Recurrent attacks of status epilepticus as predominant symptom in 3-methylcrotonyl-CoA carboxylase deficiency

Dırık, Eray; Yış, Uluç; Paşaoğlu, Güven; Chambaz, Céline; Baumgartner, Matthias R.

doi:10.1016/j.braindev.2007.08.005

Cited by 13 publications

(12 citation statements)

References 14 publications

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“…Severe metabolic decompensation following acute stress (usually following infections or increased protein load) with acidosis and seizures leading to permanent neurological damage or death is also observed in the affected patients (Eminoglu et al 2009;Sweetman and Williams 2001). Brain imaging usually shows cerebral edema, ventricular dilatation, leukodystrophy, and cerebral atrophy particularly in subcortical areas of frontal, temporal, and parietal lobes (Baykal et al 2005;de Kremer et al 2002;Dirik et al 2008;Murayama et al 1997). Although brain dysfunction and abnormalities are predominant features in 3MCCD, the pathogenesis of the cerebral damage in this disorder is virtually unknown.…”

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confidence: 97%

3-Methylcrotonylglycine Disrupts Mitochondrial Energy Homeostasis and Inhibits Synaptic Na+,K+-ATPase Activity in Brain of Young Rats

et al. 2011

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Deficiency of 3-methylcrotonyl-CoA carboxylase activity is an inherited metabolic disease biochemically characterized by accumulation and high urinary excretion of 3-methylcrotonylglycine (3MCG), and also of 3-hydroisovalerate in lesser amounts. Affected patients usually have neurologic dysfunction, brain abnormalities and cardiomyopathy, whose pathogenesis is still unknown. The present study investigated the in vitro effects of 3MCG on important parameters of energy metabolism, including CO(2) production from labeled acetate, enzyme activities of the citric acid cycle, as well as of the respiratory chain complexes I-IV (oxidative phosphorylation), creatine kinase (intracellular ATP transfer), and synaptic Na(+),K(+)-ATPase (neurotransmission) in brain cortex of young rats. 3MCG significantly reduced CO(2) production, implying that this compound compromises citric acid cycle activity. Furthermore, 3MCG diminished the activities of complex II-III of the respiratory chain, mitochondrial creatine kinase and synaptic membrane Na(+),K(+)-ATPase. Furthermore, antioxidants were able to attenuate or fully prevent the inhibitory effect of 3MCG on creatine kinase and synaptic membrane Na(+),K(+)-ATPase activities. We also observed that lipid peroxidation was elicited by 3MCG, suggesting the involvement of free radicals on 3MCG-induced effects. Considering the importance of the citric acid cycle and the electron flow through the respiratory chain for brain energy production, creatine kinase for intracellular energy transfer, and Na(+),K(+)-ATPase for the maintenance of the cell membrane potential, the present data indicate that 3MCG potentially impairs mitochondrial brain energy homeostasis and neurotransmission. It is presumed that these pathomechanisms may be involved in the neurological damage found in patients affected by 3-methylcrotonyl-CoA carboxylase deficiency.

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confidence: 97%

3-Methylcrotonylglycine Disrupts Mitochondrial Energy Homeostasis and Inhibits Synaptic Na+,K+-ATPase Activity in Brain of Young Rats

et al. 2011

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“…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%

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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“…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].…”

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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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Recurrent attacks of status epilepticus as predominant symptom in 3-methylcrotonyl-CoA carboxylase deficiency

Cited by 13 publications

References 14 publications

3-Methylcrotonylglycine Disrupts Mitochondrial Energy Homeostasis and Inhibits Synaptic Na+,K+-ATPase Activity in Brain of Young Rats

3-Methylcrotonylglycine Disrupts Mitochondrial Energy Homeostasis and Inhibits Synaptic Na+,K+-ATPase Activity in Brain of Young Rats

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

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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