Isolated biotin‐resistant deficiency of 3‐methylcrotonyl‐CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome

Bannwart, C.; Wermuth, Bendicht; Baumgartner, R.; Suormala, Terttu; Wiesmann, Ulrich

doi:10.1007/bf01800223

Cited by 40 publications

(32 citation statements)

References 10 publications

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“…Clinical and biochemical data of ten patients have been reported in the literature: 001 (3), 002 (2), 003 (19), 004 (20), 006 (21), 007 (22), 010 (23), 011 (24), 012 (25), and 016 (4). Fibroblasts or DNA of the remaining patients were referred by B.T.…”

Section: Patients Complementation Analysis and MCC Assaymentioning

confidence: 99%

“…Probands 010 and 015, homozygous for truncating mutations in MCCA or MCCB (Tables 1 and 2), have, in one case, no symptoms and, in the other, a mild phenotype with late onset and no residual damage (23). By contrast, probands 011, 001, and 002, homozygous for missense mutations MCCA-R385S, MCCB-S173L, and -E99Q, have a severe phenotype with early-onset, major neurological involvement and, in one case, a fatal outcome (Table 1) (2,3,24). Proband 016, an adult Amish patient homozygous for the same MCCB-E99Q, has only mild symptoms (4).…”

Section: Population Frequency Of Selected Mcca and Mccb Allelesmentioning

confidence: 99%

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The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency

Baumgartner¹,

Almashanu²,

Suormala³

et al. 2001

J. Clin. Invest.

119

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Section: Patients Complementation Analysis and MCC Assaymentioning

confidence: 99%

Section: Population Frequency Of Selected Mcca and Mccb Allelesmentioning

confidence: 99%

The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency

Baumgartner¹,

Almashanu²,

Suormala³

et al. 2001

J. Clin. Invest.

119

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“…1). The clinical course has been shown to vary considerably, ranging from entirely asymptomatic to death in infancy [Bannwart et al, 1992;Mourmans et al, 1995]. Severe and mild phenotypes are not clearly defined.…”

Section: Introductionmentioning

confidence: 97%

Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity ofMCCA andMCCB mutations and impact on risk assessment

et al. 2006

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New technology enables expansion of newborn screening (NBS) of inborn errors aimed to prevent adverse outcome. In conditions with a large share of asymptomatic phenotypes, the potential harm created by NBS must carefully be weighed against benefit. Policies vary throughout the United States, Australia, and Europe due to limited data on outcome and treatability of candidate screening conditions. We elaborated the rationale for decision making in 3-methylcrotonyl-coenzyme A (CoA) carboxylase deficiency (MCCD), which afflicts leucine catabolism, with reported outcomes ranging from asymptomatic to death. In Bavaria, we screened 677,852 neonates for 25 conditions, including MCCD, based on elevated concentrations of 3-hydroxyisovalerylcarnitine (3-HIVA-C). Genotypes of MCCA (MCCC1) and MCCB (MCCC2) were assessed in identified newborns, their relatives, and in individuals (n = 17) from other regions, and correlated to biochemical and clinical phenotypes. NBS revealed eight newborns and six relatives with MCCD, suggesting a higher frequency than previously assumed (1:84,700). We found a strikingly heterogeneous spectrum of 22 novel and eight reported mutations. Allelic variants were neither related to biochemical nor anamnestic data of our probands showing all asymptomatic or benign phenotypes. Comparative analysis of case reports with NBS data implied that only few individuals (< 10%) develop symptoms. In addition, none of the symptoms reported so far can clearly be attributed to MCCD. MCCD is a genetic condition with low clinical expressivity and penetrance. It largely represents as nondisease. So far, there are no genetic or biochemical markers that would identify the few individuals potentially at risk for harmful clinical expression. The low ratio of benefit to harm was pivotal to the decision to exclude MCCD from NBS in Germany. MCCD may be regarded as exemplary of the ongoing controversy arising from the inclusion of potentially asymptomatic conditions, which generates a psychological burden for afflicted families and a financial burden for health care systems.

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“…Mutations in these genes cause MCC deficiency (also known as methylcrotonylglycinuria (Mckusick 210200/210210)), an autosomal recessive disorder with a variable phenotype ranging from severe neonatal onset to asymptomatic forms in adults (Baumgartner et al 2001;Gallardo et al 2001). Some patients present in the neonatal period with seizures and hypotonia (Bannwart et al 1992;Lehnert et al 1996); others are asymptomatic women discovered only by detection of abnormal metabolites in the neonatal screening samples of their healthy babies (Gibson et al 1998). Most patients, however, are asymptomatic until an episode of acute metabolic decompensation following intercurrent illness in early childhood leads to their diagnosis.…”

Section: -Methylcrotonyl-coa Carboxylase (Mcc) Deficiencymentioning

confidence: 99%

Molecular mechanism of dominant expression in 3‐methylcrotonyl‐CoA carboxylase deficiency

Baumgartner

2005

J of Inher Metab Disea

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Summary: Most enzyme deficiencies in humans are inherited as autosomal recessive traits. The term dominant negative is applied to mutant alleles in which a mutant protein interferes in one way or another with the function of the normal protein being produced from the wild-type allele in a heterozygote. Such a dominant negative effect usually involves homomeric or heteromeric proteins. 3-Methylcrotonyl-CoA carboxylase (MCC) is a heteromeric mitochondrial enzyme comprised of biotin containing MCCa subunits and smaller MCCb subunits, encoded by the genes MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype ranging from severe neonatal to asymptomatic adult forms. Patients with MCC deficiency have a characteristic organic aciduria with greatly increased excretion of 3-hydroxyisovaleric acid (3-HIVA) and 3-methylcrotonylglycine (3-MCG). Here, two patients with elevated excretion of 3-MCG and 3-HIVA and partial deficiency of MCC are discussed, one of them with severe neurological symptoms. Both showed evidence of biotin responsiveness and were heterozygous for the missense mutation MCCA-R385S. Evidence is presented that MCCA-R385S is a dominant negative allele leading to biochemical abnormalities and clinical symptoms in heterozygous individuals and that it is responsive to pharmacological doses of biotin in vivo. SIGNIFICANCE OF DOMINANT AND RECESSIVE MUTANT ALLELESBy definition, a phenotype expressed in the same way in both homozgotes and heterozygotes is dominant, whereas a phenotype expressed only in homozygotes or compound heterozygotes (or, for X-linked traits, hemizygotes) is recessive. In practice, this definition is too rigid to be useful. The distinction between dominant and recessive inheritance is not absolute and usually refers to the clinical phenotype

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Isolated biotin‐resistant deficiency of 3‐methylcrotonyl‐CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome

Cited by 40 publications

References 10 publications

The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency

The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency

Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity ofMCCA andMCCB mutations and impact on risk assessment

Molecular mechanism of dominant expression in 3‐methylcrotonyl‐CoA carboxylase deficiency

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