Molecular heterogeneity of variant isovaleryl-CoA dehydrogenase from cultured isovaleric acidemia fibroblasts.

Ikeda, Yasuyuki; Keese, Susan M; Tanaka, Kay

doi:10.1073/pnas.82.20.7081

Cited by 34 publications

(36 citation statements)

References 19 publications

(9 reference statements)

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“…A significant proportion of the mutant alleles lead to abnormal splicing of the IVD RNA and subsequent complete lack of IVD protein [Vockley et al, 1991;Vockley et al, 2000]. Studies of the bioprocessing of IVD protein in fibroblasts from patients with IVA have reflected the effects of these mutations but have not provided insight into the clinical variability seen in the disorder [Ikeda et al, 1985b;Vockley et al, 1991]. In general, genotype and phenotype have not been well correlated.…”

Section: Molecular Findingsmentioning

confidence: 99%

“…Fibroblasts, lymphocytes, and amniocytes all have measurable amounts of IVD activity and serve as ready sources of tissue for this purpose [Ensenauer et al, 2004;Kleij et al, 1995;Mohsen et al, 1998;Vockley et al, 1991]. While significant residual activity blunts the level of abnormal metabolites, correlation between clinical presentation and enzyme activity has been poor [Hyman and Tanaka, 1986;Ikeda et al, 1985b;Vockley et al, 1991].…”

Section: Biochemical Diagonosis and Follow Upmentioning

confidence: 99%

“…Molecular analysis of the IVD gene in patients with symptomatic IVA has identified numerous point mutations in the protein coding region that lead to the production of an inactive or unstable protein (Fig. 2) [Ikeda et al, 1985b;Mohsen et al, 1998;Vockley et al, 1992a;Vockley et al, 1992b;Vockley et al, 1991;Vockley et al, 2000]. Some of these have been shown to cause only a mild alteration in enzyme function, correlating to some extent with a mild clinical phenotype in patients [Mohsen et al, 1998;Nasser et al, 2004].…”

Section: Molecular Findingsmentioning

confidence: 99%

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Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Vockley

Ensenauer

2006

American J of Med Genetics Pt C

192

161

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Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra-and inter-familial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years.

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Section: Molecular Findingsmentioning

confidence: 99%

Section: Biochemical Diagonosis and Follow Upmentioning

confidence: 99%

Section: Molecular Findingsmentioning

confidence: 99%

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Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Vockley

Ensenauer

2006

American J of Med Genetics Pt C

192

161

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“…The levels of abnormal metabolites identified in patients, however, did not reliably differentiate between patients carrying splicing mutation and those with coding gene mutations. Thus, neither mutant genotype nor urine isovalerylglycine concentration provided any insight into the clinical course of patients, a conclusion reached in other patient populations as well [10,21].…”

Section: Discussionmentioning

confidence: 99%

Different spectrum of mutations of isovaleryl-CoA dehydrogenase (IVD) gene in Korean patients with isovaleric acidemia

Lee

Vockley

et al. 2007

Molecular Genetics and Metabolism

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Isovaleric acidemia (IVA) is an autosomal recessive inborn error of the leucine metabolism that is caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD). Recent application of tandem mass spectrometry to newborn screening has allowed a significant expansion of the recognition of individuals with IVD deficiency. Although many patients have been reported worldwide, there are no genetically confirmed patients in Korea. This study characterizes IVD mutations in seven Korean IVA patients from six unrelated families. Bi-directional sequencing analysis identified two novel variations affecting consensus splice sites (c.144+1G>T in intron 1 and c.457-3_2CA>GG in intron 4) and three novel variations altering coding sequences (c.149G>T; Arg21Leu, c. 832A>G; Ser249Gly, and c.1135T>G; Phe350-Val). Five patients from four families were found to be compound heterozygotes while two unrelated patients were homozygous for the c. 457-3_2CA>GG variation. Reverse-transcription polymerase chain reaction confirmed that both intron variations cause aberrant splicing. Furthermore, analysis of cultured lymphocyte extracts of the seven patients showed no detectable enzyme activity and reduced levels of IVD protein (<10.0% of control) in all samples. These results confirm IVD mutations in Korean patients with IVA and reveal that the mutation spectrum is different from previously reported patients.

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“…1.3.99.10) (19). Heterogeneity for this enzyme in patients with isovaleric acidemia has been noted (20). The gene for isovaleryl-CoA dehydrogenase has been cloned and assigned to the lone arm of human chromosome 15 (2 1 ).…”

Section: Iva Isovaleric Acid Ivg Isovalerylglycine Msud Maple Syrumentioning

confidence: 99%

The Treatment of Isovaleric Acidemia with Glycine Supplement

et al. 1988

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ABSTRACT. Although dietary leucine restriction and supplemental glycine are used to treat patients with isovaleric acidemia [deficient isovaleryl-CoA-dehydrogenase (E.C. 1.3.99.10)], little quantitative information is available regarding their optimum relationship. Herein we compare different glycine supplements and quantitate isovalerylglycine produced in two patients with clinically different forms of isovaleric acidemia during restricted leucine intake and during oral leucine loading. We found that under stable conditions of leucine restriction, 150 mg glycine/kg/day is an optimum glycine supplement and that glycine supplements of more than 250 mg/kg/day may result in reduced isovalerylglycine production; that when isovaleric acid accumulation is increased, glycine supplements to 600 mg/ kg/day will increase isovalerylglycine production; and that the phenotype of isovaleric acidemia is related not only to the extent of impaired isovaleryl-CoA dehydrogenase, but also the ability to detoxify accumulated isovaleryl CoA to isovalerylglycine. (Pediatr Res 24: 9-13, 1988)

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Molecular heterogeneity of variant isovaleryl-CoA dehydrogenase from cultured isovaleric acidemia fibroblasts.

Abstract: Variants of isovaleryl-CoA dehydrogenase (IVDHase, EC 1.3.99.10) in 15 isovaleric acidemia fibroblast lines were analyzed using [3sS]methionine labeling, immunoprecipitation with anti-rat IVDHase antiserum, and NaDod-

Cited by 34 publications

References 19 publications

Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity

Different spectrum of mutations of isovaleryl-CoA dehydrogenase (IVD) gene in Korean patients with isovaleric acidemia

The Treatment of Isovaleric Acidemia with Glycine Supplement

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