3-Hydroxyisobutyryl-Coa Hydrolase Deficiency
A number sign (#) is used with this entry because 3-hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD) is caused by homozygous or compound heterozygous mutation in the HIBCH gene (610690) on chromosome 2q32.
Description3-Hydroxyisobutyryl-CoA hydrolase deficiency is an autosomal recessive inborn error of metabolism characterized by severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia (summary by Ferdinandusse et al., 2013).
Clinical FeaturesBrown et al. (1982) found deficiency of beta-hydroxyisobutyryl-CoA deacylase, an enzyme unique to valine metabolism, in a male infant who was born to first-cousin parents and died at age 3 months with multiple physical malformations (dysmorphic facies, multiple vertebral anomalies, tetralogy of Fallot, and, at autopsy, agenesis of the cingulate gyrus and corpus callosum). A metabolic abnormality was suspected because of urinary excretion of cysteine and cysteamine conjugates of methacrylic acid. The CoA ester of this compound is an intermediate in the pathway of valine oxidation. Subsequent investigation revealed a deficiency of beta-hydroxyisobutyryl-CoA deacylase, an enzyme unique to valine metabolism. The enzyme defect results in accumulation of methacrylyl-CoA, a highly reactive compound, which readily undergoes addition reactions with free sulfhydryl groups. Brown et al. (1982) suggested that tissue damage due to reactions between methacrylyl-CoA and important sulfhydryl-containing enzymes and cofactors may be responsible for the teratogenic effects. This was viewed as an example of an inborn error of metabolism with effects due to intracellular accumulation of a small amount of a highly toxic intermediate metabolite rather than the accumulation in the body fluids of high levels of metabolites of relatively low toxicity. Recessive inheritance seemed quite certain because both parents had intermediate levels of enzyme activity. See also 3-hydroxyisobutyric aciduria (236795).
Loupatty et al. (2007) described a second patient with HIBCH deficiency, who was the first child of healthy, nonconsanguineous white parents and was born at term following an uneventful pregnancy. He appeared well until 4 months of age when his parents noted head bobbing. This was followed by a delay in motor milestones and then by ataxia and a loss of skills. He was able to roll over at age 5 months but lost this ability at age 10 months. From age 9 months, he started to have transient absences and episodes of eye rolling. Examination at age 11 months revealed an alert, interactive child who had no nystagmus but constant titubation of the head. He had marked truncal ataxia and was unable to sit unsupported. At age 14 months, following 2 days of coryza and lethargy, he became acutely unwell, with a reduced level of consciousness and metabolic acidosis, and required intubation and ventilatory support. As he recovered from this episode of acute encephalopathy he developed dystonia, predominantly affecting the right arm and leg. Both the patient of Brown et al. (1982) and the patient of Loupatty et al. (2007) demonstrated delayed development of motor skills, hypotonia, initial poor feeding, and a deterioration of neurologic function during the first stages of life. However, whereas the first patient showed agenesis of the cingulate gyrus and the corpus callosum, no structural brain abnormalities were found in the second patient. Moreover, the brain anomalies in the second patient, as indicated by CT and MRI scans, were predominantly in the basal ganglia and consistent with Leigh syndrome. The second patient manifested no dysmorphic facial features and no congenital heart disease and was still living at the time of report.
Ferdinandusse et al. (2013) reported 2 brothers, born of distantly related Pakistani parents, with a severe neurodegenerative disorder resulting in death in the first years of life. The patients presented in early infancy with delayed psychomotor development or developmental regression, hypotonia, recurrent vomiting, and seizures. Brain imaging showed abnormal signals in the globi pallidi reminiscent of Leigh syndrome. Laboratory studies showed increased lactate; 1 patient had increased hydroxy-C4-carnitine. Skeletal muscle biopsy showed decreased activity of mitochondrial respiratory enzyme complexes II, II+III, and IV as well as decreased activity of the pyruvate dehydrogenase complex (PDC) in 1 patient; these values were normal in the other patient.
Reuter et al. (2014) reported a 5-year-old boy, born of consanguineous Tunisian parents, with HIBCHD. He showed normal development until about 7 months of age, after which he showed hypotonia, psychomotor delay, and strabismus. Serial brain imaging showed a progressive reduction in brain volume, enlarged ventricles, and increasing signal abnormalities of the basal ganglia, reminiscent of Leigh syndrome. He never learned to sit independently and never acquired language. He developed refractory epilepsy at age 3 years and possible optic atrophy with blindness at age 4. Additional features included increased limb muscle tone with hyperreflexia, a central coordination disorder, cryptorchidism, and nystagmus. The results of laboratory investigations and muscle biopsy were inconsistent at first, but eventually showed increased blood lactate, increased blood hydroxy-C4-carnitine, and depletion of mtDNA and decreases in multiple mitochondrial respiratory enzyme activities in skeletal muscle. The findings were consistent with a defect in mitochondrial energy metabolism.
Stiles et al. (2015) reported 2 sibs, born of first-cousin Lebanese parents, with HIBCH deficiency. These were the 2 oldest HIBCHD patients described to that time. Patient 1, a girl, the product of in vitro fertilization (IVF), was born at 38 weeks' gestation by cesarean section after an uneventful pregnancy. Her brother, patient 2, was the second child of a triplet pregnancy conceived by IVF. The presentation of both patients was consistent with that of previously described patients. Loss of milestones was followed by neurodegeneration within the first year of life. Both patients showed dystonia, spastic quadriplegia, and absent reflexes in the lower extremities before the age of 1 year. Early brain MRI abnormalities included bilateral, symmetrical T2 hyperintensity in the basal ganglia, specifically the globus pallidus, with corresponding restricted diffusion in the acute/subacute phase. The patients also showed asymmetric cerebral peduncle involvement and transient T2 hyperintensity in the caudate nuclei, which had previously been reported in patients with HIBCH deficiency. The disorder evolved into a slowly progressive encephalopathy. In the second decade of life, truncal hypotonia remained along with more pronounced hypertonia in extremities, with intermittent dystonia in the trunk, extremities and face. Both patients were still able to interact and partially communicate with sounds and facial expression. No other organ system complications were apparent. The initial edema, bilateral T2 in the MRI, transiently improved after a 2- to 4-year interval. However, in later stages of disease, cystic encephalomalacia and atrophy developed in the basal ganglia. Extensive metabolic evaluation was normal. A muscle biopsy from patient 1 showed normal histology, including cytochrome c oxidase (COX) stain, and normal respiratory chain activity. Stiles et al. (2015) demonstrated elevated hydroxy-C4-carnitine in newborn screening cards for these 2 sibs. Stiles et al. (2015) stated that to their knowledge, progression of MRI findings in HIBCH deficiency over a period of several years had not previously been illustrated.
Peters et al. (2015) reported a female patient with HIBCHD who presented at the age of 5 months with hypotonia, developmental delay, and cerebral atrophy on MRI. Urine tandem mass spectrometry screening showed large increases in the cysteine conjugate of methacrylate previously described in HIBCHD. 3-hydroxyisobutyryl-CoA hydrolase activity in fibroblasts was below the limit of detection of the enzyme assay. Urine metabolite investigations showed increases in 3-hydroxyisobutyryl-carnitine, 2,3-dihydroxy-2-methylbutyrate, and several metabolites indicating accumulation and subsequent metabolism of methacrylyl-CoA and acryloyl-CoA. The metabolites derived from acryloyl-CoA were also increased in patients with inborn errors of propionyl-CoA metabolism, indicating the involvement of a secondary propionyl-CoA pathway utilizing 3-hydroxyisobutyryl-CoA hydrolase. Peters et al. (2015) reported that with the exception of 3-hydroxyisobutyryl carnitine, the metabolite abnormalities were essentially the same as those observed in patients with ECHS1 deficiency (ECHS1D; 616277).
Population GeneticsStiles et al. (2015) reported the estimated incidence of HIBCH deficiency in the general population to range from 1 in 127,939 in East Asians to 1 in 551,545 in Europeans.
Molecular GeneticsUsing immunoblot analysis, Loupatty et al. (2007) demonstrated absence of the HIBCH protein in the patient reported by Brown et al. (1982) and an apparently low expression of the HIBCH protein in their own patient. In the patient of Brown et al. (1982), they demonstrated a homozygous IVS3-9T-G mutation in the HIBCH gene (610690.0001) and in their own patient demonstrated compound heterozygosity for a missense mutation (Y122C; 610690.0002) and a splice acceptor site mutation (610690.0003).
In 2 sibs with HIBCHD, born of distantly related Pakistani parents, Ferdinandusse et al. (2013) identified a homozygous missense mutation in the HIBCH gene (G317E; 610690.0004). Fibroblast activity of HIBCH was below the level of detection in both patients.
In a 5-year-old boy, born of consanguineous Tunisian parents, with HIBCHD, Reuter et al. (2014) identified a homozygous truncating mutation in the HIBCH gene (610690.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed no detectable HIBCH enzymatic activity.
Using whole-exome sequencing, Stiles et al. (2015) identified a homozygous missense mutation in the HIBCH gene (R66W; 610690.0005) in 2 sibs with HIBCHD with features of Leigh syndrome. Sanger sequencing confirmed that both affected sibs were homozygous for this variant and that each parent was heterozygous, thus confirming recessive inheritance through the pedigree.