title: Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency.
abstract: Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial rate-limiting step in mitochondrial fatty acid beta-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.
authors.affiliation: Research Unit for Molecular Medicine, Skejby Sygehus, DK 8200 Arhus N, Denmark, Germany. brage@biobase.dk
authors.forename: B S
authors.initials: BS
authors.lastname: Andresen
authors.forename: S
authors.initials: S
authors.lastname: Olpin
authors.forename: B J
authors.initials: BJ
authors.lastname: Poorthuis
authors.forename: H R
authors.initials: HR
authors.lastname: Scholte
authors.forename: C
authors.initials: C
authors.lastname: Vianey-Saban
authors.forename: R
authors.initials: R
authors.lastname: Wanders
authors.forename: L
authors.initials: L
authors.lastname: Ijlst
authors.forename: A
authors.initials: A
authors.lastname: Morris
authors.forename: M
authors.initials: M
authors.lastname: Pourfarzam
authors.forename: K
authors.initials: K
authors.lastname: Bartlett
authors.forename: E R
authors.initials: ER
authors.lastname: Baumgartner
authors.forename: J B
authors.initials: JB
authors.lastname: deKlerk
authors.forename: L D
authors.initials: LD
authors.lastname: Schroeder
authors.forename: T J
authors.initials: TJ
authors.lastname: Corydon
authors.forename: H
authors.initials: H
authors.lastname: Lund
authors.forename: V
authors.initials: V
authors.lastname: Winter
authors.forename: P
authors.initials: P
authors.lastname: Bross
authors.forename: L
authors.initials: L
authors.lastname: Bolund
authors.forename: N
authors.initials: N
authors.lastname: Gregersen
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain; D044944:Acyl-CoA Dehydrogenases / Q000172:deficiency* / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D018387:Codon, Initiator; D005091:Exons; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA