X-linked adrenoleukodystrophy in Spain. Identification of 26 novel mutations in the ABCD1 gene in 80 patients. Improvement of genetic counseling in 162 relative females

• Published in: Clinical genetics 2005-05, Vol.67 (5), p.418-424
• Main Authors: Coll, MJ, Palau, N, Camps, C, Ruiz, M, Pàmpols, T, Girós, M
• Format: Article
• Language: English
• Subjects: Adrenoleukodystrophy - diagnosis; Adrenoleukodystrophy - genetics; Adult; ATP Binding Cassette Transporter, Sub-Family D, Member 1; ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; DNA Mutational Analysis; Errors of metabolism; Fatty Acids - genetics; Female; General aspects. Genetic counseling; Genetic Counseling; Genetic testing; Genetics; Genotype; Genotype & phenotype; Humans; Lipids (lysosomal enzyme disorders, storage diseases); Male; Medical disorders; Medical genetics; Medical sciences; Metabolic diseases; Mutation; mutations; Pedigree; Phenotype; Polymorphism, Genetic; Spain; X-ALD
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2005.00423.x

In this study, we analyzed the ABCD1 gene in 80 X‐linked adrenoleukodystrophy (X‐ALD) patients from 62 unrelated families. We identified 53 different mutations, of which 26 are novel and two are non‐pathogenic sequence variants (L516L and 3′UTR, 2246C/G) that have been previously described. The Spanish population had significant allelic heterogeneity, in which most of the mutations were exclusive to a single family 47/53 (88.7%). Only six mutations (Y174S, G277R, FsE471, R518Q, P543L, and R554H) were found in more than one family. Mutations G277R, P543L, and R554H were the most frequent, each of them being found in three patients (5%). Intra‐familiar phenotype variability was observed in most of the families, but in one, with the novel mutation R120P, only the adult mild phenotype was present (five hemizygous family members). We detected 80 heterozygous women by mutation analysis, but only 78 of them showed increased very‐long‐chain fatty acid levels. In conclusion, this study extends the spectrum of mutations in X‐ALD and facilitates the identification of heterozygous females. Our results are also consistent with previous studies reporting the difficulty of predicting genotype–phenotype correlation.