ABCD1 translation-initiator mutation demonstrates genotype-phenotype correlation for AMN

Background: Inherited mutations of the X-linked adrenoleukodystrophy (X-ALD ) gone (ABCD1) cause two neuropathologically distinct disorders: cerebral a drenoleukodystrophy (ALD) and adrenomycloneuropathy (AMN). The biochemical hallmark of these disorders is a reduction of very long chain fatty acid (V LCFA) beta -oxidation with accumulation of VLCFA esters in neural white mat ter. More than 300 mutations of the ABCD1 gene have been described. Genotyp e-phenotype correlation in X-ALD has not been demonstrated; indeed, the two disorders coexist in individual pedigrees and in homozygotic twin pairs. M ethods: The authors have identified one large kindred with a highly concord ant AMN phenotype resembling an X-linked dominant hereditary spastic parapa resis. All obligate female carriers are clinically affected. The ABCD1 gene was examined by direct sequencing of genomic DNA and full-length cDNA. Mut ant gene transcription was analyzed by reverse transcriptase PCR. ALD prote in (ALDP) expression was tested by Western blotting and indirect immunofluo rescence. VLCFA beta -oxidation was examined by in vitro assay. Results: Th e authors have identified a novel deletion of the ABCD1 gene ATG translatio n initiation codon. The authors have demonstrated that an N-terminal trunca ted ALDP, missing the first 65 amino acids, is expressed by internal initia tion of translation and is correctly trafficked to peroxisomes. They have d ocumented complete penetrance of this mutant in all female carriers. They h ave also shown that VLCFA beta -oxidation is reduced to 20% of normal in as sociation with this mutant ALDP. Conclusion: It appears that initiation of translation at an internal AUG codon generates a truncated ALDP that unifor mly leads to an AMN phenotype in this family. Possible models for action of this truncated ALDP and full disease penetrance in heterozygotes are revie wed.