title: X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism.
abstract: 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%.
authors.affiliation: DNA Diagnostic Laboratory, Johns Hopkins University School of Medicine, CMSC1004, 600 N. Wolfe Street, Baltimore, MD 21287, USA. ywang117@jhu.edu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Rachel
authors.initials: R
authors.lastname: Busin
authors.forename: Catherine
authors.initials: C
authors.lastname: Reeves
authors.forename: Lena
authors.initials: L
authors.lastname: Bezman
authors.forename: Gerald
authors.initials: G
authors.lastname: Raymond
authors.forename: Cicely J
authors.initials: CJ
authors.lastname: Toomer
authors.forename: Paul A
authors.initials: PA
authors.lastname: Watkins
authors.forename: Ann
authors.initials: A
authors.lastname: Snowden
authors.forename: Ann
authors.initials: A
authors.lastname: Moser
authors.forename: Sakkubai
authors.initials: S
authors.lastname: Naidu
authors.forename: Genila
authors.initials: G
authors.lastname: Bibat
authors.forename: Stacy
authors.initials: S
authors.lastname: Hewson
authors.forename: Karen
authors.initials: K
authors.lastname: Tam
authors.forename: Joe T R
authors.initials: JT
authors.lastname: Clarke
authors.forename: Lawrence
authors.initials: L
authors.lastname: Charnas
authors.forename: Gail
authors.initials: G
authors.lastname: Stetten
authors.forename: Barbara
authors.initials: B
authors.lastname: Karczeski
authors.forename: Garry
authors.initials: G
authors.lastname: Cutting
authors.forename: Steven
authors.initials: S
authors.lastname: Steinberg
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005190:Family; D017809:Fatal Outcome; D005260:Female; D006066:Gonads / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation / Q000235:genetics*
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters