Pathogenicity of novel ABCD1 variants: The need for biochemical testing in the era of advanced genetics

Mol Genet Metab. 2016 Jun;118(2):123-7. doi: 10.1016/j.ymgme.2016.03.009. Epub 2016 Apr 3.


X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. In male patients, an increased plasma VLCFA levels in combination with a pathogenic mutation in ABCD1 confirms the diagnosis. Recent studies have shown that many women with ALD also develop myelopathy. Correct diagnosis is important for management including genetic counseling. Diagnosis in women can only be confirmed when VLCFA levels are elevated or when a known pathogenic ABCD1 mutation is identified. However, in 15-20% of women with ALD VLCFA plasma levels are not elevated. Demonstration that a novel sequence variant is pathogenic can be a challenge when VLCFA levels are in the normal range. Here we report two women with a clinical presentation compatible with ALD, an ABCD1 variation (p.Arg17His and p.Ser358Pro) of unknown significance, but with normal VLCFA levels. We developed a diagnostic test that is based on generating clonal cell lines that express only one of the two alleles. Subsequent biochemical studies enabled us to show that the two sequence variants were not pathogenic, thereby excluding the diagnosis ALD in these women. We conclude that the clonal approach is an important addition to the existing diagnostic array.

Keywords: Carrier testing; Diagnosis; Metabolic disease; Peroxisome.

Publication types

  • Case Reports

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily D, Member 1 / genetics*
  • ATP Binding Cassette Transporter, Subfamily D, Member 1 / metabolism
  • Adrenoleukodystrophy / blood
  • Adrenoleukodystrophy / diagnosis*
  • Adrenoleukodystrophy / genetics*
  • Adult
  • Alleles
  • Cell Line
  • DNA Mutational Analysis
  • Fatty Acids / blood
  • Female
  • Genetic Carrier Screening / methods*
  • Genetic Variation
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Peroxisomes / metabolism
  • Spinal Cord Diseases / diagnosis
  • Spinal Cord Diseases / genetics


  • ABCD1 protein, human
  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • Fatty Acids