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dc.contributor.author | Bisschoff, Michelle![]() |
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dc.contributor.author | Smuts, Izelle![]() |
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dc.contributor.author | Dercksen, Marli![]() |
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dc.contributor.author | Schoonen, Maryke![]() |
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dc.contributor.author | Vorster, Barend C.![]() |
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dc.contributor.author | Van der Watt, George![]() |
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dc.contributor.author | Spencer, Careni![]() |
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dc.contributor.author | Naidu, Kireshnee![]() |
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dc.contributor.author | Henning, Franclo![]() |
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dc.contributor.author | Meldau, Surita![]() |
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dc.contributor.author | McFarland, Robert![]() |
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dc.contributor.author | Taylor, Robert W.![]() |
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dc.contributor.author | Patel, Krutik![]() |
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dc.contributor.author | Fassad, Mahmoud R.![]() |
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dc.contributor.author | Vandrovcova, Jana![]() |
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dc.contributor.author | Wanders, Ronald J.A.![]() |
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dc.contributor.author | Van der Westhuizen, Francois H.![]() |
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dc.date.accessioned | 2024-01-29T08:25:14Z | |
dc.date.available | 2024-01-29T08:25:14Z | |
dc.date.issued | 2024-01 | |
dc.description | AVAILABILITY OF DATA AND MATERIALS : Previous data and samples were made available by the Centre for Human Metabolomics (NWU), SU, and UCT. New samples were collected with the help of paediatric and adult neurologists via Steve Biko Academic Hospital, Tygerberg Hospital, and Red Cross War Memorial Children’s Hospital. The datasets generated and/or analysed during the current study are not publicly available due to the data sharing policy of the ICGNMD study, but are available from the corresponding author on reasonable request. | en_US |
dc.description | ADDITIONAL FILE 1 : Additional Clinical Information. | en_US |
dc.description | ADDITIONAL FILE 2 : Additional Metabolic Information. | en_US |
dc.description | ADDITIONAL FILE 3 : Additional Structural Information. | en_US |
dc.description.abstract | 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. | en_US |
dc.description.department | Paediatrics and Child Health | en_US |
dc.description.librarian | hj2024 | en_US |
dc.description.sdg | None | en_US |
dc.description.sponsorship | Open access funding provided by North-West University. A Medical Research Council (MRC) strategic award; the National Research Foundation (NRF) of South Africa; the South African Medical Research Council (SAMRC); the Wellcome Centre for Mitochondrial Research; the Mitochondrial Disease Patient Cohort (UK); the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease; the Lily Foundation; the UK NIHR Biomedical Research Centre for Ageing and Age-related Disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust; the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children; the MRC; Mito Foundation, and the Pathological Society (UK). | en_US |
dc.description.uri | https://ojrd.biomedcentral.com | en_US |
dc.identifier.citation | Bisschoff, M., Smuts, I., Dercksen, M. et al. Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study. Orphanet Journal of Rare Diseases 19, 15 (2024). https://doi.org/10.1186/s13023-023-03014-8. | en_US |
dc.identifier.issn | 1750-1172 (online) | |
dc.identifier.other | 10.1186/s13023-023-03014-8 | |
dc.identifier.uri | http://hdl.handle.net/2263/94131 | |
dc.language.iso | en | en_US |
dc.publisher | BMC | en_US |
dc.rights | © The Author(s) 2024. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License. | en_US |
dc.subject | Multiple acyl-CoA dehydrogenase deficiency (MADD) | en_US |
dc.subject | Electron transfer flavoprotein-ubiquinone oxidoreductase gene (ETFDH) | en_US |
dc.subject | South Africa (SA) | en_US |
dc.subject | Glutaric aciduria type II | en_US |
dc.subject | Riboflavin | en_US |
dc.subject | International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) | en_US |
dc.title | Clinical, biochemical, and genetic spectrum of MADD in a South African cohort : an ICGNMD study | en_US |
dc.type | Article | en_US |