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 | 2021 Jul
REPOSITORIES: biostudies-literature
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3-Hydroxyisobutyryl-CoA hydrolase deficiency in an infant with developmental delay and high anion gap acidosis.
Saneifard Hedyeh H Mosallanejad Asieh A Fallahzadeh Aida A Sheikhy Ali A
Clinical case reports 20210723 7
Due to the rarity of this disorder, paying attention to diagnostic clues is important. Low valine formula seems to be effective in improvement of patient's symptoms. Prevention of consanguineous marriage is the best way to prevent this disease. ...[more]
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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.
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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.
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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.
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Project description:BackgroundObesity is associated with low serum bicarbonate, an indicator of metabolic acidosis and a CKD risk factor. To further characterize acid-base disturbance and subclinical metabolic acidosis in this population, we examined prospective associations of body mass index (BMI) with elevated anion gap and whether anion gap values in obesity associate with low bicarbonate.MethodsData from adult outpatients (n=94,448) in the Bronx, New York were collected from 2010 to 2018. Mixed effects models and Cox proportional hazards models were used to examine associations of BMI with elevated anion gap and anion gap metabolic acidosis and of baseline anion gap with incident low bicarbonate and anion gap metabolic acidosis. Anion gap was defined using traditional and albumin-corrected calculations.ResultsGreater BMI was associated with higher anion gap over time and with progressively greater risk of developing an elevated anion gap (hazard ratio [HR] for body mass index [BMI]≥40 kg/m2 versus 18 to <25 kg/m2, 1.32; 95% confidence interval [95% CI], 1.23 to 1.42 for traditional and HR for BMI≥40 kg/m2 versus 18 to <25 kg/m2, 1.74; 95% CI, 1.63 to 1.85 for corrected). Higher BMI was also associated with increased risk of developing anion gap metabolic acidosis (HR for BMI≥40 kg/m2, 1.53; 95% CI, 1.39 to 1.69). Among patients with obesity, higher anion gap was associated with increased risk of incident low bicarbonate (HR for fourth versus first quartile, 1.29; 95% CI, 1.23 to 1.44 for traditional and HR for fourth versus first quartile, 1.36; 95% CI, 1.26 to 1.48 for corrected) and higher risk of anion gap metabolic acidosis (HR for fourth versus first quartile, 1.78; 95% CI, 1.59 to 1.99).ConclusionsObesity is characterized by unmeasured anion accumulation and acid retention or overproduction. Modest elevations in anion gap among patients with obesity are associated with previously unrecognized anion gap metabolic acidosis.
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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.
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Project description:BackgroundObesity is a recently identified risk factor for metabolic acidosis and anion gap elevations in the absence of CKD. Metabolic acidosis is a treatable condition with substantial adverse effects on human health. Additional investigations are needed to characterize at-risk populations and explore potential mechanisms. We hypothesized metabolic syndrome (MetS) and waist circumference (WC) would be closely associated with this pathology.MethodsAdult participants from NHANES 1999-2018 meeting study criteria were compiled as main (n=31,163) and fasting (n=12,860) cohorts. Regression models adjusted for dietary acid, eGFR, and other factors examined associations of WC and MetS features with anion gap metabolic acidosis and its components (serum bicarbonate ≤23 mEq/L and anion gap >95th percentile).ResultsGreater WC and MetS features were associated with progressively lower bicarbonate, higher anion gap, and greater odds ratios (OR) of metabolic acidosis (MA) and anion gap metabolic acidosis (AGMA). Compared with the reference, participants with the highest WC had ORs for MA and AGMA of 2.26; 95% CI, 1.96 to 2.62 and 2.89; 95% CI, 1.97 to 4.21; those with three and four versus zero MetS features had ORs for AGMA of 2.52; 95% CI, 1.95 to 2.94 and 3.05; 95% CI, 2.16 to 3.82. Associations of body mass index with outcomes were attenuated or absent after adjustment for WC or MetS. Findings were preserved after excluding eGFR <90 ml/min per 1.73 m2 and albuminuria. A lower MA cutoff (<22 mEq/L) raised the estimate of association between MetS and MA (OR for three and four vs zero features: 3.56; 95% CI, 2.53 to 5.02 and 5.44; 95% CI, 3.66 to 8.08).ConclusionsMetabolic diseases are characterized by metabolic acidosis and anion gap elevations. Metabolic dysfunction may predispose patients without CKD to systemic acidosis from endogenous sources. Comprehensive acid-base analyses may be informative in patients with metabolic diseases.
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