The 3‐methylglutaconic acidurias: what's new?

Wortmann, Saskia B.; Kluijtmans, Leo A. J.; Engelke, Udo F. H.; Wevers, Ron A.; Morava, Éva

doi:10.1007/s10545-010-9210-7

Cited by 78 publications

(79 citation statements)

References 77 publications

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“…There is a rapidly growing group of IEMs with a syndromic phenotype reviewed by Wortmann, Kluijtmans, Engelke, Wevers, and Morava (2012) and Wortmann et al (2013) causing secondary 3‐methylglutaconic aciduria (3‐MGA) due to defective phospholipid remodeling or mitochondrial membrane associated disorders. The excretion of 3‐MGC can be highly variable or intermittently normal in secondary 3‐MGA and is generally less than levels seen in primary 3‐MGA due to AUH .…”

Section: Discussionmentioning

confidence: 99%

Clinical, biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

Fitzsimons

Alston

Bonnen

et al. 2018

American J of Med Genetics Pt A

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Short‐chain enoyl‐CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile‐onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteristic abnormal biochemical findings are secondary to dysfunction of valine metabolism. We describe four patients from two consanguineous families (one Pakistani and one Irish Traveler), who presented in infancy with LS. Urine organic acid analysis by GC/MS showed increased levels of erythro‐2,3‐dihydroxy‐2‐methylbutyrate and 3‐methylglutaconate (3‐MGC). Increased urine excretion of methacrylyl‐CoA and acryloyl‐CoA related metabolites analyzed by LC‐MS/MS, were suggestive of SCEH deficiency; this was confirmed in patient fibroblasts. Both families were shown to harbor homozygous pathogenic variants in the ECHS1 gene; a c.476A > G (p.Gln159Arg) ECHS1variant in the Pakistani family and a c.538A > G, p.(Thr180Ala) ECHS1 variant in the Irish Traveler family. The c.538A > G, p.(Thr180Ala) ECHS1 variant was postulated to represent a Canadian founder mutation, but we present SNP genotyping data to support Irish ancestry of this variant with a haplotype common to the previously reported Canadian patients and our Irish Traveler family. The presence of detectable erythro‐2,3‐dihydroxy‐2‐methylbutyrate is a nonspecific marker on urine organic acid analysis but this finding, together with increased excretion of 3‐MGC, elevated plasma lactate, and normal acylcarnitine profile in patients with a Leigh‐like presentation should prompt consideration of a diagnosis of SCEH deficiency and genetic analysis of ECHS1. ECHS1 deficiency can be added to the list of conditions with 3‐MGA.

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Section: Discussionmentioning

confidence: 99%

Clinical, biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

Fitzsimons

Alston

Bonnen

et al. 2018

American J of Med Genetics Pt A

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“…AUH = 3-methylglutaconyl-CoA hydra-tase (enzyme deficient in 3-MGAuria type I). HMG-CoA = 3-hydroxy-3-methylglutaryl CoA (adapted from (Wortmann et al 2010a)) these patients 30 % are reported with 3-MGA-uria (Gibson et al 1992;Jakobs et al 1991;Knerr et al 2003;Krauch et al 2002;Lichter-Konecki et al 1993). Curiously, mitochondrial deletions presenting with the Kearns-Sayre phenotype do not lead to 3-MGA-uria.…”

Section: Correlation Of 3-mga-uria With Specific Mitochondrial Disordersmentioning

confidence: 99%

3‐Methylglutaconic aciduria—lessons from 50 genes and 977 patients

Wortmann

Kluijtmans

Rodenburg

et al. 2013

J of Inher Metab Disea

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Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven,

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“…Another indication of a possible HuChrX-link in MCC deficiency was the report wherein six of eight patients who presented with metabolites of MCC deficiency, but for whom no MCC mutations could be detected were males [17]. The incidence of 3-methylglutaconic aciduria Type-I, another autosomal recessive disorder of the leucine catabolism, also seems to be higher in males than in females [16,102]. The apparent HuChrX link in both MCC and MCGAType-I deficiencies could be coincidental, but should be further investigated.…”

Section: Discussionmentioning

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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The 3‐methylglutaconic acidurias: what's new?

Cited by 78 publications

References 77 publications

Clinical, biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

Clinical, biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

3‐Methylglutaconic aciduria—lessons from 50 genes and 977 patients

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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