ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 g ene, which encodes a peroxisomal ABC half-transporter (ALDP) involved in th e import of very long-chain fatty acids (VLCFA) into the peroxisome. The di sease is characterized by a striking and unpredictable variation in phenoty pic expression. Phenotypes include the rapidly progressive childhood cerebr al form (CCALD), the milder adult form, adrenomyeloneuropathy (AMN), and va riants without neurologic involvement. There is no apparent correlation bet ween genotype and phenotype. In males, unambiguous diagnosis can be achieve d by demonstration of elevated levels of VLCFA in plasma. In 15 to 20% of o bligate heterozygotes, however, test results are false-negative. Therefore, mutation analysis is the only reliable method for the identification of he terozygotes. Since most X-ALD kindreds have a unique mutation, a great numb er of mutations have been identified in the ABCD1 gene in the last seven ye ars. In order to catalog and facilitate the analysis of these mutations, we have established a mutation database for X-ALD (http://www.x-ald.nl). In t his review we report a detailed analysis of all 406 X-ALD mutations current ly included in the database. Also, we present 47 novel mutations. In additi on, we review the various X-ALD phenotypes, the different diagnostic tools, and the need for extended family screening for the identification of new p atients. Hum Mutat 18:499-515, 2001. (C) 2001 Wiley-Liss, Inc.