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Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency

Lookup NU author(s): Dr Morteza Pourfarzam, Professor Kim Bartlett


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Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial rate-limiting step in mitochondrial fatty acid P-oxidation. VLCAD deficiency is clinically heterogenous, with three major phenotypes: a severe childhood form, with early onset, high mortality, and high incidence of cardiomyopathy; a milder childhood form, with later onset, usually with hypoketotic hypoglycemia as the main presenting feature, low mortality and rare cardiomyopathy; and an adult form, with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria, usually triggered by exercise or fasting. To examine whether these different phenotypes are due to differences in the VLCAD genotype, we investigated 58 different mutations in 55 unrelated patients representing all known clinical phenotypes and correlated the mutation type with the clinical phenotype. Our results show a clear relationship between the nature of the mutation and the severity of disease. Patients with the severe childhood phenotype have mutations that result in no residual enzyme activity, whereas patients with the milder childhood and adult phenotypes have mutations that may result in residual enzyme activity. This clear genotype-phenotype relationship is in sharp contrast to what has been observed in medium-chain acyl-CoA dehydrogenase deficiency, in which no correlation between genotype and phenotype can be established.

Publication metadata

Author(s): Bartlett K; Pourfarzam M; Andresen BS; Olpin S; Poorthuis BJHM; Scholte HR; Vianey-Saban C; Wanders R; Ijlst L; Morris A; Baumgartner ER; deKlerk JBC; Schroeder LD; Corydon TJ; Lund H; Winter V; Bross P; Bolund L; Gregersen N

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 1999

Volume: 64

Issue: 2

Pages: 479-494

Print publication date: 01/02/1999

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1086/302261


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