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

Mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) 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).

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.

Haack et al. (2015) reported 10 unrelated individuals who presented with a combination of mitochondrial encephalopathy, deafness, epilepsy, optic nerve atrophy, and cardiomyopathy. Brain MRIs were performed in 9 patients and showed white matter changes in 5 early-onset, severely affected patients, and bilateral T2 hyperintensities in the basal ganglia in 4 less severely affected patients. MR spectroscopy of the basal ganglia showed elevated lactate in 3 of 7 individuals. 2-Methyl-2,3,-dihydroxybutyrate was elevated in the urine of 3 of 4 patients tested, and higher levels appeared to correlate with severe disease expression. Four patients died before the age of 7.5 (range, 4 months to 7.5 years) and 6 patients were alive at the time of reporting (range, 2-31 years). Analysis of enzymes involved in oxidative phosphorylation in muscle tissue and/or fibroblasts showed mild and inconsistent changes in 4 of 8 patients tested, including abnormalities in pyruvate oxidation or ATP production and decreased activity of complex I or complex IV, in 1 patient each.

Tetreault et al. (2015) reported 4 patients from 3 apparently unrelated French Canadian families who had developmental regression in early infancy, failure to thrive, and nystagmus. Three patients had optic atrophy and sensorineural hearing loss. Three patients had episodic neurologic changes, and in 2 the changes were in the context of viral infections. All 4 patients had brain MRI abnormalities including T2 weighted hyperintensities of the basal ganglia. MRS showed a lactate peak in 1 patient. Studies in patient fibroblasts showed normal pyruvate dehydrogenase activity in 2 patients and slightly decreased pyruvate dehydrogenase activity in 1 patient. Cytochrome c oxidase and succinate cytochrome c reductase activity was normal in fibroblasts from all patients. Respiratory chain studies in muscle showed a slight reduction in complex I and complex III activity in 1 patient, and normal activity in the other 3 patients.

Fitzsimons et al. (2018) reported 4 patients with ECHS1D, 3 of whom were sibs. Age range of clinical presentation was 2 weeks to 5 months. All 4 patients had elevated erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconic acid on urine organic acids. In 2 patients, analysis of urine metabolites showed elevated acryloyl cysteamine, N-acetyl-acryloyl-cysteine, methacryl-L-cysteine, and N-acetyl-methacryl-cysteine. All patients also had at least one elevated plasma lactate measurement. MRIs in all patients showed abnormal signal in the bilateral basal ganglia. In 2 patients, prominent sulci and volume loss were noted. In 1 patient there was thinning of the corpus callosum and cerebral and cerebellar atrophy. Three patients had a lactate peak on MRS, and 3 patients had seizures. All patients had developmental delay with regression, and all required feeding support for poor weight gain, 1 via nasogastric tube and 3 via PEG tube. All patients were deceased, with age of death ranging from 13 months to 4 years.

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

In 2 sibs with ECHS1D, Peters et al. (2014) identified compound heterozygous mutations in the ECHS1 gene (A158D, 602292.0001 and c.414+3G-C, 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 (M1R, 602292.0003 and A2V, 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.

In 10 unrelated families segregating ECHS1D, Haack et al. (2015) identified homozygous or compound heterozygous mutations in the ECHS1 gene. In 1 family (F3), 3 affected sibs (proband 68552), born to consanguineous Pakistani parents, were homozygous for a missense mutation (Q159R; 602292.0007). In 2 unrelated families (F1 and F10), patient 346 and patient 52236 were compound heterozygous for the Q159R mutation and different second mutations (N59S, 602292.0008 and E77Q, 602292.0009), respectively. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the mutations in the family. Immunoblotting on fibroblasts from the 2 compound heterozygous patients showed reduced expression of the ECHS1 protein and reduced palmitate-dependent respiration; fibroblasts from 1 of these patients showed reduced 2-enoyl-CoA hydratase activity.

In 4 patients with ECHS1D from 3 unrelated French Canadian families, Tetreault et al. (2015) identified compound heterozygous mutations in the ECHS1 gene. All 3 had a T180A missense mutation (602292.0010) with a different second mutation (see, e.g., 602292.0011 and 602292.0012). All of the mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. All 4 mutations occurred in the ECHS1 enoyl-CoA hydratase/isomerase domain and were predicted to decrease protein stability.

In 3 Irish Traveler sibs and a Pakistani patient with ECHS1D, Fitzsimons et al. (2018) identified homozygosity for the previously identified T180A and Q159R mutations in the ECHS1 gene, respectively. Erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconic acid were elevated on urine organic acids of all patients. Muscle and fibroblast testing was carried out in 1 sib and the Pakistani patient. Fibroblasts showed markedly decreased ECHS1 enzyme activity and absence of ECHS1 on Western blot analysis. PDH activity and beta oxidation studies were normal. Activities of respiratory chain complexes I, II, and IV were normal, and activity of complexes II+III was decreased in muscle.