HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase

Abstract

BackgroundDeficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance or expression of mitochondrial DNA. Impaired biosynthesis of iron-sulphur clusters and lipoic acid can lead to pyruvate dehydrogenase complex (PDHc) deficiency in addition to multiple RC deficiencies, known as the multiple mitochondrial dysfunctions syndrome.MethodsTwo brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis.ResultsSpecific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G <A; p.Gly317Glu in the HIBCH gene, which segregated with infantile-onset neurodegeneration within the family.ConclusionsHIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.

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

“…Only Patient 1 and Patient 3 had muscle biopsies performed, showing a mild secondary PDH deficiency in Patient 1 while Patient 3 had reduced complex III activity, which would support published data (Bedoyan et al, 2017; Ferdinandusse et al, 2013; Sakai et al, 2015). …”

“…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).…”

Leigh map: A novel computational diagnostic resource for mitochondrial disease

“…The addition of drug targets (a current feature of the MINERVA platform) to the Leigh Map could potentially provide insight into the effectiveness of various agents in treating mitochondrial disease in specific genetic contexts. For example, patients with SLC19A3 mutations respond dramatically to biotin and thiamine therapy,21 whereas those with HIBCH mutations may benefit from N‐acetyl cysteine 22. cDNA and protein mutations and annotations regarding animal models are also useful potential supplements to the Leigh Map.…”

Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus

“…Gene defects highlighted in red have been linked to epilepsy. [17]. The pathomechanism of this disorder appears to be via oxidation of critical cysteine residues in multiple OXPHOS enzymes and other mitochondrial proteins by the highly toxic metabolite 3-methacrylyl-CoA that accumulates in HIBCH deficiency [17].…”