Early infantile presentation of 3-methylcrotonyl CoA carboxylase deficiency: a case report (original) (raw)
Related papers
Molecular Genetics and Metabolism, 2013
Background and methods: There are considerable uncertainty and debate regarding all aspects of newborn screenpositive cases of 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD), including diagnostic criteria, clinical spectrum, morbidity, prognosis, and appropriate management. To address some of these questions, we queried data from the California Newborn Screening Program's Screening Information System (SIS) and available scanned laboratory reports on cases of 3-MCCD reported by 15 state contracted metabolic specialty care centers born between July 2005 and December 2010. We evaluated the completeness and utility of the database as a tool for clinical disease characterization. Results: During the study period, 2,959,108 infants were screened and 71 infants were diagnosed with 3-MCCD for an overall incidence of 1:41,676. The availability of diagnostic biochemical laboratory data varied significantly from subject to subject. Using a new case classification based on biochemical severity, we found that 8 of the cases met our criteria for biochemically severe (category 1), 19 cases met our criteria for biochemically mild (category 2) that we suspect to possibly be hypomorphic variants or heterozygote carriers, and 44 cases could not be classified (category 3) as mild or severe based on the data available in SIS. Documentation of the treatment regimens also varied significantly with 49% receiving dietary modification and 44% receiving carnitine. 15% of cases were documented to have experienced at least one of the following symptoms: lethargy, vomiting, irritability, ketosis, poor feeding, or poor tone. The majority of the subjects were completely developmentally age appropriate at their last assessment. Conclusions: The results suggest that a significant portion of the 3-MCCD "confirmed" cases have a mild biochemical phenotype. Moreover the majority of cases had insufficient data entered to allow for adequate clinical characterization of the cases. These findings raise the concern that a significant number of individuals receiving treatment for 3-MCCD may not have a clinically significant condition. Additionally, the utility of this data system could be improved if centers provided complete confirmatory test results and more specific documentation of clinical outcomes and health/developmental status. Further studies, including a clinical chart review, are necessary to validate the data and further characterize this cohort.
Gene, 2016
Communicated by Johannes Zschocke Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder that appears to be the most frequent organic aciduria detected in tandem mass spectrometry (TMS)-based neonatal screening programs. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. MCC is a heteromeric mitochondrial enzyme composed of biotin containing α subunits and smaller β subunits, encoded by MCCA and MCCB, respectively. We report mutation analysis in 28 MCC-deficient probands, 19 of whom were asymptomatic newborns detected by TMS newborn screening, and nine presented with clinical symptoms. Ten have mutations in MCCA, and 18 in MCCB. We identified 10 novel MCCA and 14 novel MCCB mutant alleles including missense, nonsense, frameshift and splice site mutations, and show that three of the missense mutations result in severely decreased MCC activity when expressed in MCCdeficient cell lines. Our data demonstrate no clear correlation between genotype and phenotype suggesting that factors other than the genotype at the MCC loci have a major influence on the phenotype of MCC deficiency.
Molecular Genetics and Metabolism, 2008
3-MCC deficiency is among the most common inborn errors of metabolism identified on expanded newborn screening (1:36,000 births). However, evidence-based guidelines for diagnosis and management of this disorder are lacking. Using the traditional Delphi method, a panel of 15 experts in inborn errors of metabolism was convened to develop consensus-based clinical practice guidelines for the diagnosis and management of 3-MCC screen-positive infants and their mothers. The Oxford Centre for Evidence-based Medicine system was used to grade the literature review and create recommendations graded from A (evidence level of randomized clinical trials) to D (expert opinion).
Human …, 2006
Communicated by Ronald Wanders 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 5 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 (o10%) 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. Hum Mutat 27(8),
A newborn screening approach to diagnose 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency
JIMD Reports
3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessively inherited metabolic disorder. Patients suffer from avoidable neurologically devastating metabolic decompensations and thus would benefit from newborn screening (NBS). The diagnosis is currently made by measuring dry blood spot acylcarnitines (C5OH and C6DC) followed by urinary organic acid profiling for the differential diagnosis from several other disorders. Using untargeted metabolomics (reversed-phase UHPLC coupled to an Orbitrap Elite hybrid mass spectrometer) of plasma samples from 5 HMGCLD patients and 19 age-matched controls, we found 3-methylglutaconic acid and 3-hydroxy-3-methylglutaric acid, together with 3-hydroxyisovalerylcarnitine as
Molecular Genetics and Metabolism, 2012
Isolated 3-Methylcrotonyl-CoA carboxylase deficiency (MCC deficiency) is an organic aciduria presenting with a highly variable phenotype and has been part of newborn screening programs in various countries, in particular in the US. Here we present enzymatic and genetic characterisation of 22 individuals with increased 3-hydroxyisovalerylcarnitine and/or 3-methylcrotonylglycine suggesting MCC deficiency, but only partially reduced 3-methylcrotonyl-CoA carboxylase activity. Among these, 21 carried a single mutant allele in either MCCC1 (n= 20) or MCCC2 (n= 1). Our results suggest that heterozygosity for such a single deleterious mutation may lead to misdiagnosis of MCC deficiency.
The Molecular Basis of Human 3-Methylcrotonyl-CoA Carboxylase Deficiency
Journal of Clinical …, 2001
Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine catabolism that appears to be the most frequent organic aciduria detected in tandem mass spectrometrybased neonatal screening programs. The ...
Evidence-based neonatal screening for inborn errors of metabolism
Current Paediatrics, 2004
Newborn screening is on the verge of a major revolution. Screening for inborn errors of metabolism (IEM) throughout the United Kingdom (UK) commenced in the 1960s, with the introduction of testing for phenylketonuria. Subsequently, programmes for diagnosis of a number of other conditions in newborn infants, with neonatal bloodspots, have been developed. Tandem mass spectrometry is a technological advance giving rise to the potential for a major expansion in newborn screening for IEMs. This has led to the development of a study to establish whether neonatal screening should be extended to include medium chain acyl CoA dehydrogenase deficiency. A pilot newborn screening service for MCADD has commenced covering approximately half the births in the UK. Samples for tandem mass spectrometry should be collected as part of the diagnostic work-up for neonates and children presenting with a possible inborn error of metabolism, particularly fat oxidation defects.