Two Single Nucleotide Deletions in the ABCD1 Gene Causing Distinct Phenotypes of X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a rare inborn error of the peroxisomal metabolism caused by pathologic variants in the ATP-binding cassette transporter type D, member 1 (ABCD1) gene located on the X-chromosome. ABCD1 protein, also known as adrenoleukodystrophy protein, is responsible for transport of the very long chain fatty acids (VLCFA) from cytoplasm into the peroxisomes. Therefore, altered function or lack of the ABCD1 protein leads to accumulation of VLCFA in various tissues and blood plasma leading to either rapidly progressive leukodystrophy (cerebral ALD), progressive adrenomyeloneuropathy (AMN), or isolated primary adrenal insufficiency (Addison's disease). We report two distinct single nucleotide deletions in the ABCD1 gene, c.253delC [p.Arg85Glyfs*18] in exon 1, leading to both cerebral ALD and to AMN phenotype in one family, and c.1275delA [p.Phe426Leufs*15] in exon 4, leading to AMN and primary adrenal insufficiency in a second family. For the latter variant, we demonstrate reduced mRNA expression and a complete absence of the ABCD1 protein in PBMC. Distinct mRNA and protein expression in the index patient and heterozygous carriers does not associate with VLCFA concentration in plasma, which is in line with the absence of genotype-phenotype correlation in X-ALD.

Automated summary

X-linked adrenoleukodystrophy (X-ALD) is a rare genetic disorder caused by mutations in the ABCD1 gene, leading to abnormal metabolism of very long chain fatty acids (VLCFA) and subsequent accumulation in tissues. This can result in cerebral ALD, AMN, or Addison's disease. We report two different deletions in the ABCD1 gene, resulting in different phenotypes in two families. There is no correlation between mRNA and protein expression and VLCFA concentration in plasma.