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

Abstract

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 ETFDH. Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the ICGNMD 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. Lastly, segregation analyses and, for the two main variants, haplotype and allele frequencies were determined in the four largest SA populations. Results Twelve unrelated families (ten of White SA and two of mixed ancestry) 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 c.[1067G > A] and c.[1067G > A];c.[976G > C] genotypes, causing types I and I/II MADD, respectively. These, along with three less severe genotypes, c.[1067G > A];c.[1448C > T], c.[740G > T];c.[1448C > T], and c.[287dup*];c.[1448C > T]), resulting in types II/III MADD, presented before the age of five years, depending on time and maintenance of intervention. By contrast, the c.[1448C > T] genotype, that causes type III MADD, 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 South African population-specific allele frequencies of < 0.00067–0.00084%. Conclusions This study reveals the first extensive MADD genotype–phenotype profile in the diverse and understudied SA population, in which MADD is most prevalent in the White population. Altogether, this study provides the data required to support early screening followed by genetic counselling, and patient-specific treatment of MADD in South Africa.