Isolated 3-Methylcrotonyl-CoA Carboxylase Deficiency: Evidence for an Allele-Specific Dominant Negative Effect and Responsiveness to Biotin Therapy

Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing α subunits and smaller β subunits, encoded by MCCA and MCCB, respectivel...

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Published in:	American journal of human genetics Vol. 75; no. 5; pp. 790 - 800
Main Authors:	Baumgartner, Matthias R., Dantas, M.Fernanda, Suormala, Terttu, Almashanu, Shlomo, Giunta, Cecilia, Friebel, Dolores, Gebhardt, Boris, Fowler, Brian, Hoffmann, Georg F., Baumgartner, E.Regula, Valle, David
Format:	Journal Article
Language:	English
Published:	Chicago, IL Elsevier Inc 01-11-2004 University of Chicago Press The American Society of Human Genetics
Subjects:	Alleles Base Sequence Biological and medical sciences Biotin - metabolism Biotin - therapeutic use Carbon-Carbon Ligases - deficiency Carbon-Carbon Ligases - genetics DNA Mutational Analysis Dose-Response Relationship, Drug Errors of metabolism Fibroblasts - metabolism Gene Expression General aspects. Genetic counseling Genetic Vectors - genetics Germany Glycine - analogs & derivatives Glycine - urine Greece Humans Infant, Newborn Male Medical genetics Medical sciences Metabolic diseases Miscellaneous hereditary metabolic disorders Mitochondrial Diseases - drug therapy Molecular Sequence Data Mutation - genetics Reverse Transcriptase Polymerase Chain Reaction Sequence Analysis, DNA Transfection Valerates - urine Greece Germany Carbon-carbon ligases Human Enzyme Pathogenesis Deficiency Metabolic diseases Biotin Genetic determinism Genetic disease Methylcrotonoyl-CoA carboxylase Allele Sensitivity Treatment Ligases Carboxylase Genetics Dominant character
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Summary:	Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing α subunits and smaller β subunits, encoded by MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype that ranges from severe neonatal to asymptomatic adult forms. No reported patients have responded to biotin therapy. Here, we describe two patients with a biochemical and, in one case, clinical phenotype of MCC deficiency, both of whom were responsive to biotin. The first patient presented at 3 months with seizures and progressive psychomotor retardation. Metabolic investigation at 2 years revealed elevated excretion of 3-MCG and 3-HIVA, suggesting MCC deficiency. High-dose biotin therapy was associated with a dramatic reduction in seizures, normalization of the electroencephalogram, and correction of the organic aciduria, within 4 weeks. MCC activity in fibroblasts was 25% of normal levels. The second patient, a newborn detected by tandem-mass-spectrometry newborn screening, displayed the same biochemical phenotype and remained asymptomatic with biotin up to the age of 18 months. In both patients, sequence analysis of the complete open reading frames of MCCA and MCCB revealed heterozygosity for MCCA-R385S and for the known polymorphic variant MCCA-P464H but revealed no other coding alterations. MCCA-R385S is unusual, in that it has a normal amount of MCCα protein but confers no MCC activity. We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA–wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Case Study-2 ObjectType-Feature-4 ObjectType-Report-1 ObjectType-Article-3
ISSN:	0002-9297 1537-6605
DOI:	10.1086/425181