Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy

Background: X-linked adrenoleukodystrophy (ALD) is an inherited disease cha racterized by progressive neurologic dysfunction, occasionally associated w ith adrenal insufficiency. The classic form of AID usually has onset in chi ldhood (childhood cerebral ALD), with rapid neurologic deterioration leadin g to a vegetative state. Adult-onset cerebral ALD also presents with rapidl y progressive neurologic dysfunction. Milder phenotypes such as adrenomyelo neuropathy and Addison disease only also have been recognized. Despite disc overy of the causative gene, a molecular basis for the diverse clinical pre sentations remains to be elucidated. Objectives: To conduct mutational analyses in 29 Japanese patients with ALD from 29 unrelated families, to obtain knowledge of the spectrum of mutatio ns in this gene, and to study genotype-phenotype correlations in Japanese p atients. Methods: The 29 patients comprised 13 patients with childhood cerebral ALD, 11 patients with adult-onset cerebral ALD, and 5 patients with adrenomyelo neuropathy. We conducted detailed mutational analyses of 29 unrelated Japan ese patients with ALD by genomic Southern blot analysis and direct nucleoti de sequence analysis of reverse transcriptase-polymerase chain reaction pro ducts derived from total RNA that was extracted from cultured skin fibrobla sts, lymphoblastoid cells, or peripheral blood leukocytes. Results: Three patients with adult-onset cerebral ALD were identified as ha ving large genomic rearrangements. The remaining 26 patients were identifie d as having 21 independent mutations, including 12 novel mutations resultin g in small nucleotide alterations in the ALD gene, Eighteen (69%) of 26 mut ations were missense mutations. Most missense mutations involved amino acid s conserved in homologous gene products, including PMF70, mALDRP, and Pxa1p . The AG dinucleotide deletion at position 1081-1082, which has been report ed previously to be the most common mutation in white patients (12-17%), wa s also identified as the most common mutation in Japanese patients (12%). A ll phenotypes were associated with mutations resulting in protein truncatio n or subtle amino acid changes. There were no differences in phenotypic exp ressions between missense mutations involving conserved amino acids and tho se involving nonconserved amino acids. Conclusion: There are no obvious correlations be tween the phenotypes of pa tients with ALD and their genotypes, suggesting that other genetic or envir onmental factors modify the phenotypic expressions of ALD.