Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study.

Autor: Bisschoff M; Focus area for Human Metabolomics, North-West University, Potchefstroom, South Africa., Smuts I; Department of Paediatrics, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa., Dercksen M; Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa., Schoonen M; Focus area for Human Metabolomics, North-West University, Potchefstroom, South Africa., Vorster BC; Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa., van der Watt G; Division of Chemical Pathology, National Health Laboratory Services, University of Cape Town, Cape Town, South Africa., Spencer C; Division of Human Genetics, Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa., Naidu K; Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa., Henning F; Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa., Meldau S; Division of Chemical Pathology, National Health Laboratory Services, University of Cape Town, Cape Town, South Africa., McFarland R; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK., Taylor RW; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK., Patel K; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Fassad MR; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Vandrovcova J; Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK., Wanders RJA; Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, The Netherlands., van der Westhuizen FH; Focus area for Human Metabolomics, North-West University, Potchefstroom, South Africa. Francois.VanDerWesthuizen@nwu.ac.za.
Jazyk: angličtina
Zdroj: Orphanet journal of rare diseases [Orphanet J Rare Dis] 2024 Jan 14; Vol. 19 (1), pp. 15. Date of Electronic Publication: 2024 Jan 14.
DOI: 10.1186/s13023-023-03014-8
Abstrakt: Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the variants occurring in the electron transfer flavoprotein-ubiquinone oxidoreductase gene (ETFDH). Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the International Centre for Genomic Medicine in Neuromuscular Diseases study, we recruited a cohort of patients diagnosed with MADD from academic medical centres across SA over a three-year period. The aim was to extensively profile the clinical, biochemical, and genomic characteristics of MADD in this understudied population.
Methods: Clinical evaluations and whole exome sequencing were conducted on each patient. Metabolic profiling was performed before and after treatment, where possible. The recessive inheritance and phase of the variants were established via segregation analyses using Sanger sequencing. Lastly, the haplotype and allele frequencies were determined for the two main variants in the four largest SA populations.
Results: Twelve unrelated families (ten of White SA and two of mixed ethnicity) with clinically heterogeneous presentations in 14 affected individuals were observed, and five pathogenic ETFDH variants were identified. Based on disease severity and treatment response, three distinct groups emerged. The most severe and fatal presentations were associated with the homozygous c.[1067G > A];c.[1067G > A] and compound heterozygous c.[976G > C];c.[1067G > A] genotypes, causing MADD types I and I/II, respectively. These, along with three less severe compound heterozygous genotypes (c.[1067G > A];c.[1448C > T], c.[740G > T];c.[1448C > T], and c.[287dupA*];c.[1448C > T]), resulting in MADD types II/III, presented before the age of five years, depending on the time and maintenance of intervention. By contrast, the homozygous c.[1448C > T];c.[1448C > T] genotype, which causes MADD type III, presented later in life. Except for the type I, I/II and II cases, urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine. Furthermore, genetic analyses of the most frequent variants (c.[1067G > A] and c.[1448C > T]) revealed a shared haplotype in the region of ETFDH, with SA population-specific allele frequencies of < 0.00067-0.00084%.
Conclusions: This study reveals the first extensive genotype-phenotype profile of a MADD patient cohort from the diverse and understudied SA population. The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population.
(© 2024. The Author(s).)
Databáze: MEDLINE
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