X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism

X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disorder affecting adrenal glands, testes and myelin stability that is caused by mutations in the ABCD1 (NM_000033) gene. Males with X-ALD may be diagnosed by the demonstration of elevated very long chain fatty acid (VLCFA) levels in...

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Published in:	Molecular genetics and metabolism Vol. 104; no. 1-2; pp. 160 - 166
Main Authors:	Wang, Ying, Busin, Rachel, Reeves, Catherine, Bezman, Lena, Raymond, Gerald, Toomer, Cicely J., Watkins, Paul A., Snowden, Ann, Moser, Ann, Naidu, Sakkubai, Bibat, Genila, Hewson, Stacy, Tam, Karen, Clarke, Joe T.R., Charnas, Lawrence, Stetten, Gail, Karczeski, Barbara, Cutting, Garry, Steinberg, Steven
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-09-2011
Subjects:	ABCD1 Adrenoleukodystrophy - genetics Adrenomyeloneuropathy ATP Binding Cassette Transporter, Sub-Family D, Member 1 ATP-Binding Cassette Transporters - genetics Base Sequence Child Child, Preschool De novo mutations DNA Mutational Analysis Exons - genetics Family Fatal Outcome Female Gonads - pathology Heterozygote Humans Male Molecular Sequence Data Mosaicism Mosaicism, gonadal Mosaicism, somatic Mutation - genetics X-linked adrenoleukodystrophy Adrenomyeloneuropathy Mosaicism, somatic De novo mutations Mosaicism, gonadal ABCD1 X-linked adrenoleukodystrophy
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Summary:	X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disorder affecting adrenal glands, testes and myelin stability that is caused by mutations in the ABCD1 (NM_000033) gene. Males with X-ALD may be diagnosed by the demonstration of elevated very long chain fatty acid (VLCFA) levels in plasma. In contrast, only 80% of female carriers have elevated plasma VLCFA; therefore targeted mutation analysis is the most effective means for carrier detection. Amongst 489 X-ALD families tested at Kennedy Krieger Institute, we identified 20 cases in which the ABCD1 mutation was de novo in the index case, indicating that the mutation arose in the maternal germ line and supporting a new mutation rate of at least 4.1% for this group. In addition, we identified 10 cases in which a de novo mutation arose in the mother or the grandmother of the index case. In two of these cases studies indicated that the mothers were low level gonosomal mosaics. In a third case biochemical, molecular and pedigree analysis indicated the mother was a gonadal mosaic. To the best of our knowledge mosaicism has not been previously reported in X-ALD. In addition, we identified one pedigree in which the maternal grandfather was mosaic for the familial ABCD1 mutation. Less than 1% of our patient population had evidence of gonadal or gonosomal mosaicism, suggesting it is a rare occurrence for this gene and its associated disorders. However, the residual maternal risk for having additional ovum carrying the mutant allele identified in an index case that appears to have a de novo mutation is at least 13%.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1096-7192 1096-7206
DOI:	10.1016/j.ymgme.2011.05.016