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Mondesert E, Baud B, Roubertie A, Benoist JF, Grillet PE, Cristol JP, Francois-Heude MC, Schiff M, Badiou S. Disorder of intracellular cobalamin metabolism: Importance of rapid diagnostic illustrated by a case report of early-onset methylmalonic aciduria and homocystinuria, cobalamin C type. Heliyon 2025; 11:e42086. [PMID: 39916850 PMCID: PMC11795796 DOI: 10.1016/j.heliyon.2025.e42086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 12/24/2024] [Accepted: 01/16/2025] [Indexed: 02/09/2025] Open
Abstract
Methylmalonic aciduria and homocystinuria, cobalamin C type (cblC), constitute the most common inborn error of intracellular cobalamin metabolism. Here, we report the case of a 6-month-old child, presenting severe subacute neurological decline associated with failure to thrive. Biochemical tests indicated a disorder of intracellular cobalamin metabolism, with elevated urinary and plasma methylmalonic acid levels associated with high plasma homocysteine concentrations, with normal plasma vitamin B12 concentrations. Diagnosis was later confirmed by genetic analysis which identified two pathogenic variants on the MMACHC gene: c.271dupA (p.Arg91lysfs∗14) paternal allele and c.388T > C (p.Tyr130His) maternal allele. The patient responded well to hydroxocobalamin treatment, with a rapid recovery of symptoms and a normal growth at 2.8 years of follow-up. This case illustrates the importance of early diagnosis of cobalamin metabolism disorders by prescribing adequate biochemical tests.
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Affiliation(s)
- Etienne Mondesert
- Department of Biochemistry, University Hospital of Montpellier, Montpellier, France
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM U 1298, Montpellier, France
| | - Bastien Baud
- Department of Biochemistry, University Hospital of Montpellier, Montpellier, France
| | - Agathe Roubertie
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM U 1298, Montpellier, France
- Department of Pediatric Neurology, University Hospital of Montpellier, Montpellier, France
| | - Jean-François Benoist
- Department of Biochemistry, Assistance Publique-Hôpitaux de Paris, Paris, France
- Université Paris-Saclay, Paris, France
| | - Pierre-Edouard Grillet
- Department of Biochemistry, University Hospital of Montpellier, Montpellier, France
- PhyMedExp, Université de Montpellier (UM), Inserm, CNRS, Montpellier, France
| | - Jean-Paul Cristol
- Department of Biochemistry, University Hospital of Montpellier, Montpellier, France
- PhyMedExp, Université de Montpellier (UM), Inserm, CNRS, Montpellier, France
| | | | - Manuel Schiff
- Reference Center for Inborn Errors of Metabolism, Department of Pediatrics, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris cité, Paris, France
| | - Stéphanie Badiou
- Department of Biochemistry, University Hospital of Montpellier, Montpellier, France
- PhyMedExp, Université de Montpellier (UM), Inserm, CNRS, Montpellier, France
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Esser AJ, Sastre S, Dinh TLJ, Tanner V, Wingert V, Klotz K, Jacobsen DW, Spiekerkoetter U, Schilling O, Zeida A, Radi R, Hannibal L. A Noncatalytic Cysteine Residue Modulates Cobalamin Reactivity in the Human B 12 Processing Enzyme CblC. Biochemistry 2025; 64:692-709. [PMID: 39862167 DOI: 10.1021/acs.biochem.4c00613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2025]
Abstract
Human CblC catalyzes the indispensable processing of dietary vitamin B12 by the removal of its β-axial ligand and an either one- or two-electron reduction of its cobalt center to yield cob(II)alamin and cob(I)alamin, respectively. Human CblC possesses five cysteine residues of an unknown function. We hypothesized that Cys149, conserved in mammals, tunes the CblC reactivity. To test this, we recreated an evolutionary early variant of CblC, namely, Cys149Ser, as well as Cys149Ala. Surprisingly, substitution of Cys149 for serine or alanine led to faster observed rates of glutathione-driven dealkylation of MeCbl compared to wild-type CblC. The reaction yielded aquacobalamin and stoichiometric formation of S-methylglutathione as the demethylation products. Determination of end-point oxidized glutathione revealed significantly uncoupled electron transfer in both mutants compared with the wild type. Long incubation times revealed the conversion of aquacobalamin to cob(II)alamin in the presence of oxygen in mutants Cys149Ser and Cys149Ala but not in wild-type CblC, all without an effect on dealkylation rates. This finding is reminiscent of the catalytic behavior of CblC from Caenorhabditis elegans, wherein Cys149 is naturally substituted by Ser, and the reaction mechanism differs from that of human CblC precisely by the unusual stabilization of cob(II)alamin in the presence of oxygen. Thus, Cys149 tunes the catalytic activity of human CblC by minimizing uncoupled electron transfer that forms GSSG. This occurs at the expense of a slower observed rate constant for the demethylation of MeCbl. This adjustment is compatible with diminished needs for intracellular turnover of cobalamins and with life under increased oxygen concentration.
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Affiliation(s)
- Anna J Esser
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg im Breisgau 79106, Germany
| | - Santiago Sastre
- Departamento de Biofísica, Facultad de Medicina, and Programa de Doctorado en Química, Facultad de Química, Universidad de la República, Montevideo 11800, Uruguay
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
| | - Thien-Ly Julia Dinh
- Institute of Surgical Pathology, Medical Center, University of Freiburg, Freiburg im Breisgau 79106, Germany
| | - Viola Tanner
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg im Breisgau 79106, Germany
| | - Victoria Wingert
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg im Breisgau 79106, Germany
| | - Katharina Klotz
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg im Breisgau 79106, Germany
| | - Donald W Jacobsen
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
| | - Ute Spiekerkoetter
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg im Breisgau 79106, Germany
| | - Oliver Schilling
- Institute of Surgical Pathology, Medical Center, University of Freiburg, Freiburg im Breisgau 79106, Germany
| | - Ari Zeida
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
| | - Rafael Radi
- Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
| | - Luciana Hannibal
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg im Breisgau 79106, Germany
- CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg im Breisgau 79104, Germany
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Krams C, Esser AJ, Klenzendorf M, Klotz K, Spiekerkoetter U, Jacobsen DW, Smith CA, Maggiolo AO, Hannibal L. The cobalamin processing enzyme of Trichoplax adhaerens. J Biol Chem 2025; 301:108089. [PMID: 39675711 DOI: 10.1016/j.jbc.2024.108089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 11/23/2024] [Accepted: 12/10/2024] [Indexed: 12/17/2024] Open
Abstract
Cobalamin (Cbl) is an essential cofactor for methionine synthase and methylmalonyl-CoA mutase, but it must first undergo chemical processing for utilization in animals. In humans, this processing comprises β-axial ligand cleavage and Cbl reduction and is performed by the enzyme MMACHC (HsCblC). Although the functionality of CblC is well-understood in higher-order organisms, little is known about the evolutionary origin of these enzymes and the reactivity of CblCs in lower-order organisms with unique environmental and cellular conditions. Therefore, we investigated the CblC of Trichoplax adhaerens (TaCblC), a marine organism considered to be one of the earliest evolutionarily diverging and simplest living animals. The TaCblC sequence contained conserved residues important for Cbl processing in higher-order organisms. The predicted structure of TaCblC closely resembled known CblC structures and had features consistent with Cbl and cosubstrate binding capabilities. Recombinantly expressed TaCblC could bind and process several Cbl analogues using glutathione or NADH as cosubstrates, similarly to previously characterized CblCs, but with variable rates and dependencies on the presence of oxygen. Notably, TaCblC dealkylates methylcobalamin at a rate ca. 2-times higher than HsCblC, although this comes with a lower ratio of product to glutathione oxidation, suggesting higher unproductive electron transfer in the TaCblC system. This reflects differences in cellular conditions of the more ancient homologue, which lives in low oxygen levels and an environment of low Cbl bioavailability (∼2 pm in sea water).
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Affiliation(s)
- Caroline Krams
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Anna J Esser
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Melissa Klenzendorf
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Katharina Klotz
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Ute Spiekerkoetter
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Donald W Jacobsen
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Clyde A Smith
- Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, California, USA; Department of Chemistry, Stanford University, Stanford, California, USA
| | - Ailiena O Maggiolo
- Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, California, USA
| | - Luciana Hannibal
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
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Zheng P, Yu C, Xie L, Ji X, Feng S, Gao Y, Wei X, Wu W, Chen Q. Accelerating the diagnosis of Chinese cblC type MMA patients by multiplex PCR sequencing method. Pediatr Res 2025:10.1038/s41390-025-03841-4. [PMID: 39815091 DOI: 10.1038/s41390-025-03841-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 11/05/2024] [Accepted: 12/09/2024] [Indexed: 01/18/2025]
Abstract
BACKGROUND CblC type methylmalonic aciduria (cblC disease) is the most common inborn error of vitamin B12 metabolism and due to mutations in the MMACHC gene. The earlier the diagnosis, the better the prognosis. Therefore, convenient and inexpensive detection method is needed. METHODS This study selected mutational hot-spot regions in the MMACHC gene which harbors more than 90% of mutant alleles responsible for cblC disease in China. Subsequently, a hot-spot regions multi-PCR Sanger sequencing method (HsRMSS) was designed. The accuracy and efficiency of HsRMSS was validated using samples from 20 cblC families with known MMACHC gene mutations and 50 healthy volunteers. In addition, patients' clinical phenotypes and molecular genetic features were analyzed. RESULTS A total of 16 different mutations were identified in 20 cblC families. Among them, the most common mutations were c.609 G>A (26/80, 32.5%), c.567dupT (10/80, 12.5%), c.80A>G (8/80, 10.0%), c.658_660delAAG (8/80, 10.0%) and c.394C>T (6/80, 7.5%), which accounted for over 70% of disease alleles. The HsRMSS results were the same as the results using the whole exon sequencing, with a coincidence rate of 100%. CONCLUSION The HsRMSS targeting the mutational hot-spots of MMACHC gene could be a promising tool to accurately and rapidly diagnose cblC disease in China. IMPACT This study reported the development and validation of a hot-spot regions multi-PCR Sanger sequencing method for targeting hotspots which harbor most of the common MMACHC gene mutations reported in Chinese patients with cblC disease. The approach could have a potential clinical application as a rapid diagnosis and screening tool for suspected children with cblC type MMA and population carrier, owing to its high throughput, low cost, and high sensitivity and specificity.
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Affiliation(s)
- Ping Zheng
- Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics, Beijing, China
| | - Chaoji Yu
- Beijing Huanuo Aomei Gene Biotech Co. Ltd, Beijing, China
| | - Lina Xie
- Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics, Beijing, China
| | - Xinna Ji
- Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics, Beijing, China
| | - Shuo Feng
- Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics, Beijing, China
| | - Yanyan Gao
- Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics, Beijing, China
| | - Xing Wei
- Beijing Huanuo Aomei Gene Biotech Co. Ltd, Beijing, China
| | - Wenli Wu
- Beijing Huanuo Aomei Gene Biotech Co. Ltd, Beijing, China
| | - Qian Chen
- Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics, Beijing, China.
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Olivieri G, Greco B, Cairoli S, Catesini G, Lepri FR, Orazi L, Mallardi M, Martinelli D, Ricci D, Simeoli R, Dionisi‐Vici C. Improved biochemical and neurodevelopmental profiles with high-dose hydroxocobalamin therapy in cobalamin C defect. J Inherit Metab Dis 2025; 48:e12787. [PMID: 39152755 PMCID: PMC11670441 DOI: 10.1002/jimd.12787] [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: 10/16/2023] [Revised: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 08/19/2024]
Abstract
Cobalamin C (Cbl-C) defect causes methylmalonic acidemia, homocystinuria, intellectual disability and visual impairment, despite treatment adherence. While international guidelines recommend parenteral hydroxocobalamin (OH-Cbl) as effective treatment, dose adjustments remain unclear. We assessed OH-Cbl therapy impact on biochemical, neurocognitive and visual outcomes in early-onset Cbl-C patients treated with different OH-Cbl doses over 3 years. Group A (n = 5), diagnosed via newborn screening (NBS), received high-dose OH-Cbl (median 0.55 mg/kg/day); Group B1 (n = 3), NBS-diagnosed, received low-dose OH-Cbl (median 0.09 mg/kg/day); Group B2 (n = 12), diagnosed on clinical bases, received low-dose OH-Cbl (median 0.06 mg/kg/day). Biochemical analyses revealed better values of homocysteine, methionine and methylmalonic acid in Group A compared to Group B1 (p < 0.01, p < 0.05 and p < 0.01, respectively) and B2 (p < 0.001, p < 0.01 and p < 0.001, respectively). Neurodevelopmental assessment showed better outcome in Group A compared to low-dose treated Groups B1 and B2, especially in Developmental Quotient, Hearing and Speech and Performance subscales without significant differences between Group B2 and Group B1. Maculopathy was detected in 100%, 66% and 83% of patients in the three groups, respectively. This study showed that "high-dose" OH-Cbl treatment in NBS-diagnosed children with severe early-onset Cbl-C defect led to a significant improvement in the metabolic profile and in neurocognitive outcome, compared to age-matched patients treated with a "low-dose" regimen. Effects on maculopathy seem unaffected by OH-Cbl dosage. Our findings, although observed in a limited number of patients, may contribute to improve the long-term outcome of Cbl-C patients.
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Affiliation(s)
- Giorgia Olivieri
- Division of Metabolic Diseases and HepatologyBambino Gesù Children's Hospital, IRCCSRomeItaly
| | - Benedetta Greco
- Division of Metabolic Diseases and HepatologyBambino Gesù Children's Hospital, IRCCSRomeItaly
| | - Sara Cairoli
- Division of Metabolic Diseases and HepatologyBambino Gesù Children's Hospital, IRCCSRomeItaly
| | - Giulio Catesini
- Division of Metabolic Diseases and HepatologyBambino Gesù Children's Hospital, IRCCSRomeItaly
| | - Francesca Romana Lepri
- Laboratory of Medical Genetics, Translational Cytogenomics Research UnityBambino Gesù Children's Hospital, IRCCSRomeItaly
| | - Lorenzo Orazi
- National Centre of Services and Research for the Prevention of Blindness and Rehabilitation of Visually Impaired, IAPB Italia OnlusRomeItaly
- Ophthalmology UnitFondazione Policlinico Universitario A. Gemelli, IRCCSRomeItaly
| | - Maria Mallardi
- Clinical Psychology UnitFondazione Policlinico Universitario A. Gemelli, IRCCSRomeItaly
| | - Diego Martinelli
- Division of Metabolic Diseases and HepatologyBambino Gesù Children's Hospital, IRCCSRomeItaly
| | - Daniela Ricci
- National Centre of Services and Research for the Prevention of Blindness and Rehabilitation of Visually Impaired, IAPB Italia OnlusRomeItaly
- Pediatric Neurology UnitFondazione Policlinico Universitario A. Gemelli, IRCCSRomeItaly
| | - Raffaele Simeoli
- Division of Metabolic Diseases and HepatologyBambino Gesù Children's Hospital, IRCCSRomeItaly
| | - Carlo Dionisi‐Vici
- Division of Metabolic Diseases and HepatologyBambino Gesù Children's Hospital, IRCCSRomeItaly
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Karuntu JS, Almushattat H, Nguyen XTA, Plomp AS, Wanders RJA, Hoyng CB, van Schooneveld MJ, Schalij-Delfos NE, Brands MM, Leroy BP, van Karnebeek CDM, Bergen AA, van Genderen MM, Boon CJF. Syndromic Retinitis Pigmentosa. Prog Retin Eye Res 2024:101324. [PMID: 39733931 DOI: 10.1016/j.preteyeres.2024.101324] [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: 07/17/2024] [Revised: 12/13/2024] [Accepted: 12/16/2024] [Indexed: 12/31/2024]
Abstract
Retinitis pigmentosa (RP) is a progressive inherited retinal dystrophy, characterized by the degeneration of photoreceptors, presenting as a rod-cone dystrophy. Approximately 20-30% of patients with RP also exhibit extra-ocular manifestations in the context of a syndrome. This manuscript discusses the broad spectrum of syndromes associated with RP, pathogenic mechanisms, clinical manifestations, differential diagnoses, clinical management approaches, and future perspectives. Given the diverse clinical and genetic landscape of syndromic RP, the diagnosis may be challenging. However, an accurate and timely diagnosis is essential for optimal clinical management, prognostication, and potential treatment. Broadly, the syndromes associated with RP can be categorized into ciliopathies, inherited metabolic disorders, mitochondrial disorders, and miscellaneous syndromes. Among the ciliopathies associated with RP, Usher syndrome and Bardet-Biedl syndrome are the most well-known. Less common ciliopathies include Cohen syndrome, Joubert syndrome, cranioectodermal dysplasia, asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, and RHYNS syndrome. Several inherited metabolic disorders can present with RP including Zellweger spectrum disorders, adult Refsum disease, α-methylacyl-CoA racemase deficiency, certain mucopolysaccharidoses, ataxia with vitamin E deficiency, abetalipoproteinemia, several neuronal ceroid lipofuscinoses, mevalonic aciduria, PKAN/HARP syndrome, PHARC syndrome, and methylmalonic acidaemia with homocystinuria type cobalamin (cbl) C disease. Due to the mitochondria's essential role in supplying continuous energy to the retina, disruption of mitochondrial function can lead to RP, as seen in Kearns-Sayre syndrome, NARP syndrome, primary coenzyme Q10 deficiency, SSBP1-associated disease, and long chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Lastly, Cockayne syndrome and PERCHING syndrome can present with RP, but they do not fit the abovementioned hierarchy and are thus categorized as 'Miscellaneous'. Several first-in-human clinical trials are underway or in preparation for some of these syndromic forms of RP.
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Affiliation(s)
- Jessica S Karuntu
- Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
| | - Hind Almushattat
- Department of Ophthalmology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Xuan-Thanh-An Nguyen
- Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
| | - Astrid S Plomp
- Department of Human Genetics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development Institute, Amsterdam, the Netherlands
| | - Ronald J A Wanders
- Department of Paediatrics, Division of Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands; Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Carel B Hoyng
- Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Mary J van Schooneveld
- Department of Ophthalmology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Marion M Brands
- Amsterdam Reproduction & Development Institute, Amsterdam, the Netherlands; Department of Paediatrics, Division of Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn errors of metabolism, Amsterdam, The Netherlands
| | - Bart P Leroy
- Department of Ophthalmology & Center for Medical Genetics, Ghent University, Ghent, Belgium; Department of Head & Skin, Ghent University, Ghent, Belgium
| | - Clara D M van Karnebeek
- Department of Paediatrics, Division of Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands; Emma Center for Personalized Medicine, Departments of Pediatrics and Human Genetics, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Arthur A Bergen
- Department of Human Genetics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Emma Center for Personalized Medicine, Departments of Pediatrics and Human Genetics, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Maria M van Genderen
- Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands; Diagnostic Center for Complex Visual Disorders, Zeist, the Netherlands
| | - Camiel J F Boon
- Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands; Department of Ophthalmology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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7
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Pinales BE, Palomino CE, Rosas-Acosta G, Francia G, Quintana AM. Dissecting the role of vitamin B 12 metabolism in craniofacial development through analysis of clinical phenotypes and model organism discoveries. Differentiation 2024:100831. [PMID: 39676000 DOI: 10.1016/j.diff.2024.100831] [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: 09/02/2024] [Revised: 12/03/2024] [Accepted: 12/09/2024] [Indexed: 12/17/2024]
Abstract
Vitamin B12, otherwise known as cobalamin, is an essential water-soluble vitamin that is obtained from animal derived dietary sources. Mutations in the genes that encode proteins responsible for cobalamin uptake, transport, or processing cause inborn errors of cobalamin metabolism, a group of disorders characterized by accumulation of homocysteine and methylmalonic acid, neurodevelopmental defects, ocular dysfunction, anemia, and failure to thrive. Mild to moderate craniofacial phenotypes have been observed but these phenotypes are not completely penetrant and have not been consistently recognized in the literature. However, in the most recent decade, animal models of cblX and cblC, two cobalamin disorder complementation groups, have documented craniofacial phenotypes. These data indicate a function for cobalamin in facial development. In this review, we performed a literature review of all cobalamin complementation groups to identify which groups, and which human variants, are associated with dysmorphic features, microcephaly, or marfanoid phenotypes. We identified dysmorphic facial features in cblC, cblX, cblG, cblF, and cblJ, which are caused by mutations in MMACHC, HCFC1, MTR, LMBRD1, and ABCD4, respectively. Other complementation groups were associated primarily with microcephaly. Animal models (zebrafish and mouse) of cblC and cblX support these clinical phenotypes and have demonstrated neural crest cell deficits that include reduced expression of prdm1a, sox10, and sox9, key molecular markers of neural crest development. Characterization of a zebrafish mmachc germline mutant also suggests atypical chondrocyte development. Collectively, these data demonstrate an essential role for cobalamin in facial development and warrant future mechanistic inquiries that dissect the cellular and molecular mechanisms underlying human facial phenotypes in cobalamin disorders.
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Affiliation(s)
- Briana E Pinales
- Department of Biological Sciences, University of Texas El Paso, 500 W. University Ave 79968, El Paso, TX, USA
| | - Carlos E Palomino
- Department of Biological Sciences, University of Texas El Paso, 500 W. University Ave 79968, El Paso, TX, USA
| | - German Rosas-Acosta
- Department of Biological Sciences, University of Texas El Paso, 500 W. University Ave 79968, El Paso, TX, USA
| | - Giulio Francia
- Department of Biological Sciences, University of Texas El Paso, 500 W. University Ave 79968, El Paso, TX, USA
| | - Anita M Quintana
- Department of Biological Sciences, University of Texas El Paso, 500 W. University Ave 79968, El Paso, TX, USA.
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8
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Beyzaei Z, Moravej H, Imanieh MH, Inaloo S, Geramizadeh B. Clinical spectrum and genetic variation of six patients with methylmalonic aciduria (MMA); a report from Iran. BMC Pediatr 2024; 24:795. [PMID: 39633313 PMCID: PMC11616211 DOI: 10.1186/s12887-024-05291-z] [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: 10/05/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
OBJECTIVE Methylmalonic acidemia (MMAs) is known as a severe, complex, and lethal disorder of methylmalonate and cobalamin. The patients with MMA may have developmental, neurological, and metabolic disorders such as liver disease. Here, we aim to evaluate 6 Iranian patients suspected to MMA disorder. STUDY DESIGN We will provide genetic results, biochemical analysis and treatment for these patients. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and variant screening in probands by whole exome sequencing (WES) were performed. RESULTS A total of six homozygous variants were identified, including five previously identified variants and one novel variant, in the two MMA-causing genes as follows: c.577G > C, c.290 + 69G > T, c.662T > A, c.290 + 69G > T of MMAB, and c.100dupA, c.394 C > T of MMACHC. Sanger sequencing confirmed the identified variants. Additionally, metabolomics data analysis reliably identified elevated C3 and MMA levels, as well as abnormalities in the amino acid profile, indicating the presence of pathogenic variants. CONCLUSIONS Our findings expand the global spectrum of genotypes in MMA. While WES, combined with metabolomics and biochemical analysis, offers valuable insights for accurate diagnosis and subtyping of MMA, it is most beneficial in complex cases where clinical findings are unclear.
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Affiliation(s)
- Zahra Beyzaei
- Shiraz Transplant Research Center (STRC), Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hossein Moravej
- Department of Pediatric Endocrinology, Shiraz University of Medical Sciences, Shiraz, Iran
- Neonatal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hadi Imanieh
- Gastroenterology and Hepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sorour Inaloo
- Neuroscience Research Centers, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Shiraz Transplant Research Center (STRC), Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Pathology, Shiraz University of Medical Sciences, Khalili St., Research Tower, Seventh Floor, Shiraz Transplant Research Center (STRC), Shiraz, Iran.
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9
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Georgiou T, Grafakou O, Malekkou A, Athanasiou E, Ioannou I, Choleva V, Dionysiou M, Mavrikiou G, Demetriadou A, Anastasiadou V, Drousiotou A, Petrou PP. A case series of Cypriot patients with CblC defect: Clinical, biochemical and molecular characteristics. Mol Genet Metab Rep 2024; 41:101158. [PMID: 39584041 PMCID: PMC11585715 DOI: 10.1016/j.ymgmr.2024.101158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/05/2024] [Accepted: 11/05/2024] [Indexed: 11/26/2024] Open
Abstract
Methylmalonic aciduria and homocystinuria, CblC type, is an inborn error of intracellular vitamin B12 (cobalamin) metabolism caused, in the majority of cases, by mutations in the MMACHC gene. Five Cypriot patients (four males and one female) were diagnosed with a CblC defect. Age at diagnosis ranged from 10 days to 9 months. We present here the clinical, biochemical and molecular findings of these patients. Our retrospective study indicates that all patients were carriers of the known p.Arg91LysfsTer14 variant in either a homozygous or compound heterozygous state with other known MMACHC pathogenic variants. Out of three patients sharing the same genotype the one diagnosed and initiated treatment in the neonatal period displayed an improved clinical outcome.
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Affiliation(s)
- Theodoros Georgiou
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Olga Grafakou
- Inborn Errors of Metabolism Clinic, Archbishop Makarios III Hospital, Nicosia, Cyprus
| | - Anna Malekkou
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Emilia Athanasiou
- Clinical Genetics Department, Archbishop Makarios III Hospital, Nicosia, Cyprus
| | - Ioannis Ioannou
- Paediatric Neurology Clinic, Archbishop Makarios III Hospital, Nicosia, Cyprus
| | - Vivi Choleva
- Ophthalmology Clinic, Archbishop Makarios III Hospital, Nicosia, Cyprus
| | - Maria Dionysiou
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Gabriella Mavrikiou
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Anthi Demetriadou
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | | | - Anthi Drousiotou
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Petros P. Petrou
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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10
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Ahmed S, Cai L, Akbar F, Siddiqui A, DeBerardinis RJ, Ni M, Vu H, Afroze B. Evaluation of the clinical, biochemical, and molecular spectrum of Cobalamin C (CblC) defect in 33 patients from Pakistan. Scand J Clin Lab Invest 2024; 84:391-397. [PMID: 39225018 DOI: 10.1080/00365513.2024.2394983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 08/13/2024] [Accepted: 08/18/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Cobalamin C is the most common inborn error of intracellular cobalamin metabolism caused by biallelic pathogenic variants in the MMACHC gene, leading to impaired conversion of dietary vitamin B12 into its two metabolically active forms, methylcobalamin and adenosylcobalamin. Biochemical hallmarks are elevated plasma total homocysteine (HCYs) and low methionine accompanied by methylmalonic aciduria. This study aimed to evaluate the clinical, biochemical, and molecular analysis of Pakistani patients with CblC defect. METHODS Medical charts, urine organic acid (UOA) chromatograms, plasma amino acid levels, plasma tHcy and MMACHC gene results of patients presenting at the Biochemical Genetics Clinic, AKUH from 2013-2021 were reviewed. Details were collected on a pre-structured questionnaire. SPSS 22 was used for data analysis. RESULTS CblC was found in 33 cases (Male:Female 19:14). The median age of symptoms onset and diagnosis were 300 (IQR:135-1800) and 1380 (IQR: 240-2730) days. The most common clinical features were cognitive impairment (n = 29), seizures (n = 23), motor developmental delay (n = 20), hypotonia (n = 17), and sparse/hypopigmented scalp hair (n = 16). The MMACHC gene sequencing revealed homozygous pathogenic variant c.394C > T, (p.Arg132*) in 32 patients, whereas c.609G > A, (p.TRP203*) in one patient whose ancestors had settled in Pakistan from China decades ago. The median age of treatment initiation was 1530 (IQR: 240-2790). The median pre-treatment HCYs levels were 134 (IQR:87.2-155.5) compared to post-treatment levels of 33.3 (IQR: 27.3-44.95) umol/L. CONCLUSIONS Thirty-three cases of CblC defect from a single center underscores a significant number of the disorder within Pakistan. Late diagnosis emphasizes the need for increased clinical awareness and adequate diagnostic facilities.
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Affiliation(s)
- Sibtain Ahmed
- Section of Chemical Pathology, Department of Pathology and Laboratory Medicine, Aga Khan University
| | - Ling Cai
- Quantitative Biomedical Research Center, Peter O'Donnell School of Public Health, UT Southwestern, TX, USA
| | - Fizza Akbar
- Department of Paediatrics & Child Health, Aga Khan University Hospital, Karachi
| | - Ayra Siddiqui
- Medical College, Aga Khan University Hospital, Karachi
| | - Ralph J DeBerardinis
- Children's Medical Center Research Institute at UT Southwestern, Texas, USA
- Howard Hughes Medical Institute, UT Southwestern, Texas, USA
| | - Min Ni
- Children's Medical Center Research Institute at UT Southwestern, Texas, USA
| | - Hieu Vu
- Children's Medical Center Research Institute at UT Southwestern, Texas, USA
| | - Bushra Afroze
- Quantitative Biomedical Research Center, Peter O'Donnell School of Public Health, UT Southwestern, TX, USA
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11
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Zhou W, Li H, Song J, Suo F, Gu M, Qi S. Healthy Plasma Exosomes Exert Potential Neuroprotective Effects against Methylmalonic Acid-Induced Hippocampal Neuron Injury. ACS Chem Neurosci 2024; 15:3022-3033. [PMID: 39026168 DOI: 10.1021/acschemneuro.4c00224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2024] Open
Abstract
Exosomes have shown good potential for alleviating neurological deficits and delaying memory deterioration, but the neuroprotective effects of exosomes remain unknown. Methylmalonic acidemia is a metabolic disorder characterized by the accumulation of methylmalonic acid (MMA) in various tissues that inhibits neuronal survival and function, leading to accelerated neurological deterioration. Effective therapies to mitigate these symptoms are lacking. The purpose of this study was to explore the neuroprotective effects of plasma exosomes on cells and a mouse model of MMA-induced injury. We evaluated the ability of plasma exosomes to reduce the neuronal apoptosis, cross the blood-brain barrier, and affect various parameters related to neuronal function. MMA promoted cell apoptosis, disrupted the metabolic balance, and altered the expression of B-cell lymphoma-2 (Bcl-2), Bcl2-associated X (Bax), and synaptophysin-1 (Syp-1), and these changes may be involved in MMA-induced neuronal apoptosis. Additionally, plasma exosomes normalized learning and memory and protected against MMA-induced neuronal apoptosis. Our findings indicate that neurological deficits are linked to the pathogenesis of methylmalonic acidemia, and healthy plasma exosomes may exert neuroprotective and therapeutic effects by altering the expression of exosomal microRNAs, facilitating neuronal functional recovery in the context of this inherited metabolic disease. Intravenous plasma-derived exosome treatment may be a novel clinical therapeutic strategy for methylmalonic acidemia.
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Affiliation(s)
- Wei Zhou
- Research Center for Biochemistry and Molecular Biology and Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou 221004, P.R China
- Newborn Screening Center, The Affiliated Xuzhou Maternity and Child Health Care Hospital of Xuzhou Medical University, Xuzhou 221009, P.R China
| | - Huizhong Li
- Newborn Screening Center, The Affiliated Xuzhou Maternity and Child Health Care Hospital of Xuzhou Medical University, Xuzhou 221009, P.R China
| | - Jinxiu Song
- Pharmacology College, Xuzhou Medical University, Xuzhou 221004, P.R China
| | - Feng Suo
- Newborn Screening Center, The Affiliated Xuzhou Maternity and Child Health Care Hospital of Xuzhou Medical University, Xuzhou 221009, P.R China
| | - Maosheng Gu
- Newborn Screening Center, The Affiliated Xuzhou Maternity and Child Health Care Hospital of Xuzhou Medical University, Xuzhou 221009, P.R China
| | - Suhua Qi
- Research Center for Biochemistry and Molecular Biology and Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou 221004, P.R China
- Pharmacology College, Xuzhou Medical University, Xuzhou 221004, P.R China
- Medical and Technology School, Xuzhou Medical University, Xuzhou 221004, P.R China
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12
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Mucha P, Kus F, Cysewski D, Smolenski RT, Tomczyk M. Vitamin B 12 Metabolism: A Network of Multi-Protein Mediated Processes. Int J Mol Sci 2024; 25:8021. [PMID: 39125597 PMCID: PMC11311337 DOI: 10.3390/ijms25158021] [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: 06/03/2024] [Revised: 07/12/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024] Open
Abstract
The water-soluble vitamin, vitamin B12, also known as cobalamin, plays a crucial role in cellular metabolism, particularly in DNA synthesis, methylation, and mitochondrial functionality. Its deficiency can lead to hematological and neurological disorders; however, the manifestation of these clinical outcomes is relatively late. It leads to difficulties in the early diagnosis of vitamin B12 deficiency. A prolonged lack of vitamin B12 may have severe consequences including increased morbidity to neurological and cardiovascular diseases. Beyond inadequate dietary intake, vitamin B12 deficiency might be caused by insufficient bioavailability, blood transport disruptions, or impaired cellular uptake and metabolism. Despite nearly 70 years of knowledge since the isolation and characterization of this vitamin, there are still gaps in understanding its metabolic pathways. Thus, this review aims to compile current knowledge about the crucial proteins necessary to efficiently accumulate and process vitamin B12 in humans, presenting these systems as a multi-protein network. The epidemiological consequences, diagnosis, and treatment of vitamin B12 deficiency are also highlighted. We also discuss clinical warnings of vitamin B12 deficiency based on the ongoing test of specific moonlighting proteins engaged in vitamin B12 metabolic pathways.
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Affiliation(s)
- Patryk Mucha
- Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland; (P.M.); (F.K.); (R.T.S.)
| | - Filip Kus
- Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland; (P.M.); (F.K.); (R.T.S.)
- Laboratory of Protein Biochemistry, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, 80-307 Gdansk, Poland
| | - Dominik Cysewski
- Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland;
| | - Ryszard T. Smolenski
- Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland; (P.M.); (F.K.); (R.T.S.)
| | - Marta Tomczyk
- Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland; (P.M.); (F.K.); (R.T.S.)
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13
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Gupta N, Endrakanti M, Bhat M, Rao N, Kaur R, Kabra M. Clinical and Molecular Spectrum of Patients with Methylmalonic Acidemia. Indian J Pediatr 2024; 91:675-681. [PMID: 37420116 DOI: 10.1007/s12098-023-04651-4] [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: 11/02/2022] [Accepted: 03/17/2023] [Indexed: 07/09/2023]
Abstract
OBJECTIVES To study the clinical and molecular spectrum of Methylmalonic acidemia (MMA). METHODS In this retrospective study, the records of 30 MMA patients were evaluated for their phenotype, biochemical abnormalities, genotype, and outcomes. RESULTS Thirty patients with MMA (age range 0-21 y) from 27 unrelated families were enrolled. Family history and consanguinity were noted in 10/27 (37%) and 11/27 (41%) families respectively. Acute metabolic decompensation was more common (57%) than chronic presentation. Biochemical work-up was suggestive of isolated MMA (n = 18) and MMA with homocystinuria (n = 9) respectively. Molecular testing in 24 families showed 21 pathogenic or likely pathogenic variants with MMA cblC as the commonest molecular subtype (n = 8). B12 responsiveness, an important determinant of long-term outcome, was observed in eight patients [MMAA (n = 3) and MMACHC (n = 5)]. Mortality was 30% (n = 9/30) with a high proportion of early-onset severe disease and fatal outcome in isolated MMA mut0 (4/4) and MMA cblB (3/3), as compared to MMA cblA (1/5) and MMA cblC (1/10). CONCLUSIONS This study cohort had MMA cblC subtype as the most common type of MMA followed by the MMA mutase defect. Outcomes in MMA are influenced by the type of molecular defect, age, and severity of presentation. Early detection and management is likely to result in better outcomes.
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Affiliation(s)
- Neerja Gupta
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Room 840, 8th floor, Mother and Child Block, Ansari Nagar, New Delhi, 110029, India.
| | - Mounika Endrakanti
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Room 840, 8th floor, Mother and Child Block, Ansari Nagar, New Delhi, 110029, India
| | - Meenakshi Bhat
- Centre for Human Genetics, Bangalore, Karnataka, 560100, India
| | - Nivedita Rao
- Centre for Human Genetics, Bangalore, Karnataka, 560100, India
| | - Ravneet Kaur
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Room 840, 8th floor, Mother and Child Block, Ansari Nagar, New Delhi, 110029, India
| | - Madhulika Kabra
- Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Room 840, 8th floor, Mother and Child Block, Ansari Nagar, New Delhi, 110029, India
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14
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Golabi M, Kazemi D, Chadeganipour AS, Fouladseresht H, Sullman MJM, Ghezelbash B, Dastgerdi AY, Eskandari N. The Role of Cobalamin in Multiple Sclerosis: An Update. Inflammation 2024:10.1007/s10753-024-02075-6. [PMID: 38902541 DOI: 10.1007/s10753-024-02075-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/29/2024] [Accepted: 06/03/2024] [Indexed: 06/22/2024]
Abstract
Multiple sclerosis (MS) is a neurodegenerative condition that results in axonal and permanent damage to the central nervous system, necessitating healing owing to autoimmune reactions and persistent neuroinflammation. Antioxidant and anti-inflammatory drugs are essential for the management of oxidative stress and neuroinflammation. Additionally, multivitamin supplementation, particularly vitamin B12 (cobalamin), may be beneficial for neuronal protection. Although there is no documented connection between vitamin B12 deficiency and MS, researchers have explored its potential as a metabolic cause. This review highlights the therapeutic benefits of cobalamin (Cbl) in patients with MS.
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Affiliation(s)
- Marjan Golabi
- Applied Physiology Research Center, Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Danial Kazemi
- Student Research Committee, Isfahan University of Medical Science, Isfahan, Iran
| | | | - Hamed Fouladseresht
- Applied Physiology Research Center, Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mark J M Sullman
- Department of Life and Health Sciences, University of Nicosia, Nicosia, Cyprus
- Department of Social Sciences, University of Nicosia, Nicosia, Cyprus
| | - Behrooz Ghezelbash
- Laboratory Hematology and Blood Banking, School of Allied Medical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ava Yeganegi Dastgerdi
- Department of Cell and Molecular Biology, Falavarjan Branch, Islamic Azad University of Science, Isfahan, Iran
| | - Nahid Eskandari
- Applied Physiology Research Center, Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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15
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Hjalmarsson C, Backelin C, Thoren A, Bergh N, Sloan JL, Manoli I, Venditti CP, Dellgren G. Severe heart failure in a unique case of cobalamin-C-deficiency resolved with LVAD implantation and subsequent heart transplantation. Mol Genet Metab Rep 2024; 39:101089. [PMID: 38745823 PMCID: PMC11090888 DOI: 10.1016/j.ymgmr.2024.101089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 05/02/2024] [Accepted: 05/02/2024] [Indexed: 05/16/2024] Open
Abstract
Introduction Cobalamin c deficiency (cblC), an inborn error of vitamin B12 metabolism, is caused by mutations of the MMACHC gene. It usually leads to a multisystemic disease; 50% of all patients with cblC have various structural heart defects. Severe congestive heart failure (HF) may also occur and its prognosis is poorly documented. Case report We present the case of a young man who had been diagnosed with cblC due to C331T mutation in the MMACHC gene at the age of 3 days and had been treated with substitution therapy (OH-Cbl, mecobalamine, carnitine, betaine, and calcium folinate) since then. He had mildly impaired cognitive function; an ectopic hypophysis/pituitary insufficiency, with adequate hormone replacement therapy; obstructive sleep apnea syndrome, treated with CPAP, bronchial asthma, and obesity (BMI of 30). The liver and kidney functions were normal. He developed severe dilated cardiomyopathy and HF at the age of 12y. With medical treatment, his condition improved and he was stable (NYHA class II) for several years. Six years later, his status deteriorated rapidly, as he developed advanced HF, INTERMACS 3. The cardiac ultrasound revealed dilated ventricles with severely depressed ejection fraction (EF), increased filling pressures, and pulmonary hypertension (sPAP 60 mmHg). Cardiac MRI showed extremely dilated chambers (LVedv 609 mL, RVedv 398 mL) with pronounced non-compaction, and a left ventricle EF of 13%. A primary prophylactic ICD and a left ventricular assist device (LVAD/HM3) were implanted, and the patient was subsequently listed for heart transplantation (HTx). After 25 months on the waiting list, he underwent an uncomplicated HTx. However postoperatively, he got two episodes of cardiac tamponade, as well as mediastinitis, treated with antibiotics and vaccum assisted closure. He developed severe kidney failure, which fully recovered after two months, and was treated successfully for an early moderate allograft rejection (ISHT 2). At the latest outward visit, twelve months after HTx, the patient was doing excellent. Summary To the best of our knowledge, this is the first ever reported case of a patient with CblC undergoing an LVAD implantation and subsequently a HTx. Although both interventions were complicated with bleeding events, this seems to be a treatment option for advanced HF in patients with CblC.
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Affiliation(s)
- Clara Hjalmarsson
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Charlotte Backelin
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Thoren
- Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Anaesthesiology and Intensive Care Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Niklas Bergh
- Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jennifer L. Sloan
- National Human Genome Research Institute, National Institutes of Health, Bethesda, USA
| | - Irini Manoli
- National Human Genome Research Institute, National Institutes of Health, Bethesda, USA
| | - Charles P. Venditti
- National Human Genome Research Institute, National Institutes of Health, Bethesda, USA
| | - Göran Dellgren
- Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
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16
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Demaret T, Bédard K, Soucy JF, Watkins D, Allard P, Levtova A, O'Brien A, Brunel-Guitton C, Rosenblatt DS, Mitchell GA. The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients. Mol Genet Metab 2024; 142:108345. [PMID: 38387306 DOI: 10.1016/j.ymgme.2024.108345] [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: 12/20/2023] [Revised: 02/08/2024] [Accepted: 02/09/2024] [Indexed: 02/24/2024]
Abstract
Mutations in MMACHC cause cobalamin C disease (cblC, OMIM 277400), the commonest inborn error of vitamin B12 metabolism. In cblC, deficient activation of cobalamin results in methylcobalamin and adenosylcobalamin deficiency, elevating methylmalonic acid (MMA) and total plasma homocysteine (tHcy). We retrospectively reviewed the medical files of seven cblC patients: three compound heterozygotes for the MMACHC (NM_015506.3) missense variant c.158T>C p.(Leu53Pro) in trans with the common pathogenic mutation c.271dupA (p.(Arg91Lysfs*14), "compounds"), and four c.271dupA homozygotes ("homozygotes"). Compounds receiving hydroxocobalamin intramuscular injection monotherapy had age-appropriate psychomotor performance and normal ophthalmological examinations. In contrast, c.271dupA homozygotes showed marked psychomotor retardation, retinopathy and feeding problems despite penta-therapy (hydroxocobalamin, betaine, folinic acid, l-carnitine and acetylsalicylic acid). Pretreatment levels of plasma and urine MMA and tHcy were higher in c.271dupA homozygotes than in compounds. Under treatment, levels of the compounds approached or entered the reference range but not those of c.271dupA homozygotes (tHcy: compounds 9.8-32.9 μM, homozygotes 41.6-106.8 (normal (N) < 14); plasma MMA: compounds 0.14-0.81 μM, homozygotes, 10.4-61 (N < 0.4); urine MMA: compounds 1.75-48 mmol/mol creatinine, homozygotes 143-493 (N < 10)). Patient skin fibroblasts all had low cobalamin uptake, but this was milder in compound cells. Also, the distribution pattern of cobalamin species was qualitatively different between cells from compounds and from homozygotes. Compared to the classic cblC phenotype presented by c.271dupA homozygous patients, c.[158T>C];[271dupA] compounds had mild clinical and biochemical phenotypes and responded strikingly to hydroxocobalamin monotherapy.
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Affiliation(s)
- Tanguy Demaret
- Medical Genetics Division, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada; Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium
| | - Karine Bédard
- Medical Genetics Division, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada; Laboratoire de Diagnostic Moléculaire, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Département de Pathologie et Biologie Cellulaire, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Jean-François Soucy
- Medical Genetics Division, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada
| | - David Watkins
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada
| | - Pierre Allard
- Medical Genetics Division, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada; Department of Biochemistry, CHU Sainte-Justine, Montréal, Québec, Canada
| | - Alina Levtova
- Service de Médecine Génique, Département de Médecine, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Alan O'Brien
- Service de Médecine Génique, Département de Médecine, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Catherine Brunel-Guitton
- Medical Genetics Division, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada; Division of Biochemical Genetics, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, British Columbia, Canada
| | - David S Rosenblatt
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada
| | - Grant A Mitchell
- Medical Genetics Division, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.
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17
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Wang Y, Xu Y, Zhou C, Cheng Y, Qiao N, Shang Q, Xia L, Song J, Gao C, Qiao Y, Zhang X, Li M, Ma C, Fan Y, Peng X, Wu S, Lv N, Li B, Sun Y, Zhang B, Li T, Li H, Zhang J, Su Y, Li Q, Yuan J, Liu L, Moreno-De-Luca A, MacLennan AH, Gecz J, Zhu D, Wang X, Zhu C, Xing Q. Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy. Nat Med 2024; 30:1395-1405. [PMID: 38693247 DOI: 10.1038/s41591-024-02912-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 03/06/2024] [Indexed: 05/03/2024]
Abstract
Cerebral palsy (CP) is the most common motor disability in children. To ascertain the role of major genetic variants in the etiology of CP, we conducted exome sequencing on a large-scale cohort with clinical manifestations of CP. The study cohort comprised 505 girls and 1,073 boys. Utilizing the current gold standard in genetic diagnostics, 387 of these 1,578 children (24.5%) received genetic diagnoses. We identified 412 pathogenic and likely pathogenic (P/LP) variants across 219 genes associated with neurodevelopmental disorders, and 59 P/LP copy number variants. The genetic diagnostic rate of children with CP labeled at birth with perinatal asphyxia was higher than the rate in children without asphyxia (P = 0.0033). Also, 33 children with CP manifestations (8.5%, 33 of 387) had findings that were clinically actionable. These results highlight the need for early genetic testing in children with CP, especially those with risk factors like perinatal asphyxia, to enable evidence-based medical decision-making.
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Affiliation(s)
- Yangong Wang
- Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China
| | - Yiran Xu
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Chongchen Zhou
- Rehabilitation Department, Henan Key Laboratory of Child Genetics and Metabolism, Children's Hospital of Zhengzhou University, Zhengzhou, China
| | - Ye Cheng
- Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China
- Shanghai Center for Women and Children's Health, Shanghai, China
| | - Niu Qiao
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine (Shanghai), and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Qing Shang
- Rehabilitation Department, Henan Key Laboratory of Child Genetics and Metabolism, Children's Hospital of Zhengzhou University, Zhengzhou, China
| | - Lei Xia
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Juan Song
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Chao Gao
- Rehabilitation Department, Henan Key Laboratory of Child Genetics and Metabolism, Children's Hospital of Zhengzhou University, Zhengzhou, China
| | - Yimeng Qiao
- Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Xiaoli Zhang
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Ming Li
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Caiyun Ma
- Rehabilitation Department, Henan Key Laboratory of Child Genetics and Metabolism, Children's Hospital of Zhengzhou University, Zhengzhou, China
| | - Yangyi Fan
- Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China
| | - Xirui Peng
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Silin Wu
- Department of Neurosurgery, The Affiliated Zhongshan Hospital of Fudan University, Shanghai, China
| | - Nan Lv
- Rehabilitation Department, Henan Key Laboratory of Child Genetics and Metabolism, Children's Hospital of Zhengzhou University, Zhengzhou, China
| | - Bingbing Li
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Yanyan Sun
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Bohao Zhang
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Tongchuan Li
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Hongwei Li
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Jin Zhang
- Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China
- Shanghai Center for Women and Children's Health, Shanghai, China
| | - Yu Su
- Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China
| | - Qiaoli Li
- Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China
| | - Junying Yuan
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Lei Liu
- Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China
| | - Andres Moreno-De-Luca
- Department of Radiology, Neuroradiology Section, Kingston Health Sciences Centre, Queen's University Faculty of Health Sciences, Kingston, Ontario, Canada
| | - Alastair H MacLennan
- Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
| | - Jozef Gecz
- Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
| | - Dengna Zhu
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Xiaoyang Wang
- Centre for Perinatal Medicine and Health, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Changlian Zhu
- Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China.
| | - Qinghe Xing
- Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China.
- Shanghai Center for Women and Children's Health, Shanghai, China.
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18
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Van de Vondel L, De Winter J, Timmerman V, Baets J. Overarching pathomechanisms in inherited peripheral neuropathies, spastic paraplegias, and cerebellar ataxias. Trends Neurosci 2024; 47:227-238. [PMID: 38360512 DOI: 10.1016/j.tins.2024.01.004] [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: 08/18/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/17/2024]
Abstract
International consortia collaborating on the genetics of rare diseases have significantly boosted our understanding of inherited neurological disorders. Historical clinical classification boundaries were drawn between disorders with seemingly different etiologies, such as inherited peripheral neuropathies (IPNs), spastic paraplegias, and cerebellar ataxias. These clinically defined borders are being challenged by the identification of mutations in genes displaying wide phenotypic spectra and by shared pathomechanistic themes, which are valuable indications for therapy development. We highlight common cellular alterations that underlie this genetic landscape, including alteration of cytoskeleton, axonal transport, mitochondrial function, and DNA repair response. Finally, we discuss venues for future research using the long axonopathies of the PNS as a model to explore other neurogenetic disorders.
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Affiliation(s)
- Liedewei Van de Vondel
- Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
| | - Jonathan De Winter
- Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium
| | - Vincent Timmerman
- Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Jonathan Baets
- Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
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19
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Arhip L, Brox-Torrecilla N, Romero I, Motilla M, Serrano-Moreno C, Miguélez M, Cuerda C. Late-onset methylmalonic acidemia and homocysteinemia (cblC disease): systematic review. Orphanet J Rare Dis 2024; 19:20. [PMID: 38245797 PMCID: PMC10799514 DOI: 10.1186/s13023-024-03021-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 01/11/2024] [Indexed: 01/22/2024] Open
Abstract
INTRODUCTION Combined methylmalonic acidemia and homocystinuria, cblC type is an inborn error of intracellular cobalamin metabolism and the most common one. The age of onset ranges from prenatal to adult. The disease is characterised by an elevation of methylmalonic acid (MMA) and homocysteine and a decreased production of methionine. The aim is to review existing scientific literature of all late onset cblC patients in terms of clinical symptoms, diagnosis, and outcome. METHODS A bibliographic database search was undertaken in PubMed (MEDLINE) complemented by a reference list search. We combined search terms regarding cblC disease and late onset. Two review authors performed the study selection, data extraction and quality assessment. RESULTS Of the sixty-five articles included in this systematic review, we collected a total of 199 patients. The most frequent clinical symptoms were neuropathy/myelopathy, encephalopathy, psychiatric symptoms, thrombotic microangiopathy, seizures, kidney disease, mild to severe pulmonary hypertension with heart failure and thrombotic phenomena. There were different forms of supplementation used in the different studies collected and, within these studies, some patients received several treatments sequentially and/or concomitantly. The general outcome was: 64 patients recovered, 78 patients improved, 4 patients did not improve, or the disease progressed, and 12 patients died. CONCLUSIONS Most scientific literature regarding the late onset cblC disease comes from case reports and case series. In most cases treatment initiation led to an improvement and even recovery of some patients. The lack of complete recovery underlines the necessity for increased vigilance in unclear clinical symptoms for cblC disease.
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Affiliation(s)
- Loredana Arhip
- Unidad de Nutrición Clínica y Dietética, Hospital General Universitario Gregorio Marañón, Calle del Doctor Esquerdo 46, 28007, Madrid, Spain.
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
| | | | | | - Marta Motilla
- Unidad de Nutrición Clínica y Dietética, Hospital General Universitario Gregorio Marañón, Calle del Doctor Esquerdo 46, 28007, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Clara Serrano-Moreno
- Unidad de Nutrición Clínica y Dietética, Hospital General Universitario Gregorio Marañón, Calle del Doctor Esquerdo 46, 28007, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - María Miguélez
- Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
| | - Cristina Cuerda
- Unidad de Nutrición Clínica y Dietética, Hospital General Universitario Gregorio Marañón, Calle del Doctor Esquerdo 46, 28007, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Universidad Complutense Madrid, Madrid, Spain
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20
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Mathew AR, Di Matteo G, La Rosa P, Barbati SA, Mannina L, Moreno S, Tata AM, Cavallucci V, Fidaleo M. Vitamin B12 Deficiency and the Nervous System: Beyond Metabolic Decompensation-Comparing Biological Models and Gaining New Insights into Molecular and Cellular Mechanisms. Int J Mol Sci 2024; 25:590. [PMID: 38203763 PMCID: PMC10778862 DOI: 10.3390/ijms25010590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/16/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Vitamin B12 (VitB12) is a micronutrient and acts as a cofactor for fundamental biochemical reactions: the synthesis of succinyl-CoA from methylmalonyl-CoA and biotin, and the synthesis of methionine from folic acid and homocysteine. VitB12 deficiency can determine a wide range of diseases, including nervous system impairments. Although clinical evidence shows a direct role of VitB12 in neuronal homeostasis, the molecular mechanisms are yet to be characterized in depth. Earlier investigations focused on exploring the biochemical shifts resulting from a deficiency in the function of VitB12 as a coenzyme, while more recent studies propose a broader mechanism, encompassing changes at the molecular/cellular levels. Here, we explore existing study models employed to investigate the role of VitB12 in the nervous system, including the challenges inherent in replicating deficiency/supplementation in experimental settings. Moreover, we discuss the potential biochemical alterations and ensuing mechanisms that might be modified at the molecular/cellular level (such as epigenetic modifications or changes in lysosomal activity). We also address the role of VitB12 deficiency in initiating processes that contribute to nervous system deterioration, including ROS accumulation, inflammation, and demyelination. Consequently, a complex biological landscape emerges, requiring further investigative efforts to grasp the intricacies involved and identify potential therapeutic targets.
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Affiliation(s)
- Aimee Rachel Mathew
- Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (A.R.M.); (A.M.T.)
| | - Giacomo Di Matteo
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, 00185 Rome, Italy; (G.D.M.); (L.M.)
| | - Piergiorgio La Rosa
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, 00185 Rome, Italy;
- European Center for Brain Research, IRCCS Fondazione Santa Lucia, 00179 Rome, Italy
| | - Saviana Antonella Barbati
- Departmental Faculty of Medicine and Surgery, UniCamillus-Saint Camillus International University of Health Sciences, 00131 Rome, Italy;
| | - Luisa Mannina
- Department of Chemistry and Technology of Drugs, Sapienza University of Rome, 00185 Rome, Italy; (G.D.M.); (L.M.)
| | - Sandra Moreno
- Department of Science, University Roma Tre, 00146 Rome, Italy;
- Laboratory of Neurodevelopment, Neurogenetics and Neuromolecular Biology, IRCCS Fondazione Santa Lucia, 00179 Rome, Italy
| | - Ada Maria Tata
- Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (A.R.M.); (A.M.T.)
- Research Centre of Neurobiology “Daniel Bovet”, Sapienza University of Rome, 00185 Rome, Italy
| | - Virve Cavallucci
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy
| | - Marco Fidaleo
- Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; (A.R.M.); (A.M.T.)
- Research Center for Nanotechnology Applied to Engineering (CNIS), Sapienza University of Rome, 00185 Rome, Italy
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21
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Sun M, Dai Y. Late-onset cobalamin C deficiency type in adult with cognitive and behavioral disturbances and significant cortical atrophy and cerebellar damage in the MRI: a case report. Front Neurol 2023; 14:1308289. [PMID: 38148982 PMCID: PMC10749923 DOI: 10.3389/fneur.2023.1308289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/21/2023] [Indexed: 12/28/2023] Open
Abstract
Background Late-onset cobalamin C (cblC) deficiency is associated with a wide range of neurological and psychiatric symptoms, hematological manifestations, anorexia, renal failure, ocular abnormalities, dermatitis, and pancreatitis. However, the neuroimaging characteristics of late-onset cblC deficiency remain insufficiently documented. Common findings include diffuse white matter swelling, varying degrees of severe leukoaraiosis, hydrocephalus, corpus callosum atrophy, and symmetric bilateral basal ganglia lesions. In this report, we present a case of late-onset cblC deficiency in adults presenting with cerebellar ataxia as the primary symptom. The MRI findings revealed bilateral lateral cerebellar hemispheres exhibiting symmetric hyperintensity, primarily observed in diffusion-weighted imaging (DWI), which is a rarely reported imaging change in this context. Case presentation Our patient was a male who experienced symptoms starting at the age of 30 years, including unsteady walking, apparent cerebellar ataxia, and cognitive impairment upon nervous system examination. Brain magnetic resonance imaging (MRI) exhibited symmetric hyperintensity in the bilateral lateral cerebellar hemispheres, predominantly manifested in DWI, without any enhancement. Subsequently, significantly elevated blood total homocysteine and urinary methylmalonic acid levels were observed. Genetic analysis confirmed the presence of MMACHC compound heterozygous mutants c.482G > A and c.609G > A, thus confirming the diagnosis of cblC deficiency. These variants were classified as likely pathogenic following the guidelines of the American College of Medical Genetics and Genomics (ACMG) and were verified using Sanger sequencing. Following treatment, the patient experienced improvements in walking ability and cognition, a significant decrease in blood total homocysteine levels, and reversal of the imaging lesions. In conclusion Late-onset cblC deficiency presents with diverse clinical and imaging manifestations. Early diagnosis and treatment are crucial in achieving a favorable prognosis. This case serves as a reminder to clinicians not to overlook genetic metabolic disorders, particularly those causing multisite damage, in adult patients with undiagnosed neurological disorders, especially those affecting the cerebellum. Notably, methylmalonic acidemia should be considered within the spectrum of bilateral cerebellar lesions.
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Affiliation(s)
| | - Yingjie Dai
- Department of Neurology, General Hospital of Northern Theater Command, Shenyang, China
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22
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Antony P, Baby B, Ali A, Vijayan R, Al Jasmi F. Interaction of Glutathione with MMACHC Arginine-Rich Pocket Variants Associated with Cobalamin C Disease: Insights from Molecular Modeling. Biomedicines 2023; 11:3217. [PMID: 38137438 PMCID: PMC10740964 DOI: 10.3390/biomedicines11123217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/20/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is required by the body to metabolize cobalamin (Cbl). Due to its complex structure and cofactor forms, Cbl passes through an extensive series of absorptive and processing steps before being delivered to mitochondrial methyl malonyl-CoA mutase and cytosolic methionine synthase. Depending on the cofactor attached, MMACHC performs either flavin-dependent reductive decyanation or glutathione (GSH)-dependent dealkylation. The alkyl groups of Cbl have to be removed in the presence of GSH to produce intermediates that can later be converted into active cofactor forms. Pathogenic mutations in the GSH binding site, such as R161Q, R161G, R206P, R206W, and R206Q, have been reported to cause Cbl diseases. The impact of these variations on MMACHC's structure and how it affects GSH and Cbl binding at the molecular level is poorly understood. To better understand the molecular basis of this interaction, mutant structures involving the MMACHC-MeCbl-GSH complex were generated using in silico site-directed point mutations and explored using molecular dynamics (MD) simulations. The results revealed that mutations in the key arginine residues disrupt GSH binding by breaking the interactions and reducing the free energy of binding of GSH. Specifically, variations at position 206 appeared to produce weaker GSH binding. The lowered binding affinity for GSH in the variant structures could impact metabolic pathways involving Cbl and its trafficking.
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Affiliation(s)
- Priya Antony
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Bincy Baby
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Amanat Ali
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Ranjit Vijayan
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- The Big Data Analytics Center, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Fatma Al Jasmi
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Department of Pediatrics, Tawam Hospital, Al Ain P.O. Box 15258, United Arab Emirates
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23
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Mascarenhas R, Guha A, Li Z, Ruetz M, An S, Seravalli J, Banerjee R. Cobalt-Sulfur Coordination Chemistry Drives B 12 Loading onto Methionine Synthase. J Am Chem Soc 2023:10.1021/jacs.3c07941. [PMID: 37916782 PMCID: PMC11063128 DOI: 10.1021/jacs.3c07941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
Abstract
Cobalt-sulfur (Co-S) coordination is labile to both oxidation and reduction chemistry and is rarely seen in nature. Cobalamin (or vitamin B12) is an essential cobalt-containing organometallic cofactor in mammals and is escorted via an intricate network of chaperones to a single cytoplasmic target, methionine synthase. In this study, we report that the human cobalamin trafficking protein, MMADHC, exploits the chemical lability of Co-S coordination for cofactor off-loading onto methionine synthase. Cys-261 on MMADHC serves as the β-axial ligand to cobalamin. Complex formation between MMADHC and methionine synthase is signaled by loss of the lower axial nitrogen ligand, leading to five-coordinate thiolato-cobalamin. Nucleophilic displacement by the vicinal thiolate, Cys-262, completes cofactor transfer to methionine synthase and release of a cysteine disulfide-containing MMADHC. The physiological relevance of this mechanism is supported by clinical variants of MMADHC, which impair cofactor binding and off-loading, explaining the molecular basis of the associated homocystinuria.
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Affiliation(s)
- Romila Mascarenhas
- Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Arkajit Guha
- Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Zhu Li
- Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Markus Ruetz
- Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Sojin An
- Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Javier Seravalli
- Department of Biological Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, United States
| | - Ruma Banerjee
- Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
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24
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Scalais E, Geron C, Pierron C, Cardillo S, Schlesser V, Mataigne F, Borde P, Regal L. Would, early, versus late hydroxocobalamin dose intensification treatment, prevent cognitive decline, macular degeneration and ocular disease, in 5 patients with early-onset cblC deficiency? Mol Genet Metab 2023; 140:107681. [PMID: 37604084 DOI: 10.1016/j.ymgme.2023.107681] [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: 12/04/2022] [Revised: 08/03/2023] [Accepted: 08/04/2023] [Indexed: 08/23/2023]
Abstract
In early-onset (EO) cblC deficiency (MMACHC), hydroxocobalamin dose-intensification (OHCBL-DI) improved biochemical and clinical outcome. In mammals, Cobalamin is reduced, in a reaction mediated by MMACHC. Pathogenic variants in MMACHC disrupt the synthesis pathway of methyl-cobalamin (MetCbl) and 5'-deoxy-adenosyl-cobalamin (AdoCbl), cofactors for both methionine synthase (MS) and methyl-malonyl-CoA mutase (MCM) enzymes. In 5 patients (pts.), with EO cblC deficiency, biochemical and clinical responses were studied following OHCbl-DI (mean ± SD 6,5 ± 3,3 mg/kg/day), given early, before age 5 months (pts. 1, 2, 3 and 4) or lately, at age 5 years (pt. 5). In all pts., total homocysteine (tHcy), methyl-malonic acid (MMA) and Cob(III)alamin levels were measured. Follow-up was performed during 74/12 years (pts. 1, 2, 3), 33/12 years (pt. 4) and 34/12 years (pt. 5). OHCbl was delivered intravenously or subcutaneously. Mean ± SD serum Cob(III)alamin levels were 42,2 × 106 ± 28, 0 × 106 pg/ml (normal: 200-900 pg/ml). In all pts., biomarkers were well controlled. All pts., except pt. 5, who had poor vision, had central vision, mild to moderate nystagmus, and with peri-foveolar irregularity in pts. 1, 2 and 4, yet none had the classic bulls' eye maculopathy and retinal degeneration characteristic of pts. with EO cblC deficiency. Only pt. 5, had severe cognitive deficiency. Both visual and cognitive functions were better preserved with early than with late OHCBL-DI. OHCBL-DI is suggested to bypass MMACHC, subsequently to be rescued by methionine synthase reductase (MSR) and adenosyl-transferase (ATR) to obtain Cob(I)alamin resulting in improved cognitive and retinal function in pts. with EO cblC deficiency.
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Affiliation(s)
- Emmanuel Scalais
- Department of Pediatrics, Division of Pediatric Neurology, Centre Hospitalier de Luxembourg, Luxembourg.
| | - Christine Geron
- Department of Pediatrics, Neonatal Center, Pediatric Intensive Care, Centre Hospitalier de Luxembourg, Luxembourg
| | - Charlotte Pierron
- Department of Pediatrics, Neonatal Center, Pediatric Intensive Care, Centre Hospitalier de Luxembourg, Luxembourg
| | - Sandra Cardillo
- Service d'Ophtalmologie, Centre Hospitalier de Luxembourg, Luxembourg
| | - Vincent Schlesser
- Laboratoire de Chimie et Hématologie, Centre Hospitalier de Luxembourg, Luxembourg
| | - Frédéric Mataigne
- Service de Neuroradiologie, Centre Hospitalier de Luxembourg, Luxembourg
| | - Patricia Borde
- Service de Biochimie, Laboratoire National de Santé, Dudelange, Luxembourg
| | - Luc Regal
- Pediatric Neurology and Metabolism, UZ, VUB, Vrije Universiteit Brussels, Brussels, Belgium
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25
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Ding S, Ling S, Liang L, Qiu W, Zhang H, Chen T, Zhan X, Xu F, Gu X, Han L. Late-onset cblC defect: clinical, biochemical and molecular analysis. Orphanet J Rare Dis 2023; 18:306. [PMID: 37770946 PMCID: PMC10536707 DOI: 10.1186/s13023-023-02890-4] [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: 04/19/2023] [Accepted: 08/25/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND cblC defect is the most common type of methylmalonic acidemia in China. Patients with late-onset form (>1 year) are often misdiagnosed due to heterogeneous symptoms. This study aimed to describe clinical characteristics and evaluate long-term outcomes of Chinese patients with late-onset cblC defect. METHODS A total of 85 patients with late-onset cblC defect were enrolled. Clinical data, including manifestations, metabolites, molecular diagnosis, treatment and outcome, were summarized and analyzed. RESULTS The age of onset ranged from 2 to 32.8 years old (median age 8.6 years, mean age 9.4 years). The time between first symptoms and diagnosis ranged from a few days to 20 years (median time 2 months, mean time 20.7 months). Neuropsychiatric symptoms were presented as first symptoms in 68.2% of cases, which were observed frequently in schoolchildren or adolescents. Renal involvement and cardiovascular disease were observed in 20% and 8.2% of cases, respectively, which occurred with the highest prevalence in preschool children. Besides the initial symptoms, the disease progressed in most patients and cognitive decline became the most frequent symptom overall. The levels of propionylcarnitine, propionylcarnitine / acetylcarnitine ratio, methylmalonic acid, methylcitric acid and homocysteine, were decreased remarkably after treatment (P<0.001). Twenty-four different mutations of MMACHC were identified in 78 patients, two of which were novel. The c.482G>A variant was the most frequent mutated allele in this cohort (25%). Except for 16 patients who recovered completely, the remaining patients were still left with varying degrees of sequelae in a long-term follow-up. The available data from 76 cases were analyzed by univariate analysis and multivariate logistic regression analysis, and the results showed that the time from onset to diagnosis (OR = 1.025, P = 0. 024) was independent risk factors for poor outcomes. CONCLUSIONS The diagnosis of late-onset cblC defect is often delayed due to poor awareness of its various and nonspecific symptoms, thus having an adverse effect on the prognosis. It should be considered in patients with unexplained neuropsychiatric and other conditions such as renal involvement, cardiovascular diseases or even multiple organ damage. The c.482G>A variant shows the highest frequency in these patients. Prompt treatment appears to be beneficial.
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Affiliation(s)
- Si Ding
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Shiying Ling
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Lili Liang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Wenjuan Qiu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Huiwen Zhang
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Ting Chen
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Xia Zhan
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Feng Xu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Xuefan Gu
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Lianshu Han
- Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China.
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Chen Q, Tang J, Zhang H, Qin L. Case report: Desquamating dermatitis, bilateral cerebellar lesions in a late-onset methylmalonic acidemia patient. Front Neurol 2023; 14:1255128. [PMID: 37808496 PMCID: PMC10556654 DOI: 10.3389/fneur.2023.1255128] [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: 07/08/2023] [Accepted: 08/28/2023] [Indexed: 10/10/2023] Open
Abstract
Introduction Cobalamin C (cblC) deficiency is a rare hereditary disorder affecting intracellular cobalamin metabolism, primarily caused by mutations in MMACHC. This condition is characterized by combined methylmalonic acidemia and hyperhomocysteinemia, displaying a wide range of clinical manifestations involving multiple organs. Owing to its uncommon occurrence and diverse clinical phenotypes, diagnosing cblC deficiency is challenging and often leads to delayed or missed diagnoses. Case description In this report, we present a case of late-onset cblC deficiency with brown desquamating dermatitis on the buttocks. Magnetic resonance imaging (MRI) of the brain revealed bilateral cerebellar abnormalities. The suspicion of an inherited metabolic disorder was raised by abnormal serum amino acid and acylcarnitine levels, along with increased urine methylmalonic acid and serum homocysteine levels. Whole-exome sequencing helped identify a homozygous variant (c.482G>A) in MMACHC, confirming the diagnosis of cblC deficiency. However, despite receiving treatment with hydroxocobalamin and betaine, the patient did not experience clinical improvement, which may be attributed to the delayed diagnosis as indicated by the declining homocysteine and methylmalonic acid levels. Conclusion Collectively, we emphasize the significance of recognizing the skin lesions and observing serial MRI changes in patients with cblC deficiency. Our case underscores the importance of early diagnosis and timely therapeutic intervention for this severe yet frequently manageable condition.
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Affiliation(s)
| | | | | | - Lixia Qin
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Dirim AB, Safak S, Balci MC, Ozyavuz P, Garayeva N, Tiryaki TO, Oto OA, Ozluk Y, Kilicaslan I, Solakoglu S, Artan AS, Yazici H, Turkmen A, Ozturk S. Concurrent Cobalamin C and Plasminogen Deficiencies in a Patient with Chronic Thrombotic Microangiopathy. Nephron Clin Pract 2023; 148:54-62. [PMID: 37611544 DOI: 10.1159/000533417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 07/07/2023] [Indexed: 08/25/2023] Open
Abstract
BACKGROUND Although most patients with atypical hemolytic uremic syndrome (aHUS) have variants in genes participating in alternative complement pathways, rare variants in non-complement pathway-related genes, including DGKE, INF2, MMACHC, PLG, and THBD, have also been described. CASE PRESENTATION We report an 18-year-old male patient with renal biopsy-proven chronic thrombotic microangiopathy that raised suspicion of aHUS. Whole-exome sequencing revealed a novel pathogenic homozygous MMACHC c.484G>T (p.Gly162Trp) variant. Subsequently, clinical and laboratory findings confirmed cobalamin C (Cbl C) deficiency. Also, homozygous missense c.1112C>T PLG (p.Thr371Ile) variant was detected (it had been reported as a variant of unknown significance). However, the low serum plasminogen (PLG) activity proved the pathogenicity of c.1112C>T. Hence, the patient was diagnosed with concurrent Cbl C and PLG deficiencies. Segregation analysis revealed that the mother and father had the same heterozygous PLG and MMACHC variants. PLG variants have generally been described in aHUS patients concomitant with complement gene variants in the literature; therefore, the association between aHUS and PLG variants is controversial. The possible contribution of PLG deficiency to thrombotic microangiopathy was also discussed in this case. CONCLUSION Non-complement-mediated aHUS is an exceptional disorder. A limited number of genes are involved in this entity. To our knowledge, this is the first aHUS patient diagnosed with both Cbl C and PLG deficiencies in the literature.
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Affiliation(s)
- Ahmet Burak Dirim
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
- Department of Genetics, Istanbul University Aziz Sancar Institute of Experimental Medicine, Graduate School of Health Sciences, Istanbul University, Istanbul, Turkey
| | - Seda Safak
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mehmet Cihan Balci
- Division of Pediatric Metabolic Disorders, Department of Pediatrics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Pelin Ozyavuz
- Department of Genetics, Haseki Teaching and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Nurane Garayeva
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Tarik Onur Tiryaki
- Division of Hematology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Ozgur Akin Oto
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Yasemin Ozluk
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Isin Kilicaslan
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Seyhun Solakoglu
- Department of Histology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Ayse Serra Artan
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Halil Yazici
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Aydin Turkmen
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Savas Ozturk
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Mascarenhas R, Guha A, Li Z, Ruetz M, An S, Seravalli J, Banerjee R. Cobalt-sulfur coordination chemistry drives B 12 loading onto methionine synthase. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.25.550549. [PMID: 37546824 PMCID: PMC10402061 DOI: 10.1101/2023.07.25.550549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
Cobalt-sulfur (Co-S) coordination is labile to both oxidation and reduction chemistry and is rarely seen in Nature. Cobalamin (or vitamin B 12 ) is an essential cobalt-containing organometallic cofactor in mammals, and is escorted via an intricate network of chaperones to a single cytoplasmic target, methionine synthase. In this study, we report that the human cobalamin trafficking protein, MMADHC, exploits the chemical lability of Co-S coordination, for cofactor off-loading onto methionine synthase. Cys-261 on MMADHC serves as the β-axial ligand to cobalamin. Complex formation between MMADHC and methionine synthase is signaled by loss of the lower axial nitrogen ligand, leading to five-coordinate thiolato-cobalamin. Nucleophilic displacement by the vicinal thiolate, Cys-262, completes cofactor transfer to methionine synthase and release of a cysteine disulfide-containing MMADHC. The physiological relevance of this mechanism is supported by clinical variants of MMADHC, which impair cofactor binding and off-loading, explaining the molecular basis of the associated homocystinuria.
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Gacita AM, Bicknese A, Kim K, Zelko F, Baker J. Child Neurology: Reversible Dementia in an 18-Year-Old Woman Due to Undiagnosed Cobalamin-G Deficiency: A Case Report. Neurology 2023; 101:e215-e219. [PMID: 36797065 PMCID: PMC10351559 DOI: 10.1212/wnl.0000000000207146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 01/19/2023] [Indexed: 02/18/2023] Open
Abstract
Cobalamin-G deficiency is an inborn error of metabolism which disrupts the biochemical utilization of vitamin B12 to covert homocysteine to methionine in the remethylation pathway. Typically, affected patients present within the first year of life with anemia, developmental delay, and metabolic crisis. Few case reports of cobalamin-G deficiency reference a later onset phenotype primarily defined by neuropsychiatric symptoms. We report an 18-year-old woman who presented with a 4-year history of progressively worsening dementia, encephalopathy, epilepsy, and regression of adaptive functioning, with an initially normal metabolic workup. Whole-exome sequencing identified variants in the MTR gene, suspicious for cobalamin-G deficiency. Additional biochemical testing after genetic testing supported this diagnosis. Since treatment with leucovorin, betaine, and B12 injections, we have seen a gradual return to normal cognitive function. This case report expands the phenotypic range of cobalamin-G deficiency and offers rationale for genetic and metabolic testing in cases of dementia in the second decade of life.
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Affiliation(s)
- Anthony M Gacita
- From the Department of Genetics, Genomics, and Metabolism (A.M.G., K.K., J.B.), Department of Neurology (A.B.), and Department of Psychiatry and Behavioral Health (F.Z.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL
| | - Alma Bicknese
- From the Department of Genetics, Genomics, and Metabolism (A.M.G., K.K., J.B.), Department of Neurology (A.B.), and Department of Psychiatry and Behavioral Health (F.Z.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL
| | - Katherine Kim
- From the Department of Genetics, Genomics, and Metabolism (A.M.G., K.K., J.B.), Department of Neurology (A.B.), and Department of Psychiatry and Behavioral Health (F.Z.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL
| | - Frank Zelko
- From the Department of Genetics, Genomics, and Metabolism (A.M.G., K.K., J.B.), Department of Neurology (A.B.), and Department of Psychiatry and Behavioral Health (F.Z.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL
| | - Joshua Baker
- From the Department of Genetics, Genomics, and Metabolism (A.M.G., K.K., J.B.), Department of Neurology (A.B.), and Department of Psychiatry and Behavioral Health (F.Z.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL.
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Liu YP, He RX, Chen ZH, Kang LL, Song JQ, Liu Y, Shi CY, Chen JY, Dong H, Zhang Y, Li MQ, Jin Y, Qin J, Yang YL. Case report: An asymptomatic mother with an inborn error of cobalamin metabolism (cblC) detected through high homocysteine levels during prenatal diagnosis. Front Nutr 2023; 10:1124387. [PMID: 37252234 PMCID: PMC10213673 DOI: 10.3389/fnut.2023.1124387] [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: 12/28/2022] [Accepted: 04/14/2023] [Indexed: 05/31/2023] Open
Abstract
Background The most common disorder of the intracellular cobalamin metabolism pathway is the combined methylmalonic acidemia and homocysteinemia, cblC type (cblC). There is a variation in its clinical spectrum ranging from severe neonatal-onset forms that are highly fatal to later-onset forms which are milder. In this study, the first case of an asymptomatic Chinese woman with a defect in congenital cobalamin (cblC type) metabolism at prenatal diagnosis due to elevated homocysteine level is identified. Case presentation The proband, a male child born to a 29-year-old G1P0 mother, admitted to local hospital with feeding disorder, intellectual disability, seizures, microcephaly, as well as heterophthalmos. The level of the urine methylmalonic was elevated. Equally found were increased blood propionylcarnitine (C3) and propionylcarnitine/free carnitine ratio (C3/C0) and decreased methionine levels. The plasma total homocysteine level was elevated at 101.04 μmol/L (normal < 15 μmol/L). The clinical diagnosis of combined methylmalonic acidemia and homocysteinemia was supported. Four years later, the mother of the boy married again and came to us for prenatal diagnosis exactly 15 weeks after her last menstrual period. Subsequently, there is an increase in the amniotic fluid methylmalonate. The level of the amniotic fluid total homocysteine was marginally high. A considerably elevated amniotic fluid C3 was equally observed. In addition, there is a respective significant increase in the plasma and urine total homocysteine at 31.96 and 39.35 μmol/L. After the sequencing of MMACHC genes, it is found that the boy, a proband carried a homozygous mutation of the MMACHC at c.658_660delAAG. While the boy's mother, she carries two mutations in MMACHC: c.658_660delAAG and c.617G>A. The fetus is a carrier of the MMACHC gene. Following the administration of routine treatment, the mother remained symptom-free in the course of pregnancy, and she gave birth to a healthy boy. Conclusion Variable and nonspecific symptoms characterized the cblC type of methylmalonic acidemia combined with homocysteinemia. Both biochemical assays and mutation analysis are recommended as crucial complementary techniques.
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Affiliation(s)
- Yu-Peng Liu
- Department of Pediatrics, Peking University People's Hospital, Beijing, China
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Ru-Xuan He
- Department of Respiratory, Beijing Children′s Hospital, Capital Medical University, Beijing, China
| | - Zhe-Hui Chen
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Lu-Lu Kang
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jin-Qing Song
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Yi Liu
- Department of Clinical Laboratory, China-Japan Friendship Hospital, Beijing, China
| | - Chun-Yan Shi
- Department of Gynaecology and Obstetrics, Peking University First Hospital, Beijing, China
| | - Jun-Ya Chen
- Department of Gynaecology and Obstetrics, Peking University First Hospital, Beijing, China
| | - Hui Dong
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Yao Zhang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Meng-Qiu Li
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Ying Jin
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Jiong Qin
- Department of Pediatrics, Peking University People's Hospital, Beijing, China
| | - Yan-Ling Yang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
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Paz D, Pinales BE, Castellanos BS, Perez I, Gil CB, Madrigal LJ, Reyes-Nava NG, Castro VL, Sloan JL, Quintana AM. Abnormal chondrocyte development in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant. Differentiation 2023; 131:74-81. [PMID: 37167860 PMCID: PMC11373873 DOI: 10.1016/j.diff.2023.04.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/10/2023] [Accepted: 04/24/2023] [Indexed: 05/13/2023]
Abstract
Variants in the MMACHC gene cause combined methylmalonic acidemia and homocystinuria cblC type, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism. cblC is associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models of Mmachc deletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts. MMACHC encodes an enzyme required for cobalamin processing and variants in this gene result in the accumulation of two metabolites: methylmalonic acid (MMA) and homocysteine (HC). Interestingly, other inborn errors of cobalamin metabolism, such as cblX syndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in cblX syndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutations in MMACHC cause craniofacial defects are yet to be completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model of cblC (hg13) and performed restoration experiments with either a wildtype or a cobalamin binding deficient MMACHC protein. Homozygous mutants did not display gross morphological defects in facial development but did have abnormal chondrocyte nuclear organization and an increase in the average number of neighboring cell contacts, both phenotypes were fully penetrant. Abnormal chondrocyte nuclear organization was not associated with defects in the localization of neural crest specific markers, sox10 (RFP transgene) or barx1. Both nuclear angles and the number of neighboring cell contacts were fully restored by wildtype MMACHC and a cobalamin binding deficient variant of the MMACHC protein. Collectively, these data suggest that mutation of MMACHC causes mild to moderate craniofacial phenotypes that are independent of cobalamin binding.
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Affiliation(s)
- David Paz
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA
| | - Briana E Pinales
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA
| | - Barbara S Castellanos
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA
| | - Isaiah Perez
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA
| | - Claudia B Gil
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA
| | - Lourdes Jimenez Madrigal
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA
| | - Nayeli G Reyes-Nava
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA
| | - Victoria L Castro
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA
| | - Jennifer L Sloan
- Metabolic Medicine Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Anita M Quintana
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, USA.
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McCorvie TJ, Ferreira D, Yue WW, Froese DS. The complex machinery of human cobalamin metabolism. J Inherit Metab Dis 2023; 46:406-420. [PMID: 36680553 DOI: 10.1002/jimd.12593] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/22/2023]
Abstract
Vitamin B12 (cobalamin, Cbl) is required as a cofactor by two human enzymes, 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) and methylmalonyl-CoA mutase (MMUT). Within the body, a vast array of transporters, enzymes and chaperones are required for the generation and delivery of these cofactor forms. How they perform these functions is dictated by the structure and interactions of the proteins involved, the molecular bases of which are only now being elucidated. In this review, we highlight recent insights into human Cbl metabolism and address open questions in the field by employing a protein structure and interactome based perspective. We discuss how three very similar proteins-haptocorrin, intrinsic factor and transcobalamin-exploit slight structural differences and unique ligand receptor interactions to effect selective Cbl absorption and internalisation. We describe recent advances in the understanding of how endocytosed Cbl is transported across the lysosomal membrane and the implications of the recently solved ABCD4 structure. We detail how MMACHC and MMADHC cooperate to modify and target cytosolic Cbl to the client enzymes MTR and MMUT using ingenious modifications to an ancient nitroreductase fold, and how MTR and MMUT link with their accessory enzymes to sustainably harness the supernucleophilic potential of Cbl. Finally, we provide an outlook on how future studies may combine structural and interactome based approaches and incorporate knowledge of post-translational modifications to bring further insights.
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Affiliation(s)
- Thomas J McCorvie
- Biosciences Institute, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Douglas Ferreira
- Biosciences Institute, The Medical School, Newcastle University, Newcastle upon Tyne, UK
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Wyatt W Yue
- Biosciences Institute, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - D Sean Froese
- Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, University of Zürich, Zürich, Switzerland
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Paz D, Pinales BE, Castellanos BS, Perez I, Gil CB, Madrigal LJ, Reyes-Nava NG, Castro VL, Sloan JL, Quintana AM. Abnormal chondrocyte intercalation in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.20.524982. [PMID: 36711998 PMCID: PMC9882310 DOI: 10.1101/2023.01.20.524982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Variants in the MMACHC gene cause combined methylmalonic acidemia and homocystinuria cblC type, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism. cblC is associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models of Mmachc deletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts. MMACHC encodes an enzyme required for cobalamin processing and variants in this gene result in the accumulation of two metabolites: methylmalonic acid (MMA) and homocysteine (HC). Interestingly, other inborn errors of cobalamin metabolism, such as cblX syndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in cblX syndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutation of MMACHC cause craniofacial defects have not been completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model of cblC ( hg13 ) and performed restoration experiments with either wildtype or a cobalamin binding deficient MMACHC protein. Homozygous mutants did not display gross morphological defects in facial development, but did have abnormal chondrocyte intercalation, which was fully penetrant. Abnormal chondrocyte intercalation was not associated with defects in the expression/localization of neural crest specific markers, sox10 or barx1 . Most importantly, chondrocyte organization was fully restored by wildtype MMACHC and a cobalamin binding deficient variant of MMACHC protein. Collectively, these data suggest that mutation of MMACHC causes mild to moderate craniofacial phenotypes that are independent of cobalamin binding.
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Affiliation(s)
- David Paz
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968 USA
| | - Briana E Pinales
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968 USA
| | - Barbara S Castellanos
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968 USA
| | - Isaiah Perez
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968 USA
| | - Claudia B Gil
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968 USA
| | - Lourdes Jimenez Madrigal
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968 USA
| | - Nayeli G Reyes-Nava
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968 USA
| | - Victoria L Castro
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968 USA
| | - Jennifer L Sloan
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968 USA
| | - Anita M Quintana
- Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968 USA
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Chen T, Sui C, Lin S, Guo B, Wang Y, Yang L. Follow-up study of neuropsychological scores of infant patients with cobalamin C defects and influencing factors of cerebral magnetic resonance imaging characteristics. Front Neurosci 2022; 16:1093850. [PMID: 36590295 PMCID: PMC9795007 DOI: 10.3389/fnins.2022.1093850] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 11/28/2022] [Indexed: 12/15/2022] Open
Abstract
Purpose The purpose of this study was to investigate whether baseline cerebral magnetic resonance imaging (MRI) characteristics could predict therapeutic responsiveness in patients with cobalamin C (cblC) defects. Materials and methods The cerebral MRI results of 40 patients with cblC defects were evaluated by a neuroradiologist. Neuropsychological scores and imaging data were collected. Neuropsychological tests were performed before and after standardized treatment. Results Thirty-eight patients initially underwent neuropsychological testing [developmental quotient (DQ)]. CblC defects with cerebellar atrophy, corpus callosum thinning and ventricular dilation had significantly lower DQs than those without (P < 0.05). Through a multivariate linear stepwise regression equation after univariate analysis, ventricular dilation was the most valuable predictor of lower DQs. Thirty-six patients (94.7%) underwent follow-up neuropsychological testing. The pre- and post-treatment DQ values were not significantly different (Z = -1.611, P = 0.107). The post-treatment DQ classification (normal, moderately low, or extremely low) showed nearly no change compared to the pretreatment DQ classification (k = 0.790, P < 0.001). Conclusion Ventricular dilation, cerebral atrophy and corpus callosum thinning are the main MRI abnormalities of cblC defects, and these manifestations are significantly correlated with delayed development in children. MRI findings can be considered an important tool for determining the severity of cblC defects.
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Affiliation(s)
- Tao Chen
- Department of Clinical Laboratory, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Chaofan Sui
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Suna Lin
- Department of Scientific Research and Foreign Affairs, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Bin Guo
- Department of Radiology, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yuanyuan Wang
- Department of Radiology, Binzhou Medical University, Yantai, Shandong, China
| | - Linfeng Yang
- Department of Radiology, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China,*Correspondence: Linfeng Yang,
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Fitriasari S, Trainor PA. Gene-environment interactions in the pathogenesis of common craniofacial anomalies. Curr Top Dev Biol 2022; 152:139-168. [PMID: 36707210 DOI: 10.1016/bs.ctdb.2022.10.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Craniofacial anomalies often exhibit phenotype variability and non-mendelian inheritance due to their multifactorial origin, involving both genetic and environmental factors. A combination of epidemiologic studies, genome-wide association, and analysis of animal models have provided insight into the effects of gene-environment interactions on craniofacial and brain development and the pathogenesis of congenital disorders. In this chapter, we briefly summarize the etiology and pathogenesis of common craniofacial anomalies, focusing on orofacial clefts, hemifacial microsomia, and microcephaly. We then discuss how environmental risk factors interact with genes to modulate the incidence and phenotype severity of craniofacial anomalies. Identifying environmental risk factors and dissecting their interaction with different genes and modifiers is central to improved strategies for preventing craniofacial anomalies.
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Affiliation(s)
| | - Paul A Trainor
- Stowers Institute for Medical Research, Kansas City, MO, United States; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, United States.
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Cheng S, Chen W, Zhao M, Xing X, Zhao L, Ren B, Li N. Case report: A late-onset cobalamin C defect first presenting as a depression in a teenager. Front Genet 2022; 13:1012558. [PMID: 36338977 PMCID: PMC9631435 DOI: 10.3389/fgene.2022.1012558] [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: 08/05/2022] [Accepted: 10/06/2022] [Indexed: 11/18/2022] Open
Abstract
Background: The cobalamin C (cblC) defect, a common inborn disorder of cobalamin metabolism due to a genetic mutation in MMACHC, can cause combined methylmalonic acid and homocysteine accumulation in blood, urine, or both. In this article, a late-onset case was reported, and the patient first presented with depression identified with the MMACHC gene. We summarized the clinical features of the cblC defect, the relationship between genotype and phenotype, and the clinical experience concerning the diagnosis and treatment of the cblC defect. Case presentation: Initially presented with depression, the 16-year-old female patient showed progressive abnormal gait and bilateral lower limb weakness after 3 months. Blood routine examination suggested severe hyperhomocysteinemia, and screening for urine organic acids found elevated methylmalonic acid. Family gene sequencing showed mutations detected in MMACHC. She had a compound heterozygous mutation, while the c.271dupA (p.R91Kfs∗14) was only detected in her father and the c.482 G>A (p.R161Q) was only detected in her mother. Hence, she was diagnosed with a cblC defect and treated with B vitamin supplements. The muscle strength of both lower limbs improved notably. Conclusion: This case indicated that depression could be a presenting sign of cblC-type methylmalonic aciduria and homocysteinemia, and enhanced the genotype–phenotype relationship of the cblC defect, which will contribute to further understanding of this emerging disease.
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Affiliation(s)
- Siqi Cheng
- Department of Neurology, Hebei General Hospital, Shijiazhuang, China
| | - Weihong Chen
- Department of Neurology, Hebei General Hospital, Shijiazhuang, China
| | - Mingmin Zhao
- Graduate School, Hebei North University, Chengde, China
| | - Xing Xing
- Department of Neurology, Hebei General Hospital, Shijiazhuang, China
| | - Lei Zhao
- Department of Neurology, Hebei General Hospital, Shijiazhuang, China
| | - Bowen Ren
- Department of Neurology, Hebei General Hospital, Shijiazhuang, China
| | - Na Li
- Department of Neurology, Hebei General Hospital, Shijiazhuang, China
- *Correspondence: Na Li,
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Zhang TP, Li R, Wang LJ, Tang F, Li HM. Clinical relevance of vitamin B12 level and vitamin B12 metabolic gene variation in pulmonary tuberculosis. Front Immunol 2022; 13:947897. [PMID: 36275653 PMCID: PMC9583150 DOI: 10.3389/fimmu.2022.947897] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 09/09/2022] [Indexed: 11/14/2022] Open
Abstract
The aim of this study was to assess the association of vitamin B12 level and single nucleotide polymorphisms (SNPs) in vitamin B12 metabolic genes with pulmonary tuberculosis (PTB) in Chinese Han population. The plasma vitamin B12 expression level was detected using ELISA. Ten SNPs in six key genes (TCN1, TCN2, CUBN, MMACHC, FUT6, and MUT) of vitamin B12 metabolic pathway were included for genotyping by the SNPscan technique among 454 PTB patients and 467 controls. Our results found that vitamin B12 level was significantly reduced in PTB patients when compared with controls. There was no significant association between TCN1 rs526934, TCN2 rs1801198, CUBN rs7906242, rs10904861, rs1801222, MMACHC rs10789465, FUT6 rs3760776, rs3760775, MUT rs9473555, rs9381784 variants, and PTB susceptibility. TCN2 rs1801198 CC genotype, C allele was significantly associated with hypoproteinemia in PTB patients. In CUBN, rs7906242 GG genotype, G allele, rs10904861 TT genotype, and T allele were significantly related to the decreased frequency of sputum smear-positive, and rs10904861 variant affected the occurrence of drug resistance in PTB patients. In addition, the increased frequency of CUBN rs1801222 AA genotype was significantly associated with leukopenia. The decreased frequency of MUT rs9473555 CC genotype was found in the PTB patients with hypoproteinemia. However, vitamin B12 expression was not associated with the genotype distribution of above SNPs. In conclusion, vitamin B12 level was significantly decreased in PTB patients and genetic variants in vitamin B12 metabolic genes were not contributed to PTB susceptibility. Several SNPs in TCN2, CUBN, and MUT gene might associate with multiple clinical manifestations in PTB.
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Affiliation(s)
- Tian-Ping Zhang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Rui Li
- Department of Nosocomial Infection Management, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li-Jun Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fei Tang
- Department of Interventional Pulmonology and Endoscopic Diagnosis and Treatment Center, Anhui Chest Hospital, Hefei, China
- *Correspondence: Hong-Miao Li, ; Fei Tang,
| | - Hong-Miao Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
- *Correspondence: Hong-Miao Li, ; Fei Tang,
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Chen Z, Dong H, Liu Y, He R, Song J, Jin Y, Li M, Liu Y, Liu X, Yan H, Qi J, Wang F, Xiao H, Zheng H, Kang L, Li D, Zhang Y, Yang Y. Late-onset cblC deficiency around puberty: a retrospective study of the clinical characteristics, diagnosis, and treatment. Orphanet J Rare Dis 2022; 17:330. [PMID: 36056359 PMCID: PMC9438293 DOI: 10.1186/s13023-022-02471-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 08/13/2022] [Indexed: 11/12/2022] Open
Abstract
Background cblC deficiency is the most common type of methylmalonic aciduria in China. Late-onset patients present with various non-specific symptoms and are usually misdiagnosed. The purpose of this study is to investigate the clinical features of patients with late-onset cblC deficiency and explore diagnosis and management strategies around puberty. Results This study included 56 patients (35 males and 21 females) with late-onset cblC deficiency who were admitted to our clinic between 2002 and September 2021. The diagnosis was confirmed by metabolic and genetic tests. The clinical and biochemical features, disease triggers, outcome, and associated genetic variants were examined. The onset age ranged from 10 to 20 years (median age, 12 years). Fifteen patients (26.8%) presented with symptoms after infection or sports training. Further, 46 patients (82.1%) had neuropsychiatric diseases; 11 patients (19.6%), cardiovascular diseases; and 6 patients (10.7%), pulmonary hypertension. Renal damage was observed in 6 cases (10.7%). Genetic analysis revealed 21 variants of the MMACHC gene in the 56 patients. The top five common variants detected in 112 alleles were c.482G > A (36.6%), c.609G > A (16.1%), c.658_660delAAG (9.8%), c.80A > G (8.0%), and c.567dupT (6.3%). Thirty-nine patients carried the c.482G > A variant. Among 13 patients who exhibited spastic paraplegia as the main manifestation, 11 patients carried c.482G > A variants. Six patients who presented with psychotic disorders and spastic paraplegia had compound heterozygotic c.482G > A and other variants. All the patients showed improvement after metabolic treatment with cobalamin, l-carnitine, and betaine, and 30 school-aged patients returned to school. Two female patients got married and had healthy babies. Conclusions Patients with late-onset cblC deficiency present with a wide variety of neuropsychiatric symptoms and other presentations, including multiple organ damage. As a result, cb1C deficiency can easily be misdiagnosed as other conditions. Metabolic and genetic studies are important for accurate diagnosis, and metabolic treatment with cobalamin, l-carnitine, and betaine appears to be beneficial. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02471-x.
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Affiliation(s)
- Zhehui Chen
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
| | - Hui Dong
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
| | - Yupeng Liu
- Department of Pediatrics, Peking University People's Hospital, Beijing, 100034, China
| | - Ruxuan He
- Department of Respiratory Medicine II, Beijing Children's Hospital Affiliated to Capital Medical University, Beijing, 100045, China
| | - Jinqing Song
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
| | - Ying Jin
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
| | - Mengqiu Li
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
| | - Yi Liu
- Department of Clinical Laboratory, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Xueqin Liu
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
| | - Hui Yan
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
| | - Jianguang Qi
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
| | - Fang Wang
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
| | - Huijie Xiao
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China
| | - Hong Zheng
- Department of Pediatrics, First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, China
| | - Lulu Kang
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Dongxiao Li
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450053, China
| | - Yao Zhang
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China.
| | - Yanling Yang
- Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China.
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Esser AJ, Mukherjee S, Dereven‘kov IA, Makarov SV, Jacobsen DW, Spiekerkoetter U, Hannibal L. Versatile Enzymology and Heterogeneous Phenotypes in Cobalamin Complementation Type C Disease. iScience 2022; 25:104981. [PMID: 36105582 PMCID: PMC9464900 DOI: 10.1016/j.isci.2022.104981] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Nutritional deficiency and genetic errors that impair the transport, absorption, and utilization of vitamin B12 (B12) lead to hematological and neurological manifestations. The cblC disease (cobalamin complementation type C) is an autosomal recessive disorder caused by mutations and epi-mutations in the MMACHC gene and the most common inborn error of B12 metabolism. Pathogenic mutations in MMACHC disrupt enzymatic processing of B12, an indispensable step before micronutrient utilization by the two B12-dependent enzymes methionine synthase (MS) and methylmalonyl-CoA mutase (MUT). As a result, patients with cblC disease exhibit plasma elevation of homocysteine (Hcy, substrate of MS) and methylmalonic acid (MMA, degradation product of methylmalonyl-CoA, substrate of MUT). The cblC disorder manifests early in childhood or in late adulthood with heterogeneous multi-organ involvement. This review covers current knowledge on the cblC disease, structure–function relationships of the MMACHC protein, the genotypic and phenotypic spectra in humans, experimental disease models, and promising therapies.
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Zhou L, Yang Q. A teenager with combined methylmalonic aciduria and homocystinuria (CblC type) presenting with neurological symptoms and congenital heart diseases: a case report. Neurocase 2022; 28:388-392. [PMID: 36219783 DOI: 10.1080/13554794.2022.2132870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Combined methylmalonic acidemia and homocystinuria, is a rare autosomal recessive disorder due to defective intracellular cobalamin metabolism. We report an 18-year-old Chinese male who presented with hypermyotonia, seizures, and congenital heart diseases. Mutation analysis revealed c.365A>T and c.482 G>A mutations in the MMACHC gene, diagnosed with methylmalonic aciduria and homocystinuria (CblC type). After treatment with vitamin B12, L-carnitine, betaine, and folate, which resulted in an improvement in his clinical symptoms and laboratory values. This case emphasizes that inborn errors of metabolism should be considered for a teenager presenting with challenging or neurologic symptoms, especially when combined with unexplained heart diseases.
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Affiliation(s)
- Li Zhou
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qin Yang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Aliyar A, Endrakanti M, Singh RK, Elavarasi A, Gupta N, Vibha D, Tripathi M. Late-onset cobalamin C disease: rare but treatable. Pract Neurol 2022; 22:practneurol-2022-003447. [PMID: 35803728 DOI: 10.1136/practneurol-2022-003447] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2022] [Indexed: 11/04/2022]
Abstract
Cobalamin C disease is the most common inborn error of cobalamin metabolism, resulting from mutations in methylmalonic aciduria and homocystinuria type C protein (MMACHC) gene. There is associated elevation of homocysteine and methylmalonic acid and decreased synthesis of methionine. It is a multisystem disorder characterised by cognitive impairment, psychiatric manifestations, haematological manifestations and thromboembolic phenomena. Its variable clinical presentation and wide age distribution at presentation necessitates a high index of diagnostic suspicion. The diagnosis is suggested by amino acid chromatography and confirmed by sequencing analysis of the MMACHC gene Parenteral hydroxycobalamin and betaine can bring significant clinical and biochemical improvement and is the recommended long-term therapy.
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Affiliation(s)
- Aminu Aliyar
- Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Mounika Endrakanti
- Division of Genetics, Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Rajesh K Singh
- Neurology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Neerja Gupta
- Division of Genetics, Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Deepti Vibha
- Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Manjari Tripathi
- Neurology, All India Institute of Medical Sciences, New Delhi, India
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Liu F, Wu Y, Li Z, Wan R. Identification of MMACHC and ZEB2 mutations causing coexistent cobalamin C disease and Mowat-Wilson syndrome in a 2-year-old girl. Clin Chim Acta 2022; 533:31-39. [PMID: 35709987 DOI: 10.1016/j.cca.2022.06.004] [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: 03/06/2022] [Revised: 05/29/2022] [Accepted: 06/03/2022] [Indexed: 11/26/2022]
Abstract
Cobalamin C (cblC) disease and Mowat-Wilson syndrome (MWS) are rare hereditary diseases. To date, there have been no reports of people suffering from these two genetic diseases, or whether there is any correlation between the two diseases. We reported a 2-year-old girl with both cblC disease and MWS. The patient initially manifested as slow weight gain, hypotonia, broad nasal bridge, high forehead, high palate arch, ear crease, patent ductus arteriosus, atrial and ventricular septal defect and bilateral mild ventriculomegaly in the neonatal period. However, as the baby grew older, the typical facial features became more prominent, and overall developmental delays were noted at the subsequent follow-up, with the motor and cognitive development significantly lagging behind that of other children of the same age. At 26 days old, laboratory tests revealed remarkably elevated levels of serum homocysteine, C3/C2 and urine organic acid. Whole-exome sequencing detected compound heterozygous variants in MMACHC, including one previously reported mutation [c.609G > A (p.W203X) and a novel missense mutation[ c.643 T > C (p.Y215H)]. The computer simulations of the protein structure analysis of the novel missense mutation showed the variant p.Y215H replaced a neutral amino acid with a strongly basic lysine, which broken the local structure by changing the carbon chain skeleton and decreasing the interaction with adjacent amino acid. This is expected to damage the utilization of vitamin B12 and influence the synthesis of AdoCbl and MeCbl, contributing to its pathogenicity. Thus, clinical and genetic examinations confirmed the cblC disease. Another heterozygous variant in ZEB2 [NM_014795; loss1(exon:2-10)(all); 127901 bp] was detected by whole-exome sequencing. The heterozygous 3.04 Mb deletion in EB2 [GRCH37]del(2)(q22.2q22.3) (chr2:142237964-145274917) was also confirmed by genome-wide copy number variations (CNVs) scan, which was pathogenic and led to the diagnosis of Mowat-Wilson syndrome. The biochemical indicators associated with cblC disease in the patient were well controlled after treatment with vitamin B12 and betaine. Here, a patient with coexisting cblC disease and MWS caused by different pathogenic genes was reported, which enriched the clinical research on these two rare genetic diseases.
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Affiliation(s)
- Fang Liu
- Department of Pediatrics, the 980th Hospital of the People's Liberation Army Joint Service Support Force (Bethune International Peace Hospital), Shijiazhuang 050082, Hebei, China.
| | - Yuanyuan Wu
- Department of Genetics and Reproduction, the 980th Hospital of the People's Liberation Army Joint Service Support Force (Bethune International Peace Hospital), Shijiazhuang 050082, Hebei, China
| | - Zhi Li
- Department of Pediatrics, the 980th Hospital of the People's Liberation Army Joint Service Support Force (Bethune International Peace Hospital), Shijiazhuang 050082, Hebei, China
| | - Ruihua Wan
- Department of Pediatrics, the 980th Hospital of the People's Liberation Army Joint Service Support Force (Bethune International Peace Hospital), Shijiazhuang 050082, Hebei, China
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Wood WD, Elmaghrabi A, Gotway G, Wolf MTF. The roles of homocysteinemia and methylmalonic acidemia in kidney injury in atypical hemolytic uremic syndrome caused by cobalamin C deficiency. Pediatr Nephrol 2022; 37:1415-1418. [PMID: 34854955 PMCID: PMC9160205 DOI: 10.1007/s00467-021-05372-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 11/01/2021] [Accepted: 11/01/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Cobalamin C (cblC), a vitamin B12 processing protein, plays a crucial role in metabolism for the conversion of homocysteine to methionine and methylmalonyl-CoA to succinyl-CoA. CblC deficiency, an inborn error of cobalamin processing, is a rare cause of atypical hemolytic-uremic syndrome (aHUS) and results in hyperhomocysteinemia and methylmalonic aciduria. Both substances are thought to contribute to thrombotic microangiopathy (TMA) in cblC deficiency patients. However, the roles of homocysteine and methylmalonic acid (MMA) in these patients remain unclear. We want to shed more light on the contributions of homocysteine and MMA levels as contributing factors for thrombotic microangiopathy (TMA)/aHUS by a follow-up of a cblC deficiency patient over 6 years. CASE DIAGNOSIS A 27-day-old Hispanic female presented with abnormal C3-carnitine on her newborn screen, poor feeding, decreased activity, and oligouria. She was diagnosed with cblC deficiency after laboratory results revealed elevated serum homocysteine, and serum MMA along with genetic testing showing a homozygous pathogenic frameshift variant in MMACHC. The patient developed aHUS and acute kidney injury (AKI), which resolved after appropriate therapy. Over 6 years, she continued to have normal kidney function with no thrombocytopenia despite persistently elevated homocysteine and MMA levels. CONCLUSION We question the roles of homocysteine and MMA as causative of aHUS/TMA in cblC deficiency as they remained elevated during follow-up but did not result in aHUS/TMA or AKI. Hyperhomocysteinemia and/or MMA caused by other metabolic diseases do not result in aHUS/TMA or AKI. This suggests that other nephrotoxic factors may trigger aHUS/TMA in cblC patients.
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Affiliation(s)
- William D Wood
- Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ayah Elmaghrabi
- Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Garrett Gotway
- Pediatric Genetics and Metabolism, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Matthias T F Wolf
- Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Passantino R, Mangione MR, Ortore MG, Costa MA, Provenzano A, Amenitsch H, Sabbatella R, Alfano C, Martorana V, Vilasi S. Investigation on a MMACHC mutant from cblC disease: The c.394C>T variant. BIOCHIMICA ET BIOPHYSICA ACTA. PROTEINS AND PROTEOMICS 2022; 1870:140793. [PMID: 35618206 DOI: 10.1016/j.bbapap.2022.140793] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 06/15/2023]
Abstract
The cblC disease is an inborn disorder of the vitamin B12 (cobalamin, Cbl) metabolism characterized by methylmalonic aciduria and homocystinuria. The clinical consequences of this disease are devastating and, even when early treated with current therapies, the affected children manifest symptoms involving vision, growth, and learning. The illness is caused by mutations in the gene codifying for MMACHC, a 282aa protein that transports and transforms the different Cbl forms. Here we present data on the structural properties of the truncated protein p.R132X resulting from the c.394C > T mutation that, along with c.271dupA and c.331C > T, is among the most common mutations in cblC. Although missing part of the Cbl binding domain, p.R132X is associated to late-onset symptoms and, therefore, it is supposed to retain residual function. However, to our knowledge structural-functional studies on c.394C > T mutant aimed at verifying this hypothesis are still lacking. By using a biophysical approach including Circular Dichroism, fluorescence, Small Angle X-ray Scattering, and Molecular Dynamics, we show that the mutant protein MMACHC-R132X retains secondary structure elements and remains compact in solution, partly preserving its binding affinity for Cbl. Insights on the fragile stability of MMACHC-R132X-Cbl are provided.
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Affiliation(s)
- Rosa Passantino
- Biophysics Institute, National Research Council, Palermo 90143, Italy
| | | | - Maria Grazia Ortore
- Dept. Life and Environmental Sciences, Marche Polytechnic University, Ancona 60131, Italy
| | | | | | | | | | | | | | - Silvia Vilasi
- Biophysics Institute, National Research Council, Palermo 90143, Italy.
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Chen J, Zhao Z, Shen H, Bing Q, Li N, Guo X, Hu J. Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations. BMC Neurol 2022; 22:180. [PMID: 35578252 PMCID: PMC9109329 DOI: 10.1186/s12883-022-02708-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 05/09/2022] [Indexed: 11/10/2022] Open
Abstract
Background Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by lower-limb spastic paraplegia with highly genetic and clinical heterogeneity. However, the clinical sign of spastic paraplegia can also be seen in a variety of hereditary neurologic diseases with bilateral corticospinal tract impairment. The purpose of this study is to identify the disease spectrum of spastic paraplegia, and to broaden the coverage of genetic testing and recognize clinical, laboratorial, electrophysiological and radiological characteristics to increase the positive rate of diagnosis. Methods Twenty-seven cases were screened out to have definite or suspected pathogenic variants from clinically suspected HSP pedigrees through HSP-associated sequencing and/or expanded genetic testing. One case was performed for enzyme detection of leukodystrophy without next-generation sequencing. In addition, detailed clinical, laboratorial, electrophysiological and radiological characteristics of the 28 patients were presented. Results A total of five types of hereditary neurological disorders were identified in 28 patients, including HSP (15/28), leukodystrophy (5/28), hereditary ataxia (2/28), methylmalonic acidemia/methylenetetrahydrofolate reductase deficiency (5/28), and Charcot-Marie-tooth atrophy (1/28). Patients in the HSP group had chronic courses, most of whom were lower limbs spasticity, mainly with axonal neuropathy, and thinning corpus callosum, white matter lesions and cerebellar atrophy in brain MRI. In the non-HSP groups, upper and lower limbs both involvement was more common. Patients with homocysteine remethylation disorders or Krabbe’s disease or autosomal recessive spastic ataxia of Charlevoix-Saguenay had diagnostic results in laboratory or imaging examination. A total of 12 new variants were obtained. Conclusions HSP had widespread clinical and genetic heterogeneity, and leukodystrophy, hereditary ataxia, Charcot-Marie-Tooth atrophy and homocysteine remethylation disorders accounted for a significant proportion of the proposed HSP. These diseases had different characteristics in clinical, laboratorial, electrophysiological, and radiological aspects, which could help differential diagnosis. Genetic analysis could ultimately provide a clear diagnosis, and broadening the scope of genetic testing could improve the positive rate of diagnosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12883-022-02708-z.
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Affiliation(s)
- Jiannan Chen
- Department of Neuromuscular Disease, The Third Affiliated Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei, 050000, PR China
| | - Zhe Zhao
- Department of Neuromuscular Disease, The Third Affiliated Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei, 050000, PR China
| | - Hongrui Shen
- Department of Neuromuscular Disease, The Third Affiliated Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei, 050000, PR China
| | - Qi Bing
- Department of Neuromuscular Disease, The Third Affiliated Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei, 050000, PR China
| | - Nan Li
- Department of Neuromuscular Disease, The Third Affiliated Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei, 050000, PR China
| | - Xuan Guo
- Department of Neuromuscular Disease, The Third Affiliated Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei, 050000, PR China
| | - Jing Hu
- Department of Neuromuscular Disease, The Third Affiliated Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei, 050000, PR China.
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Zuhra K, Szabo C. The two faces of cyanide: an environmental toxin and a potential novel mammalian gasotransmitter. FEBS J 2022; 289:2481-2515. [PMID: 34297873 PMCID: PMC9291117 DOI: 10.1111/febs.16135] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/15/2021] [Accepted: 07/22/2021] [Indexed: 12/16/2022]
Abstract
Cyanide is traditionally viewed as a cytotoxic agent, with its primary mode of action being the inhibition of mitochondrial Complex IV (cytochrome c oxidase). However, recent studies demonstrate that the effect of cyanide on Complex IV in various mammalian cells is biphasic: in lower concentrations (nanomolar to low micromolar) cyanide stimulates Complex IV activity, increases ATP production and accelerates cell proliferation, while at higher concentrations (high micromolar to low millimolar) it produces the previously known ('classic') toxic effects. The first part of the article describes the cytotoxic actions of cyanide in the context of environmental toxicology, and highlights pathophysiological conditions (e.g., cystic fibrosis with Pseudomonas colonization) where bacterially produced cyanide exerts deleterious effects to the host. The second part of the article summarizes the mammalian sources of cyanide production and overviews the emerging concept that mammalian cells may produce cyanide, in low concentrations, to serve biological regulatory roles. Cyanide fulfills many of the general criteria as a 'classical' mammalian gasotransmitter and shares some common features with the current members of this class: nitric oxide, carbon monoxide, and hydrogen sulfide.
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Affiliation(s)
- Karim Zuhra
- Chair of PharmacologySection of MedicineUniversity of FribourgSwitzerland
| | - Csaba Szabo
- Chair of PharmacologySection of MedicineUniversity of FribourgSwitzerland
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Watkins D, Rosenblatt DS. Inherited defects of cobalamin metabolism. VITAMINS AND HORMONES 2022; 119:355-376. [PMID: 35337626 DOI: 10.1016/bs.vh.2022.01.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Cobalamin (vitamin B12) is required for activity of the enzymes methylmalonyl-CoA mutase and methionine synthase in human cells. Inborn errors affecting cobalamin uptake or metabolism are characterized by accumulation of the substrates for these enzymes, methylmalonic acid and homocysteine, in blood and urine. Inborn errors affecting synthesis of the adenosylcobalamin coenzyme required by methylmalonyl-CoA mutase (cblA and cblB) result in isolated methylmalonic aciduria; inborn errors affecting synthesis of the methylcobalamin coenzyme required by methionine synthase (cblE and cblG) result in isolated homocystinuria. Combined methylmalonic aciduria and homocystinuria is seen in patients with impaired intestinal cobalamin absorption (intrinsic factor deficiency, Imerslund-Gräsbeck syndrome) and with defects affecting synthesis of both cobalamin coenzymes (cblC, cblD, cblF and cblJ). A series of disorders caused by pathogenic variant mutations affecting gene regulators (transcription factors) of the MMACHC gene have recently been described (HCFC1 [cblX disorder] and deficiencies of THAP11, and ZNF143 [the cblK disorder]).
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Affiliation(s)
- David Watkins
- Department of Human Genetics, McGill University, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
| | - David S Rosenblatt
- Department of Human Genetics, McGill University, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
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Ailliet S, Vandenberghe R, Schiemsky T, Van Overbeke L, Demaerel P, Meersseman W, Cassiman D, Vermeersch P. A case of vitamin B12 deficiency neurological syndrome in a young adult due to late-onset cobalamin C (CblC) deficiency: a diagnostic challenge. Biochem Med (Zagreb) 2022; 32:020802. [PMID: 35464742 PMCID: PMC8996322 DOI: 10.11613/bm.2022.020802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/24/2022] [Indexed: 11/28/2022] Open
Abstract
Vitamin B12 deficiency can present with neurologic and psychiatric symptoms without macrocytic anaemia. We describe a case of late-onset cobalamin C deficiency which typically presents with normal serum vitamin B12 concentrations, posing an additional diagnostic challenge. A 23-year-old woman with decreased muscle strength and hallucinations was diagnosed with ‘catatonic depression’ and admitted to a residential mental health facility. She was referred to our hospital for further investigation 3 months later. Heteroanamnesis revealed that the symptoms had been evolving progressively over several months. Magnetic resonance imaging (MRI) of the brain showed diffuse symmetrical white matter lesions in both hemispheres. Routine laboratory tests including vitamin B12 and folic acid were normal except for a slight normocytic, normochromic anaemia. Over the next 6 weeks her symptoms deteriorated, and she became unresponsive to stimuli. A new MRI scan showed progression of the white matter lesions. The neurologist requested plasma homocysteine (Hcys) which was more than 8 times the upper limit of normal. Further testing revealed increased methylmalonic acid and the patient was diagnosed with adult-onset cobalamin C deficiency. This case illustrates that Hcys and/or methylmalonic acid should be determined in patients presenting with neuropsychiatric symptoms suggestive of vitamin B12 deficiency with a normal serum vitamin B12 to rule out a late-onset cobalamin C deficiency.
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Affiliation(s)
- Scott Ailliet
- Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Rik Vandenberghe
- Clinical Department of Neurology, University Hospitals Leuven, Leuven, Belgium
| | - Toon Schiemsky
- Clinical Department of Laboratory Medicine, Ziekenhuis Oost-Limburg, Belgium
| | - Lode Van Overbeke
- Center of Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Philippe Demaerel
- Clinical Department of Radiology, University Hospitals Leuven, Leuven, Belgium
| | - Wouter Meersseman
- Center of Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium
| | - David Cassiman
- Center of Metabolic Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Pieter Vermeersch
- Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
- Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
- Corresponding author:
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Hu S, Kong X. The genotype analysis and prenatal genetic diagnosis among 244 pedigrees with methylmalonic aciduria in China. Taiwan J Obstet Gynecol 2022; 61:290-298. [PMID: 35361390 DOI: 10.1016/j.tjog.2022.02.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/10/2021] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES To investigate the phenotypes, biochemical features and genotypes for 244 pedigrees with methylmalonic aciduria (MMA) in China, and to perform the prenatal genetic diagnosis by chorionic villus for these pedigrees. MATERIALS AND METHODS Gene analyses were performed for 244 pedigrees. There are 130 pedigrees, chorionic villus sampling was performed on the pregnant women to conduct the prenatal diagnosis. RESULTS Among 244 patients, 168 (68.9%) cases were combined methylmalonic aciduria and homocystinuria, 76 (31.1%) cases were isolated methylmalonic aciduria. All the patients were diagnosed with MMA by their clinical manifestation, elevated blood propionylcarnitine, propionylcarnitine to acetylcarnitine ratio, and/or urine/blood methylmalonic acid with or without homocysteine. MMACHC, MMUT, SUCLG1 and LMBRD1 gene variants were found in 236 (96.7%) pedigrees included 6 probands with only one heterozygous variant out of 244 cases. For the 130 pedigrees who received a prenatal diagnosis, 22 fetuses were normal, 69 foetuses were carriers of heterozygous variants, and the remaining 39 foetuses harboured compound heterozygous variants or homozygous variants. The follow-up results were consistent with the prenatal diagnosis. CONCLUSION The present study indicates genetic heterogeneity in MMA patients. Genetic analysis is a convenient method for prenatal diagnosis that will aid in avoiding the delivery of MMA patients.
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Affiliation(s)
- Shuang Hu
- The First Affiliated Hospital of Zhengzhou University, Genetic and Prenatal Diagnosis Center, No.1 Jianshe East Road, Zhengzhou, Henan, CN 450052, China.
| | - Xiangdong Kong
- The First Affiliated Hospital of Zhengzhou University, Genetic and Prenatal Diagnosis Center, No.1 Jianshe East Road, Zhengzhou, Henan, CN 450052, China.
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Structural Study of the Complex of cblC Methylmalonic Aciduria and Homocystinuria-Related Protein MMACHC with Cyanocobalamin. CRYSTALS 2022. [DOI: 10.3390/cryst12040468] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
MMACHC is an essential protein for the body to metabolise vitamin B12, and its deficiency will cause cblC-type methylmalonic aciduria and homocystinuria. MMACHC can interact with cyanocobalamin (a type of vitamin B12) cofactor and plays an important role in targeting cyanocobalamin to the enzyme of interest. In this paper, the GST-tag fusion-tagged MMACHC protein was successfully expressed by Escherichia coli (E. coli) low-temperature induction, and the high-purity MMACHC protein was successfully purified by affinity chromatography and gel filtration. Further, the crystal structure of MMACHC and cyanocobalamin complex was obtained with a resolution of 1.93 Å using X-ray diffraction. By analysing the complex structure of MMACHC and cyanocobalamin, we revealed the reasons for the diversity of MMACHC substrates and explained the reasons for the differences in disease conditions caused by different MMACHC site mutations. The acquisition of the complex structure of MMACHC and cyanocobalamin will play a significant role in promoting research on the metabolic pathway of vitamin B12.
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