A distinct variant of intermediate maple syrup urine disease

M. C. Gonzalez-Rios, D. T. Chuang, R. P. Cox, K. Schmidt, K. Knopf, S. Packman

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Branched chain α-ketoacid dehydrogenase (BCKAD) deficiency, or maple syrup urine disease (MSUD), can be categorized as classical, intermediate, intermittent or thiamine responsive, based on generally concordant in vitro BCKAD activity and severity of phenotype. We present clinical and enzymatic data on a boy with intermediate maple syrup urine disease, and suggest that he represents a novel category of mutation. He presented at age 10 months in ketoacidotic coma, with a history of irritability, poor feeding and growth and developmental delay. Branched chain amino acid restriction effected normal growth and developmental parameters by age 42 months. In contrast to previous patients with intermediate MSUD, his fibroblasts and fibroblast extracts failed to decarboxylate [1-14C]-α-ketoisovalerate (KIV). The defect is not in mitochondrial transport of substrate, but rather in the catalytic activity of the E1 component of the BCKAD. Disrupted cells of the proband exhibited negligible BCKAD activity over a wide range of keto acid substrate concentrations, irrespective of the presence of added thiamine pyrophosphate (TPP). These results differ from the sigmoidal kinetics observed using classical MSUD extracts, and the hyperbolic kinetics with control preparations under the same assay conditions. We propose that the structurally altered enzyme possesses reduced but not negligible activity in vivo, and exists as an unstable complex in vitro under assay conditions used, even in the presence of added TPP.

Original languageEnglish (US)
Pages (from-to)153-159
Number of pages7
JournalClinical Genetics
Volume27
Issue number2
StatePublished - 1985

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3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Maple Syrup Urine Disease
Thiamine Pyrophosphate
Fibroblasts
Keto Acids
Branched Chain Amino Acids
Thiamine
Coma
Growth
Phenotype
Mutation
Enzymes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Gonzalez-Rios, M. C., Chuang, D. T., Cox, R. P., Schmidt, K., Knopf, K., & Packman, S. (1985). A distinct variant of intermediate maple syrup urine disease. Clinical Genetics, 27(2), 153-159.

A distinct variant of intermediate maple syrup urine disease. / Gonzalez-Rios, M. C.; Chuang, D. T.; Cox, R. P.; Schmidt, K.; Knopf, K.; Packman, S.

In: Clinical Genetics, Vol. 27, No. 2, 1985, p. 153-159.

Research output: Contribution to journalArticle

Gonzalez-Rios, MC, Chuang, DT, Cox, RP, Schmidt, K, Knopf, K & Packman, S 1985, 'A distinct variant of intermediate maple syrup urine disease', Clinical Genetics, vol. 27, no. 2, pp. 153-159.
Gonzalez-Rios MC, Chuang DT, Cox RP, Schmidt K, Knopf K, Packman S. A distinct variant of intermediate maple syrup urine disease. Clinical Genetics. 1985;27(2):153-159.
Gonzalez-Rios, M. C. ; Chuang, D. T. ; Cox, R. P. ; Schmidt, K. ; Knopf, K. ; Packman, S. / A distinct variant of intermediate maple syrup urine disease. In: Clinical Genetics. 1985 ; Vol. 27, No. 2. pp. 153-159.
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N2 - Branched chain α-ketoacid dehydrogenase (BCKAD) deficiency, or maple syrup urine disease (MSUD), can be categorized as classical, intermediate, intermittent or thiamine responsive, based on generally concordant in vitro BCKAD activity and severity of phenotype. We present clinical and enzymatic data on a boy with intermediate maple syrup urine disease, and suggest that he represents a novel category of mutation. He presented at age 10 months in ketoacidotic coma, with a history of irritability, poor feeding and growth and developmental delay. Branched chain amino acid restriction effected normal growth and developmental parameters by age 42 months. In contrast to previous patients with intermediate MSUD, his fibroblasts and fibroblast extracts failed to decarboxylate [1-14C]-α-ketoisovalerate (KIV). The defect is not in mitochondrial transport of substrate, but rather in the catalytic activity of the E1 component of the BCKAD. Disrupted cells of the proband exhibited negligible BCKAD activity over a wide range of keto acid substrate concentrations, irrespective of the presence of added thiamine pyrophosphate (TPP). These results differ from the sigmoidal kinetics observed using classical MSUD extracts, and the hyperbolic kinetics with control preparations under the same assay conditions. We propose that the structurally altered enzyme possesses reduced but not negligible activity in vivo, and exists as an unstable complex in vitro under assay conditions used, even in the presence of added TPP.

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