Submission Details

The relationship between ABCD1 and adrenoleukodystrophy (ABCD1 deficiency), including X-linked cerebral adrenoleukodystrophy and adrenomyeloneuropathy (AMN), and isolated adrenal insufficiency, inherited in the X-linked pattern, has been evaluated using the ClinGen Clinical Validity Framework as of November, 2020. This association was made using case-level and experimental data. The ABCD1 gene encodes an ATP-binding cassette half-transporter (ALDP) located in peroxisomes. Using positional cloning, Moser et al. (1993) discovered that this gene was partially deleted in 6 of 85 unrelated patients with adrenoleukodystrophy (ALD), who exhibit neurological symptoms as well as the pathognomonic feature of very long chain fatty acid (VLCFA) accumulation. Since then, several hundreds of inherited and de novo variants (including missense, nonsense, splice site, delins and structural arrangements) have been associated with ABCD1 deficiency, many of which have decreased or absent protein expression and localization at the peroxisomes (PMIDs: 7825602, 8651290, 11748843, 15811009, 21700483).

Summary of Case Level Data (12 points): The association is seen in at least 33 probands in 4 publications (PMID: 15811009, 8651290, 7825602, 21700483). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.

The mechanism for disease is expected to be hemizygous loss of function. Female carriers are sometimes symptomatic with elevated VLCFA levels.

Summary of Experimental Data (6 points): ALDP is shown to be reduced or absent in expression in patients with ABCD1 deficiency. Mice deficient in ALDP do not phenocopy the neurologic disturbances typical of childhood-onset ALD, but do exhibit VLCFA accumulation (PMID: 9256488, 7878038). However, mouse models do recapitulate the adult-onset AMN phenotype (11875044, 15489218). ALDP interacts with PEX19, another peroxisome membrane protein that is implicated in peroxisome biogenesis disorders. Rescue in patient cells has been shown with expression of recombinant ALDP restoring peroxisome beta-oxidation. Lentiviral-mediated gene therapy in ALD patients has shown to mitigate major functional disabilities in childhood patients with ALD (PMID: 28976817). Blocking ABCD1 in healthy fibroblasts leads to VLCFA accumulation similar to that seen in patients with XALD (PMID: 23671276).

In summary, ABCD1 is definitively associated with adrenoleukodystrophy (ABCD1 deficiency). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Peroxisomal Disorders GCEP on December 18, 2020 (SOP Version 7).