3-Methylcrotonyl-CoA carboxylase deficiency in an infant with cardiomyopathy, in her brother with developmental delay and in their asymptomatic father

Visser, Gepke; Suormala, Terttu; Smit, Gerrit; Reijngoud, Dirk-Jan; Bink-Boelkens, Mte; Niezen-Koning, Klaziena; Baumgartner, E. R.

doi:10.1007/pl00008366

Cited by 27 publications

(16 citation statements)

References 22 publications

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“…The reported clinical picture in the literature is heterogeneous, ranging from fatal cases (Gallardo et al 2001;Baykal et al 2005) to asymptomatic adult cases (Gallardo et al 2001) including mothers diagnosed due to abnormal newborn screening results in their infants (Grunert et al 2012). Clinical presentation varies even within families (Visser et al 2000;Eminoglu et al 2009). Neurological abnormalities have been reported (Baykal et al 2005) including one case of multiple sclerosis (Darin et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…A variety of other symptoms, mostly neurological, have been reported but most patients are asymptomatic. The clinical picture may show extensive intrafamiliar variation (Visser et al 2000;Baumgartner et al 2004;Darin et al 2007;Dirik et al 2008;Eminoglu et al 2009;Grunert et al 2012). However, most children detected through newborn screening remain asymptomatic (Stadler et al 2006;Lam et al 2013;Koeberl et al 2003).…”

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confidence: 99%

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Is l-Carnitine Supplementation Beneficial in 3-Methylcrotonyl-CoA Carboxylase Deficiency?

et al. 2014

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Background: 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCd) is an autosomal recessive disorder in the catabolism of leucine. In the present study, we investigated the current and prior medical condition of patients with 3-MCCd in the Faroe Islands and their carnitine levels in blood, urine and muscle tissue with and without L-carnitine supplementation to evaluate the current treatment strategy of not recommending L-carnitine supplementation to Faroese 3-MCCd patients.Methods: Blood and urine samples and muscle biopsies were collected from patients at inclusion and at 3 months. Eight patients received L-carnitine supplementation when recruited; five did not. Included patients who received supplementation were asked to stop L-carnitine, the others were asked to initiate L-carnitine supplementation during the study. Symptoms were determined by review of hospital medical records and questionnaires answered at baseline and after the intervention.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Is l-Carnitine Supplementation Beneficial in 3-Methylcrotonyl-CoA Carboxylase Deficiency?

et al. 2014

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“…The death of one individual at the age of 6.5 months appears not directly related to MCCD (cardiac arrest after accidental obstruction of the endotracheal tube) [Wiesmann et al, 1998]. Nine children [Beemer et al, 1982;Kobori et al, 1989;Tsai et al, 1989;Jurecki and Packman, 1992;Mourmans et al, 1995;Pearson et al, 1995;Ihara et al, 1997] and one adult [Visser et al, 2000] did not show any clinical signs (27%), while a large subgroup developed mild, mostly neurological, symptoms. The time points when first clinical symptoms arise are spread between the first day of life [Bannwart et al, 1992;Murayama et al, 1997;Wiesmann et al, 1998] and 4.7 years of age [Beemer et al, 1982].…”

Section: Clinical Phenotypes Of Reported Individuals With Mccd: Analymentioning

confidence: 98%

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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“…This is evident from the often broad spectrum of clinical symptoms and highly variable time of onset for the same disease [4, [6][7][8][9][10]. One such disease is isolated 3-methylcrotonylCoA carboxylase (MCC) deficiency (MIM #210200 and MIM This article is available from: //www.raredisorders.imedpub.com/ #210210) [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Berg¹,

Erasmus²,

Suormala³

et al. 2016

J Rare Disord Diagn Ther

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We report on the first case of marginal 3-methylcrotonyl-CoA carboxylase (MCC) deficiency in South Africa. Urinary 3-hydroxyisovaleric acid and 3-methylcrotonylglycine were detected in four males of a non-consanguineous family. Only the index patient (NWU001) had non-specific symptoms, the others were asymptomatic. The inherited metabolite profile and partially reduced MCC activity were indicative of marginal MCC deficiency. In vivo L-leucine loading confirmed a reduced flux through the leucine degradation pathway. No known deleterious mutations were detected in the open reading frames of MCCC1 and MCCC2. NWU001 was heterozygous for a SNP in MCCC1 (rs2270968; c.1391A>C, p.H464P). NWU002 was heterozygous for a MCCC2 splice variant which skips exon 7 and causes an in frame deletion of 38 amino acids that is identical to a predicted shorter MCCC2 isoform-2 (Q9HCC0-2). Whole genome expression profiles from cultured skin fibroblasts of NWU001 and NWU002 and two healthy adults using Affymetrix ® HuExST1.0 arrays detected 14237 significantly differentially expressed transcript IDs of which only 1277 have known annotation and gene association. The underlying molecular interactions, secondary signalling responses and functional relationships of these 1277 transcripts were inspected following a knowledge-based functional analyses approach using Ingenuity Pathway Analysis software. The transcriptome had a footprint of oxidative stress, disruption of energy homeostasis, inflammation, impaired cellular maintenance and repair mechanisms. Of note was the significant up regulation of the fatty acid amide hydrolase variant 2 (FAAH2) HuChrX transcript in the anandamide degradation canonical pathway. The observations that the two MCC transcripts were not significantly differentially expressed and that more than 90% of the significantly differently expressed transcripts are still poorly annotated further support the notion that secondary factors other than the MCC loci impact on the MCC deficiency phenome.

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3-Methylcrotonyl-CoA carboxylase deficiency in an infant with cardiomyopathy, in her brother with developmental delay and in their asymptomatic father

Cited by 27 publications

References 22 publications

Is l-Carnitine Supplementation Beneficial in 3-Methylcrotonyl-CoA Carboxylase Deficiency?

Is l-Carnitine Supplementation Beneficial in 3-Methylcrotonyl-CoA Carboxylase Deficiency?

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

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

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