3-Hydroxyisobutyryl-CoA hydrolase deficiency in an infant with developmental delay and high anion gap acidosis.
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ABSTRACT:
SUBMITTER: Saneifard H
PROVIDER: S-EPMC8299097 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We report a patient presenting with developmental delay, Leigh-like abnormalities on MRI and elevated 3-hydroxyisovaleric acid levels. Upon whole-exome sequencing, he was diagnosed with 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, and hence subjected to specific dietary treatment. HIBCH deficiency should be considered in the differential diagnosis of Leigh-like disease and/or organic aciduria.
| S-EPMC6389474 | biostudies-literature
Project description:Objective3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is a rare metabolic disease of valine metabolism. Only 22 cases of HIBCH deficiency have been reported in the literature. Our algorithm could help in the diagnosis of this disease.MethodsHIBCH gene analysis was performed in all cases.ResultsThe common features of our five patients from the same family with a developmental delay, seizures, and neurological regression were the elevation of 3-hydroxy-isobutyryl-carnitine and Leigh-like abnormalities. Unlike other patients in the literature, our patients were diagnosed with HIBCH gene analysis, rather than whole exome sequencing (WES). In all our cases, a missense c.452C>T, p. Ser151Leu homozygous novel pathogenic mutation was detected in the HIBCH gene.ConclusionIn cases where HIBCH deficiency is considered in our differential diagnosis algorithm, HIBCH gene analysis, which is cost-effective, should be performed instead of WES, and the number of cases should be increased in the literature.
| S-EPMC8370149 | biostudies-literature
Project description:3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency (OMIM 250620) is an autosomal recessive inborn error of valine catabolism characterized by severely delayed psychomotor development, progressive neurodegeneration, recurrent metabolic attacks with intercurrent illness, increased lactic acid, cerebral atrophy, and brain lesions in the basal ganglia. HIBCH gene defect is a very rare organic aciduria and also might cause secondary mitochondrial dysfunction. We report a 12-month-old severely affected female infant with a novel homozygous c.556C>G; p.R186G variant in the HIBCH gene presenting with axial hypotonia, severe developmental delay, and brain lesions in the basal ganglia and provide an overview of the literature. When suspected, newborn and selective screening with tandem mass analyses should include hydroxy-C4-carnitine to diagnose this disorder. However, in some cases, mostly in those with milder phenotype, diagnosis may be missed due to normal hydroxy-C4 carnitine levels.
| S-EPMC7445567 | biostudies-literature
Project description:Since methylmalonyl-CoA epimerase appears to be absent in the majority of photosynthetic organisms, including diatoms, (S)-methylmalonyl-CoA, the intermediate of isoleucine (Ile) catabolism, cannot be metabolized to (R)-methylmalonyl-CoA then to succinyl-CoA. In this study, propionyl-CoA carboxylase (PCC) RNAi silenced strains and 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) overexpression strains were constructed to elucidate the Ile degradation pathway and its influence on lipid accumulation in Phaeodactylum tricornutum based on growth, neutral lipid content and metabolite profile analysis. Knockdown of PCC disturbed the metabolism of Ile through propionyl-CoA to methylmalonyl-CoA, as illustrated by much higher Ile content at day 6. However, Ile decreased to comparable levels to the wild-type at day 10. PCC silencing redirected propionyl-CoA to acetyl-CoA via a modified ?-oxidation pathway, and transcript levels for some branched-chain amino acid (BCAA) degradation-related genes, especially HIBCH, significantly upregulated in the PCC mutant, which enhanced the BCAA degradations and thus resulted in higher triacylglycerol (TAG) content. Overexpression of HIBCH accelerates Ile degradation and results in a lowered Ile content in the overexpression strains, thus enhancing carbon skeletons to the tricarboxylic acid cycle and giving rise to increasing TAG accumulation. Our study provides a good strategy to obtain high-lipid-yield transgenic diatoms by modifying the propionyl-CoA metabolism.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'.
| S-EPMC5516118 | biostudies-literature
Project description:Only a single patient with 3-hydroxyisobutyryl-CoA hydrolase deficiency has been described in the literature, and the molecular basis of this inborn error of valine catabolism has remained unknown until now. Here, we present a second patient with 3-hydroxyisobutyryl-CoA hydrolase deficiency, who was identified through blood spot acylcarnitine analysis showing persistently increased levels of hydroxy-C(4)-carnitine. Both patients manifested hypotonia, poor feeding, motor delay, and subsequent neurological regression in infancy. Additional features in the newly identified patient included episodes of ketoacidosis and Leigh-like changes in the basal ganglia on a magnetic resonance imaging scan. In cultured skin fibroblasts from both patients, the 3-hydroxyisobutyryl-CoA hydrolase activity was deficient, and virtually no 3-hydroxyisobutyryl-CoA hydrolase protein could be detected by western blotting. Molecular analysis in both patients uncovered mutations in the HIBCH gene, including one missense mutation in a conserved part of the protein and two mutations affecting splicing. A carefully interpreted acylcarnitine profile will allow more patients with 3-hydroxyisobutyryl-CoA hydrolase deficiency to be diagnosed.
| S-EPMC1785315 | biostudies-literature
Project description:Coenzyme B(12)-dependent acyl-CoA mutases are radical enzymes catalyzing reversible carbon skeleton rearrangements in carboxylic acids. Here, we describe 2-hydroxyisobutyryl-CoA mutase (HCM) found in the bacterium Aquincola tertiaricarbonis as a novel member of the mutase family. HCM specifically catalyzes the interconversion of 2-hydroxyisobutyryl- and (S)-3-hydroxybutyryl-CoA. Like isobutyryl-CoA mutase, HCM consists of a large substrate- and a small B(12)-binding subunit, HcmA and HcmB, respectively. However, it is thus far the only acyl-CoA mutase showing substrate specificity for hydroxylated carboxylic acids. Complete loss of 2-hydroxyisobutyric acid degradation capacity in hcmA and hcmB knock-out mutants established the central role of HCM in A. tertiaricarbonis for degrading substrates bearing a tert-butyl moiety, such as the fuel oxygenate methyl tert-butyl ether (MTBE) and its metabolites. Sequence analysis revealed several HCM-like enzymes in other bacterial strains not related to MTBE degradation, indicating that HCM may also be involved in other pathways. In all strains, hcmA and hcmB are associated with genes encoding for a putative acyl-CoA synthetase and a MeaB-like chaperone. Activity and substrate specificity of wild-type enzyme and active site mutants HcmA I90V, I90F, and I90Y clearly demonstrated that HCM belongs to a new subfamily of B(12)-dependent acyl-CoA mutases.
| S-EPMC3346121 | biostudies-literature
Project description:Metabolic disorders sometimes cause accumulation of metabolic byproducts which are manifested as cytoplasmic vacuoles in lymphocytes. We report the case of an infant with final diagnosis of GM1 gangliosidosis who initially presented with developmental delay and peripheral blood vacuolated lymphocytes. Blood film review is recommended in children suspicious for metabolic disorders.
| S-EPMC4706402 | biostudies-other
Project description:DNA repair mechanisms such as nucleotide excision repair (NER) and translesion synthesis (TLS) are dependent on proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory protein. Recently, homozygosity for p.Ser228Ile mutation in the PCNA gene was reported in patients with neurodegeneration and impaired NER. Using exome sequencing, we identified a homozygous deleterious mutation, c.648delAG, in the PARP10 gene, in a patient suffering from severe developmental delay. In agreement, PARP10 protein was absent from the patient cells. We have previously shown that PARP10 is recruited by PCNA to DNA damage sites and is required for DNA damage resistance. The patient cells were significantly more sensitive to hydroxyurea and UV-induced DNA damage than control cells, resulting in increased apoptosis, indicating DNA repair impairment in the patient cells. PARP10 deficiency joins the long list of DNA repair defects associated with neurodegenerative disorders, including ataxia telangiectasia, xeroderma pigmentosum, Cockayne syndrome, and the recently reported PCNA mutation.
| S-EPMC5096377 | biostudies-literature
Project description:BackgroundThe ratio of Δ anion gap and Δ bicarbonate (ΔAG/ΔHCO3) is used to detect coexisting acid-base disorders in patients with high anion gap metabolic acidosis. Classic teaching holds that, in lactic acidosis, the ΔAG/ΔHCO3 is 1:1 within the first few hours of onset and subsequently rises to 1.8:1. However, this classic 1:1 stoichiometry in early lactic acidosis was derived primarily from animal models and only limited human data. The objective of this study was to examine the ΔAG/ΔHCO3 within the first hours of the development of lactic acidosis.MethodsData were obtained prospectively from a convenience sample of adult (age >18 years) trauma-designated patients at a single level-1 trauma center. Venous samples, including a chemistry panel and serum lactate, were drawn before initiation of intravenous fluid resuscitation.ResultsA total of 108 patients were included. Of these, 63 patients had normal serum lactate levels (≤2.1 mmol/L) with a mean AG of 7.1 mEq/L, the value used to calculate subsequent ΔAG values. ΔAG/ΔHCO3 was calculated for 45 patients who had elevated serum lactate levels (>2.1 mmol/L). The mean ΔAG/ΔHCO3 for all patients with elevated serum lactate levels was 1.86 (SD, 1.40).ConclusionsThe mean ΔAG/ΔHCO3 was 1.86 within the first hours of the development of lactic acidosis due to hypovolemic shock, confirming a small prior human study. This contradicts the traditional belief that, in lactic acidosis, the ΔAG/ΔHCO3 is 1:1 within the first several hours. The classic 1:1 stoichiometry was determined on the basis of animal models in which lactic acid is infused into the extracellular space, facilitating extracellular buffering of protons by bicarbonate. In contrast, our results demonstrate a higher initial ΔAG/ΔHCO3 ratio in early endogenous lactic acidosis in humans. Our analysis indicates this is likely due to unmeasured anions contributing to an elevation in AG.
| S-EPMC8785742 | biostudies-literature
Project description:Bacterial coenzyme B12-dependent 2-hydroxyisobutyryl-CoA mutase (HCM) is a radical enzyme catalyzing the stereospecific interconversion of (S)-3-hydroxybutyryl- and 2-hydroxyisobutyryl-CoA. It consists of two subunits, HcmA and HcmB. To characterize the determinants of substrate specificity, we have analyzed the crystal structure of HCM from Aquincola tertiaricarbonis in complex with coenzyme B12 and the substrates (S)-3-hydroxybutyryl- and 2-hydroxyisobutyryl-CoA in alternative binding. When compared with the well studied structure of bacterial and mitochondrial B12-dependent methylmalonyl-CoA mutase (MCM), HCM has a highly conserved domain architecture. However, inspection of the substrate binding site identified amino acid residues not present in MCM, namely HcmA Ile(A90) and Asp(A117). Asp(A117) determines the orientation of the hydroxyl group of the acyl-CoA esters by H-bond formation, thus determining stereospecificity of catalysis. Accordingly, HcmA D117A and D117V mutations resulted in significantly increased activity toward (R)-3-hydroxybutyryl-CoA. Besides interconversion of hydroxylated acyl-CoA esters, wild-type HCM as well as HcmA I90V and I90A mutant enzymes could also isomerize pivalyl- and isovaleryl-CoA, albeit at >10 times lower rates than the favorite substrate (S)-3-hydroxybutyryl-CoA. The nonconservative mutation HcmA D117V, however, resulted in an enzyme showing high activity toward pivalyl-CoA. Structural requirements for binding and isomerization of highly branched acyl-CoA substrates such as 2-hydroxyisobutyryl- and pivalyl-CoA, possessing tertiary and quaternary carbon atoms, respectively, are discussed.
| S-EPMC4392272 | biostudies-literature