Mutations in the Gene Encoding 3-Hydroxyisobutyryl-CoA Hydrolase Results in Progressive Infantile Neurodegeneration

Abstract

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.

Leigh syndrome: One disorder, more than 75 monogenic causes

“…Some of these defects appear to cause secondary defects of PDHc or OXPHOS enzymes, which may show variability across patients and tissues. 78,[80][81][82] Such secondary defects have not been reported in patients with biotinidase deficiency due to BTD mutations, a treatable condition that can manifest as LS (see Table 2), 83,84 although there is evidence of ATP deficiency and complex IV inhibition from animal and cellular models. 85,86 Mutations in the phospholipid remodeling protein SERAC1 and apoptosis-inducing factor AIFM1 may impair OXPHOS by reducing the stability of the mitochondrial membrane.…”

“…However, the relevance of this to pathogenesis is unclear, as is the contribution of primary effects of these disorders such as perturbed valine catabolism. 80,81 Instead, an accumulation of toxic reactive metabolites has been suggested to be the mechanism by which ECHS1 and HIBCH mutations impair OXPHOS and PDHc activity, 81,88 similar to the toxic accumulation of sulfide due to ETHE1 mutations described above. 43 Although it may not be the primary consequence of mutation, an indirect effect on mitochondrial energy generation can therefore be sufficient to cause the development of LS.…”

Clinical, biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

“…Deficiency of SCEH which converts unsaturated trans ‐2‐enoyl‐CoA species to the corresponding 3( S )‐hydroxyacyl‐CoA (Haack et al, 2015; Peters et al, 2014; Sakai et al, 2015; Tetreault et al, 2015) and deficiency of HIBCH (Brown et al, 1982; Ferdinandusse et al, 2013; Loupatty et al, 2007; Soler‐Alfonso et al, 2015; Stiles et al, 2015) that catalyses the conversion of 3‐OH‐isobutyryl‐CoA to 3‐OH‐isobutyrate, the fourth and fifth steps of valine degradation, respectively, have been associated with LS or Leigh‐like syndrome and deficiencies of multiple mitochondrial respiratory chain enzymes.…”

“…Accumulation of toxic methacrylyl‐CoA and acryloyl‐CoA, two highly reactive intermediates that spontaneously react with sulfhydryl groups of, for example, cysteine, and cysteamine, is suspected to cause brain pathology and the biochemical pattern found in HIBCH and SCEH deficiencies (Ferdinandusse et al, 2013; Loupatty et al, 2007; Peters et al, 2014). SCEH also catalyzes the second step of the β‐oxidation of short‐chain fatty acids, that is, the hydration of α,β‐unsaturated enoyl‐CoAs to produce β‐hydroxyacyl‐CoAs (Kanazawa et al, 1993).…”

Disorders of Leucine, Isoleucine, and Valine Metabolism

“…Unusual cysteine and cysteamine conjugates of methacrylic acid were detected in urine. In fi broblasts from both patients, 3-hydroxyisobutyryl-CoA hydrolase activity was defi cient and molecular analysis revealed mutations in the HIBCH gene (Loupatty et al 2007 ).…”