Mitochondrial Short-Chain Enoyl-Coa Hydratase 1 Deficiency

A number sign (#) is used with this entry because of evidence that mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) is caused by compound heterozygous mutation in the ECHS1 gene (602292) on chromosome 10q26.

Description

Mitochondrial short-chain enoyl-CoA hydratase-1 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 Peters et al., 2014).

Clinical Features

Peters et al. (2014) reported 2 sibs, born of unrelated parents of Greek ancestry, with a severe neurologic disorder resulting in death from cardiorespiratory failure at ages 4 and 8 months. Both patients presented at birth with hypotonia, poor suck, and episodic apnea. One of the patients also had vertical nystagmus as well as cardiac abnormalities, including ventricular septal defect and severe progressive hypertrophic obstructive cardiomyopathy. The patients showed little developmental progress. Brain imaging showed progressive generalized atrophy of the cerebrum, brainstem, and cerebellum, thinning of the corpus callosum, and T2-weighted hyperintensities in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome. Laboratory studies revealed increased serum and cerebrospinal fluid lactate, and both patients had decreased activities of the pyruvate dehydrogenase complex (PDC). Skeletal muscle biopsy of 1 of the patients showed normal activities of mitochondrial respiratory chain enzymes. Urinary analysis showed increased levels of S-(2-carboxypropyl)cysteine, suggesting a defect in the valine catabolic pathway. The patients also had increased levels of 2-methyl-2,3-dihydroxybutyrate. Additional studies showed normal levels of 3-hydroxyisobutyryl-carnitine, suggesting a defect in ECHS1 rather than HIBCH (610690); sequencing of the HIBCH gene did not reveal any pathogenic mutations.

Sakai et al. (2015) reported a 4-year-old boy, born of unrelated parents, with a severe neurologic disorder apparent since early infancy. He had delayed psychomotor development with inability to sit unsupported as well as absence of speech, hearing impairment, nystagmus, hypotonia, spasticity, and athetotic movements. Brain imaging showed T2-weighted hyperintensities consistent with Leigh syndrome. Laboratory studies showed increased lactate and increased urinary glyoxylate. Skeletal muscle samples showed a combined deficiency of the activities of mitochondrial respiratory enzymes, including complex I (39% of controls), complex III (34% of controls), and complex IV (64% of controls), although electrophoresis studies showed that assembly of these complexes was normal.

Yamada et al. (2015) reported a 7-year-old girl and her 5-year-old brother with ECHS1D, who were born of unrelated Japanese parents. Both sibs presented with dystonia between 7 and 10 months of age, after which regression of psychomotor development became apparent. Brain imaging showed T2-weighted hyperintensities in the putamen, globus pallidus, caudate nucleus, and substantia nigra. At examination, both patients bent backward forcefully and had no language. Neither patient had seizures. The condition worsened with viral infection, resulting in death in the 5-year-old boy. Analysis of mitochondrial respiratory chain activities was normal in the fibroblasts of the older sister, and blood and cerebrospinal fluid lactate were not increased, but urinary lactate was increased. There was also increased urinary N-acetyl-S-cysteine, a metabolite of methacrylyl-CoA, and mildly increased 2,3-dihydroxy-2-methylbutyrate. Yamada et al. (2015) concluded that the patients had a relatively milder form of ECHS1D with defective valine catabolic and beta-oxidation pathways, and suggested that N-acetyl-S-cysteine would be a good candidate metabolic marker for the disorder.

Inheritance

The transmission pattern of ECHS1D in the family reported by Peters et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs with ECHS1D, Peters et al. (2014) identified compound heterozygous mutations in the ECHS1 gene (602292.0001 and 602292.0002). Patient fibroblasts showed significantly decreased ECHS1 activity and absence of the normal protein by immunoblot analysis. Peters et al. (2014) postulated that the enzymatic defect caused accumulation of the metabolites methacrylyl-CoA and acryloyl-CoA, which are toxic reactive intermediates that may have caused the brain pathology. Decreased activity of the PDC may also have been a secondary effect. The metabolic abnormalities in these patients appeared to be confined to the valine pathway, since fatty acid and isoleucine metabolites were normal.

In a boy with ECHS1D, Sakai et al. (2015) identified compound heterozygous mutations in the ECHS1 gene (602292.0003 and 602292.0004). The mutations, which were found by targeted exome sequencing, segregated with the disorder in the family. Patient cells also showed a combined mitochondrial respiratory chain deficiency, which was rescued by expression of wildtype ECHS1. These findings suggested a link between ECHS1 and the mitochondrial respiratory chain. Sakai et al. (2015) speculated that ECHS1 deficiency induced metabolic abnormalities resulting in the accumulation of toxic metabolites, such as glyoxylate, that secondarily inhibited normal mitochondrial respiratory function.

In 2 sibs, born of unrelated Japanese parents, with ECHS1D, Yamada et al. (2015) identified compound heterozygous missense mutations in the ECHS1 gene (N59S, 602292.0005 and A138V, 602292.0006). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. ECHS1 activity towards different substrates was decreased to between 2.6% and 6.2% of normal controls. In vitro functional expression studies showed that the D59S mutant was nonfunctional, whereas the A138V mutant had about 30% residual activity.