Maternal gonadal mosaicism causing ornithine transcarbamylase deficiency

• Published in: American journal of medical genetics Vol. 85; no. 5; p. 452
• Main Authors: Bowling, F, McGown, I, McGill, J, Cowley, D, Tuchman, M
• Format: Journal Article
• Language: English
• Published: United States 27.08.1999
• Subjects: Abortion, Induced; Adult; Amino Acid Metabolism, Inborn Errors - embryology; Amino Acid Metabolism, Inborn Errors - enzymology; Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Substitution; Chorionic Villi Sampling; Exons; Female; Genomic Imprinting; Humans; Infant, Newborn; Male; Mosaicism; Ornithine Carbamoyltransferase - genetics; Ornithine Carbamoyltransferase Deficiency Disease; Pedigree; Point Mutation; X Chromosome
• ISSN: 0148-7299
• DOI: 10.1002/(SICI)1096-8628(19990827)85:5<452::AID-AJMG4>3.0.CO;2-4

Ornithine transcarbamylase (OTC) deficiency (McKusick 311250), an X-linked inherited disorder, often presents in males with severe neonatal onset of hyperammonemia. Maternal gonadal mosaicism in OTC deficiency was postulated previously, but no cases have been reported. We report on a family in which two consecutive males were affected with OTC deficiency, which was proven biochemically with characteristic metabolites and absent enzyme activity in liver. OTC genotyping in both brothers showed a new mutation in exon 6 (Met206Arg: ATG-->AGG), which encodes part of the equatorial H6 alpha-helix. Biochemical investigations confirmed normal results in the mother and grandmother and the absence of OTC activity in the affected males. Genotyping of the mother and grandmother was performed on peripheral blood leukocytes and skin fibroblasts and showed no mutation in the somatic cells. The recurrence of OTC deficiency in offsprings of a woman with normal genotype strongly suggests gonadal mosaicism. Gonadal mosaicism needs to be considered when counseling couples in which the mother has had a previously affected child with OTC deficiency but apparently is not a carrier.