3-Methylcrotonyl-CoA carboxylase deficiency: Mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening

Abstract

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 alpha subunits and smaller beta 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 MCC-deficient 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.

Newborn Screening By Tandem Mass Spectrometry: Impacts, Implications and Perspectives

“…Another limitation of MS/MS is raised by the diagnostic dilemma when one or several markers are the same for more than one disease. For instance C5OH is a marker of severe disease such as holocarboxylase synthase deficiency as well as a marker for a generally benign condition, namely 3 methylcrotonylCoA Carboxylase deficiency (Dantas et al, 2005;Koeberl et al, 2003). Despite these limitations, implementation of tandem mass spectrometry has generated a significant evolution in newborn screening programs, often referred-to as a paradigm shift.…”

Biochemical Characterisation and Whole Genome Expression Profiling of Cultured Skin Fibroblasts from Two South African Adults with Urinary 3-Hydroxyisovaleric Acid and 3-Methylcrotonylglycine

“…MCC deficiency is regarded as a disease with a low penetrance [19] since less than 10% of individuals with a metabolite profile indicative of MCC deficiency develops [14]. The clinical, biochemical, and enzymatic characterization of MCC deficiency have been well documented, but the pathomechanism remains largely unknown [9,15,[20][21][22][23][24][25][26].…”

“…The beta subunit is encoded by the MCCC2 (formerly called MCCB) gene located on chromosome 5q12-q13 and has 17 coding exons [31][32][33]. About 132 disease-causing mutations have been reported for the MCCC1 and MCCC2 genes [19] but no prevalent mutation has been identified and there is no clear genotype-phenotype correlation [17,21,31]. The MCC activity of patients with deleterious homozygous or compound heterozygous mutations is usually reduced to <5% of the mean activity of the controls [15,21,22,31], but a few cases have been reported with residual MCC activity, up to 34% [19,22,26] and some individuals with urinary metabolites indicative of MCC deficiency who only have a single heterozygous MCC mutation have almost normal MCC activity [17].…”

“…About 132 disease-causing mutations have been reported for the MCCC1 and MCCC2 genes [19] but no prevalent mutation has been identified and there is no clear genotype-phenotype correlation [17,21,31]. The MCC activity of patients with deleterious homozygous or compound heterozygous mutations is usually reduced to <5% of the mean activity of the controls [15,21,22,31], but a few cases have been reported with residual MCC activity, up to 34% [19,22,26] and some individuals with urinary metabolites indicative of MCC deficiency who only have a single heterozygous MCC mutation have almost normal MCC activity [17]. There is an increasing awareness of the difficulty to diagnose MCC deficiency because some patients present with an atypical metabolic profile with only trace amounts or even no detectable urinary MCG [22], the variability and non-specific nature of its symptoms and the growing number of individuals presenting with MCC deficiency associated metabolites but with only a single mutation in MCCC1 or MCCC2 [17].…”

Uneventful clinical courses of Korean patients with methylcrotonylglycinuria and their common mutations

“…7 Patients with MCG show a highly variable clinical phenotype, ranging from asymptomatic to severe, and they usually show normal growth and development without an experience of acute metabolic crisis, even without treatment. 8,9 However, a few reports underscore the importance of medical intervention because some patients can experience metabolic decompensation accompanying various stressful events including infection, and manifest a lot of symptoms such as frequent infections, feeding difficulty, vomiting, lethargy, apnea, hypotonia, seizure, mental retardation and death in the situation of metabolic crisis. [9][10][11][12][13] Therefore, there still exists a controversy over the necessity of aggressive medical intervention for MCG, or even the need for neonatal screening for MCG.…”