
| | - Bryan C. Bergman
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Joseph T. Brozinick
- Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, IN, USA
| | - David E. James
- Charles Perkins Centre, School of life and Environmental Sciences, University of Sydney, Sydney, Australia
- Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia
| | - James G. Burchfield
- Charles Perkins Centre, School of life and Environmental Sciences, University of Sydney, Sydney, Australia
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16
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Ding WY, Kuzmuk V, Hunter S, Lay A, Hayes B, Beesley M, Rollason R, Hurcombe JA, Barrington F, Masson C, Cathery W, May C, Tuffin J, Roberts T, Mollet G, Chu CJ, McIntosh J, Coward RJ, Antignac C, Nathwani A, Welsh GI, Saleem MA. Adeno-associated virus gene therapy prevents progression of kidney disease in genetic models of nephrotic syndrome. Sci Transl Med 2023; 15:eabc8226. [PMID: 37556557 DOI: 10.1126/scitranslmed.abc8226] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 07/21/2023] [Indexed: 08/11/2023]
Abstract
Gene therapy for kidney diseases has proven challenging. Adeno-associated virus (AAV) is used as a vector for gene therapy targeting other organs, with particular success demonstrated in monogenic diseases. We aimed to establish gene therapy for the kidney by targeting a monogenic disease of the kidney podocyte. The most common cause of childhood genetic nephrotic syndrome is mutations in the podocyte gene NPHS2, encoding podocin. We used AAV-based gene therapy to rescue this genetic defect in human and mouse models of disease. In vitro transduction studies identified the AAV-LK03 serotype as a highly efficient transducer of human podocytes. AAV-LK03-mediated transduction of podocin in mutant human podocytes resulted in functional rescue in vitro, and AAV 2/9-mediated gene transfer in both the inducible podocin knockout and knock-in mouse models resulted in successful amelioration of kidney disease. A prophylactic approach of AAV 2/9 gene transfer before induction of disease in conditional knockout mice demonstrated improvements in albuminuria, plasma creatinine, plasma urea, plasma cholesterol, histological changes, and long-term survival. A therapeutic approach of AAV 2/9 gene transfer 2 weeks after disease induction in proteinuric conditional knock-in mice demonstrated improvement in urinary albuminuria at days 42 and 56 after disease induction, with corresponding improvements in plasma albumin. Therefore, we have demonstrated successful AAV-mediated gene rescue in a monogenic renal disease and established the podocyte as a tractable target for gene therapy approaches.
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Affiliation(s)
- Wen Y Ding
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Valeryia Kuzmuk
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
- Purespring Therapeutics, Rolling Stock Yard, 188 York Way, London N7 9AS, UK
| | - Sarah Hunter
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Abigail Lay
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Bryony Hayes
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Matthew Beesley
- Department of Histopathology, Cheltenham General Hospital, Cheltenham GL53 7AN, UK
| | - Ruth Rollason
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Jennifer A Hurcombe
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Fern Barrington
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Catrin Masson
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - William Cathery
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Carl May
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Jack Tuffin
- Purespring Therapeutics, Rolling Stock Yard, 188 York Way, London N7 9AS, UK
| | - Timothy Roberts
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Geraldine Mollet
- Laboratoire des Maladies Rénales Héréditaires, Inserm UMR 1163, Institut Imagine, Université Paris Cité, Paris 75015, France
| | - Colin J Chu
- Academic Unit of Ophthalmology, Bristol Medical School, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Jenny McIntosh
- Research Department of Haematology, UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6BT, UK
| | - Richard J Coward
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Corinne Antignac
- Laboratoire des Maladies Rénales Héréditaires, Inserm UMR 1163, Institut Imagine, Université Paris Cité, Paris 75015, France
| | - Amit Nathwani
- Research Department of Haematology, UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6BT, UK
| | - Gavin I Welsh
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
| | - Moin A Saleem
- Bristol Renal, Bristol Medical School, Dorothy Hodgkin Building, University of Bristol, Bristol BS1 3NY, UK
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17
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Marasa M, Ahram DF, Rehman AU, Mitrotti A, Abhyankar A, Jain NG, Weng PL, Piva SE, Fernandez HE, Uy NS, Chatterjee D, Kil BH, Nestor JG, Felice V, Robinson D, Whyte D, Gharavi AG, Appel GB, Radhakrishnan J, Santoriello D, Bomback A, Lin F, D’Agati VD, Jobanputra V, Sanna-Cherchi S. Implementation and Feasibility of Clinical Genome Sequencing Embedded Into the Outpatient Nephrology Care for Patients With Proteinuric Kidney Disease. Kidney Int Rep 2023; 8:1638-1647. [PMID: 37547535 PMCID: PMC10403677 DOI: 10.1016/j.ekir.2023.05.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/01/2023] [Accepted: 05/22/2023] [Indexed: 08/08/2023] Open
Abstract
Introduction The diagnosis and management of proteinuric kidney diseases such as focal segmental glomerulosclerosis (FSGS) are challenging. Genetics holds the promise to improve clinical decision making for these diseases; however, it is often performed too late to enable timely clinical action and it is not implemented within routine outpatient nephrology visits. Methods We sought to test the implementation and feasibility of clinical rapid genome sequencing (GS) in guiding decision making in patients with proteinuric kidney disease in real-time and embedded in the outpatient nephrology setting. Results We enrolled 10 children or young adults with biopsy-proven FSGS (9 cases) or minimal change disease (1 case). The mean age at enrollment was 16.2 years (range 2-30). The workflow did not require referral to external genetics clinics but was conducted entirely during the nephrology standard-of-care appointments. The total turn-around-time from enrollment to return-of-results and clinical decision averaged 21.8 days (12.4 for GS), which is well within a time frame that allows clinically relevant treatment decisions. A monogenic or APOL1-related form of kidney disease was diagnosed in 5 of 10 patients. The genetic findings resulted in a rectified diagnosis in 6 patients. Both positive and negative GS findings determined a change in pharmacological treatment. In 3 patients, the results were instrumental for transplant evaluation, donor selection, and the immunosuppressive treatment. All patients and families received genetic counseling. Conclusion Clinical GS is feasible and can be implemented in real-time in the outpatient care to help guiding clinical management. Additional studies are needed to confirm the cost-effectiveness and broader utility of clinical GS across the phenotypic and demographic spectrum of kidney diseases.
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Affiliation(s)
- Maddalena Marasa
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | - Dina F. Ahram
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | | | - Adele Mitrotti
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | | | - Namrata G. Jain
- Division of Pediatric Nephrology, Department of Pediatrics, Columbia University, New York, USA
| | - Patricia L. Weng
- Division of Pediatric Nephrology, Department of Pediatrics, UCLA Medical Center and UCLA Medical Center-Santa Monica, Los Angeles, California, USA
| | - Stacy E. Piva
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | - Hilda E. Fernandez
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | - Natalie S. Uy
- Division of Pediatric Nephrology, Department of Pediatrics, Columbia University, New York, USA
| | - Debanjana Chatterjee
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | - Byum H. Kil
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | - Jordan G. Nestor
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | | | | | - Dilys Whyte
- Pediatric Specialty Center of Good Samaritan Hospital Medical Center, Babylon, New York, USA
| | - Ali G. Gharavi
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | - Gerald B. Appel
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | - Jai Radhakrishnan
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | - Dominick Santoriello
- Department of Pathology and Cell Biology, Renal Pathology Division, Columbia University Medical Center, New York, USA
| | - Andrew Bomback
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
| | - Fangming Lin
- Division of Pediatric Nephrology, Department of Pediatrics, Columbia University, New York, USA
| | - Vivette D. D’Agati
- Department of Pathology and Cell Biology, Renal Pathology Division, Columbia University Medical Center, New York, USA
| | - Vaidehi Jobanputra
- The New York Genome Center, New York, USA
- Department of Pathology and Cell Biology, Columbia University, New York, USA
| | - Simone Sanna-Cherchi
- Division of Nephrology, Department of Medicine, Columbia University, New York, USA
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18
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Staiano C, García-Corzo L, Mantle D, Turton N, Millichap LE, Brea-Calvo G, Hargreaves I. Biosynthesis, Deficiency, and Supplementation of Coenzyme Q. Antioxidants (Basel) 2023; 12:1469. [PMID: 37508007 PMCID: PMC10375973 DOI: 10.3390/antiox12071469] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Originally identified as a key component of the mitochondrial respiratory chain, Coenzyme Q (CoQ or CoQ10 for human tissues) has recently been revealed to be essential for many different redox processes, not only in the mitochondria, but elsewhere within other cellular membrane types. Cells rely on endogenous CoQ biosynthesis, and defects in this still-not-completely understood pathway result in primary CoQ deficiencies, a group of conditions biochemically characterised by decreased tissue CoQ levels, which in turn are linked to functional defects. Secondary CoQ deficiencies may result from a wide variety of cellular dysfunctions not directly linked to primary synthesis. In this article, we review the current knowledge on CoQ biosynthesis, the defects leading to diminished CoQ10 levels in human tissues and their associated clinical manifestations.
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Affiliation(s)
- Carmine Staiano
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Departamento de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, 41013 Sevilla, Spain
| | - Laura García-Corzo
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Departamento de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, 41013 Sevilla, Spain
| | | | - Nadia Turton
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Merseyside L3 5UX, UK
| | - Lauren E Millichap
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Merseyside L3 5UX, UK
| | - Gloria Brea-Calvo
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Departamento de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, 41013 Sevilla, Spain
| | - Iain Hargreaves
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Merseyside L3 5UX, UK
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19
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Guile MD, Jain A, Anderson KA, Clarke CF. New Insights on the Uptake and Trafficking of Coenzyme Q. Antioxidants (Basel) 2023; 12:1391. [PMID: 37507930 PMCID: PMC10376127 DOI: 10.3390/antiox12071391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/30/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
Coenzyme Q (CoQ) is an essential lipid with many cellular functions, such as electron transport for cellular respiration, antioxidant protection, redox homeostasis, and ferroptosis suppression. Deficiencies in CoQ due to aging, genetic disease, or medication can be ameliorated by high-dose supplementation. As such, an understanding of the uptake and transport of CoQ may inform methods of clinical use and identify how to better treat deficiency. Here, we review what is known about the cellular uptake and intracellular distribution of CoQ from yeast, mammalian cell culture, and rodent models, as well as its absorption at the organism level. We discuss the use of these model organisms to probe the mechanisms of uptake and distribution. The literature indicates that CoQ uptake and distribution are multifaceted processes likely to have redundancies in its transport, utilizing the endomembrane system and newly identified proteins that function as lipid transporters. Impairment of the trafficking of either endogenous or exogenous CoQ exerts profound effects on metabolism and stress response. This review also highlights significant gaps in our knowledge of how CoQ is distributed within the cell and suggests future directions of research to better understand this process.
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Affiliation(s)
- Michael D Guile
- Department of Chemistry & Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, CA 90059, USA
| | - Akash Jain
- Department of Chemistry & Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, CA 90059, USA
| | - Kyle A Anderson
- Department of Chemistry & Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, CA 90059, USA
| | - Catherine F Clarke
- Department of Chemistry & Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, CA 90059, USA
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20
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Garcia-Becerra C, Rojas A, Höcht C, Bernabeu E, Chiappetta D, Tevez S, Lucangioli S, Flor S, Tripodi V. Characterization and bioavailability of a novel coenzyme Q 10 nanoemulsion used as an infant formula supplement. Int J Pharm 2023; 634:122656. [PMID: 36716829 DOI: 10.1016/j.ijpharm.2023.122656] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/16/2023] [Accepted: 01/25/2023] [Indexed: 01/29/2023]
Abstract
Supplementation with Coenzyme Q10 (CoQ10), in patients with its deficiency, has greater odds of success if the treatment is carried out early with an appropriate formulation. For neonatal CoQ10 deficiency, infant formula supplementation could be an attractive option. However, solid CoQ10 cannot be solubilized or dispersed in milk matrix leading to an inefficient CoQ10 dosage and poor intestinal absorption. We developed and characterized a high-dose CoQ10 oil-in-water (O/W) nanoemulsion suitable to supplement infant formula without modifying its organoleptic characteristics. CoQ10 powder and soy lecithin were solubilized in an oil phase consisted of Labrasol® and LabrafacTM. The aqueous phase was Tween 80, TPGS, methylparaben and propylparaben. O/W nanoemulsion was prepared by adding dropwise the oil phase to the aqueous phase under stirring to a final concentration of CoQ10 9.5 % w/w followed by ultrasonic homogenization. Pharmacotechnical parameters were determined. This formulation resulted to be easily to be dispersed in milk matrix, stable for at least 90 days, with no cytotoxicity in in vitro assays, and higher bioavailability than CoQ10 powder. CoQ10 nanoemulsion supplementation in the infant formula facilitates the individualized administration for the child with accurate dosage, overcome swallowing difficulties and in turn could increase the treatment adherence and efficacy.
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Affiliation(s)
- Cristian Garcia-Becerra
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Tecnología Farmacéutica, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentina
| | - Ana Rojas
- Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Industrias-ITAPROQ, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
| | - Christian Höcht
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentina
| | - Ezequiel Bernabeu
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Tecnología Farmacéutica, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
| | - Diego Chiappetta
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Tecnología Farmacéutica, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
| | - Sergio Tevez
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Buenos Aires, Argentina; PROANALISIS S.A., Av. San Martín 2355, B1661HVJ Bella Vista, Provincia de Buenos Aires, Argentina
| | - Silvia Lucangioli
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Tecnología Farmacéutica, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
| | - Sabrina Flor
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Tecnología Farmacéutica, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
| | - Valeria Tripodi
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Tecnología Farmacéutica, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéutica y Biofarmacia (InTecFyB), Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
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21
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Watanabe C, Osaka H, Watanabe M, Miyauchi A, Jimbo EF, Tokuyama T, Uosaki H, Kishita Y, Okazaki Y, Onuki T, Ebihara T, Aizawa K, Murayama K, Ohtake A, Yamagata T. Total and reduced/oxidized forms of coenzyme Q 10 in fibroblasts of patients with mitochondrial disease. Mol Genet Metab Rep 2023; 34:100951. [PMID: 36632326 PMCID: PMC9826971 DOI: 10.1016/j.ymgmr.2022.100951] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 01/05/2023] Open
Abstract
Coenzyme Q10 (CoQ10) is involved in ATP production through electron transfer in the mitochondrial respiratory chain complex. CoQ10 receives electrons from respiratory chain complex I and II to become the reduced form, and then transfers electrons at complex III to become the oxidized form. The redox state of CoQ10 has been reported to be a marker of the mitochondrial metabolic state, but to our knowledge, no reports have focused on the individual quantification of reduced and oxidized CoQ10 or the ratio of reduced to total CoQ10 (reduced/total CoQ10) in patients with mitochondrial diseases. We measured reduced and oxidized CoQ10 in skin fibroblasts from 24 mitochondrial disease patients, including 5 primary CoQ10 deficiency patients and 10 respiratory chain complex deficiency patients, and determined the reduced/total CoQ10 ratio. In primary CoQ10 deficiency patients, total CoQ10 levels were significantly decreased, however, the reduced/total CoQ10 ratio was not changed. On the other hand, in mitochondrial disease patients other than primary CoQ10 deficiency patients, total CoQ10 levels did not decrease. However, the reduced/total CoQ10 ratio in patients with respiratory chain complex IV and V deficiency was higher in comparison to those with respiratory chain complex I deficiency. Measurement of CoQ10 in fibroblasts proved useful for the diagnosis of primary CoQ10 deficiency. In addition, the reduced/total CoQ10 ratio may reflect the metabolic status of mitochondrial disease.
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Affiliation(s)
- Chika Watanabe
- Department of Pediatrics, Jichi Medical University, Tochigi, Japan
| | - Hitoshi Osaka
- Department of Pediatrics, Jichi Medical University, Tochigi, Japan
- Corresponding author at: Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
| | - Miyuki Watanabe
- Department of Pediatrics, Jichi Medical University, Tochigi, Japan
| | - Akihiko Miyauchi
- Department of Pediatrics, Jichi Medical University, Tochigi, Japan
| | - Eriko F. Jimbo
- Department of Pediatrics, Jichi Medical University, Tochigi, Japan
| | - Takeshi Tokuyama
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Hideki Uosaki
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Yoshihito Kishita
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
- Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan
| | - Yasushi Okazaki
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
- Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Takanori Onuki
- Center for Medical Genetics and Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
| | - Tomohiro Ebihara
- Center for Medical Genetics and Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
| | - Kenichi Aizawa
- Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi, Japan
| | - Kei Murayama
- Center for Medical Genetics and Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
| | - Akira Ohtake
- Department of Clinical Genomics & Pediatrics, Faculty of Medicine, Saitama Medical University, Saitama, Japan
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22
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Deshwal S, Onishi M, Tatsuta T, Bartsch T, Cors E, Ried K, Lemke K, Nolte H, Giavalisco P, Langer T. Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7. Nat Cell Biol 2023; 25:246-257. [PMID: 36658222 PMCID: PMC9928583 DOI: 10.1038/s41556-022-01071-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 12/06/2022] [Indexed: 01/21/2023]
Abstract
Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.
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Affiliation(s)
- Soni Deshwal
- grid.419502.b0000 0004 0373 6590Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Mashun Onishi
- grid.419502.b0000 0004 0373 6590Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Takashi Tatsuta
- grid.419502.b0000 0004 0373 6590Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Tim Bartsch
- grid.419502.b0000 0004 0373 6590Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Eileen Cors
- grid.419502.b0000 0004 0373 6590Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Katharina Ried
- grid.419502.b0000 0004 0373 6590Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Kathrin Lemke
- grid.419502.b0000 0004 0373 6590Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Hendrik Nolte
- grid.419502.b0000 0004 0373 6590Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Patrick Giavalisco
- grid.419502.b0000 0004 0373 6590Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Thomas Langer
- Max Planck Institute for Biology of Ageing, Cologne, Germany. .,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
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Wang S, Jain A, Novales NA, Nashner AN, Tran F, Clarke CF. Predicting and Understanding the Pathology of Single Nucleotide Variants in Human COQ Genes. Antioxidants (Basel) 2022; 11:antiox11122308. [PMID: 36552517 PMCID: PMC9774615 DOI: 10.3390/antiox11122308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 11/23/2022] Open
Abstract
Coenzyme Q (CoQ) is a vital lipid that functions as an electron carrier in the mitochondrial electron transport chain and as a membrane-soluble antioxidant. Deficiencies in CoQ lead to metabolic diseases with a wide range of clinical manifestations. There are currently few treatments that can slow or stop disease progression. Primary CoQ10 deficiency can arise from mutations in any of the COQ genes responsible for CoQ biosynthesis. While many mutations in these genes have been identified, the clinical significance of most of them remains unclear. Here we analyzed the structural and functional impact of 429 human missense single nucleotide variants (SNVs) that give rise to amino acid substitutions in the conserved and functional regions of human genes encoding a high molecular weight complex known as the CoQ synthome (or Complex Q), consisting of the COQ3-COQ7 and COQ9 gene products. Using structures of COQ polypeptides, close homologs, and AlphaFold models, we identified 115 SNVs that are potentially pathogenic. Further biochemical characterizations in model organisms such as Saccharomyces cerevisiae are required to validate the pathogenicity of the identified SNVs. Collectively, our results will provide a resource for clinicians during patient diagnosis and guide therapeutic efforts toward combating primary CoQ10 deficiency.
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Wu M, Chen Y, Chiu I, Wu M. Genetic Insight into Primary Glomerulonephritis. Nephrology (Carlton) 2022; 27:649-657. [DOI: 10.1111/nep.14074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/18/2022] [Accepted: 06/06/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Mei‐Yi Wu
- Division of Nephrology, Department of Internal Medicine Taipei Medical University‐Shuang Ho Hospital New Taipei City Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine Taipei Medical University Taipei Taiwan
- Institute of Epidemiology and Preventive Medicine, College of Public Health National Taiwan University Taipei Taiwan
- TMU Research Center of Urology and Kidney Taipei Medical University Taipei Taiwan
| | - Ying‐Chun Chen
- Division of Nephrology, Department of Internal Medicine Taipei Medical University‐Shuang Ho Hospital New Taipei City Taiwan
| | - I‐Jen Chiu
- Division of Nephrology, Department of Internal Medicine Taipei Medical University‐Shuang Ho Hospital New Taipei City Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine Taipei Medical University Taipei Taiwan
- TMU Research Center of Urology and Kidney Taipei Medical University Taipei Taiwan
| | - Mai‐Szu Wu
- Division of Nephrology, Department of Internal Medicine Taipei Medical University‐Shuang Ho Hospital New Taipei City Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine Taipei Medical University Taipei Taiwan
- TMU Research Center of Urology and Kidney Taipei Medical University Taipei Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine Taipei Medical University Taipei Taiwan
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25
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Liu X, Du H, Sun Y, Shao L. Role of abnormal energy metabolism in the progression of chronic kidney disease and drug intervention. Ren Fail 2022; 44:790-805. [PMID: 35535500 PMCID: PMC9103584 DOI: 10.1080/0886022x.2022.2072743] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Chronic kidney disease (CKD) is a severe clinical syndrome with significant socioeconomic impact worldwide. Orderly energy metabolism is essential for normal kidney function and energy metabolism disorders are increasingly recognized as an important player in CKD. Energy metabolism disorders are characterized by ATP deficits and reactive oxygen species increase. Oxygen and mitochondria are essential for ATP production, hypoxia and mitochondrial dysfunction both affect the energy production process. Renin-angiotensin and adenine signaling pathway also play important regulatory roles in energy metabolism. In addition, disturbance of energy metabolism is a key factor in the development of hereditary nephropathy such as autosomal dominant polycystic kidney disease. Currently, drugs with clinically clear renal function protection, such as Angiotensin II Type 1 receptor blockers and fenofibrate, have been proven to improve energy metabolism disorders. The sodium-glucose co-transporter inhibitors 2 that can mediate glucose metabolism disorders not only delay the progress of diabetic nephropathy, but also have significant protective effects in non-diabetic nephropathy. Hypoxia-inducible factor enhances ATP production to the kidney by improving renal oxygen supply and increasing glycolysis, and the mitochondria targeted peptides (SS-31) plays a protective role by stabilizing the mitochondrial inner membrane. Moreover, several drugs are being studied and are predicted to have potential renal protective properties. We propose that the regulation of energy metabolism represents a promising strategy to delay the progression of CKD.
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Affiliation(s)
- Xuyan Liu
- Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Huasheng Du
- Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Yan Sun
- Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Leping Shao
- Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
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26
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Drovandi S, Lipska-Ziętkiewicz BS, Ozaltin F, Emma F, Gulhan B, Boyer O, Trautmann A, Xu H, Shen Q, Rao J, Riedhammer KM, Heemann U, Hoefele J, Stenton SL, Tsygin AN, Ng KH, Fomina S, Benetti E, Aurelle M, Prikhodina L, Schreuder MF, Tabatabaeifar M, Jankowski M, Baiko S, Mao J, Feng C, Liu C, Sun S, Deng F, Wang X, Clavé S, Stańczyk M, Bałasz-Chmielewska I, Fila M, Durkan AM, Levart TK, Dursun I, Esfandiar N, Haas D, Bjerre A, Anarat A, Benz MR, Talebi S, Hooman N, Ariceta G, Schaefer F. Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency. Kidney Int 2022; 102:604-612. [DOI: 10.1016/j.kint.2022.04.029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 04/13/2022] [Accepted: 04/29/2022] [Indexed: 12/17/2022]
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27
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Drovandi S, Lipska-Ziętkiewicz BS, Ozaltin F, Emma F, Gulhan B, Boyer O, Trautmann A, Ziętkiewicz S, Xu H, Shen Q, Rao J, Riedhammer KM, Heemann U, Hoefele J, Stenton SL, Tsygin AN, Ng KH, Fomina S, Benetti E, Aurelle M, Prikhodina L, Schijvens AM, Tabatabaeifar M, Jankowski M, Baiko S, Mao J, Feng C, Deng F, Rousset-Rouviere C, Stańczyk M, Bałasz-Chmielewska I, Fila M, Durkan AM, Levart TK, Dursun I, Esfandiar N, Haas D, Bjerre A, Anarat A, Benz MR, Talebi S, Hooman N, Ariceta G, Schaefer F. Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy. Kidney Int 2022; 102:592-603. [PMID: 35483523 DOI: 10.1016/j.kint.2022.02.040] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 02/21/2022] [Accepted: 02/28/2022] [Indexed: 12/14/2022]
Abstract
Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, MitoNET,and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.
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28
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Mechanisms of podocyte injury and implications for diabetic nephropathy. Clin Sci (Lond) 2022; 136:493-520. [PMID: 35415751 PMCID: PMC9008595 DOI: 10.1042/cs20210625] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 02/25/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023]
Abstract
Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, and diabetic nephropathy (DN). Moreover, albuminuria is an important feature of all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining the permselectivity of the glomerular filtration barrier (GFB) and injury of the podocyte, leading to foot process (FP) effacement and podocyte loss, the unifying underlying mechanism of proteinuric glomerulopathies. The metabolic insult of hyperglycemia is of paramount importance in the pathogenesis of DN, while insults leading to podocyte damage are poorly defined in other proteinuric glomerulopathies. However, shared mechanisms of podocyte damage have been identified. Herein, we will review the role of haemodynamic and oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, and both mitochondrial and autophagic dysfunction in the pathogenesis of the podocyte damage, focussing particularly on their role in the pathogenesis of DN. Gaining a better insight into the mechanisms of podocyte injury may provide novel targets for treatment. Moreover, novel strategies for boosting podocyte repair may open the way to podocyte regenerative medicine.
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29
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Xie J, Jiang J, Guo Q. Primary Coenzyme Q10 Deficiency-7 and Pathogenic COQ4 Variants: Clinical Presentation, Biochemical Analyses, and Treatment. Front Genet 2022; 12:776807. [PMID: 35154243 PMCID: PMC8826242 DOI: 10.3389/fgene.2021.776807] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 12/14/2021] [Indexed: 11/13/2022] Open
Abstract
Primary Coenzyme Q10 Deficiency-7 (COQ10D7) is a rare mitochondrial disorder caused by pathogenic COQ4 variants. In this review, we discuss the correlation of COQ4 genotypes, particularly the East Asian-specific c.370G > A variant, with the clinical presentations and therapeutic effectiveness of coenzyme Q10 supplementation from an exon-dependent perspective. Pathogenic COQ4 variants in exons 1–4 are associated with less life-threating presentations, late onset, responsiveness to CoQ10 therapy, and a relatively long lifespan. In contrast, pathogenic COQ4 variants in exons 5–7 are associated with early onset, unresponsiveness to CoQ10 therapy, and early death and are more fatal. Patients with the East Asian-specific c.370G > A variant displays intermediate disease severity with multi-systemic dysfunction, which is between that of the patients with variants in exons 1–4 and 5–7. The mechanism underlying this exon-dependent genotype-phenotype correlation may be associated with the structure and function of COQ4. Sex is shown unlikely to be associated with disease severity. While point-of-care high-throughput sequencing would be useful for the rapid diagnosis of pathogenic COQ4 variants, whereas biochemical analyses of the characteristic impairments in CoQ10 biosynthesis and mitochondrial respiratory chain activity, as well as the phenotypic rescue of the CoQ10 treatment, are necessary to confirm the pathogenicity of suspicious variants. In addition to CoQ10 derivatives, targeted drugs and gene therapy could be useful treatments for COQ10D7 depending on the in-depth functional investigations and the development of gene editing technologies. This review provides a fundamental reference for the sub-classification of COQ10D7 and aim to advance our knowledge of the pathogenesis, clinical diagnosis, and prognosis of this disease and possible interventions.
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Affiliation(s)
- Jieqiong Xie
- United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen, China
| | - Jiayang Jiang
- United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen, China.,School of Medicine, Huaqiao University, Quanzhou, China
| | - Qiwei Guo
- United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen, China
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30
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Liang R, Chen X, Zhang Y, Law CF, Yu S, Jiao J, Yang Q, Wu D, Zhang G, Chen H, Wang M, Yang H, Wang A. Clinical features and gene variation analysis of COQ8B nephropathy: Report of seven cases. Front Pediatr 2022; 10:1030191. [PMID: 36843884 PMCID: PMC9948246 DOI: 10.3389/fped.2022.1030191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 12/02/2022] [Indexed: 02/11/2023] Open
Abstract
OBJECTIVE COQ8B nephropathy is a relatively rare autosomal recessive kidney disease characterized by proteinuria and a progressive deterioration of renal function, eventually leading to end-stage renal disease (ESRD). The objective is to study the characteristics and correlation between the genotype and the clinical phenotype of COQ8B nephropathy. METHODS This is a retrospective study focusing on the clinical characteristics of seven COQ8B nephropathy patients diagnosed by gene sequencing. Basic clinical information, clinical manifestations, examinations, imaging, genomes, pathology, treatments, and prognosis of the patients were reviewed. RESULTS Of the seven patients, two were male children and five were female children. The median age at the disease onset was 5 years and 3 months. The initial main clinical manifestations were proteinuria and renal insufficiency. Four patients had severe proteinuria, four had focal segmental glomerulosclerosis (FSGS) diagnosed by a renal biopsy, and two had nephrocalcinosis after an ultrasound was performed on them. There were no other clinical manifestations such as neuropathy, muscle atrophy, and so on in all of them. Their gene mutations were all exon variants, which were classified as heterozygous or homozygous variants by performing family verification analysis. Compound heterozygous variants were predominant in all, and all gene variants were inherited from their parents. One novel mutation, c.1465c>t, was found in this study. This gene mutation resulted from changes in the amino acid sequence, thus leading to an abnormal protein structure. Two patients with early diagnosis of COQ8B nephropathy presented with no renal insufficiency and were treated with oral coenzyme Q10 (CoQ10), and they maintained normal renal function. For the remaining five who were treated with CoQ10 following renal insufficiency, the deterioration of renal function could not be reversed, and they progressed to ESRD within a short time (median time: 7 months). A follow-up of these patients showed normal renal function with a CoQ10 supplement. CONCLUSION For unexplained proteinuria, renal insufficiency, or steroid-resistant nephrotic syndrome, gene sequencing should be considered, in addition to renal biopsy, as early as possible. Timely diagnosis of COQ8B nephropathy and early supplementation of sufficient CoQ10 can help control the progression of the disease and significantly improve the prognosis.
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Affiliation(s)
- Rui Liang
- Department of Pediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Xuelan Chen
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Ying Zhang
- Department of Pediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Chak-Fun Law
- Center for Biomedicine and Innovations, Faculty of Medicine, Macau University Science and Technology, Taipa, China
| | - Sijie Yu
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Jia Jiao
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Qin Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Daoqi Wu
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Gaofu Zhang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Han Chen
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Mo Wang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Haiping Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Anshuo Wang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
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31
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Sachdeva S, Khan S, Davalos C, Avanthika C, Jhaveri S, Babu A, Patterson D, Yamani AJ. Management of Steroid-Resistant Nephrotic Syndrome in Children. Cureus 2021; 13:e19363. [PMID: 34925975 PMCID: PMC8654081 DOI: 10.7759/cureus.19363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2021] [Indexed: 11/23/2022] Open
Abstract
Nephrotic syndrome (NS) affects 115-169 children per 100,000, with rates varying by ethnicity and location. Immune dysregulation, systemic circulating substances, or hereditary structural abnormalities of the podocyte are considered to have a role in the etiology of idiopathic NS. Following daily therapy with corticosteroids, more than 85% of children and adolescents (often aged 1 to 12 years) with idiopathic nephrotic syndrome have full proteinuria remission. Patients with steroid-resistant nephrotic syndrome (SRNS) do not demonstrate remission after four weeks of daily prednisolone therapy. The incidence of steroid-resistant nephrotic syndrome in children varies between 35 and 92 percent. A third of SRNS patients have mutations in one of the important podocyte genes. An unidentified circulating factor is most likely to blame for the remaining instances of SRNS. The aim of this article is to explore and review the genetic factors and management of steroid-resistant nephrotic syndrome. An all language literature search was conducted on MEDLINE, COCHRANE, EMBASE, and Google Scholar till September 2021. The following search strings and Medical Subject Headings (MeSH) terms were used: “Steroid resistance”, “nephrotic syndrome”, “nephrosis” and “hypoalbuminemia”. We comprehensively reviewed the literature on the epidemiology, genetics, current treatment protocols, and management of steroid-resistant nephrotic syndrome. We found that for individuals with non-genetic SRNS, calcineurin inhibitors (cyclosporine and tacrolimus) constitute the current mainstay of treatment, with around 70% of patients achieving full or partial remission and an acceptable long-term prognosis. Patients with SRNS who do not react to calcineurin inhibitors or other immunosuppressive medications may have deterioration in kidney function and may develop end-stage renal failure. Nonspecific renal protective medicines, such as angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers, and anti-lipid medications, slow the course of the illness. Recurrent focal segmental glomerulosclerosis in the allograft affects around a third of individuals who get a kidney transplant, and it frequently responds to a combination of plasma exchange, rituximab, and increased immunosuppression. Despite the fact that these results show a considerable improvement in outcome, further multicenter controlled studies are required to determine the optimum drugs and regimens to be used.
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Affiliation(s)
| | - Syeda Khan
- Medicine and Surgery, Dow University of Health Sciences, Karachi, PAK
| | | | - Chaithanya Avanthika
- Medicine and Surgery, Karnataka Institute of Medical Sciences, Hubli, IND.,Pediatrics, Karnataka Institute of Medical Sciences, Hubli, IND
| | - Sharan Jhaveri
- Internal Medicine, Smt. NHL Municipal Medical College (MMC), Ahmedabad, IND
| | - Athira Babu
- Pediatrics, Saudi German Hospital, Dubai, ARE
| | | | - Abdullah J Yamani
- Pediatric Medicine, Coast General Teaching and Referral Hospital, Mombasa, KEN
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32
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Primary coenzyme Q10 nephropathy, a potentially treatable form of steroid-resistant nephrotic syndrome. Pediatr Nephrol 2021; 36:3515-3527. [PMID: 33479824 PMCID: PMC8295399 DOI: 10.1007/s00467-020-04914-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 11/28/2020] [Accepted: 12/31/2020] [Indexed: 12/18/2022]
Abstract
Steroid-resistant nephrotic syndrome (SRNS) is a genetically heterogeneous kidney disease that is the second most frequent cause of kidney failure in the first 2 decades of life. Despite the identification of mutations in more than 39 genes as causing SRNS, and the localization of its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain poorly understood and no universally safe and effective therapy exists to treat patients with this condition. Recently, genetic research has identified a subgroup of SRNS patients whose kidney pathology is caused by primary coenzyme Q10 (CoQ10) deficiency due to recessive mutations in genes that encode proteins in the CoQ10 biosynthesis pathway. Clinical and preclinical studies show that primary CoQ10 deficiency may be responsive to treatment with CoQ10 supplements bypassing the biosynthesis defects. Coenzyme Q10 is an essential component of the mitochondrial respiratory chain, where it transports electrons from complexes I and II to complex III. Studies in yeast and mammalian model systems have recently identified the molecular functions of the individual CoQ10 biosynthesis complex proteins, validated these findings, and provided an impetus for developing therapeutic compounds to replenish CoQ10 levels in the tissues/organs and thus prevent the destruction of tissues due to mitochondrial OXPHOS deficiencies. In this review, we will summarize the clinical findings of the kidney pathophysiology of primary CoQ10 deficiencies and discuss recent advances in the development of therapies to counter CoQ10 deficiency in tissues.
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33
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Navas P, Cascajo MV, Alcázar-Fabra M, Hernández-Camacho JD, Sánchez-Cuesta A, Rodríguez ABC, Ballesteros-Simarro M, Arroyo-Luque A, Rodríguez-Aguilera JC, Fernández-Ayala DJM, Brea-Calvo G, López-Lluch G, Santos-Ocaña C. Secondary CoQ 10 deficiency, bioenergetics unbalance in disease and aging. Biofactors 2021; 47:551-569. [PMID: 33878238 DOI: 10.1002/biof.1733] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/24/2021] [Indexed: 12/21/2022]
Abstract
Coenzyme Q10 (CoQ10 ) deficiency is a rare disease characterized by a decreased accumulation of CoQ10 in cell membranes. Considering that CoQ10 synthesis and most of its functions are carried out in mitochondria, CoQ10 deficiency cases are usually considered a mitochondrial disease. A relevant feature of CoQ10 deficiency is that it is the only mitochondrial disease with a successful therapy available, the CoQ10 supplementation. Defects in components of the synthesis machinery caused by mutations in COQ genes generate the primary deficiency of CoQ10 . Mutations in genes that are not directly related to the synthesis machinery cause secondary deficiency. Cases of CoQ10 deficiency without genetic origin are also considered a secondary deficiency. Both types of deficiency can lead to similar clinical manifestations, but the knowledge about primary deficiency is deeper than secondary. However, secondary deficiency cases may be underestimated since many of their clinical manifestations are shared with other pathologies. This review shows the current state of secondary CoQ10 deficiency, which could be even more relevant than primary deficiency for clinical activity. The analysis covers the fundamental features of CoQ10 deficiency, which are necessary to understand the biological and clinical differences between primary and secondary CoQ10 deficiencies. Further, a more in-depth analysis of CoQ10 secondary deficiency was undertaken to consider its origins, introduce a new way of classification, and include aging as a form of secondary deficiency.
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Affiliation(s)
- Plácido Navas
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - María V Cascajo
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - María Alcázar-Fabra
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - Juan D Hernández-Camacho
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - Ana Sánchez-Cuesta
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - Ana Belén Cortés Rodríguez
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
- Laboratorio de Fisiopatología Celular y Bioenergética, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
| | - Manuel Ballesteros-Simarro
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - Antonio Arroyo-Luque
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - Juan Carlos Rodríguez-Aguilera
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
- Laboratorio de Fisiopatología Celular y Bioenergética, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
| | - Daniel J M Fernández-Ayala
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - Gloria Brea-Calvo
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - Guillermo López-Lluch
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
| | - Carlos Santos-Ocaña
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, Madrid, Spain
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Alcázar-Fabra M, Rodríguez-Sánchez F, Trevisson E, Brea-Calvo G. Primary Coenzyme Q deficiencies: A literature review and online platform of clinical features to uncover genotype-phenotype correlations. Free Radic Biol Med 2021; 167:141-180. [PMID: 33677064 DOI: 10.1016/j.freeradbiomed.2021.02.046] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/13/2021] [Accepted: 02/26/2021] [Indexed: 12/13/2022]
Abstract
Primary Coenzyme Q (CoQ) deficiencies are clinically heterogeneous conditions and lack clear genotype-phenotype correlations, complicating diagnosis and prognostic assessment. Here we present a compilation of all the symptoms and patients with primary CoQ deficiency described in the literature so far and analyse the most common clinical manifestations associated with pathogenic variants identified in the different COQ genes. In addition, we identified new associations between the age of onset of symptoms and different pathogenic variants, which could help to a better diagnosis and guided treatment. To make these results useable for clinicians, we created an online platform (https://coenzymeQbiology.github.io/clinic-CoQ-deficiency) about clinical manifestations of primary CoQ deficiency that will be periodically updated to incorporate new information published in the literature. Since CoQ primary deficiency is a rare disease, the available data are still limited, but as new patients are added over time, this tool could become a key resource for a more efficient diagnosis of this pathology.
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Affiliation(s)
- María Alcázar-Fabra
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA and CIBERER, Instituto de Salud Carlos III, Seville, 41013, Spain
| | | | - Eva Trevisson
- Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy; Istituto di Ricerca Pediatrica, Fondazione Città della Speranza, Padova, 35128, Italy.
| | - Gloria Brea-Calvo
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA and CIBERER, Instituto de Salud Carlos III, Seville, 41013, Spain.
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Markin AM, Khotina VA, Zabudskaya XG, Bogatyreva AI, Starodubova AV, Ivanova E, Nikiforov NG, Orekhov AN. Disturbance of Mitochondrial Dynamics and Mitochondrial Therapies in Atherosclerosis. Life (Basel) 2021; 11:life11020165. [PMID: 33672784 PMCID: PMC7924632 DOI: 10.3390/life11020165] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/13/2021] [Accepted: 02/17/2021] [Indexed: 12/13/2022] Open
Abstract
Mitochondrial dysfunction is associated with a wide range of chronic human disorders, including atherosclerosis and diabetes mellitus. Mitochondria are dynamic organelles that undergo constant turnover in living cells. Through the processes of mitochondrial fission and fusion, a functional population of mitochondria is maintained, that responds to the energy needs of the cell. Damaged or excessive mitochondria are degraded by mitophagy, a specialized type of autophagy. These processes are orchestrated by a number of proteins and genes, and are tightly regulated. When one or several of these processes are affected, it can lead to the accumulation of dysfunctional mitochondria, deficient energy production, increased oxidative stress and cell death—features that are described in many human disorders. While severe mitochondrial dysfunction is known to cause specific and mitochondrial disorders in humans, progressing damage of the mitochondria is also observed in a wide range of other chronic diseases, including cancer and atherosclerosis, and appears to play an important role in disease development. Therefore, correction of mitochondrial dynamics can help in developing new therapies for the treatment of these conditions. In this review, we summarize the recent knowledge on the processes of mitochondrial turnover and the proteins and genes involved in it. We provide a list of known mutations that affect mitochondrial function, and discuss the emerging therapeutic approaches.
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Affiliation(s)
- Alexander M. Markin
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 117418 Moscow, Russia; (A.M.M.); (V.A.K.); (A.I.B.); (N.G.N.); (A.N.O.)
| | - Viktoria A. Khotina
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 117418 Moscow, Russia; (A.M.M.); (V.A.K.); (A.I.B.); (N.G.N.); (A.N.O.)
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8, Baltiyskaya St., 125315 Moscow, Russia
| | - Xenia G. Zabudskaya
- FSBI National Medical Research Center of Oncology named after N.N. Blokhin of the Ministry of Health of Russia, 115478 Moscow, Russia;
| | - Anastasia I. Bogatyreva
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 117418 Moscow, Russia; (A.M.M.); (V.A.K.); (A.I.B.); (N.G.N.); (A.N.O.)
| | - Antonina V. Starodubova
- Federal Research Centre for Nutrition, Biotechnology and Food Safety, Ustinsky Passage, 109240 Moscow, Russia;
| | - Ekaterina Ivanova
- Department of Basic Research, Institute of Atherosclerosis Research, 121609 Moscow, Russia
- Correspondence: ; Tel./Fax: +7-(495)4159594
| | - Nikita G. Nikiforov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 117418 Moscow, Russia; (A.M.M.); (V.A.K.); (A.I.B.); (N.G.N.); (A.N.O.)
- National Medical Research Center of Cardiology, Institute of Experimental Cardiology, 117418 Moscow, Russia
- Institute of Gene Biology, Centre of collective usage, 119344 Moscow, Russia
| | - Alexander N. Orekhov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 117418 Moscow, Russia; (A.M.M.); (V.A.K.); (A.I.B.); (N.G.N.); (A.N.O.)
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8, Baltiyskaya St., 125315 Moscow, Russia
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Pitceathly RD, Keshavan N, Rahman J, Rahman S. Moving towards clinical trials for mitochondrial diseases. J Inherit Metab Dis 2021; 44:22-41. [PMID: 32618366 PMCID: PMC8432143 DOI: 10.1002/jimd.12281] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/22/2020] [Accepted: 06/30/2020] [Indexed: 12/11/2022]
Abstract
Primary mitochondrial diseases represent some of the most common and severe inherited metabolic disorders, affecting ~1 in 4,300 live births. The clinical and molecular diversity typified by mitochondrial diseases has contributed to the lack of licensed disease-modifying therapies available. Management for the majority of patients is primarily supportive. The failure of clinical trials in mitochondrial diseases partly relates to the inefficacy of the compounds studied. However, it is also likely to be a consequence of the significant challenges faced by clinicians and researchers when designing trials for these disorders, which have historically been hampered by a lack of natural history data, biomarkers and outcome measures to detect a treatment effect. Encouragingly, over the past decade there have been significant advances in therapy development for mitochondrial diseases, with many small molecules now transitioning from preclinical to early phase human interventional studies. In this review, we present the treatments and management strategies currently available to people with mitochondrial disease. We evaluate the challenges and potential solutions to trial design and highlight the emerging pharmacological and genetic strategies that are moving from the laboratory to clinical trials for this group of disorders.
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Affiliation(s)
- Robert D.S. Pitceathly
- Department of Neuromuscular DiseasesUCL Queen Square Institute of Neurology and The National Hospital for Neurology and NeurosurgeryLondonUK
| | - Nandaki Keshavan
- Mitochondrial Research GroupUCL Great Ormond Street Institute of Child HealthLondonUK
- Metabolic UnitGreat Ormond Street Hospital for Children NHS Foundation TrustLondonUK
| | - Joyeeta Rahman
- Mitochondrial Research GroupUCL Great Ormond Street Institute of Child HealthLondonUK
| | - Shamima Rahman
- Mitochondrial Research GroupUCL Great Ormond Street Institute of Child HealthLondonUK
- Metabolic UnitGreat Ormond Street Hospital for Children NHS Foundation TrustLondonUK
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Lee JM, Kronbichler A, Shin JI, Oh J. Current understandings in treating children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2021; 36:747-761. [PMID: 32086590 PMCID: PMC7910243 DOI: 10.1007/s00467-020-04476-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 12/22/2019] [Accepted: 01/07/2020] [Indexed: 12/27/2022]
Abstract
Steroid-resistant nephrotic syndrome (SRNS) remains a challenge for paediatric nephrologists. SRNS is viewed as a heterogeneous disease entity including immune-based and monogenic aetiologies. Because SRNS is rare, treatment strategies are individualized and vary among centres of expertise. Calcineurin inhibitors (CNI) have been effectively used to induce remission in patients with immune-based SRNS; however, there is still no consensus on treating children who become either CNI-dependent or CNI-resistant. Rituximab is a steroid-sparing agent for patients with steroid-sensitive nephrotic syndrome, but its efficacy in SRNS is controversial. Recently, several novel monoclonal antibodies are emerging as treatment option, but their efficacy remains to be seen. Non-immune therapies, such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, have been proven efficacious in children with SRNS and are recommended as adjuvant agents. This review summarizes and discusses our current understandings in treating children with idiopathic SRNS.
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Affiliation(s)
- Jiwon M. Lee
- Department of Pediatrics, Chungnam National University Hospital, Daejeon, South Korea
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, C.P.O. Box 8044, Seoul, 120-752 South Korea ,Division of Pediatric Nephrology, Severance Children’s Hospital, Seoul, South Korea ,Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Jun Oh
- Department of Pediatrics Nephrology, University Hamburg-Eppendorf, Martinistrasse, 52 20246, Hamburg, Germany.
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Tiet MY, Lin Z, Gao F, Jennings MJ, Horvath R. Targeted Therapies for Leigh Syndrome: Systematic Review and Steps Towards a 'Treatabolome'. J Neuromuscul Dis 2021; 8:885-897. [PMID: 34308912 PMCID: PMC8673543 DOI: 10.3233/jnd-210715] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Leigh syndrome (LS) is the most frequent paediatric clinical presentation of mitochondrial disease. The clinical phenotype of LS is highly heterogeneous. Though historically the treatment for LS is largely supportive, new treatments are on the horizon. Due to the rarity of LS, large-scale interventional studies are scarce, limiting dissemination of information of therapeutic options to the wider scientific and clinical community. OBJECTIVE We conducted a systematic review of pharmacological therapies of LS following the guidelines for FAIR-compliant datasets. METHODS We searched for interventional studies within Clincialtrials.gov and European Clinical trials databases. Randomised controlled trials, observational studies, case reports and case series formed part of a wider MEDLINE search. RESULTS Of the 1,193 studies initially identified, 157 met our inclusion criteria, of which 104 were carried over into our final analysis. Treatments for LS included very few interventional trials using EPI-743 and cysteamine bitartrate. Wider literature searches identified case series and reports of treatments repleting glutathione stores, reduction of oxidative stress and restoration of oxidative phosphorylation. CONCLUSIONS Though interventional randomised controlled trials have begun for LS, the majority of evidence remains in case reports and case series for a number of treatable genes, encoding cofactors or transporter proteins of the mitochondria. Our findings will form part of the international expert-led Solve-RD efforts to assist clinicians initiating treatments in patients with treatable variants of LS.
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Affiliation(s)
- May Yung Tiet
- Department of Clinical Neurosciences, School of Clinical Medicine, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
| | - Zhiyuan Lin
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Fei Gao
- Department of Clinical Neurosciences, School of Clinical Medicine, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
| | - Matthew James Jennings
- Department of Clinical Neurosciences, School of Clinical Medicine, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
| | - Rita Horvath
- Department of Clinical Neurosciences, School of Clinical Medicine, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK
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Schijvens AM, van de Kar NC, Bootsma-Robroeks CM, Cornelissen EA, van den Heuvel LP, Schreuder MF. Mitochondrial Disease and the Kidney With a Special Focus on CoQ 10 Deficiency. Kidney Int Rep 2020; 5:2146-2159. [PMID: 33305107 PMCID: PMC7710892 DOI: 10.1016/j.ekir.2020.09.044] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 09/29/2020] [Indexed: 12/13/2022] Open
Abstract
Mitochondrial cytopathies include a heterogeneous group of diseases that are characterized by impaired oxidative phosphorylation, leading to multi-organ involvement and progressive clinical deterioration. Most mitochondrial cytopathies that cause kidney symptoms are characterized by tubular defects, but glomerular, tubulointerstitial, and cystic diseases have also been described. Mitochondrial cytopathies can result from mitochondrial or nuclear DNA mutations. Early recognition of defects in the coenzyme Q10 (CoQ10) biosynthesis is important, as patients with primary CoQ10 deficiency may be responsive to treatment with oral CoQ10 supplementation, in contrast to most mitochondrial diseases. A literature search was conducted to investigate kidney involvement in genetic mitochondrial cytopathies and to identify mitochondrial and nuclear DNA mutations involved in mitochondrial kidney disease. Furthermore, we identified all reported cases to date with a CoQ10 deficiency with glomerular involvement, including 3 patients with variable renal phenotypes in our clinic. To date, 144 patients from 95 families with a primary CoQ10 deficiency and glomerular involvement have been described based on mutations in PDSS1, PDSS2, COQ2, COQ6, and COQ8B/ADCK4. This review provides an overview of kidney involvement in genetic mitochondrial cytopathies with a special focus on CoQ10 deficiency.
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Affiliation(s)
- Anne M. Schijvens
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Nijmegen, the Netherlands
| | - Nicole C. van de Kar
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Nijmegen, the Netherlands
| | - Charlotte M. Bootsma-Robroeks
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Nijmegen, the Netherlands
| | - Elisabeth A. Cornelissen
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Nijmegen, the Netherlands
| | - Lambertus P. van den Heuvel
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Nijmegen, the Netherlands
- Department of Development and Regeneration,University Hospital Leuven, Leuven, Belgium
| | - Michiel F. Schreuder
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Nijmegen, the Netherlands
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Human Mitochondrial Pathologies of the Respiratory Chain and ATP Synthase: Contributions from Studies of Saccharomyces cerevisiae. Life (Basel) 2020; 10:life10110304. [PMID: 33238568 PMCID: PMC7700678 DOI: 10.3390/life10110304] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 12/14/2022] Open
Abstract
The ease with which the unicellular yeast Saccharomyces cerevisiae can be manipulated genetically and biochemically has established this organism as a good model for the study of human mitochondrial diseases. The combined use of biochemical and molecular genetic tools has been instrumental in elucidating the functions of numerous yeast nuclear gene products with human homologs that affect a large number of metabolic and biological processes, including those housed in mitochondria. These include structural and catalytic subunits of enzymes and protein factors that impinge on the biogenesis of the respiratory chain. This article will review what is currently known about the genetics and clinical phenotypes of mitochondrial diseases of the respiratory chain and ATP synthase, with special emphasis on the contribution of information gained from pet mutants with mutations in nuclear genes that impair mitochondrial respiration. Our intent is to provide the yeast mitochondrial specialist with basic knowledge of human mitochondrial pathologies and the human specialist with information on how genes that directly and indirectly affect respiration were identified and characterized in yeast.
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Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency. Orphanet J Rare Dis 2020; 15:320. [PMID: 33187544 PMCID: PMC7662744 DOI: 10.1186/s13023-020-01600-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 10/26/2020] [Indexed: 12/20/2022] Open
Abstract
Background Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).
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Transcription factor Kruppel-like factor 5 positively regulates the expression of AarF domain containing kinase 4. Mol Biol Rep 2020; 47:8419-8427. [PMID: 33033902 DOI: 10.1007/s11033-020-05882-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 09/26/2020] [Accepted: 09/30/2020] [Indexed: 02/04/2023]
Abstract
AarF domain containing kinase 4 (ADCK4) is identified as a candidate gene associated with hereditary nephrotic syndrome (NS). Kruppel-like factor 5 (KLF5) is reported to promote podocyte survival by blocking the ERK/p38 MAPK pathways. Both ADCK4 and KLF5 are involved in the occurrence and development of podocyte disease, but their interaction remains unclear. Firstly, we found that the mRNA levels of ADCK4 and KLF5 decreased in NS patients, and both levels showed an obvious linear relationship. Secondly, we cloned the ADCK4 promoter region and examined its promoter activity in Hela, A549, and HEK 293 cell lines. Deletion analysis showed that the region - 116/- 4 relative to the transcriptional start site (TSS) was the core region of ADCK4 promoter. Thirdly, mutation analysis showed that putative binding sites for KLF5 contributed to the ADCK4 promoter activity. In HEK293 cells, we found that KLF5 upregulated the mRNA and protein levels of ADCK4. Finally, our chromatin immunoprecipitation assay found that KLF5 could bind to the specific region of ADCK4 promoter. These results showed that KLF5 can positively regulate the transcriptional activity of ADCK4.
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Lee KH, Cha M, Lee BH. Neuroprotective Effect of Antioxidants in the Brain. Int J Mol Sci 2020; 21:ijms21197152. [PMID: 32998277 PMCID: PMC7582347 DOI: 10.3390/ijms21197152] [Citation(s) in RCA: 259] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/18/2020] [Accepted: 09/23/2020] [Indexed: 12/29/2022] Open
Abstract
The brain is vulnerable to excessive oxidative insults because of its abundant lipid content, high energy requirements, and weak antioxidant capacity. Reactive oxygen species (ROS) increase susceptibility to neuronal damage and functional deficits, via oxidative changes in the brain in neurodegenerative diseases. Overabundance and abnormal levels of ROS and/or overload of metals are regulated by cellular defense mechanisms, intracellular signaling, and physiological functions of antioxidants in the brain. Single and/or complex antioxidant compounds targeting oxidative stress, redox metals, and neuronal cell death have been evaluated in multiple preclinical and clinical trials as a complementary therapeutic strategy for combating oxidative stress associated with neurodegenerative diseases. Herein, we present a general analysis and overview of various antioxidants and suggest potential courses of antioxidant treatments for the neuroprotection of the brain from oxidative injury. This review focuses on enzymatic and non-enzymatic antioxidant mechanisms in the brain and examines the relative advantages and methodological concerns when assessing antioxidant compounds for the treatment of neurodegenerative disorders.
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Affiliation(s)
- Kyung Hee Lee
- Department of Dental Hygiene, Division of Health Science, Dongseo University, Busan 47011, Korea;
| | - Myeounghoon Cha
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Bae Hwan Lee
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Korea;
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
- Correspondence: ; Tel.: +82-2-2228-1711
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Early-onset COQ8B (ADCK4) glomerulopathy in a child with isolated proteinuria: a case report and literature review. BMC Nephrol 2020; 21:406. [PMID: 32957916 PMCID: PMC7507654 DOI: 10.1186/s12882-020-02038-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 08/23/2020] [Indexed: 02/06/2023] Open
Abstract
Background Herein, a 3-year-old boy presented with hidden-onset isolated proteinuria was reported. The disease was induced by COQ8B (previously termed ADCK4) compound heterozygous variants, including c.[271C > T] and c.[737G > A], which were inherited from his father and mother, respectively. Case presentation The patient visited our clinic due to non-nephrotic range proteinuria for 3 months, but no obvious abnormality was detected in the vital signs or laboratory test results. Renal histopathology revealed mitochondrial nephropathy, which manifested as mild glomerular abnormalities under light microscope, together with mitochondrial proliferation and hypertrophy and crowded arrangement under electron microscope. As suggested by whole exome sequencing, the patient inherited the COQ8B compound heterozygous variants from both of his parents who showed normal phenotype. After literature review, it was confirmed that one of the variant site (c.[271C > T]) had not been reported among the East Asian populations so far. Conclusions Steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis are the most common phenotypes and renal histopathological manifestations of COQ8B variant. Nonetheless, our case shows that such variant may have hidden and mild clinical manifestations at the early onset. Therefore, early diagnosis will help to identify children at the early disease stage who have opportunity to benefit from oral coenzyme Q10 supplementation.
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Braunisch MC, Riedhammer KM, Herr PM, Draut S, Günthner R, Wagner M, Weidenbusch M, Lungu A, Alhaddad B, Renders L, Strom TM, Heemann U, Meitinger T, Schmaderer C, Hoefele J. Identification of disease-causing variants by comprehensive genetic testing with exome sequencing in adults with suspicion of hereditary FSGS. Eur J Hum Genet 2020; 29:262-270. [PMID: 32887937 PMCID: PMC7868362 DOI: 10.1038/s41431-020-00719-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 07/15/2020] [Accepted: 08/11/2020] [Indexed: 11/21/2022] Open
Abstract
In about 30% of infantile, juvenile, or adolescent patients with steroid-resistant nephrotic syndrome (SRNS), a monogenic cause can be identified. The histological finding in SRNS is often focal segmental glomerulosclerosis (FSGS). Genetic data on adult patients are scarce with low diagnostic yields. Exome sequencing (ES) was performed in patients with adult disease onset and a high likelihood for hereditary FSGS. A high likelihood was defined if at least one of the following criteria was present: absence of a secondary cause, ≤25 years of age at initial manifestation, kidney biopsy with suspicion of a hereditary cause, extrarenal manifestations, and/or positive familial history/reported consanguinity. Patients were excluded if age at disease onset was <18 years. In 7/24 index patients with adult disease onset, a disease-causing variant could be identified by ES leading to a diagnostic yield of 29%. Eight different variants were identified in six known genes associated with monogenic kidney diseases. Six of these variants had been described before as disease-causing. In patients with a disease-causing variant, the median age at disease onset and end-stage renal disease was 26 and 38 years, respectively. The overall median time to a definite genetic diagnosis was 9 years. In 29% of patients with adult disease onset and suspected hereditary FSGS, a monogenic cause could be identified. The long delay up to the definite genetic diagnosis highlights the importance of obtaining an early genetic diagnosis to allow for personalized treatment options including weaning of immunosuppressive treatment, avoidance of repeated renal biopsy, and provision of accurate genetic counseling.
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Affiliation(s)
- Matthias Christoph Braunisch
- Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.,Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Korbinian Maria Riedhammer
- Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.,Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Pierre-Maurice Herr
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Sarah Draut
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Roman Günthner
- Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.,Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Matias Wagner
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.,Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.,Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Marc Weidenbusch
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany
| | - Adrian Lungu
- Pediatric Nephrology Department, Fundeni Clinical Institute, Bucharest, Romania
| | - Bader Alhaddad
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Lutz Renders
- Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Tim M Strom
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.,Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Uwe Heemann
- Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Thomas Meitinger
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.,Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Christoph Schmaderer
- Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Julia Hoefele
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
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Fernández-Del-Río L, Kelly ME, Contreras J, Bradley MC, James AM, Murphy MP, Payne GS, Clarke CF. Genes and lipids that impact uptake and assimilation of exogenous coenzyme Q in Saccharomyces cerevisiae. Free Radic Biol Med 2020; 154:105-118. [PMID: 32387128 PMCID: PMC7611304 DOI: 10.1016/j.freeradbiomed.2020.04.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/18/2020] [Accepted: 04/28/2020] [Indexed: 12/13/2022]
Abstract
Coenzyme Q (CoQ) is an essential player in the respiratory electron transport chain and is the only lipid-soluble antioxidant synthesized endogenously in mammalian and yeast cells. In humans, genetic mutations, pathologies, certain medical treatments, and aging, result in CoQ deficiencies, which are linked to mitochondrial, cardiovascular, and neurodegenerative diseases. The only strategy available for these patients is CoQ supplementation. CoQ supplements benefit a small subset of patients, but the poor solubility of CoQ greatly limits treatment efficacy. Consequently, the efficient delivery of CoQ to the mitochondria and restoration of respiratory function remains a major challenge. A better understanding of CoQ uptake and mitochondrial delivery is crucial to make this molecule a more efficient and effective therapeutic tool. In this study, we investigated the mechanism of CoQ uptake and distribution using the yeast Saccharomyces cerevisiae as a model organism. The addition of exogenous CoQ was tested for the ability to restore growth on non-fermentable medium in several strains that lack CoQ synthesis (coq mutants). Surprisingly, we discovered that the presence of CoQ biosynthetic intermediates impairs assimilation of CoQ into a functional respiratory chain in yeast cells. Moreover, a screen of 40 gene deletions considered to be candidates to prevent exogenous CoQ from rescuing growth of the CoQ-less coq2Δ mutant, identified six novel genes (CDC10, RTS1, RVS161, RVS167, VPS1, and NAT3) as necessary for efficient trafficking of CoQ to mitochondria. The proteins encoded by these genes represent essential steps in the pathways responsible for transport of exogenously supplied CoQ to its functional sites in the cell, and definitively associate CoQ distribution with endocytosis and intracellular vesicular trafficking pathways conserved from yeast to human cells.
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Affiliation(s)
- Lucía Fernández-Del-Río
- Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA
| | - Miranda E Kelly
- Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA
| | - Jaime Contreras
- Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA
| | - Michelle C Bradley
- Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA
| | - Andrew M James
- MRC Mitochondrial Biology Unit, University of Cambridge, UK
| | - Michael P Murphy
- MRC Mitochondrial Biology Unit, University of Cambridge, UK; Department of Medicine, University of Cambridge, UK
| | - Gregory S Payne
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - Catherine F Clarke
- Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, USA.
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Justine Perrin R, Rousset‐Rouvière C, Garaix F, Cano A, Conrath J, Boyer O, Tsimaratos M. COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy. JIMD Rep 2020; 54:37-44. [PMID: 32685349 PMCID: PMC7358665 DOI: 10.1002/jmd2.12068] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 06/18/2019] [Accepted: 06/24/2019] [Indexed: 11/25/2022] Open
Abstract
INTRODUCTION Primary coenzyme Q10 (CoQ10) deficiencies are a group of mitochondrial disorders that has proven responsiveness to replacement therapy. Mutations in enzymes involved in the biosynthesis of CoQ10 genes are associated with these deficits. The clinical presentation of this rare autosomal recessive disorder is heterogeneous and depends on the gene involved. Mutations in the COQ2, COQ6, PDSS2, and ADCK4 genes are responsible for steroid-resistant nephrotic syndrome (SRNS), which is associated with extra-renal symptoms. Previous studies have reported COQ6 mutations in 11 patients from five different families presenting with SRNS and sensorineural deafness. CASE REPORTS Our study reports the cases of two brothers of Turkish origin with renal failure and sensorineural deafness associated with COQ6 mutations responsible of CoQ10 deficiency. Optical symptoms were present in the eldest, that improved with Idebenone. CONCLUSION/DISCUSSION For the first time, COQ6 mutation with optical involvement is associated with renal and hearing impairment. Although the response to replacement CoQ10 therapy was difficult to evaluate, we think that this treatment was able to stop the disease progression in both patients, and even to prevent the occurrence/development of optical and neurological impairment in the younger brother. Mitochondrial dysfunction secondary to CoQ10 deficiency should always be suspected in patients with SRNS and extra-renal symptoms. Early recognition of this genetic SRNS is mandatory since SRNS can be avoided by adequate treatment based on CoQ10 supplement or an analogue. All cases of primary CoQ10 deficiency should be treated at an early stage to limit the progression of lesions and prevent the emergence of new symptoms.
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Affiliation(s)
- R. Justine Perrin
- Assistance Public Hôpitaux de MarseilleService Multidisciplinaire TimoneMarseilleFrance
| | | | - Florentine Garaix
- Assistance Public Hôpitaux de MarseilleService Multidisciplinaire TimoneMarseilleFrance
| | - Aline Cano
- Assistance Public Hôpitaux de MarseilleService de pédiatrie et NeurologieMarseilleFrance
| | - John Conrath
- Clinique Monticelli, OphtalmologieMarseilleFrance
| | - Olivia Boyer
- Hopital NeckerNéphrologie PediatriqueParisFrance
| | - Michel Tsimaratos
- Assistance Public Hôpitaux de MarseilleService Multidisciplinaire TimoneMarseilleFrance
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Park E, Lee C, Kim NKD, Ahn YH, Park YS, Lee JH, Kim SH, Cho MH, Cho H, Yoo KH, Shin JI, Kang HG, Ha IS, Park WY, Cheong HI. Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis. J Clin Med 2020; 9:jcm9062013. [PMID: 32604935 PMCID: PMC7355646 DOI: 10.3390/jcm9062013] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 06/16/2020] [Accepted: 06/19/2020] [Indexed: 11/17/2022] Open
Abstract
Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage renal disease (ESRD) in childhood and is mostly associated with focal segmental glomerulosclerosis (FSGS). More than 50 monogenic causes of SRNS or FSGS have been identified. Recently, the mutation detection rate in pediatric patients with SRNS has been reported to be approximately 30%. In this study, genotype-phenotype correlations in a cohort of 291 Korean pediatric patients with SRNS/FSGS were analyzed. The overall mutation detection rate was 43.6% (127 of 291 patients). WT1 was the most common causative gene (23.6%), followed by COQ6 (8.7%), NPHS1 (8.7%), NUP107 (7.1%), and COQ8B (6.3%). Mutations in COQ6, NUP107, and COQ8B were more frequently detected, and mutations in NPHS2 were less commonly detected in this cohort than in study cohorts from Western countries. The mutation detection rate was higher in patients with congenital onset, those who presented with proteinuria or chronic kidney disease/ESRD, and those who did not receive steroid treatment. Genetic diagnosis in patients with SRNS provides not only definitive diagnosis but also valuable information for decisions on treatment policy and prediction of prognosis. Therefore, further genotype-phenotype correlation studies are required.
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Affiliation(s)
- Eujin Park
- Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Korea; (E.P.); (Y.H.A.); (H.G.K.); (I.-S.H.)
- Department of Pediatrics, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, Korea
| | - Chung Lee
- Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea; (C.L.); (N.K.D.K.); (W.-Y.P.)
- GENINUS Inc., Seoul 05836, Korea
| | - Nayoung K. D. Kim
- Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea; (C.L.); (N.K.D.K.); (W.-Y.P.)
- GENINUS Inc., Seoul 05836, Korea
| | - Yo Han Ahn
- Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Korea; (E.P.); (Y.H.A.); (H.G.K.); (I.-S.H.)
| | - Young Seo Park
- Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul 05505, Korea; (Y.S.P.); (J.H.L.)
| | - Joo Hoon Lee
- Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul 05505, Korea; (Y.S.P.); (J.H.L.)
| | - Seong Heon Kim
- Department of Pediatrics, Pusan National University Children’s Hospital, Yangsan 50612, Korea;
| | - Min Hyun Cho
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu 41944, Korea;
| | - Heeyeon Cho
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Kee Hwan Yoo
- Department of Pediatrics, Korea University Guro Hospital, Seoul 02841, Korea;
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea;
- Division of Pediatric Nephrology, Severance Children’s Hospital, Seoul 03722, Korea
| | - Hee Gyung Kang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Korea; (E.P.); (Y.H.A.); (H.G.K.); (I.-S.H.)
| | - Il-Soo Ha
- Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Korea; (E.P.); (Y.H.A.); (H.G.K.); (I.-S.H.)
| | - Woong-Yang Park
- Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea; (C.L.); (N.K.D.K.); (W.-Y.P.)
- GENINUS Inc., Seoul 05836, Korea
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea
| | - Hae Il Cheong
- Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Korea; (E.P.); (Y.H.A.); (H.G.K.); (I.-S.H.)
- Correspondence: ; Tel.: +82-2-2072-2810
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Abstract
Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but the majority have nonclassical multisystemic disease presentations involving virtually any organ in the body. Each child has a unique constellation of clinical features and disease trajectory, leading to enormous challenges in diagnosis and management of these heterogeneous disorders. This review discusses the classical mitochondrial syndromes presenting most frequently in childhood and then presents an organ-based perspective including systems less frequently linked to mitochondrial disease, such as skin and hair abnormalities and immune dysfunction. An approach to diagnosis is then presented, encompassing clinical evaluation and biochemical, neuroimaging and genetic investigations, and emphasizing the problem of phenocopies. The impact of next-generation sequencing is discussed, together with the importance of functional validation of novel genetic variants never previously linked to mitochondrial disease. The review concludes with a brief discussion of currently available and emerging therapies. The field of mitochondrial medicine has made enormous strides in the last 30 years, with approaching 400 different genes across two genomes now linked to primary mitochondrial disease. However, many important questions remain unanswered, including the reasons for tissue specificity and variability of clinical presentation of individuals sharing identical gene defects, and a lack of disease-modifying therapies and biomarkers to monitor disease progression and/or response to treatment.
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Affiliation(s)
- S Rahman
- Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK
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