Facultative anaerobic bacteria such as Escherichia coli have two α2β2 heterotetrameric trifunctional enzymes (TFE), catalyzing the last three steps of the β-oxidation cycle: soluble aerobic TFE (EcTFE) and membrane-associated anaerobic TFE (anEcTFE), closely related to the human mitochondrial TFE (HsTFE). The cryo-EM structure of anEcTFE and crystal structures of anEcTFE-α show that the overall assembly of anEcTFE and HsTFE is similar. However, their membrane-binding properties differ considerably. The shorter A5-H7 and H8 regions of anEcTFE-α result in weaker α-β as well as α-membrane interactions, respectively. The protruding H-H region of anEcTFE-β is therefore more critical for membrane-association. Mutational studies also show that this region is important for the stability of the anEcTFE-β dimer and anEcTFE heterotetramer. The fatty acyl tail binding tunnel of the anEcTFE-α hydratase domain, as in HsTFE-α, is wider than in EcTFE-α, accommodating longer fatty acyl tails, in good agreement with their respective substrate specificities.
- MeSH
- anaerobióza MeSH
- enoyl-CoA-hydratasa * chemie metabolismus MeSH
- Escherichia coli * genetika metabolismus MeSH
- lidé MeSH
- mitochondrie metabolismus MeSH
- oxidace-redukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD/MTPD) and medium chain acyl-CoA dehydrogenase deficiency (MCADD) were included in the expanded neonatal screening program (ENBS) in Czechia in 2009, allowing for the presymptomatic diagnosis and nutritional management of these patients. The aim of our study was to assess the nationwide impact of ENBS on clinical outcome. This retrospective study analysed acute events and chronic complications and their severity in pre-ENBS and post-ENBS cohorts. In total, 28 children (12 before, 16 after ENBS) were diagnosed with LCHADD/MTPD (incidence 0.8/100,000 before and 1.2/100,000 after ENBS). In the subgroup detected by ENBS, a significantly longer interval from birth to first acute encephalopathy was observed. In addition, improvement in neuropathy and cardiomyopathy (although statistically non-significant) was demonstrated in the post-ENBS subgroup. In the MCADD cohort, we included 69 patients (15 before, 54 after ENBS). The estimated incidence rose from 0.7/100,000 before to 4.3/100,000 after ENBS. We confirmed a significant decrease in the number of episodes of acute encephalopathy and lower proportion of intellectual disability after ENBS (p < 0.0001). The genotype-phenotype correlations suggest a new association between homozygosity for the c.1528C > G variant and more severe heart involvement in LCHADD patients.
- MeSH
- 3-hydroxyacyl-CoA-dehydrogenasy nedostatek MeSH
- acyl-CoA-dehydrogenasa nedostatek MeSH
- dítě MeSH
- hodnocení výsledků zdravotní péče MeSH
- incidence MeSH
- kardiomyopatie diagnóza dietoterapie epidemiologie MeSH
- karnitin analogy a deriváty krev MeSH
- kojenec MeSH
- lidé MeSH
- mitochondriální myopatie diagnóza dietoterapie epidemiologie MeSH
- mitochondriální trifunkční protein nedostatek MeSH
- nemoci nervového systému diagnóza dietoterapie epidemiologie MeSH
- novorozenec MeSH
- novorozenecký screening metody MeSH
- předškolní dítě MeSH
- retrospektivní studie MeSH
- rhabdomyolýza diagnóza dietoterapie epidemiologie MeSH
- stupeň závažnosti nemoci MeSH
- vrozené poruchy metabolismu tuků diagnóza dietoterapie epidemiologie MeSH
- vrozené poruchy metabolismu diagnóza MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: ECHS1 encodes a mitochondrial enzyme involved in the degradation of essential amino acids and fatty acids. Recently, ECHS1 mutations were shown to cause a new severe metabolic disorder presenting as Leigh or Leigh-like syndromes. The objective of this study was to describe a family with 2 siblings affected by different dystonic disorders as a resulting phenotype of ECHS1 mutations. METHODS: Clinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed. RESULTS: The first sibling is 17 years old and presents with generalized dystonia and severe bilateral pallidal MRI lesions after 1 episode of infantile subacute metabolic encephalopathy (Leigh-like syndrome). In contrast, the younger sibling (15 years old) only suffers from paroxysmal exercise-induced dystonia and has very mild pallidal MRI abnormalities. Both patients carry compound heterozygous ECHS1 mutations: c.232G>T (predicted protein effect: p.Glu78Ter) and c.518C>T (p.Ala173Val). Linkage analysis, exome sequencing, cosegregation, expression studies, and metabolite profiling support the pathogenicity of these mutations. Expression studies in patients' fibroblasts showed mitochondrial localization and severely reduced levels of ECHS1 protein. Increased urinary S-(2-carboxypropyl)cysteine and N-acetyl-S-(2-carboxypropyl)cysteine levels, proposed metabolic markers of this disorder, were documented in both siblings. Sequencing ECHS1 in 30 unrelated patients with paroxysmal dyskinesias revealed no further mutations. CONCLUSIONS: The phenotype associated with ECHS1 mutations might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. ECHS1 screening should be considered in patients with otherwise unexplained paroxysmal exercise-induced dystonia, in addition to those with Leigh and Leigh-like syndromes. Diet regimens and detoxifying agents represent potential therapeutic strategies. © 2016 International Parkinson and Movement Disorder Society.
Prezentujeme kazuistiku dvouletého chlapce s recidivujícími epizodami rhabdomyolýzy. Při metabolickém vyšetření v Ústavu dědičných metabolických poruch (ÚDMP) bylo u pacienta vysloveno podezření na poruchu beta-oxidace mastných kyselin (BOX MK) s dlouhým řetězcem. Výsledky dalších speciálních vyšetření na úrovni enzymů i genu vedly ke stanovení diagnózy deficitu mitochondriálního trifunkčního proteinu (MTP). V diskuzi jsou v přehledu uvedeny jednotlivé příčiny rhabdomyolýzy, její klinické projevy, diagnostický přístup i léčba.
A case report of 2-year-old boy with relapsing episodes of rhabdomyolysis is presented. The disorder of beta-oxidation of long chain fatty acid was presumed by the metabolic testing at the Institute of Inherited Metabolic Disorders. The results of further special testing on the level of enzymes and gene activities led to the diagnosis of the mitochondrial trifunctional protein (MTP) deficit. Various causes of rhabdomyolysis, its clinical manifestation, diagnostic approach and treatment are listed at a glance in the discussion.
- MeSH
- 3-hydroxyacyl-CoA dehydrogenasa mastných kyselin s dlouhým řetězcem nedostatek MeSH
- diferenciální diagnóza MeSH
- lidé MeSH
- mastné kyseliny metabolismus MeSH
- mitochondriální trifunkční protein nedostatek MeSH
- předškolní dítě MeSH
- rhabdomyolýza * diagnóza etiologie genetika metabolismus terapie MeSH
- vrozené poruchy metabolismu tuků * diagnóza komplikace patofyziologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
