HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disorders

Abstract

HIBCH (3-hydroxyisobutyryl-CoA hydrolase) deficiency (MIM #250620) is a rare autosomal recessive inborn error of metabolism, leading to a block in the catabolic pathway of the amino acid valine and presumably to accumulation of toxic valine metabolites in mitochondria. Only three families with HIBCH deficiency and biallelic HIBCH mutations have been described. We report on a further patient, first child of healthy consanguineous parents, with severe developmental delay, seizures, hyperintensities of the basal ganglia on magnetic resonance imaging (MRI), progressive brain atrophy, optic nerve atrophy, repeatedly elevated blood lactate, and respiratory chain complexes I, I + III and cytochrome c oxidase deficiencies with borderline depletion of mitochondrial DNA in muscle tissue. Laboratory findings in blood and skeletal muscle were inconsistent and did not allow a definite diagnosis, but supported the hypothesis of mitochondrial dysfunction. Homozygosity mapping and whole-exome sequencing revealed a homozygous one-base pair insertion in HIBCH. Deficiency of enzyme activity was confirmed in cultured fibroblasts. Although relatively unspecific, the clinical features were similar to those of the previously reported cases. Given the clinical variability and large number of differential diagnoses, the prevalence of HIBCH deficiency is probably underestimated. Next-generation sequencing approaches are an effective tool for identifying the underlying genetic basis in patients suspected of mitochondrial disorders.

Metabolite studies in HIBCH and ECHS1 defects: Implications for screening

“…It was first described in 1982 [2] and seven additional patients have been described [7,[10][11][12][13][14]. With the addition of the patient in this report, some clearer conclusions can be drawn regarding the phenotype of this disorder.…”

“…Confusingly, secondary deficiencies of these enzyme systems often occur in both disorders [4,7,10,11]. Indeed, our HIBCHD patient had decreased PDHC activity in cultured skin fibroblasts.…”

“…Increased hydroxy-C4 carnitine in dried blood spots or plasma has aided the diagnosis in some reported HIBCHD patients [7,10,11,13]. Retrospective review of our HIBCHD patient's newborn screening results showed that the hydroxy-C4 carnitine level of 1.2 μmol/L corresponded to the 99.97 percentile of the newborn population which prompted a revision of the cut-off to 1.0 μmol/L.…”

Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh's disease

“…This autosomal recessive condition is characterized by developmental delay of motor milestones in early infancy and neurological regression within the first year of life. MRI abnormalities are striking for bilateral involvement of the basal ganglia with varying degrees of white matter atrophy [1,2,4]. Strikingly, in all HIBCH patients reported to date, the clinical presentation and MRI findings led to a general diagnosis of Leigh syndrome (OMIM 256000).…”

“…Affected individuals have significantly decreased enzymatic activity as compared to healthy controls [1,4]. However, this assay is not readily performed in clinical laboratories.…”