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Bayramova S, Koç Yekedüz M, Köse E, Eminoğlu FT. Retrospective assessment of hepatic involvement in patients with inherited metabolic disorders: nine-year single-center experience. J Pediatr Endocrinol Metab 2025; 38:465-475. [PMID: 39995240 DOI: 10.1515/jpem-2024-0511] [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: 10/24/2024] [Accepted: 01/31/2025] [Indexed: 02/26/2025]
Abstract
OBJECTIVES This study aimed to identify clinical, laboratory, and radiological features that could serve as red flags for diagnosing inherited metabolic disorders (IMDs) with hepatic involvement in childhood. METHODS We retrospectively reviewed the medical records of 1,237 children from a pediatric metabolism department, with suspected or diagnosed IMDs. Patients with hepatic involvement were divided into two groups: Group 1 (diagnosed with IMDs) and Group 2 (undiagnosed). Demographic, clinical, laboratory, and radiological data were compared between the groups. RESULTS Hepatic involvement was observed in 415 patients (33.5 %), with 206 (49.2 %) diagnosed with IMDs. Group 1 had higher rates of consanguineous marriage and affected siblings. Complex molecule disorders (20.4 %), mitochondrial (16.0 %), and lipid metabolism disorders (16.0 %) were the most common IMDs. Dysmorphic findings were more frequent in Group 1 (28.2 vs. 16.3 %, p=0.004), while diarrhea was less common (4.4 vs. 12.0 %, p=0.005). Ammonia and lactate levels were higher in Group 1 (p<0.001 and p=0.032, respectively). Hepatomegaly was more frequent in Group 1 (53.3 vs. 22.6 %, p<0.001). Pathological abdominal ultrasonography was the only significant multivariate predictor (OR: 89.377, p=0.026). Overall survival was 87.7 %, with no difference between groups. CONCLUSIONS Consanguineous marriage, affected siblings, dysmorphic findings, absence of diarrhea, and pathological abdominal USG are key predictors of IMDs in hepatic involvement cases.
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Affiliation(s)
- Samira Bayramova
- Ankara University Faculty of Medicine, Department of Pediatrics, Ankara, Türkiye
| | - Merve Koç Yekedüz
- Ankara University Faculty of Medicine, Department of Pediatric Metabolism, Ankara, Türkiye
- Harvard Medical School, Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, MA, USA
| | - Engin Köse
- Ankara University Faculty of Medicine, Department of Pediatric Metabolism, Ankara, Türkiye
- Ankara University Rare Disease Application and Research Center, Ankara, Türkiye
| | - Fatma Tuba Eminoğlu
- Ankara University Faculty of Medicine, Department of Pediatric Metabolism, Ankara, Türkiye
- Ankara University Rare Disease Application and Research Center, Ankara, Türkiye
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Scarcella M, Fecarotta S, Alagia M, Barretta F, Uomo F, De Pasquale V, Patel HS, Strisciuglio P, Parenti G, Frisso G, Pavone LM, Ruoppolo M. Digital microfluidic platform for dried blood spot newborn screening of lysosomal storage diseases in Campania region (Italy): Findings from the first year pilot project. Mol Genet Metab 2025; 144:109008. [PMID: 39788860 DOI: 10.1016/j.ymgme.2024.109008] [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: 09/10/2024] [Revised: 12/25/2024] [Accepted: 12/26/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND Newborn screening (NBS) is a simple, non-invasive test that allows for the early identification of genetic diseases within the first days of a newborn's life. The aim of NBS is to detect potentially fatal or disabling conditions in newborns as early as possible, before the onset of disease symptoms. Early diagnosis enables timely treatments and improves the quality of life for affected patients. RESULTS A pilot project for dried blood spot (DBS) NBS of lysosomal storage diseases (LSDs), including Mucopolysaccharidosis I (MPSI, IDUA α-L-iduronidase deficiency), Pompe disease (GAA α-glucosidase acid deficiency), Gaucher disease (GBA β-glucosidase deficiency) and Fabry disease (GLA α-galactosidase deficiency), was conducted using the digital microfluidic (DMF) technique. DBS were analyzed in a multiplexed assays for the enzymatic activities of four lysosomal enzymes (IDUA, GAA, GBA, GLA), and subjects identified as deficient in any of these enzymes were referred to the clinical reference center for diagnosis confirmation. From June 6th, 2022, to May 12th, 2023, a total of 7650 newborns were analyzed and 1 subject affected by Pompe disease was identified together with two additional subjects, suspected of Pompe and Fabry disease respectively, for whom continued follow-up is mandatory to determine the phenotype. CONCLUSIONS The pilot project for DBS NBS of four LSDs in Campania Region validated the effectiveness of DMF method, established enzymatic activity cut-offs, and identified newborns referred to the clinical center for integrated diagnostics, including genetic analyses. The results suggest that this technique can effectively detect potentially affected newborns, who will require further diagnostic confirmation and clinical follow-up. This diagnostic flow chart provides the opportunity to initiate early treatments and improve LSD patients' life span.
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Affiliation(s)
- Melania Scarcella
- Department of Molecular Medicine and Medical Biotechnology, Medical School, University of Naples Federico II, 80131 Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., 80145 Naples, Italy
| | - Simona Fecarotta
- Department of Translational Medical Sciences, Medical School, University of Naples Federico II, 80131 Naples, Italy
| | - Marianna Alagia
- Department of Translational Medical Sciences, Medical School, University of Naples Federico II, 80131 Naples, Italy
| | - Ferdinando Barretta
- Department of Molecular Medicine and Medical Biotechnology, Medical School, University of Naples Federico II, 80131 Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., 80145 Naples, Italy; DAIMedLab AOU Federico II, 80131 Naples, Italy
| | - Fabiana Uomo
- Department of Molecular Medicine and Medical Biotechnology, Medical School, University of Naples Federico II, 80131 Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., 80145 Naples, Italy
| | - Valeria De Pasquale
- CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., 80145 Naples, Italy; Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, 80137 Naples, Italy
| | | | - Pietro Strisciuglio
- Department of Translational Medical Sciences, Medical School, University of Naples Federico II, 80131 Naples, Italy
| | - Giancarlo Parenti
- Department of Translational Medical Sciences, Medical School, University of Naples Federico II, 80131 Naples, Italy; Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
| | - Giulia Frisso
- Department of Molecular Medicine and Medical Biotechnology, Medical School, University of Naples Federico II, 80131 Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., 80145 Naples, Italy
| | - Luigi Michele Pavone
- Department of Molecular Medicine and Medical Biotechnology, Medical School, University of Naples Federico II, 80131 Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., 80145 Naples, Italy.
| | - Margherita Ruoppolo
- Department of Molecular Medicine and Medical Biotechnology, Medical School, University of Naples Federico II, 80131 Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., 80145 Naples, Italy.
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Parvatam S, Pistollato F, Marshall LJ, Furtmann F, Jahagirdar D, Chakraborty Choudhury M, Mohanty S, Mittal H, Meganathan S, Mishra R. Human-based complex in vitro models: their promise and potential for rare disease therapeutics. Front Cell Dev Biol 2025; 13:1526306. [PMID: 39931243 PMCID: PMC11807990 DOI: 10.3389/fcell.2025.1526306] [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: 11/11/2024] [Accepted: 01/09/2025] [Indexed: 02/13/2025] Open
Abstract
Rare diseases affect a small percentage of an individual country's population; however, with over 7,000 in total, rare diseases represent a significant disease burden impacting up to 10% of the world's population. Despite this, there are no approved treatments for almost 95% of rare diseases, and the existing treatments are cost-intensive for the patients. More than 70% of rare diseases are genetic in nature, with patient-specific mutations. This calls for the need to have personalised and patient-specific preclinical models that can lead to effective, speedy, and affordable therapeutic options. Complex in vitro models (CIVMs), including those using induced pluripotent stem cells (iPSCs), organoids, and organs-on-chips are emerging as powerful human-based pre-clinical systems with the capacity to provide efficacy data enabling drugs to move into clinical trials. In this narrative review, we discuss how CIVMs are providing insights into biomedical research on rare diseases. We also discuss how these systems are being used in clinical trials to develop efficacy models for rare diseases. Finally, we propose recommendations on how human relevant CIVMs could be leveraged to increase translatability of basic, applied and nonclinical research outcomes in the field of rare disease therapeutics in developed as well as middle-and low-income countries.
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Affiliation(s)
- Surat Parvatam
- Department of Research and Toxicology, Humane Society International/India, Hyderabad, India
| | - Francesca Pistollato
- Department of Research and Toxicology, Humane Society International/Europe, Brussels, Belgium
| | - Lindsay J. Marshall
- Animal Research Issues, The Humane Society of the United States, Washington DC, DC, United States
| | - Fabia Furtmann
- Department of Research and Toxicology, Humane Society International/Europe, Brussels, Belgium
| | - Devashree Jahagirdar
- Department of Chemical Engineering, Indian Institute of Technology (IIT), Mumbai, Maharashtra, India
| | | | - Sujata Mohanty
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, India
| | - Harshita Mittal
- Department of Research and Toxicology, Humane Society International/India, Hyderabad, India
| | - Saveetha Meganathan
- Community Engagement and Policy Stewardship, Tata Institute for Genetics and Society, Bangalore, India
| | - Rakesh Mishra
- Tata Institute for Genetics and Society, Bangalore, India
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Bajpai S, Mandal K, Naranje K, Singh A. Galactosialidosis presenting as non-immune hydrops. BMJ Case Rep 2024; 17:e260906. [PMID: 39353673 DOI: 10.1136/bcr-2024-260906] [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: 10/04/2024] Open
Abstract
Hydrops fetalis is an abnormal accumulation of fluid in two or more foetal compartments which is easily detected using prenatal ultrasonography. It can be categorised into immune and non-immune. The non-immune hydrops can result from various aetiologies, including cardiovascular, respiratory, genitourinary infections, chromosomal anomalies and metabolic causes. The metabolic causes, including lysosomal storage disorders (LSD), are increasingly being recognised as the causes of non-immune hydrops. The hydrops fetalis associated with metabolic disorders is usually severe with huge ascites, hepatosplenomegaly, thick skin, renal abnormalities, increased nuchal translucency, renal abnormalities and skeletal deformities. In this report, we describe a case of LSD, that is, galactosialidosis presenting as non-immune hydrops and its diagnosis. In utero diagnosis of the disorder without an index case is challenging. The definitive diagnosis is important for planning and management of future conceptions.
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Affiliation(s)
- Shivani Bajpai
- Pediatrics, Career Institute of Medical Sciences and Hospital, Lucknow, Uttar Pradesh, India
| | - Kausik Mandal
- Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Kirti Naranje
- Neonatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Anita Singh
- Neonatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Vakili O, Mafi A, Pourfarzam M. Liver Disorders Caused by Inborn Errors of Metabolism. Endocr Metab Immune Disord Drug Targets 2024; 24:194-207. [PMID: 37357514 DOI: 10.2174/1871530323666230623120935] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/09/2023] [Accepted: 05/18/2023] [Indexed: 06/27/2023]
Abstract
Inborn errors of metabolism (IEMs) are a vast array of inherited/congenital disorders, affecting a wide variety of metabolic pathways and/or biochemical processes inside the cells. Although IEMs are usually rare, they can be represented as serious health problems. During the neonatal period, these inherited defects can give rise to almost all key signs of liver malfunction, including jaundice, coagulopathy, hepato- and splenomegaly, ascites, etc. Since the liver is a vital organ with multiple synthetic, metabolic, and excretory functions, IEM-related hepatic dysfunction could seriously be considered life-threatening. In this context, the identification of those hepatic manifestations and their associated characteristics may promote the differential diagnosis of IEMs immediately after birth, making therapeutic strategies more successful in preventing the occurrence of subsequent events. Among all possible liver defects caused by IEMs, cholestatic jaundice, hepatosplenomegaly, and liver failure have been shown to be manifested more frequently. Therefore, the current study aims to review substantial IEMs that mostly result in the aforementioned hepatic disorders, relying on clinical principles, especially through the first years of life. In this article, a group of uncommon hepatic manifestations linked to IEMs is also discussed in brief.
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Affiliation(s)
- Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Morteza Pourfarzam
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
- Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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Sheth J, Nair A, Jee B. Lysosomal storage disorders: from biology to the clinic with reference to India. THE LANCET REGIONAL HEALTH. SOUTHEAST ASIA 2023; 9:100108. [PMID: 37383036 PMCID: PMC10305895 DOI: 10.1016/j.lansea.2022.100108] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 09/20/2022] [Accepted: 10/27/2022] [Indexed: 06/30/2023]
Abstract
Lysosomal storage disorders (LSDs) are a group of seventy different metabolic storage diseases due to accumulation of substrate mainly in the form of carbohydrate, lipids, proteins, and cellular debris. They occur due to variant in different genes that regulate lysosomal enzymes synthesis, transport, and secretion. In recent years, due to an increased availability of various therapies to treat these disorders, and increased diagnostic tools, there has been an escalated awareness of LSDs. Due to heterogeneous population and various social reasons, India is likely to have a high frequency of LSDs. Therefore, to understand the burden of various LSDs, its molecular spectrum, and understanding the phenotype-genotype correlation, Indian Council of Medical Research (ICMR) and Department of Health Research (DHR), Government of India had set up a task force in the year 2015. It has resulted in identifying common LSDs, and founder variant for some of the storage disorders and molecular spectrum of various LSDs across the country. This review describes in detail the spectrum of LSDs, its molecular epidemiology and prevention in context to Indian population.
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Affiliation(s)
- Jayesh Sheth
- FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad 380015, India
| | - Aadhira Nair
- FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad 380015, India
| | - Babban Jee
- Department of Health Research, Ministry of Health and Family Welfare, Government of India, 2nd Floor, IRCS Building, Red Cross Road, New Delhi 110001, India
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Boychuk NA, Mulrooney NS, Kelly NR, Goldenberg AJ, Silver EJ, Wasserstein MP. Parental Depression and Anxiety Associated with Newborn Bloodspot Screening for Rare and Variable-Onset Disorders. Int J Neonatal Screen 2022; 8:ijns8040059. [PMID: 36412585 PMCID: PMC9680490 DOI: 10.3390/ijns8040059] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/20/2022] [Accepted: 10/31/2022] [Indexed: 11/11/2022] Open
Abstract
The ability to screen newborns for a larger number of disorders, including many with variable phenotypes, is prompting debate regarding the psychosocial impact of expanded newborn bloodspot screening (NBS) on parents. This study compares psychological outcomes of parents of children with a range of NBS/diagnostic experiences, with a particular focus on lysosomal storage disorders (LSDs) and X-linked adrenoleukodystrophy (X-ALD) as representative disorders with complex presentations. An online cross-sectional survey with six domains was completed in 2019 by a volunteer sample of parents with at least one child born between 2013 and 2018. Parents were classified in the analysis stage into four groups based on their child's rare disorder and means of diagnosis. Stress and depression were estimated using dichotomous measures of the depression subscale of the Hospital Anxiety and Depression Scale and the Parental Stress Scale. Logistic regression models were estimated for the relationship between the parent group and stress/depression, controlling for demographic variables (region of the US, income, education, major life events, relationship to the child, number of children, parent age, and race/ethnicity). One hundred seventy-four parents were included in this analysis. Parents of children with an LSD or X-ALD diagnosis clinically may have higher odds of depression (OR: 6.06, 95% CI: 1.64-24.96) compared to parents of children with the same disorders identified through NBS, controlling for covariates. Although a similar pattern was observed for parental stress (OR: 2.85, 95% CI: 0.82-10.37), this did not reach statistical significance. Ethically expanding NBS and genome sequencing require an understanding of the impacts of early detection for complex disorders on families. These initial findings are reassuring, and may have implications as NBS expands. Given our small sample size, it is difficult to generalize these findings to all families. These preliminary trends warrant further investigation in larger and more diverse populations.
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Affiliation(s)
- Natalie A. Boychuk
- Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, NY 10467, USA
| | - Niamh S. Mulrooney
- Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, NY 10467, USA
| | - Nicole R. Kelly
- Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, NY 10467, USA
| | - Aaron J. Goldenberg
- Department of Bioethics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Ellen J. Silver
- Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, NY 10467, USA
| | - Melissa P. Wasserstein
- Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, NY 10467, USA
- Correspondence:
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Epstein Weiss T, Erez O, Hazan I, Babiev AS, Staretz Chacham O. Characterization of pregnancy outcome of women with an offspring with inborn errors of metabolism: A population-based study. Front Genet 2022; 13:1030361. [PMID: 36437917 PMCID: PMC9683332 DOI: 10.3389/fgene.2022.1030361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/10/2022] [Indexed: 11/10/2022] Open
Abstract
Introduction: Inborn errors of metabolism (IEM) are scarce, and their diagnosis is often made after birth. This has led to the perception that most fetuses affected by these disorders do not become clinically apparent during pregnancy. Our aim was to determine the obstetrical characteristics of women with an offspring affected by IEM.Methods: This population-based retrospective cohort study included all women who delivered at the Soroka University Medical Center (SUMC) from 1988 to 2017 who met the inclusion criteria. Mothers who had an offspring with IEM were included in the study group, and those who had offsprings without IEM comprised the comparison group.Results: A total of 388,813 pregnancies were included in the study, and 184 of them were complicated by a fetus with IEM. The number of Bedouin women was higher in the IEM-affected infant group than in the comparison group (90.8% vs. 53.3%, p < 0.001); women who had a fetus with IEM had a higher rate of polyhydramnios (7.1% vs. 3.2%, p = 0.005), HELLP syndrome (3.3% vs. 1.1%, p = 0.014), and preterm birth (20.7% vs. 10.1%, p < 0.001); neonates with IEM had lower mean birth weight (p < 0.001), lower Apgar scores at 1′ and 5′ minutes (p < 0.001), and a higher rate of fetal growth restriction (FGR) (p < 0.001), postpartum death <28 days (p < 0.001), and neonatal death (p < 0.001) than those in the comparison group. Pregnancies with IEM fetuses were independently associated with preterm birth (OR 2.00; CI 1.4–3), polyhydramnios (OR 2.08; CI 1.17–3.71), and FGR (OR 2.24; CI 1.2–4.19). Each family of metabolic diseases is independently associated with specific pregnancy complications (i.e., mitochondrial diseases are associated with HELLP syndrome (OR 5.6; CI 1.8–17), and lysosomal storage disease are associated with nonimmune hydrops fetalis (OR 26.4; CI 3.39–206).Conclusion: This study reports for the first time, an independent association of IEM with specific complications of pregnancy. This observation has clinical implications, as the identification of specific pregnancy complications in a population at risk for IEM can assist in the prenatal diagnosis of an affected fetus.
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Sen Sarma M, Tripathi PR. Natural history and management of liver dysfunction in lysosomal storage disorders. World J Hepatol 2022; 14:1844-1861. [PMID: 36340750 PMCID: PMC9627439 DOI: 10.4254/wjh.v14.i10.1844] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 04/21/2022] [Accepted: 09/21/2022] [Indexed: 02/06/2023] Open
Abstract
Lysosomal storage disorders (LSD) are a rare group of genetic disorders. The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage [Gaucher disease (GD) and Niemann-Pick disease] and lysosomal acid lipase deficiency [cholesteryl ester storage disease and Wolman disease (WD)]. These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension. Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders. Dyslipidemia causes micronodular cirrhosis in lipid storage disorders. These disorders must be keenly differentiated from other chronic liver diseases and non-alcoholic steatohepatitis that affect children and young adults. GD, Niemann-Pick type C, and WD also cause neonatal cholestasis and infantile liver failure. Genotype and liver phenotype correlation is variable in these conditions. Patients with LSD may survive up to 4-5 decades except for those with neonatal onset disease. The diagnosis of all LSD is based on enzymatic activity, tissue histology, and genetic testing. Enzyme replacement is possible in GD and Niemann-Pick types A and B though there are major limitations in the outcome. Those that progress invariably require liver transplantation with variable outcomes. The prognosis of Niemann-Pick type C and WD is universally poor. Enzyme replacement therapy has a promising role in cholesteryl ester storage disease. This review attempts to outline the natural history of these disorders from a hepatologist’s perspective to increase awareness and facilitate better management of these rare disorders.
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Affiliation(s)
- Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Parijat Ram Tripathi
- Department of Pediatric Gastroenterology, Ankura Hospital for Women and Children, Hyderabad 500072, India
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Giraldo P, López de Frutos L, Cebolla JJ. Recommendations for overcoming challenges in the diagnosis of lysosomal acid lipase deficiency. Expert Opin Orphan Drugs 2022. [DOI: 10.1080/21678707.2022.2131393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Pilar Giraldo
- Hematology. Hospital Quironsalud. Zaragoza. SPAIN
- Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher y otras lisosomales (FEETEG). Zaragoza. SPAIN
- Grupo de Investigación en Enfermedades Metabólicas y Hematológicas Raras (GIIS-012). Instituto de Investigación Sanitaria Aragón (ISS Aragón). SPAIN
| | - Laura López de Frutos
- Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher y otras lisosomales (FEETEG). Zaragoza. SPAIN
- Grupo de Investigación en Enfermedades Metabólicas y Hematológicas Raras (GIIS-012). Instituto de Investigación Sanitaria Aragón (ISS Aragón). SPAIN
| | - Jorge J Cebolla
- Grupo de Investigación en Enfermedades Metabólicas y Hematológicas Raras (GIIS-012). Instituto de Investigación Sanitaria Aragón (ISS Aragón). SPAIN
- Departamento de Bioquímica, Biología Molecular y Celular. Universidad de Zaragoza. SPAIN
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Comparative Proteomic Assessment of Normal vs. Polyhydramnios Amniotic Fluid Based on Computational Analysis. Biomedicines 2022; 10:biomedicines10081821. [PMID: 36009368 PMCID: PMC9404943 DOI: 10.3390/biomedicines10081821] [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: 06/08/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022] Open
Abstract
Mass spectrometry-based proteomics have become a valued tool for conducting comprehensive analyses in amniotic fluid samples with pathologies. Our research interest is the finding and characterization of proteins related to normal vs. polyhydramnios (non-immune hydrops) pregnancy. Proteomic analysis was performed on proteins isolated from fresh amniotic fluid samples. Proteins were fractionated by 2DE using a different pI range (pI 3–11, pI 4–7) and analyzed with MALDI-TOF-MS. Furthermore, by using computational analysis, identified proteins in protein maps specific to normal vs. polyhydramnios pregnancy were compared and the quantities of expressed proteins were evaluated mathematically. Comparative analysis of proteome characteristic for the same polyhydramnios pregnancy fractionated by 2DE in different pI range (3–11 and 4–7) was performed and particular protein groups were evaluated for the quantification of changes within the same protein level. Proteins of normal and polyhydramnios pregnancies were fractionated by 2DE in pI range 3–11 and in pI range 4–7. Mass spectrometry analysis of proteins has revealed that the quantity changes of the main identified proteins in normal vs. polyhydramnios pregnancy could be assigned to immune response and inflammation proteins, cellular signaling and regulation proteins, metabolic proteins, etc. Specifically, we have identified and characterized proteins associated with heart function and circulatory system and proteins associated with abnormalities in prenatal medicine. The following are: serotransferrin, prothrombin, haptoglobin, transthyretin, alpha-1-antitrypsin, zinc-alpha-2-glycprotein, haptoglobin kininogen-1, hemopexin, clusterin, lumican, afamin, gelsolin. By using computational analysis, we demonstrated that some of these proteins increased a few times in pathological pregnancy. Computer assistance analysis of 2DE images suggested that, for the better isolation of the proteins’ isoforms, those levels increased/decreased in normal vs. polyhydramnios pregnancy, and the fractionation of proteins in pI rage 3–11 and 4–7 could be substantial. We analyzed and identified by MS proteins specific for normal and polyhydramnios pregnancies. Identified protein levels increased and/or modification changed in case of non-immune hydrops fetus and in cases of cardiovascular, anemia, growth restriction, and metabolic disorders. Computational analysis for proteomic characterization empower to estimate the quantitative changes of proteins specific for normal vs. polyhydramnios pregnancies.
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Tazi K, Guy‐Viterbo V, Gheldof A, Empain A, Paternoster A, De Laet C. Ascites in infantile onset type II Sialidosis. JIMD Rep 2022; 63:316-321. [PMID: 35822090 PMCID: PMC9259393 DOI: 10.1002/jmd2.12305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 05/10/2022] [Accepted: 05/16/2022] [Indexed: 11/11/2022] Open
Abstract
Sialidosis is a rare autosomal-recessive lysosomal storage disease due to mutations in the NEU1 gene leading to a deficit of alpha-n-acetyl neuraminidase and causing aberrant accumulation of sialylated glycoproteins/peptides and oligosaccharides in the lysosomes of various organs and tissues. Type II sialidosis (dysmorphic form) is classified into three subgroups based on the age of onset and the clinical severity: Congenital or neonatal, infantile (onset 0-12 months) and juvenile form (onset 13 months-20 years). We report the case of a 3-year-old boy with sialidosis type II infantile form, who developed a voluminous ascites. To the best of our knowledge, ascites is not described in the infantile form but in the congenital form of the disease. Ascites seems to be of a multifactorial origin regarding our investigations: on the one hand, portal hypertension and on the other hypoalbuminemia maintained by proteinuria secondary to nephrosialidosis. Loss of plasma proteins in the gastrointestinal tract (protein-losing enteropathy) should also be considered in the case of portal hypertension and damages of the reticuloendothelial system.
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Affiliation(s)
- Kaoutar Tazi
- Paediatric DepartmentHôpital Universitaire des Enfants Reine Fabiola, Université Libre de BruxellesAvenue Jean Joseph Crocq 15, 1020 BrusselsBelgium
| | - Vanessa Guy‐Viterbo
- Pediatric Intensive Care UnitHôpital Universitaire des Enfants Reine Fabiola, Université Libre de BruxellesAvenue Jean Joseph Crocq 15, 1020 BrusselsBelgium
| | - Alexander Gheldof
- Center for Medical GeneticsUniversitair Ziekenhuis Brussel, Vrije Universiteit BrusselAvenue du Laerbeek 101, 1090 BrusselsBelgium
| | - Aurélie Empain
- Nutrition and Metabolic UnitHôpital Universitaire des Enfants Reine Fabiola, Université Libre de BruxellesAvenue Jean Joseph Crocq 15, 1020 BrusselsBelgium
| | - Anne Paternoster
- Paediatric DepartmentCentre Hospitalier EpiCURARoute de Mons 63, 7301 HornuBelgium
| | - Corinne De Laet
- Nutrition and Metabolic UnitHôpital Universitaire des Enfants Reine Fabiola, Université Libre de BruxellesAvenue Jean Joseph Crocq 15, 1020 BrusselsBelgium
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13
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Lau HA, Viskochil D, Tanpaiboon P, Lopez AGM, Martins E, Taylor J, Malkus B, Zhang L, Jurecka A, Marsden D. Long-term efficacy and safety of vestronidase alfa enzyme replacement therapy in pediatric subjects < 5 years with mucopolysaccharidosis VII. Mol Genet Metab 2022; 136:28-37. [PMID: 35331634 DOI: 10.1016/j.ymgme.2022.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 11/20/2022]
Abstract
Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of β-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). β-glucuronidase deficiency leads to progressive accumulation of undegraded GAGs in lysosomes of affected tissues, which may cause hydrops fetalis, short stature, hepatosplenomegaly, and cognitive impairment. An open-label, multicenter, phase II study was conducted in 8 pediatric subjects <5 years of age with MPS VII. Subjects received the recombinant human β-glucuronidase vestronidase alfa 4 mg/kg by intravenous infusion every other week for 48 weeks (treatment period). Those who completed the 48-week treatment were offered to continue treatment with vestronidase alfa 4 mg/kg for up to 240 weeks or until withdrawal of consent, discontinuation, or study termination (continuation period). The level of GAG excreted in urine (uGAG) above normal has been shown to correlate with disease severity and clinical outcomes in MPS diseases. Therefore, the primary efficacy endpoint of this study was to determine the mean percentage change in uGAG DS excretion from baseline to week 48. Statistically significant reductions in uGAG DS from baseline were observed at each visit (p < 0.0001), with a least square mean (standard error) percentage change of -60% (6.6) at week 4 (first post-baseline assessment) and -61% (6.41) at week 48 (final assessment during treatment period). Secondary efficacy endpoints included change from baseline to week 48 in growth and hepatosplenomegaly. Positive trends were observed toward increased standing height Z-score (mean [standard deviation] at baseline, -2.630 [1.17], n = 8; at week 48, -2.045 [0.27], n = 7) and growth velocity (mean [SD] Z-score at baseline, -2.59 [1.49], n = 4; at week 48, -0.39 [2.10], n = 4; p = 0.27). Hepatomegaly was resolved in 3 of 3 subjects assessed by ultrasound and in 5 of 6 subjects assessed by physical examination; splenomegaly was resolved in 1 of 3 subjects assessed by ultrasound and in 2 of 2 subjects assessed by physical examination. There were no new safety signals identified during this study. Mild-to-moderate infusion-associated reactions occurred in 4 (50%) subjects. In conclusion, long-term vestronidase alfa treatment demonstrated a rapid and sustained reduction in uGAGs, maintained growth, and improved hepatosplenomegaly in pediatric subjects with MPS VII <5 years of age. Trial registration: NCT02418455.
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Affiliation(s)
- Heather A Lau
- NYU Grossman School of Medicine, Department of Neurology, New York, NY, USA.
| | - David Viskochil
- University of Utah, Department of Pediatrics, Salt Lake City, UT, USA.
| | - Pranoot Tanpaiboon
- Rare Disease Institute, Children's National Health System, Washington, DC, USA.
| | | | - Esmeralda Martins
- Centro Hospitalar Universitário do Porto, Hospital de Santo António, Porto, Portugal.
| | - Julie Taylor
- Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
| | - Betsy Malkus
- Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
| | - Lin Zhang
- Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
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14
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Kılavuz S, Basaranoglu M, Epcacan S, Bako D, Ozer A, Donmez YN, Ceylan EI, Tukun A, Ceylaner S, Geylani H, Mungan HNO. A rare cause of hydrops fetalis in two Gaucher disease type 2 patients with a novel mutation. Metab Brain Dis 2022; 37:1283-1287. [PMID: 35254599 DOI: 10.1007/s11011-022-00942-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/22/2022] [Indexed: 01/30/2023]
Abstract
Gaucher disease type 2 is the most progressive and the rarest form of Gaucher disease, defined as the acute neuronopathic type. We presented two GD2 patients who died before three months of age due to severe septicemia, respiratory and liver failure. One was homozygous for a novel GBA variant c.590 T > A (p.197 K), and the second homozygous for the known GBA mutation c.1505G > A (p.R502H). Ichthyosis, hydrops fetalis, apnea, myoclonic seizures, and hepatosplenomegaly occurred in both patients, but hypertrophic cardiomyopathy was observed only in the second and unilateral cataract in the first patient. Due to the disease's early and rapid neurological progression, we did not administer ERT to our patients. It is strongly believed that early diagnosis is essential, and prenatal diagnosis makes genetic counselling possible for future pregnancies.
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Affiliation(s)
- Sebile Kılavuz
- Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, Van Training and Research Hospital, University of Health Sciences, Van, Turkey.
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
| | - Murat Basaranoglu
- Division of Neonatology, Department of Pediatrics, University of Health Sciences, Van Training and Research Hospital, Van, Turkey
| | - Serdar Epcacan
- Division of Pediatric Cardiology Disease, Department of Pediatrics, University of Health Sciences, Van Training and Research Hospital, Van, Turkey
| | - Derya Bako
- Divisions of Pediatric Radiology, Department of Radiology, University of Health Sciences, Van Training and Research Hospital, Van, Turkey
| | - Arife Ozer
- Division of Pediatric Infectious Disease, Department of Pediatrics, University of Health Sciences, Van Training and Research Hospital, Van, Turkey
| | - Yasemin Nuran Donmez
- Division of Pediatric Cardiology Disease, Department of Pediatrics, University of Health Sciences, Van Training and Research Hospital, Van, Turkey
| | - Emine Ipek Ceylan
- Department of Medical Genetics, University of Health Sciences, Van Training and Research Hospital, Van, Turkey
| | - Ajlan Tukun
- Department of Medical Genetics, Duzen Laboratory, Ankara, Turkey
| | - Serdar Ceylaner
- Intergen Genetic Diagnosis and Research Center, Ankara, Turkey
- Department of Medical Genetics, Medical Faculty, Lokman Hekim University, Ankara, Turkey
| | - Hadi Geylani
- Division of Pediatric Hematology, Department of Pediatrics, University of Health Sciences, Van Training and Research Hospital, Van, Turkey
| | - Halise Neslihan Onenli Mungan
- Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, Çukurova University Faculty of Medicine, Adana, Turkey
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15
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Mukherjee S, Ray SK. Inborn Errors of Metabolism Screening in Neonates: Current Perspective with Diagnosis and Therapy. Curr Pediatr Rev 2022; 18:274-285. [PMID: 35379134 DOI: 10.2174/1573396318666220404194452] [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] [Received: 08/31/2021] [Revised: 01/24/2022] [Accepted: 02/14/2022] [Indexed: 11/22/2022]
Abstract
Inborn errors of metabolism (IEMs) are rare hereditary or acquired disorders resulting from an enzymatic deformity in biochemical and metabolic pathways influencing proteins, fats, carbohydrate metabolism, or hampered some organelle function. Even though individual IEMs are uncommon, together, they represent a diverse class of genetic diseases, with new issues and disease mechanisms being portrayed consistently. IEM includes the extraordinary multifaceted nature of the fundamental pathophysiology, biochemical diagnosis, molecular level investigation, and complex therapeutic choices. However, due to the molecular, biochemical, and clinical heterogeneity of IEM, screening alone will not detect and diagnose all illnesses included in newborn screening programs. Early diagnosis prevents the emergence of severe clinical symptoms in the majority of IEM cases, lowering morbidity and death. The appearance of IEM disease can vary from neonates to adult people, with the more serious conditions showing up in juvenile stages along with significant morbidity as well as mortality. Advances in understanding the physiological, biochemical, and molecular etiologies of numerous IEMs by means of modalities, for instance, the latest molecular-genetic technologies, genome engineering knowledge, entire exome sequencing, and metabolomics, have prompted remarkable advancement in detection and treatment in modern times. In this review, we analyze the biochemical basis of IEMs, clinical manifestations, the present status of screening, ongoing advances, and efficiency of diagnosis in treatment for IEMs, along with prospects for further exploration as well as innovation.
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Affiliation(s)
- Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh-462020, India
| | - Suman Kumar Ray
- Independent Researcher, Bhopal, Madhya Pradesh-462020, India
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16
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Story B, Taghian T, Gallagher J, Koehler J, Taylor A, Randle A, Nielsen K, Gross A, Maguire A, Carl S, Johnson S, Fernau D, Diffie E, Cuddon P, Corado C, Chandra S, Sena-Esteves M, Kolodny E, Jiang X, Martin D, Gray-Edwards H. Natural history of Tay-Sachs disease in sheep. Mol Genet Metab 2021; 134:164-174. [PMID: 34456134 PMCID: PMC8811770 DOI: 10.1016/j.ymgme.2021.08.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/21/2021] [Accepted: 08/13/2021] [Indexed: 01/17/2023]
Abstract
Tay-Sachs disease (TSD) is a fatal neurodegenerative disease caused by a deficiency of the enzyme β-N-acetylhexosaminidase A (HexA). TSD naturally occurs in Jacob sheep is the only experimental model of TSD. TSD in sheep recapitulates neurologic features similar to juvenile onset and late onset TSD patients. Due to the paucity of human literature on pathology of TSD, a better natural history in the sheep TSD brain, which is on the same order of magnitude as a child's, is necessary for evaluating therapy and characterizing the pathological events that occur. To provide clinicians and researchers with a clearer understanding of longitudinal pathology in patients, we compare spectrum of clinical signs and brain pathology in mildly symptomatic (3-months), moderately symptomatic (6-months), or severely affected TSD sheep (humane endpoint at ~9-months of age). Increased GM2 ganglioside in the CSF of TSD sheep and a TSD specific biomarker on MRS (taurine) correlate with disease severity. Microglial activation and reactive astrocytes were observed globally on histopathology in TSD sheep with a widespread reduction in oligodendrocyte density. Myelination is reduced primarily in the forebrain illustrated by loss of white matter on MRI. GM2 and GM3 ganglioside were increased and distributed differently in various tissues. The study of TSD in the sheep model provides a natural history to shed light on the pathophysiology of TSD, which is of utmost importance due to novel therapeutics being assessed in human patients.
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Affiliation(s)
- Brett Story
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Toloo Taghian
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, United States of America; Department of Radiology, University of Massachusetts Medical School, Worcester, MA, United States of America
| | - Jillian Gallagher
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, United States of America
| | - Jey Koehler
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Amanda Taylor
- Auburn University, Department of Clinical Sciences Auburn University, Auburn, AL, United States of America
| | - Ashley Randle
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Kayly Nielsen
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Amanda Gross
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Annie Maguire
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America; Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Sara Carl
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Siauna Johnson
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Deborah Fernau
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, United States of America
| | - Elise Diffie
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Paul Cuddon
- Neurology Locum, Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, AL
| | - Carly Corado
- BioMarin Pharmaceutical Inc, Novato, CA, United States of America
| | - Sundeep Chandra
- BioMarin Pharmaceutical Inc, Novato, CA, United States of America
| | - Miguel Sena-Esteves
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, United States of America; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, United States of America
| | - Edwin Kolodny
- Bernard A. Marden Professor of Neurology and Chairman of the Department of Neurology, New York University, School of Medicine, NY, NY, United States of America; Head of the Division of Neurogenetics, New York University, School of Medicine, NY, NY, United States of America
| | - Xuntian Jiang
- Department of Medicine, Washington University School of Medicine, St. Louis, MI, United States of America
| | - Douglas Martin
- Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America; Neurology Locum, Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, AL
| | - Heather Gray-Edwards
- Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America; Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, United States of America; Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America; Department of Radiology, University of Massachusetts Medical School, Worcester, MA, United States of America.
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17
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Voloshchuk IN, Barinova IV, Andreeva EN, Fattakhov AR, Baydakova GV, Zakharova EY. [Perinatal lethal Gaucher disease. Case report]. Arkh Patol 2021; 83:56-60. [PMID: 34278762 DOI: 10.17116/patol20218304156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The paper describes a case of a perinatal lethal Gaucher disease in a 29-week-old fetus with non-immune hydrops, facial dysmorphia, hepatosplenomegaly, and hypoplasia of cerebellum and pons. Gaucher cells were found in the lymph nodes, spleen, lungs, thymus, cerebellum, and bone marrow. No storage cells have been detected in the placenta. There was a significant placental weight increase due to swelling. The diagnosis of Gaucher disease was confirmed by biochemical analysis (deficiency of glucocerebrosidase activity and sharply increased hexanoylsphingosine concentration) and molecular genetic techniques (the presence of two mutations of the GBA gene). Our observation shows that characteristic histologic signs of disease can be detected at early stages of development.
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Affiliation(s)
- I N Voloshchuk
- Moscow Regional Research Institute of Obstetrics and Gynecology of the Ministry of Health of the Moscow Region, Moscow Region, Russia.,Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia, Moscow, Russia
| | - I V Barinova
- Moscow Regional Research Institute of Obstetrics and Gynecology of the Ministry of Health of the Moscow Region, Moscow Region, Russia
| | - E N Andreeva
- Moscow Regional Research Institute of Obstetrics and Gynecology of the Ministry of Health of the Moscow Region, Moscow Region, Russia
| | - A R Fattakhov
- Moscow Regional Research Institute of Obstetrics and Gynecology of the Ministry of Health of the Moscow Region, Moscow Region, Russia
| | - G V Baydakova
- Federal State Budgetary Scientific Institution Research Centre for Medical Genetics named after Academician N.P. Bochkov, Moscow, Russia
| | - E Yu Zakharova
- Federal State Budgetary Scientific Institution Research Centre for Medical Genetics named after Academician N.P. Bochkov, Moscow, Russia
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18
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Abed Rabbo M, Khodour Y, Kaguni LS, Stiban J. Sphingolipid lysosomal storage diseases: from bench to bedside. Lipids Health Dis 2021; 20:44. [PMID: 33941173 PMCID: PMC8094529 DOI: 10.1186/s12944-021-01466-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/14/2021] [Indexed: 01/13/2023] Open
Abstract
Johann Ludwig Wilhelm Thudicum described sphingolipids (SLs) in the late nineteenth century, but it was only in the past fifty years that SL research surged in importance and applicability. Currently, sphingolipids and their metabolism are hotly debated topics in various biochemical fields. Similar to other macromolecular reactions, SL metabolism has important implications in health and disease in most cells. A plethora of SL-related genetic ailments has been described. Defects in SL catabolism can cause the accumulation of SLs, leading to many types of lysosomal storage diseases (LSDs) collectively called sphingolipidoses. These diseases mainly impact the neuronal and immune systems, but other systems can be affected as well. This review aims to present a comprehensive, up-to-date picture of the rapidly growing field of sphingolipid LSDs, their etiology, pathology, and potential therapeutic strategies. We first describe LSDs biochemically and briefly discuss their catabolism, followed by general aspects of the major diseases such as Gaucher, Krabbe, Fabry, and Farber among others. We conclude with an overview of the available and potential future therapies for many of the diseases. We strive to present the most important and recent findings from basic research and clinical applications, and to provide a valuable source for understanding these disorders.
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Affiliation(s)
- Muna Abed Rabbo
- Department of Biology and Biochemistry, Birzeit University, P.O. Box 14, Ramallah, West Bank, 627, Palestine
| | - Yara Khodour
- Department of Biology and Biochemistry, Birzeit University, P.O. Box 14, Ramallah, West Bank, 627, Palestine
| | - Laurie S Kaguni
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - Johnny Stiban
- Department of Biology and Biochemistry, Birzeit University, P.O. Box 14, Ramallah, West Bank, 627, Palestine.
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19
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Traub ES, Sheppard SE, Dori Y, Burns KD, Zackai EH, Ware SM, Landis BJ, Li D, Weaver DD. Chromosome 4q28.3q32.3 duplication in a patient with lymphatic malformations, craniosynostosis, and dysmorphic features. Clin Dysmorphol 2021; 30:89-92. [PMID: 32925199 PMCID: PMC7933106 DOI: 10.1097/mcd.0000000000000347] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The proband, now a 4-year-old female of mixed Caucasian and Japanese ancestry, was born at 29 weeks gestation via spontaneous vaginal delivery following a pregnancy complicated by fetal ascites, echogenic bowel, polyhydramnios, and incompetent cervix. The mother had no other pregnancy complications and had no recognized teratogen exposures throughout the pregnancy. Her length was 37 cm (37th centile), weight was 1.478 kg (80th centile), and occipitofrontal circumference (OFC) was 27 cm (20th centile). The family history was significant for maternal family members with pregnancy losses of unknown etiology: one each for the mother and maternal grandmother. The great maternal grandmother reported at least 4 or 5 pregnancy losses. Consanguinity was denied. The proband remained in the neonatal intensive care unit for the next 8 months for management of severe respiratory issues, ascites and feeding difficulties. During that time, she underwent placement of a tracheostomy, a Denver (peritoneovenous) shunt for ascitic-fluid drainage, an intravenous port and a gastrostomy tube for feeds (Fig. 1 ). Additional pertinent findings then include retinopathy of prematurity, subglottal stenosis grade IV, hypothyroidism, 11 sets of ribs, mild bilateral hydronephrosis, accessory spleen and persistent ascites (Fig. 2 ). At 20 months dysmorphologic evaluation was significant for macrocephaly, open anterior and posterior fontanelles, bicoronal craniosynostosis on CT scan, right posterior plagiocephaly, brachycephaly, cupped and prominent ears with hypoplastic antihelices, broad forehead, a short and upturned nose, telecanthus, ocular hypertelorism, depressed nasal bridge (Figure 3A –B ), moderate ascites, bilateral overriding of the second and fourth toes over the third toe, short stature and hypotonia. At this latter time, she exhibited significant developmental delays; she was unable to sit unassisted or feed herself. However, she was able to crawl, pull to a stand and sit independently. The proband could feed herself but still required a G-tube for much of her nutrition. She was nonverbal but able to use 12 signs. She continued to require a tracheostomy but only for night-time mechanical ventilation. At 33 months when last evaluated, her height was 79.2 cm (<1st centile), weight was 11.6 kg (7th centile) and OFC was 56 cm (>97th centile). The patient’s severe ascites persisted throughout the first 2 years of her life. At age 22 months, she underwent lymphatic imaging at the Children’s Hospital of Philadelphia that revealed multiple dilated perihepatic lymphatic vessels and leakage of contrast material into the peritoneum (Fig. 4A –D ). Subsequently, she underwent successful embolization of these lymphatic vessels with resolution of her ascites.
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Affiliation(s)
- Eric S. Traub
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Sarah E. Sheppard
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Yoav Dori
- Division of Cardiology, The Children’s Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania
| | - Katelyn D. Burns
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Elaine H. Zackai
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Stephanie M. Ware
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana
| | - Benjamin J. Landis
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana
| | - Dong Li
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - David D. Weaver
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
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20
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Daykin EC, Ryan E, Sidransky E. Diagnosing neuronopathic Gaucher disease: New considerations and challenges in assigning Gaucher phenotypes. Mol Genet Metab 2021; 132:49-58. [PMID: 33483255 PMCID: PMC7884077 DOI: 10.1016/j.ymgme.2021.01.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 12/13/2022]
Abstract
Gaucher disease (GD), resulting from biallelic mutations in the gene GBA1, is a monogenic recessively inherited Mendelian disorder with a wide range of phenotypic presentations. The more severe forms of the disease, acute neuronopathic GD (GD2) and chronic neuronopathic GD (GD3), also have a continuum of disease severity with an overlap in manifestations and limited genotype-phenotype correlation. In very young patients, assigning a definitive diagnosis can sometimes be challenging. Several recent studies highlight specific features of neuronopathic GD that may provide diagnostic clues. Distinguishing between the different GD types has important therapeutic implications. Currently there are limited treatment options specifically for neuronopathic GD due to the difficulty in delivering therapies across the blood-brain barrier. In this work, we present both classic and newly appreciated aspects of the Gaucher phenotype that can aid in discriminating between acute and chronic neuronopathic GD, and highlight the continuing therapeutic challenges.
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Affiliation(s)
- Emily C Daykin
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, USA
| | - Emory Ryan
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, USA
| | - Ellen Sidransky
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, USA.
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21
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Novel biomarkers for lysosomal storage disorders: Metabolomic and proteomic approaches. Clin Chim Acta 2020; 509:195-209. [PMID: 32561345 DOI: 10.1016/j.cca.2020.06.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/13/2020] [Accepted: 06/15/2020] [Indexed: 12/20/2022]
Abstract
Lysosomal storage disorders (LSDs) are characterized by the accumulation of specific disease substrates inside the lysosomes of various cells, eventually leading to the deterioration of cellular function and multisystem organ damage. With the continuous discovery and validation of novel and advanced therapies for most LSDs, there is an urgent need to discover more versatile and clinically relevant biomarkers. The utility of these biomarkers should ideally extend beyond the screening and diagnosis of LSDs to the evaluation of disease severity and monitoring of therapy. Metabolomic and proteomic approaches provide the means to the discovery and validation of such novel biomarkers. This is achieved mainly through the application of various mass spectrometric techniques to common and easily accessible biological samples, such as plasma, urine and dried blood spots. In this review, we tried to summarize the complexity of the lysosomal disorders phenotypes, their current diagnostic and therapeutic approaches, the various techniques supporting metabolomic and proteomic studies and finally we tried to explore the newly discovered biomarkers for most LSDs and their reported clinical values.
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Yañez MJ, Marín T, Balboa E, Klein AD, Alvarez AR, Zanlungo S. Finding pathogenic commonalities between Niemann-Pick type C and other lysosomal storage disorders: Opportunities for shared therapeutic interventions. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165875. [PMID: 32522631 DOI: 10.1016/j.bbadis.2020.165875] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 05/06/2020] [Accepted: 06/03/2020] [Indexed: 12/12/2022]
Abstract
Lysosomal storage disorders (LSDs) are diseases characterized by the accumulation of macromolecules in the late endocytic system and are caused by inherited defects in genes that encode mainly lysosomal enzymes or transmembrane lysosomal proteins. Niemann-Pick type C disease (NPCD), a LSD characterized by liver damage and progressive neurodegeneration that leads to early death, is caused by mutations in the genes encoding the NPC1 or NPC2 proteins. Both proteins are involved in the transport of cholesterol from the late endosomal compartment to the rest of the cell. Loss of function of these proteins causes primary cholesterol accumulation, and secondary accumulation of other lipids, such as sphingolipids, in lysosomes. Despite years of studying the genetic and molecular bases of NPCD and related-lysosomal disorders, the pathogenic mechanisms involved in these diseases are not fully understood. In this review we will summarize the pathogenic mechanisms described for NPCD and we will discuss their relevance for other LSDs with neurological components such as Niemann- Pick type A and Gaucher diseases. We will particularly focus on the activation of signaling pathways that may be common to these three pathologies with emphasis on how the intra-lysosomal accumulation of lipids leads to pathology, specifically to neurological impairments. We will show that although the primary lipid storage defect is different in these three LSDs, there is a similar secondary accumulation of metabolites and activation of signaling pathways that can lead to common pathogenic mechanisms. This analysis might help to delineate common pathological mechanisms and therapeutic targets for lysosomal storage diseases.
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Affiliation(s)
- M J Yañez
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - T Marín
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - E Balboa
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - A D Klein
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - A R Alvarez
- Laboratory of Cell Signaling, Department of Cellular and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Santiago, Chile; CARE UC, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - S Zanlungo
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Al-Kouatly HB, Felder L, Makhamreh MM, Kass SL, Vora NL, Berghella V, Berger S, Wenger DA, Luzi P. Lysosomal storage disease spectrum in nonimmune hydrops fetalis: a retrospective case control study. Prenat Diagn 2020; 40:738-745. [PMID: 32134517 DOI: 10.1002/pd.5678] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 02/27/2020] [Accepted: 02/29/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Nonimmune hydrops fetalis (NIHF) accounts for 90% of hydrops fetalis cases. About 15% to 29% of unexplained NIHF cases are caused by lysosomal storage diseases (LSD). We review the spectrum of LSD and associated clinical findings in NIHF in a cohort of patients referred to our institution. METHODS We present a retrospective case-control study of cases with NIHF referred for LSD biochemical testing at a single center. Cases diagnosed with LSD were matched to controls with NIHF and negative LSD testing and analyzed according to the STROBE criteria to the extent the retrospective nature of this study allowed. RESULTS Between January 2006 and December 2018, 28 patients with NIHF were diagnosed with a LSD. Eight types of LSD were diagnosed: galactosialidosis 8/28 (28.6%), sialic acid storage disease (SASD) 5/28 (17.9%), mucopolysaccharidosis VII 5/28 (17.9%), Gaucher 4/28 (14.3%), sialidosis 2/28 (7.1%), GM1 gangliosidosis 2/28 (7.1%), Niemann-Pick disease type C 1/28 (3.6%), and mucolipidosis II/III 1/28 (3.6%). Associated clinical features were hepatomegaly 16/21 (76.2%) vs 22/65 (33.8%), P < .05, splenomegaly 12/20 (60.0%) vs 14/58 (24.1%), P < .05, and hepatosplenomegaly 10/20 (50.0%) vs 13/58 (22.4%) P < .05. CONCLUSION The most common LSD in NIHF were galactosialidosis, SASD, mucopolysaccharidosis VII, and Gaucher disease. LSD should be considered in unexplained NIHF cases, particularly if hepatomegaly, splenomegaly, or hepatosplenomegaly is visualized on prenatal ultrasound.
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Affiliation(s)
- Huda B Al-Kouatly
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Laura Felder
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Mona M Makhamreh
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Stephanie L Kass
- Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Neeta L Vora
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Vincenzo Berghella
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Seth Berger
- Center for Genetic Medicine Research/Rare Disease Institute, Children's National Medical Center, Washington, DC, USA
| | - David A Wenger
- Lysosomal Diseases Testing Laboratory, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Paola Luzi
- Lysosomal Diseases Testing Laboratory, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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24
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Deriaz S, Serratrice C, Lidove O, Noël E, Masseau A, Lorcerie B, Jaussaud R, Marie I, Lavigne C, Cabane J, Kaminsky P, Chérin P, Maillot F. [Diagnostic journey of type 1 Gaucher Disease patients: A survey including internists and hematologists]. Rev Med Interne 2019; 40:778-784. [PMID: 31500934 DOI: 10.1016/j.revmed.2019.07.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 06/22/2019] [Accepted: 07/15/2019] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Gaucher disease (GD) is a rare genetic lysosomal storage disorder caused by a beta-glucocerebrosidase deficiency and responsible for a lysosomal storage disorder. GD is characterized by haematological, visceral and bone involvements. The aim of this study was to describe the diagnostic journey of type 1 GD patients as well as the role of the internist. METHODS A retrospective multicentric study involving type 1 GD patients has been conducted in 16 centers, between 2009 and 2011. RESULTS Fifty-five type 1 GD patients were included, under the care of an internist or an haematologist. They were originally hospitalized in 8 different specialized units. Diagnosis was established by bone-marrow aspiration in 22 patients (40%), by enzymatic assay of glucocerebrosidase activity in 15 patients (27%), and by bone-marrow biopsy in 9 patients (16%). The use of enzymatic assay became more frequent after 1990. The delay between first hospitalization due to GD symptoms and definitive diagnosis was less than one year for 38 patients. Patients with suspected GD were mainly referred to an internist physician. CONCLUSION GD seems to be better recognized and quickly diagnosed since 1990 in spite of the multiplicity of journeys. The role of the internist seems important.
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Affiliation(s)
- S Deriaz
- CHRU, université de Tours, service de médecine interne, Tours, France
| | - C Serratrice
- Service de médecine interne, hôpital Saint-Joseph, Marseille, France; Département de médecine interne et réhabilitation, hôpital universitaire de Genève, Suisse
| | - O Lidove
- Service de médecine interne, hôpital de la Croix Saint-Simon, Paris, France
| | - E Noël
- Service de médecine interne, CHRU de Strasbourg, Strasbourg, France
| | - A Masseau
- Service de médecine interne, CHRU de Nantes, Nantes, France
| | - B Lorcerie
- Service de médecine interne, CHRU de Dijon, Dijon, France
| | - R Jaussaud
- Service de médecine interne, CHRU de Reims, Reims, France
| | - I Marie
- Service de médecine interne, CHRU de Rouen, Rouen, France
| | - C Lavigne
- Service de médecine interne, CHRU d'Angers, Angers, France
| | - J Cabane
- Service de médecine interne, hôpital Saint-Antoine, Paris, France
| | - P Kaminsky
- Service de médecine interne, CHRU de Nancy, Nancy, France
| | - P Chérin
- Service de médecine interne, hôpital de la Pitié-Salpétrière, Paris, France
| | - F Maillot
- CHRU, université de Tours, service de médecine interne, Tours, France.
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25
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Schlotawa L, Dierks T, Christoph S, Cloppenburg E, Ohlenbusch A, Korenke GC, Gärtner J. Severe neonatal multiple sulfatase deficiency presenting with hydrops fetalis in a preterm birth patient. JIMD Rep 2019; 49:48-52. [PMID: 31497481 PMCID: PMC6718111 DOI: 10.1002/jmd2.12074] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 07/19/2019] [Accepted: 07/24/2019] [Indexed: 01/30/2023] Open
Abstract
Multiple sulfatase deficiency (MSD) is an ultra-rare lysosomal storage disorder (LSD). Mutations in the SUMF1 gene encoding the formylglycine generating enzyme (FGE) result in an unstable FGE protein with reduced enzymatic activity, thereby affecting the posttranslational activation of newly synthesized sulfatases. Complete absence of FGE function results in the most severe clinical form of MSD with neonatal onset and rapid deterioration. We report on a preterm infant presenting with hydrops fetalis, lung hypoplasia, and dysmorphism as major clinical signs. The patient died after 6 days from an intraventricular hemorrhage followed by multi-organ failure. MSD was caused by a homozygous SUMF1 stop mutation (c.191C>A, p.Ser64Ter). FGE protein and sulfatase activities were absent in patient fibroblasts. Hydrops fetalis is a rare symptom of LSDs and should be considered in the differential diagnosis in combination with dysmorphism. The diagnostic set up should include measurements of glycosaminoglycan excretion and lysosomal enzyme activities, among them at least two sulfatases, and molecular confirmation.
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Affiliation(s)
- Lars Schlotawa
- Department of Paediatrics and Adolescent MedicineUniversity Medical Center GöttingenGöttingenGermany
| | - Thomas Dierks
- Department of Chemistry, Biochemistry IBielefeld UniversityBielefeldGermany
| | - Sophie Christoph
- Department of Child Neurology and Metabolic Disorders, Medical Centre OldenburgUniversity Children's Hospital OldenburgOldenburgGermany
| | - Eva Cloppenburg
- Department of Neonatology, Intensive Care Medicine and Paediatric Cardiology, Medical Centre OldenburgUniversity Children's Hospital OldenburgOldenburgGermany
| | - Andreas Ohlenbusch
- Department of Paediatrics and Adolescent MedicineUniversity Medical Center GöttingenGöttingenGermany
| | - G. Christoph Korenke
- Department of Child Neurology and Metabolic Disorders, Medical Centre OldenburgUniversity Children's Hospital OldenburgOldenburgGermany
| | - Jutta Gärtner
- Department of Paediatrics and Adolescent MedicineUniversity Medical Center GöttingenGöttingenGermany
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26
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Mardy AH, Chetty SP, Norton ME, Sparks TN. A system-based approach to the genetic etiologies of non-immune hydrops fetalis. Prenat Diagn 2019; 39:732-750. [PMID: 31087399 DOI: 10.1002/pd.5479] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 04/11/2019] [Accepted: 05/09/2019] [Indexed: 12/11/2022]
Abstract
A wide spectrum of genetic causes may lead to nonimmune hydrops fetalis (NIHF), and a thorough phenotypic and genetic evaluation are essential to determine the underlying etiology, optimally manage these pregnancies, and inform discussions about anticipated prognosis. In this review, we outline the known genetic etiologies of NIHF by fetal organ system affected, and provide a systematic approach to the evaluation of NIHF. Some of the underlying genetic disorders are associated with characteristic phenotypic features that may be seen on prenatal ultrasound, such as hepatomegaly with lysosomal storage disorders, hyperechoic kidneys with congenital nephrosis, or pulmonary valve stenosis with RASopathies. However, this is not always the case, and the approach to evaluation must include prenatal ultrasound findings as well as genetic testing and many other factors. Genetic testing that has been utilized for NIHF ranges from standard chromosomal microarray or karyotype to gene panels and broad approaches such as whole exome sequencing. Family and obstetric history, as well as pathology examination, can yield additional clues that are helpful in establishing a diagnosis. A systematic approach to evaluation can guide a more targeted approach to genetic evaluation, diagnosis, and management of NIHF.
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Affiliation(s)
- Anne H Mardy
- Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, US
| | - Shilpa P Chetty
- Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, US
| | - Mary E Norton
- Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, US
| | - Teresa N Sparks
- Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, US
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27
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Parhiz H, Ketcham SA, Zou G, Ghosh B, Fratz-Berilla EJ, Ashraf M, Ju T, Madhavarao CN. Differential effects of bioreactor process variables and purification on the human recombinant lysosomal enzyme β-glucuronidase produced from Chinese hamster ovary cells. Appl Microbiol Biotechnol 2019; 103:6081-6095. [DOI: 10.1007/s00253-019-09889-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 04/30/2019] [Accepted: 05/02/2019] [Indexed: 12/17/2022]
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28
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Guerrero RB, Kloke KM, Salazar D. Inborn Errors of Metabolism and the Gastrointestinal Tract. Gastroenterol Clin North Am 2019; 48:183-198. [PMID: 31046970 DOI: 10.1016/j.gtc.2019.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Inborn errors of metabolism (IEMs) are usually recognized by characteristic neurologic and metabolic manifestations and sometimes by dysmorphism. However, IEMs can present with a wide variety of gastrointestinal manifestations, whether as the primary or a minor clinical symptom. Regardless, gastrointestinal and hepatic manifestations of IEMs are important clinical features that can help identify an underlying defect; these disorders should be taken into consideration as part of a patient's clinical assessment. It is prudent to include metabolic disorders in the differential diagnosis because in some cases, gastrointestinal symptoms may be the only presenting feature in a patient with an underlying IEM.
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Affiliation(s)
| | - Karen M Kloke
- Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | - Denise Salazar
- Quest Diagnostics, 33608 Ortega Highway, San Juan Capistrano, CA 92690, USA
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29
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Abstract
Lysosomal storage disorders are a heterogeneous group of genetic diseases characterized by defective function in one of the lysosomal enzymes. In this review paper, we describe neuroradiological findings and clinical characteristics of neuronopathic lysosomal disorders with a focus on differential diagnosis. New insights regarding pathogenesis and therapeutic perspectives are also briefly discussed.
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30
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Tao YX, Conn PM. Pharmacoperones as Novel Therapeutics for Diverse Protein Conformational Diseases. Physiol Rev 2018; 98:697-725. [PMID: 29442594 DOI: 10.1152/physrev.00029.2016] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
After synthesis, proteins are folded into their native conformations aided by molecular chaperones. Dysfunction in folding caused by genetic mutations in numerous genes causes protein conformational diseases. Membrane proteins are more prone to misfolding due to their more intricate folding than soluble proteins. Misfolded proteins are detected by the cellular quality control systems, especially in the endoplasmic reticulum, and proteins may be retained there for eventual degradation by the ubiquitin-proteasome system or through autophagy. Some misfolded proteins aggregate, leading to pathologies in numerous neurological diseases. In vitro, modulating mutant protein folding by altering molecular chaperone expression can ameliorate some misfolding. Some small molecules known as chemical chaperones also correct mutant protein misfolding in vitro and in vivo. However, due to their lack of specificity, their potential as therapeutics is limited. Another class of compounds, known as pharmacological chaperones (pharmacoperones), binds with high specificity to misfolded proteins, either as enzyme substrates or receptor ligands, leading to decreased folding energy barriers and correction of the misfolding. Because many of the misfolded proteins are misrouted but do not have defects in function per se, pharmacoperones have promising potential in advancing to the clinic as therapeutics, since correcting routing may ameliorate the underlying mechanism of disease. This review will comprehensively summarize this exciting area of research, surveying the literature from in vitro studies in cell lines to transgenic animal models and clinical trials in several protein misfolding diseases.
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Affiliation(s)
- Ya-Xiong Tao
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University , Auburn, Alabama ; and Departments of Internal Medicine and Cell Biology, Texas Tech University Health Science Center , Lubbock, Texas
| | - P Michael Conn
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University , Auburn, Alabama ; and Departments of Internal Medicine and Cell Biology, Texas Tech University Health Science Center , Lubbock, Texas
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31
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Pontillo G, Cocozza S, Brunetti A, Brescia Morra V, Riccio E, Russo C, Saccà F, Tedeschi E, Pisani A, Quarantelli M. Reduced Intracranial Volume in Fabry Disease: Evidence of Abnormal Neurodevelopment? Front Neurol 2018; 9:672. [PMID: 30174644 PMCID: PMC6107697 DOI: 10.3389/fneur.2018.00672] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 07/26/2018] [Indexed: 11/22/2022] Open
Abstract
Introduction: Lysosomal storage disorders (LSD) are often characterized by abnormal brain development, reflected by a reduction of intracranial volume (ICV). The aim of our study was to perform a volumetric analysis of intracranial tissues in Fabry Disease (FD), investigating possible reductions of ICV as a potential expression of abnormal brain development in this condition. Materials and Methods: Forty-two FD patients (15 males, mean age 43.3 ± 13.0 years) were enrolled along with 38 healthy controls (HC) of comparable age and sex. Volumetric MRI data were segmented using SPM12 to obtain intracranial tissue volumes, from which ICV values were derived. Results: Mean ICV of FD patients was 8.1% smaller compared to the control group (p < 5·10−5). Unlike what typically happens in neurodegenerative disorders, no significant differences emerged when comparing between the two groups the fractional volumes of gray matter, white matter and CSF (i.e., normalized by ICV), consistent with a harmonious volumetric reduction of intracranial structures. Discussion: The present results suggest that in FD patients an abnormality of brain development is present, expanding the current knowledge about central nervous system involvement in FD, further emphasizing the importance of an early diagnosis.
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Affiliation(s)
- Giuseppe Pontillo
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | - Sirio Cocozza
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | - Arturo Brunetti
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | - Vincenzo Brescia Morra
- Department of Neurosciences and Reproductive and Odontostomatological Sciences, University "Federico II", Naples, Italy
| | - Eleonora Riccio
- Nephrology Unit, Department of Public Health, University "Federico II", Naples, Italy
| | - Camilla Russo
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | - Francesco Saccà
- Department of Neurosciences and Reproductive and Odontostomatological Sciences, University "Federico II", Naples, Italy
| | - Enrico Tedeschi
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | - Antonio Pisani
- Nephrology Unit, Department of Public Health, University "Federico II", Naples, Italy
| | - Mario Quarantelli
- Institute of Biostructure and Bioimaging, National Research Council, Naples, Italy
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Tavasoli AR, Parvaneh N, Ashrafi MR, Rezaei Z, Zschocke J, Rostami P. Clinical presentation and outcome in infantile Sandhoff disease: a case series of 25 patients from Iranian neurometabolic bioregistry with five novel mutations. Orphanet J Rare Dis 2018; 13:130. [PMID: 30075786 PMCID: PMC6091055 DOI: 10.1186/s13023-018-0876-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 07/18/2018] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Infantile Sandhoff disease (ISD) is a GM2 gangliosidosis that is classified as a lysosomal storage disorder. The most common symptoms of affected individuals at presentation are neurologic involvement. Here we report clinical course and demographic features in a case series of infantile Sandhoff disease. Enzymatically and some genetically proven cases of ISD were extracted from the Iranian Neurometabolic Registry (INMR) in Children's Medical Center, Iran, Tehran from December 2010 to December 2016. RESULT Twenty five cases of infantile SD (13 female, 12 male) were included in this study. The age range of patients was 9-24 months with a mean of 15.8 months. The consanguinity rate of parents affected families was about 80%. The mean age of patients at disease onset was 6.4 months and the mean age at diagnosis was 14 months. Patients were diagnosed with a mean delay of 7.8 months. Eleven of patients died due to aspiration pneumonia and intractable seizure. The most common features at presentation (92%) were developmental delay or regression in speech and cognitive domains. Cherry red spots were detected in 17 patients (68%). Organomegaly was detected only in two patients. Enzyme studies showed marked reductions of both Hexosaminidase A and B in all patients. HEXB gene mutation studies performed in eight patients identified 6 different mutations, which five of them were novel. CONCLUSION Infantile SD should be considered for each child presented with neurologic symptoms such as developmental delay and regression and cherry red spots in ophthalmic examination. Organomegaly is not a frequent clinical finding in infantile SD. Additionally; there are a genetic heterogenisity among Iranian patients.
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Affiliation(s)
- Ali Reza Tavasoli
- Myelin Disorder Clinic (Iranian Neurometabolic Registery), Pediatric Neurology Division, Neurometabolic Registry Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Parvaneh
- Division of Allergy and Clinical Immunology, Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Reza Ashrafi
- Myelin Disorder Clinic (Iranian Neurometabolic Registery), Pediatric Neurology Division, Neurometabolic Registry Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Rezaei
- Myelin Disorder Clinic (Iranian Neurometabolic Registery), Pediatric Neurology Division, Neurometabolic Registry Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Johannes Zschocke
- Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
| | - Parastoo Rostami
- Growth and Development Research Center, Division of Endocrinology and metabolism, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
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33
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Hou ZS, Ulloa-Aguirre A, Tao YX. Pharmacoperone drugs: targeting misfolded proteins causing lysosomal storage-, ion channels-, and G protein-coupled receptors-associated conformational disorders. Expert Rev Clin Pharmacol 2018; 11:611-624. [DOI: 10.1080/17512433.2018.1480367] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Zhi-Shuai Hou
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA
| | - Alfredo Ulloa-Aguirre
- Red de Apoyo a la Investigación (RAI), Universidad Nacional Autónoma de México (UNAM) and Instituto Nacional de Ciencias Médicas y Nutrición SZ, Mexico City, Mexico
| | - Ya-Xiong Tao
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA
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34
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Abstract
West syndrome (WS) is an early life epileptic encephalopathy associated with infantile spasms, interictal electroencephalography (EEG) abnormalities including high amplitude, disorganized background with multifocal epileptic spikes (hypsarrhythmia), and often neurodevelopmental impairments. Approximately 64% of the patients have structural, metabolic, genetic, or infectious etiologies and, in the rest, the etiology is unknown. Here we review the contribution of etiologies due to various metabolic disorders in the pathology of WS. These may include metabolic errors in organic molecules involved in amino acid and glucose metabolism, fatty acid oxidation, metal metabolism, pyridoxine deficiency or dependency, or acidurias in organelles such as mitochondria and lysosomes. We discuss the biochemical, clinical, and EEG features of these disorders as well as the evidence of how they may be implicated in the pathogenesis and treatment of WS. The early recognition of these etiologies in some cases may permit early interventions that may improve the course of the disease.
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Affiliation(s)
- Seda Salar
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
| | - Solomon L. Moshé
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Dominick P. Purpura Department of NeuroscienceMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Department of PediatricsMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
| | - Aristea S. Galanopoulou
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Dominick P. Purpura Department of NeuroscienceMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
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35
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Getting to the Heart of the Matter: Lysosomal Storage Diseases That Manifest a Cardiac Phenotype. CURRENT GENETIC MEDICINE REPORTS 2018. [DOI: 10.1007/s40142-018-0135-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Abstract
INTRODUCTION Gaucher disease, the autosomal recessive deficiency of the lysosomal enzyme glucocerebrosidase, is associated with wide phenotypic diversity including non-neuronopathic, acute neuronopathic, and chronic neuronopathic forms. Overlap between types can render definitive diagnoses difficult. However, differentiating between the different phenotypes is essential due to the vast differences in clinical outcomes and response to therapy. Genotypic information is helpful, but cannot always be used to make clinical predictions. Current treatments for Gaucher disease, including enzyme replacement therapy and substrate reduction therapy, can reverse many of the non-neurological manifestations, but these therapies must be administered continually and are extremely costly. AREAS COVERED We reviewed the literature concerning the varied clinical presentations of Gaucher disease throughout the lifetime, along with treatment options, management goals, and current and future research challenges. A PubMed literature search was performed for relevant publications between 1991 to January 2018. EXPERT COMMENTARY Interest and research in the field of Gaucher disease is rapidly expanding. However, significant barriers remain in our ability to predict phenotype, assess disease progression using objective biomarkers, and determine optimal treatment strategy on an individual basis. As the field grows, we anticipate identification of genetic modifiers, new biomarkers, and small-molecule chaperone therapies, which may improve patient quality of life.
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Affiliation(s)
- Sam E Gary
- a Medical Genetics Branch , NHGRI, NIH , Bethesda , MD , USA
| | - Emory Ryan
- a Medical Genetics Branch , NHGRI, NIH , Bethesda , MD , USA
| | - Alta M Steward
- a Medical Genetics Branch , NHGRI, NIH , Bethesda , MD , USA
| | - Ellen Sidransky
- a Medical Genetics Branch , NHGRI, NIH , Bethesda , MD , USA
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Kazmirchuk T, Dick K, Burnside DJ, Barnes B, Moteshareie H, Hajikarimlou M, Omidi K, Ahmed D, Low A, Lettl C, Hooshyar M, Schoenrock A, Pitre S, Babu M, Cassol E, Samanfar B, Wong A, Dehne F, Green JR, Golshani A. Designing anti-Zika virus peptides derived from predicted human-Zika virus protein-protein interactions. Comput Biol Chem 2017; 71:180-187. [DOI: 10.1016/j.compbiolchem.2017.10.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 10/03/2017] [Accepted: 10/27/2017] [Indexed: 01/22/2023]
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Gumus E, Haliloglu G, Karhan AN, Demir H, Gurakan F, Topcu M, Yuce A. Niemann-Pick disease type C in the newborn period: a single-center experience. Eur J Pediatr 2017; 176:1669-1676. [PMID: 28951965 DOI: 10.1007/s00431-017-3020-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 09/09/2017] [Accepted: 09/19/2017] [Indexed: 02/07/2023]
Abstract
UNLABELLED Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder with a great variation in clinical spectrum and age at presentation. Clinical features of 10 NPC patients who presented in the newborn period between 1993 and 2015 at our center were retrospectively analyzed. Males and females were equally distributed; there was a history of parental consanguinity (n = 8) and first-degree relative with NPC (n = 3). Patients were symptomatic between 1 and 10 days (mean 3.6 ± 2.6 days). Age at diagnosis was between 1 and 30 days (mean 14.6 ± 13.3 days). Laboratory work-up included bone marrow aspiration (n = 8) and/or filipin staining (n = 4). Confirmation was done by molecular analysis, indicating NPC1 (n = 8) and NPC2 (n = 2) mutations. All patients had neonatal cholestasis and hepatosplenomegaly. Pulmonary involvement (n = 9) and fetal ascites (n = 2) were additional accompanying features. All but one died due to pulmonary complications (n = 6) and liver insufficiency (n = 3) between 1.5 and 36 months of age (mean 8.1 ± 10.8 months). Currently, one patient is alive at the age of 11 months without any neurological deficit. CONCLUSIONS Neonatal presentation is a rare form of NPC with exclusively visceral involvement in the newborn period and poor prognosis leading to premature death due to pulmonary complications and liver failure. What is known: • Neonatal presentation is a rare form of NPC with exclusively visceral involvement in the newborn period and poor prognosis leading to premature death. • Progressive liver disease is the most common cause of death among neonatal-onset NPC patients. What is new: • Natural course of neonatal-onset NPC may show variations. • Pulmonary involvement should be considered as an important cause of death in neonatal-onset cases, and appropriate precautions should be taken to prevent complications of respiratory insufficiency and airway infections.
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Affiliation(s)
- Ersin Gumus
- Department of Pediatric Gastroenterology, Hacettepe University Children's Hospital, Sihhiye, 06100, Ankara, Turkey.
| | - Goknur Haliloglu
- Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey
| | - Asuman Nur Karhan
- Department of Pediatric Gastroenterology, Hacettepe University Children's Hospital, Sihhiye, 06100, Ankara, Turkey
| | - Hulya Demir
- Department of Pediatric Gastroenterology, Hacettepe University Children's Hospital, Sihhiye, 06100, Ankara, Turkey
| | - Figen Gurakan
- Department of Pediatrics, VKV American Hospital, Istanbul, Turkey
| | - Meral Topcu
- Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey
| | - Aysel Yuce
- Department of Pediatric Gastroenterology, Hacettepe University Children's Hospital, Sihhiye, 06100, Ankara, Turkey
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Carvoeiro A, Carvalho F, Montenegro N, Matias A. Non-immune fetal hydrops of metabolic origin: a case report and a review of the literature. CASE REPORTS IN PERINATAL MEDICINE 2017. [DOI: 10.1515/crpm-2017-0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
Aim
To propose a diagnostic algorithm for non-immune fetal hydrops (NIFH) of metabolic origin based on a review of the literature and on the workup of a clinical case.
Background
The etiology of NIFH is complex and remains unexplained in 15%–25% of patients. The appropriate work up beyond an initial approach is still not well defined but it should include screening for metabolic conditions. Inborn errors of metabolism comprise a heterogeneous group of autosomal recessive rare inherited disorders, among which lysosomal storage disorder is the most common subtype.
Case description
We report a case of a 30-year-old pregnant, primiparous woman, referred to a tertiary hospital at 22 weeks of gestation because of a fetal hydrops. The second trimester obstetric ultrasound showed a hydrothorax and a large subcutaneous edema. At 30 weeks of gestation, the fetal health status deteriorated and a massive hepatomegaly was detected. The metabolic study of the amniotic fluid supernatant suggested a lysosomal disease. The ominous prognosis of the condition motivated the parents to opt for a termination of pregnancy. The autopsy study confirmed the existence of a metabolic disease.
Conclusion
The incidence of inborn errors of metabolism may be significantly higher in NIHF than reported previously. Consequently, an extensive investigation for the etiology of NIHF including the screening for metabolic disorders seems to be crucial for a definitive diagnosis.
Clinical relevance
Despite the lack of treatment options for the majority of these disorders, it is of great importance to follow an established workup, in order to identify the index case as soon as possible, as pregnancy management decisions and prenatal counselling in future pregnancies will depend on a more precise diagnosis.
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Affiliation(s)
- Ana Carvoeiro
- Faculty of Medicine, University of Porto , Department of OB/GYN of Faculty of Medicine, University of Porto , Al. Prof. Hernâni Monteiro, 4200 - 319, Porto , Portugal
| | - Filipa Carvalho
- Department of Genetics, Faculty of Medicine , University of Porto , Porto , Porugal
| | - Nuno Montenegro
- Department of OB/GYN , S. João Hospital , Porto , Portugal
- Department of OB/GYN of Faculty of Medicine , University of Porto , Porto , Portugal
| | - Alexandra Matias
- Department of OB/GYN , S. João Hospital , Porto , Portugal
- Department of OB/GYN of Faculty of Medicine , University of Porto , Porto , Portugal
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40
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Direct quantification of protein glycan phosphorylation. Biotechniques 2017; 63:117-123. [DOI: 10.2144/000114587] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 07/11/2017] [Indexed: 11/23/2022] Open
Abstract
Phosphorylation is an important post-translational modification (PTM) of proteins and a critical quality attribute for protein therapeutics, especially if it is required for protein function or sub-cellular targeting. Most current methods to quantify phosphorylation are time-consuming, indirect, or require specific instrumentation and technical skills. Here, we report the adaptation of a phosphate-specific binding dye and common laboratory instruments for quantification of relative amounts of phosphorylated glycans as well as phosphorylation of amino acid residues on the backbones of proteins. Our results show that quantification of phosphorylation using the new method agrees with published data on the number of phosphorylated glycosylation sites for two lysosomal enzymes: β-glucuronidase (GUS) and cathepsin D.
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First Report on Fetal Cerebral Polyglucosan Bodies in Mucopolysaccharidosis Type VII. Case Rep Pediatr 2017; 2017:9523427. [PMID: 28770119 PMCID: PMC5523543 DOI: 10.1155/2017/9523427] [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: 03/03/2017] [Revised: 05/16/2017] [Accepted: 06/12/2017] [Indexed: 11/17/2022] Open
Abstract
We report on the detection of discordant inclusions in the brain of a 25-week female fetus with a very rare lysosomal storage disease, namely, Sly disease (mucopolysaccharidosis (MPS) type VII), presenting with nonimmune hydrops fetalis. Besides vacuolated neurons, we found abundant deposition of polyglucosan bodies (PGBs) in the developing brain of this fetus in whom MPS-VII was corroborated by lysosomal beta-glucuronidase-deficiency detected in fetal blood and fetal skin-fibroblasts and by the presence of a heterozygous pathogenic variant in the GUSB gene in the mother. Fetal/neonatal metabolic disorders with PGB-deposition are extremely rare (particularly in relation to CNS involvement) and include almost exclusively subtypes of glycogenosis (types IV and VII). The accumulation of PGBs (particularly in the fetal brain) has so far not been depicted in Sly disease. This is the first report on such “aberrant” association. Besides, the detection of these CNS inclusions at such an early developmental stage is remarkably unique.
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Mohamed FE, Al-Gazali L, Al-Jasmi F, Ali BR. Pharmaceutical Chaperones and Proteostasis Regulators in the Therapy of Lysosomal Storage Disorders: Current Perspective and Future Promises. Front Pharmacol 2017; 8:448. [PMID: 28736525 PMCID: PMC5500627 DOI: 10.3389/fphar.2017.00448] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 06/22/2017] [Indexed: 02/05/2023] Open
Abstract
Different approaches have been utilized or proposed for the treatment of lysosomal storage disorders (LSDs) including enzyme replacement and hematopoietic stem cell transplant therapies, both aiming to compensate for the enzymatic loss of the underlying mutated lysosomal enzymes. However, these approaches have their own limitations and therefore the vast majority of LSDs are either still untreatable or their treatments are inadequate. Missense mutations affecting enzyme stability, folding and cellular trafficking are common in LSDs resulting often in low protein half-life, premature degradation, aggregation and retention of the mutant proteins in the endoplasmic reticulum. Small molecular weight compounds such as pharmaceutical chaperones (PCs) and proteostasis regulators have been in recent years to be promising approaches for overcoming some of these protein processing defects. These compounds are thought to enhance lysosomal enzyme activity by specific binding to the mutated enzyme or by manipulating components of the proteostasis pathways promoting protein stability, folding and trafficking and thus enhancing and restoring some of the enzymatic activity of the mutated protein in lysosomes. Multiple compounds have already been approved for clinical use to treat multiple LSDs like migalastat in the treatment of Fabry disease and others are currently under research or in clinical trials such as Ambroxol hydrochloride and Pyrimethamine. In this review, we are presenting a general overview of LSDs, their molecular and cellular bases, and focusing on recent advances on targeting and manipulation proteostasis, including the use of PCs and proteostasis regulators, as therapeutic targets for some LSDs. In addition, we present the successes, limitations and future perspectives in this field.
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Affiliation(s)
- Fedah E. Mohamed
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates UniversityAl Ain, United Arab Emirates
| | - Lihadh Al-Gazali
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates UniversityAl Ain, United Arab Emirates
| | - Fatma Al-Jasmi
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates UniversityAl Ain, United Arab Emirates
| | - Bassam R. Ali
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates UniversityAl Ain, United Arab Emirates
- Zayed Bin Sultan Center for Health Sciences, United Arab Emirates UniversityAl-Ain, United Arab Emirates
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Schady DA, Finegold MJ. Contemporary Evaluation of the Pediatric Liver Biopsy. Gastroenterol Clin North Am 2017; 46:233-252. [PMID: 28506363 DOI: 10.1016/j.gtc.2017.01.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver disease in the neonate, infant, child, and adolescent may manifest differently depending on the type of disorder. These disorders show marked overlap clinically and on light microscopy. Histology and ultrastructural examination are used in tandem for the diagnosis of most disorders. A final diagnosis or interpretation of the pediatric liver biopsy depends on appropriate and adequate clinical history, laboratory test results, biochemical assays, and molecular analyses, as indicated by the light microscopic and ultrastructural examination.
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Affiliation(s)
- Deborah A Schady
- Department of Pathology and Immunology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
| | - Milton J Finegold
- Department of Pathology and Immunology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
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44
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Supriya M, De T, Christopher R. Age and gender-specific reference intervals for lysosomal enzymes in dried blood spot samples: A study in Indian population. Clin Biochem 2017; 50:858-863. [PMID: 28396248 DOI: 10.1016/j.clinbiochem.2017.04.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 04/04/2017] [Accepted: 04/06/2017] [Indexed: 11/18/2022]
Abstract
OBJECTIVES The study aimed to establish age and gender-specific reference values for the activities of lysosomal enzymes (acid α-galactosidase [GLA], acid β-glucocerebrosidase [GBA], acid α-glucosidase [GAA], acid sphingomyelinase [ASM] and galactocerebrosidase [GALC]) in dried blood spots (DBS) of Indian population. DESIGN AND METHODS A total of 3797 healthy Indian subjects (1456 females and 2341 males) aged from 2days to 60years were selected for the study. Activities of 5 lysosomal enzymes were determined by tandem mass spectrometry, for newborns (<30days), infants (>1month-1year), children (>1-5years) and (>5-18years) and adults (>18years).Variations in enzyme activities based on age and gender were studied. The reference interval was defined as the central 95% range, and was determined based on age and gender. RESULTS Highly significant differences in activities were observed for GAA (p=0.001), GLA (p<0.0001), GBA (p<0.0001), ASM (p<0.0001) and GALC (p<0.0001), between different age groups. Comparison of activities between genders showed significant difference for ASM in children aged 1-5years (p=0.03) with higher activity in females, and for GLA in children aged 5-18years (p=0.004) where the activity was higher in males. Reference intervals decreased with age for all enzymes, except GAA. The ranges of GLA and GALC were higher in females, whereas GBA was higher in males. CONCLUSION The study establishes age and gender-specific reference values for the screening and identification of lysosomal storage disorders in Indian population. Our data may facilitate establishment of mass screening programs for these disorders in India.
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Affiliation(s)
- Manjunath Supriya
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Tanima De
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Rita Christopher
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India.
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45
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Supriya M, De T, Christopher R. Effect of temperature on lysosomal enzyme activity during preparation and storage of dried blood spots. J Clin Lab Anal 2017; 32. [PMID: 28345760 DOI: 10.1002/jcla.22220] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 02/25/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The use of dried blood spots (DBS) for the assay of lysosomal enzymes has facilitated the implementation of pilot studies for newborn screening for lysosomal storage disorders in various developed countries. The aim of the study was to determine the influence of ambient temperature during DBS preparation and storage on lysosomal enzyme activity in a developing, tropical country. METHODS Blood samples from 12 healthy subjects collected on a S&S 903 filter paper were dried and stored at different temperatures for different periods of time. Activities of five lysosomal enzymes (acid α-glucosidase, acid α-galactosidase, acid β-glucocerebrosidase, acid sphingomyelinase, and galactocerebrosidase) were determined by tandem mass spectrometric and fluorimetric (acid α-glucosidase and acid β-glucocerebrosidase only) assays. RESULTS The mean activities of all five enzymes decreased significantly when DBS was dried at temperatures above 24°C (P<.0001). DBS stored at 4°C, 24°C, 30°C, 37°C, and 45°C for 10 days and more, also showed significant reduction in activities of all five enzymes (P<.0001). CONCLUSION The results highlight the importance of maintaining the correct ambient temperature during DBS preparation and storage to avoid false positive results when screening for lysosomal storage disorders.
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Affiliation(s)
- Manjunath Supriya
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | - Tanima De
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | - Rita Christopher
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India
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46
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Christensen CL, Choy FYM. A Prospective Treatment Option for Lysosomal Storage Diseases: CRISPR/Cas9 Gene Editing Technology for Mutation Correction in Induced Pluripotent Stem Cells. Diseases 2017; 5:E6. [PMID: 28933359 PMCID: PMC5456334 DOI: 10.3390/diseases5010006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/15/2017] [Accepted: 02/20/2017] [Indexed: 02/06/2023] Open
Abstract
Ease of design, relatively low cost and a multitude of gene-altering capabilities have all led to the adoption of the sophisticated and yet simple gene editing system: clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9). The CRISPR/Cas9 system holds promise for the correction of deleterious mutations by taking advantage of the homology directed repair pathway and by supplying a correction template to the affected patient's cells. Currently, this technique is being applied in vitro in human-induced pluripotent stem cells (iPSCs) to correct a variety of severe genetic diseases, but has not as of yet been used in iPSCs derived from patients affected with a lysosomal storage disease (LSD). If adopted into clinical practice, corrected iPSCs derived from cells that originate from the patient themselves could be used for therapeutic amelioration of LSD symptoms without the risks associated with allogeneic stem cell transplantation. CRISPR/Cas9 editing in a patient's cells would overcome the costly, lifelong process associated with currently available treatment methods, including enzyme replacement and substrate reduction therapies. In this review, the overall utility of the CRISPR/Cas9 gene editing technique for treatment of genetic diseases, the potential for the treatment of LSDs and methods currently employed to increase the efficiency of this re-engineered biological system will be discussed.
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Affiliation(s)
- Chloe L Christensen
- Department of Biology, Centre for Biomedical Research, University of Victoria, 3800 Finnerty Rd., Victoria, BC V8P 5C2, Canada.
| | - Francis Y M Choy
- Department of Biology, Centre for Biomedical Research, University of Victoria, 3800 Finnerty Rd., Victoria, BC V8P 5C2, Canada.
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Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs). BioDrugs 2016; 30:49-74. [PMID: 26886021 DOI: 10.1007/s40259-016-0157-6] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
In recent years, remarkable advances in the ability to diagnose genetic disorders have been made. The identification of disease-causing genes allows the development of gene-specific therapies with the ultimate goal to develop personalized medicines for each patient according to their own specific genetic defect. In-depth genotyping of many different genes has revealed that ~12% of inherited genetic disorders are caused by in-frame nonsense mutations. Nonsense (non-coding) mutations are caused by point mutations, which generate premature termination codons (PTCs) that cause premature translational termination of the mRNA, and subsequently inhibit normal full-length protein expression. Recently, a gene-based therapeutic approach for genetic diseases caused by nonsense mutations has emerged, namely the so-called translational read-through (TR) therapy. Read-through therapy is based on the discovery that small molecules, known as TR-inducing drugs (TRIDs), allow the translation machinery to suppress a nonsense codon, elongate the nascent peptide chain, and consequently result in the synthesis of full-length protein. Several TRIDs are currently under investigation and research has been performed on several genetic disorders caused by nonsense mutations over the years. These findings have raised hope for the usage of TR therapy as a gene-based pharmacogenetic therapy for nonsense mutations in various genes responsible for a variety of genetic diseases.
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48
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Sheth J, Mistri M, Shah K, Chaudhary M, Godbole K, Sheth F. Lysosomal Storage Disorders in Nonimmune Hydrops Fetalis (NIHF): An Indian Experience. JIMD Rep 2016; 35:47-52. [PMID: 27928775 DOI: 10.1007/8904_2016_24] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 10/22/2016] [Accepted: 11/14/2016] [Indexed: 01/30/2023] Open
Abstract
Lysosomal storage disorders (LSD) are rare inherited neurovisceral inborn errors of metabolism which may present as nonimmune hydrops fetalis (NIHF) during pregnancy. Although causes of NIHF are highly diverse, LSDs are one of the underlying causes of NIHF. The aim of this study was to elucidate most frequent causes of LSDs presenting as NIHF in Indian population. Several fetal tissues were investigated for enzymatic diagnosis of LSDs using modified fluorometric assays in the current prospective study carried out at our national tertiary center from 2006 through 2016. Other general causes of NIHF were ruled out. Twenty-one percent (7/33) of cases were confirmed to have LSDs. Two patients were diagnosed with Hurler syndrome; two had Sly syndrome and one each of Niemann-Pick disease type A/B, Gaucher's disease, and mucolipidosis. Four of eleven cases (36%) with recurrent NIHF were found to have LSDs. In spite of extreme rarity of LSDs, they should be considered as a potential cause of NIHF, especially with recurrent NIHF. Specific investigations of LSD leading to definitive diagnosis may aid the clinician in providing accurate genetic counseling and prenatal diagnosis to the patients and help in subsequent pregnancies to the families. Furthermore, early intervention and management with enzyme replacement therapy may be planned for the lysosomal storage disorders where available.
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Affiliation(s)
- Jayesh Sheth
- FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad, 380 015, India.
| | - Mehul Mistri
- FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad, 380 015, India
| | - Krati Shah
- FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad, 380 015, India
| | - Mayank Chaudhary
- Department of Fetal Medicine, May Flower Hospital, Ahmedabad, 380 009, Gujarat, India
| | - Koumudi Godbole
- Department of Genetics, Deenanath Mangeshkar Hospital, Pune, India
| | - Frenny Sheth
- FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad, 380 015, India
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Peake RWA, Bodamer OA. Newborn Screening for Lysosomal Storage Disorders. J Pediatr Genet 2016; 6:51-60. [PMID: 28180027 DOI: 10.1055/s-0036-1593843] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 08/28/2015] [Indexed: 01/23/2023]
Abstract
Newborn screening is one of the most important public health initiatives to date, focusing on the identification of presymptomatic newborn infants with treatable conditions to reduce morbidity and mortality. The number of screening conditions continues to expand due to advances in screening technologies and the development of novel therapies. Consequently, some of the lysosomal storage disorders are now considered as candidates for newborn screening, although many challenges including identification of late-onset phenotypes remain. This review provides a critical appraisal of the current state of newborn screening for lysosomal storage disorders.
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Affiliation(s)
- Roy W A Peake
- Department of Laboratory Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Olaf A Bodamer
- Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, United States; Harvard Medical School, Boston, Massachusetts, United States
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50
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Collardeau-Frachon S, Cordier MP, Rossi M, Guibaud L, Vianey-Saban C. Antenatal manifestations of inborn errors of metabolism: autopsy findings suggestive of a metabolic disorder. J Inherit Metab Dis 2016; 39:597-610. [PMID: 27106218 DOI: 10.1007/s10545-016-9937-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 04/01/2016] [Accepted: 04/06/2016] [Indexed: 10/21/2022]
Abstract
This review highlights the importance of performing an autopsy when faced with fetal abortion or termination of pregnancy with suspicion of an inborn error of metabolism. Radiological, macroscopic and microscopic features found at autopsy as well as placental anomalies that can suggest such a diagnosis are detailed. The following metabolic disorders encountered in fetuses are discussed: lysosomal storage diseases, peroxisomal disorders, cholesterol synthesis disorders, congenital disorders of glycosylation, glycogenosis type IV, mitochondrial respiratory chain disorders, transaldolase deficiency, generalized arterial calcification of infancy, hypophosphatasia, arylsulfatase E deficiency, inborn errors of serine metabolism, asparagine synthetase deficiency, hyperphenylalaninemia, glutaric aciduria type I, non-ketotic hyperglycinemia, pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, glutamine synthase deficiency, sulfite oxidase and molybdenum cofactor deficiency.
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Affiliation(s)
- Sophie Collardeau-Frachon
- Department of Pathology, Hôpital-Femme-Mère-Enfant, Hospices Civils de Lyon, 59 bd Pinel, 69677, Bron cedex, France.
- Université Claude Bernard Lyon I, CHU de Lyon, France.
- SOFFOET, Société Française de Fœtopathologie, Lyon, France.
| | - Marie-Pierre Cordier
- Department of Genetics, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 bd Pinel, 69677, Bron cedex, France
| | - Massimiliano Rossi
- Department of Genetics, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 bd Pinel, 69677, Bron cedex, France
| | - Laurent Guibaud
- Université Claude Bernard Lyon I, CHU de Lyon, France
- Department of Fetal and Pediatric Imaging, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 bd Pinel, 69677, Bron cedex, France
| | - Christine Vianey-Saban
- Department of Department of Biochemistry, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 bd Pinel, 69677, Bron cedex, France
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