ECHS1 mutations

Inspired by a colleague's patient

Ferdinandusse S, Friederich MW, Burlina A, Ruiter JP, Coughlin CR 2nd, Dishop MK, Gallagher RC, Bedoyan JK, Vaz FM, Waterham HR, Gowan K, Chatfield K, Bloom K, Bennett MJ, Elpeleg O, Van Hove JL, Wanders RJ. Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis.2015 Jun 18;10:79.

Abstract

BACKGROUND:

Short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1) catalyzes hydration of 2-trans-enoyl-CoAs to 3(S)-hydroxy-acyl-CoAs. SCEH has a broad substrate specificity and is believed to play an important role in mitochondrial fatty acid oxidation and in the metabolism of branched-chain amino acids. Recently, the first patients with SCEH deficiency have been reported revealing only a defect in valine catabolism. We investigated the role of SCEH in fatty acid and branched-chain amino acid metabolism in four newly identified patients. In addition, because of the Leigh-like presentation, we studied enzymes involved in bioenergetics.

METHODS:

Metabolite, enzymatic, protein and genetic analyses were performed in four patients, including two siblings. Palmitate loading studies in fibroblasts were performed to study mitochondrial β-oxidation. In addition, enoyl-CoA hydratase activity was measured with crotonyl-CoA, methacrylyl-CoA, tiglyl-CoA and 3-methylcrotonyl-CoA both in fibroblasts and liver to further study the role of SCEH in different metabolic pathways. Analyses of pyruvate dehydrogenase and respiratory chain complexes were performed in multiple tissues of two patients.

RESULTS:

All patients were either homozygous or compound heterozygous for mutations in the ECHS1 gene, had markedly reduced SCEH enzymatic activity and protein level in fibroblasts. All patients presented with lactic acidosis. The first two patients presented with vacuolating leukoencephalopathy and basal ganglia abnormalities. The third patient showed a slow neurodegenerative condition with global brain atrophy and the fourth patient showed Leigh-like lesions with a single episode of metabolic acidosis. Clinical picture and metabolite analysis were not consistent with a mitochondrial fatty acid oxidation disorder, which was supported by the normal palmitate loading test in fibroblasts. Patient fibroblasts displayed deficient hydratase activity with different substrates tested. Pyruvate dehydrogenase activity was markedly reduced in particular in muscle from the most severely affected patients, which was caused by reduced expression of E2 protein, whereas E2 mRNA was increased.

CONCLUSIONS:

Despite its activity towards substrates from different metabolic pathways, SCEH appears to be only crucial in valine metabolism, but not in isoleucine metabolism, and only of limited importance for mitochondrial fatty acid oxidation. In severely affected patients SCEH deficiency can cause a secondary pyruvate dehydrogenase deficiency contributing to the clinical presentation.

Ganetzky R, Stojinski C. Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency. 2019 Jun 20. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. 

Excerpt

CLINICAL CHARACTERISTICS:

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) represents a clinical spectrum in which several phenotypes have been described: The most common phenotype presents in the neonatal period with severe encephalopathy and lactic acidosis and later manifests Leigh-like signs and symptoms. Those with presentation in the neonatal period typically have severe hypotonia, encephalopathy, or neonatal seizures within the first few days of life. Signs and symptoms typically progress quickly and the affected individual ultimately succumbs to central apnea or arrhythmia. A second group of affected individuals present in infancy with developmental regression resulting in severe developmental delay. A third group of affected individuals have normal development with isolated paroxysmal dystonia that may be exacerbated by illness or exertion. Across all three groups, T2 hyperintensity in the basal ganglia is very common, and may affect any part of the basal ganglia.

DIAGNOSIS/TESTING:

The diagnosis of ECHS1D is established in a proband by the identification of biallelic pathogenic variants in ECHS1 on molecular genetic testing or low short-chain enoyl-CoA hydratase (SCEH) activity using cultured skin fibroblasts.

MANAGEMENT:

Treatment of manifestations: Treatment of severe metabolic acidosis with bicarbonate therapy; hyperammonemia (which may be related to severe acidosis or low ATP from impaired aerobic oxidation) may be addressed by treatment of the metabolic acidosis and/or consideration of hemodialysis. Inadequate nutrition may require feeding therapy; placement of a feeding tube may be considered. Paroxysmal dystonia may respond to benzodiazepines, whereas chronic dystonia may require botulinum toxin injections. Treatment of dystonia with levodopa may also be considered. Standard treatment for seizures, cardiomyopathy, pulmonary hypertension, optic atrophy, sensorineural hearing loss, and developmental delay. Surveillance: At least annual echocardiogram, dilated eye examination, and audiologic evaluation. Routine monitoring for neurologic symptoms and developmental issues. Assessment of acid/base status and blood lactate level with all illnesses or metabolic stressors. Agents/circumstances to avoid: Mitochondrial toxins (i.e., valproic acid, prolonged propofol infusions); ketogenic diet.

GENETIC COUNSELING:

ECHS1 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% change of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal diagnosis for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if the ECHS1 pathogenic variants in the family are known.

Aretini P, Mazzanti CM, La Ferla M, Franceschi S, Lessi F, De Gregorio V, Nesti C, Valetto A, Bertini V, Toschi B, Battini R, Caligo MA. Next generation sequencing technologies for a successful diagnosis in a cold case of Leigh syndrome. BMC Neurol. 2018 Jul 20;18(1):99.

Abstract

BACKGROUND:

Leigh Syndrome (LS, OMIM 256000) is an early-onset, progressive neurodegenerative disorder characterized by broad clinical and genetic heterogeneity; it is the most frequent disorder of mitochondrial energy production in children. LS inheritance is complex because patients may present mutations in mitochondrial DNA (mtDNA) or in nuclear genes, which predominantly encode proteins involved in respiratory chain structure and assembly or in coenzyme Q10 biogenesis. However, during the last 15 years, the discovery of several genetic mutations and improved knowledge of the natural history of LS has significantly increased our understanding of this mitochondrial disorder.

CASE PRESENTATION:

Here we describe a 19-year-old male with clinical and neuroimaging LS diagnosed at 3 years of age. Genetic analyses of the whole mtDNA for maternally inherited LS (MILS) and neuropathy ataxia retinitis pigmentosa (NARP) syndrome failed to reveal any pathogenic mutations.

CONCLUSIONS:

Recently, a missense mutation in ECHS1 and a ~ 35 kb deletion in 10q26.3 involving the region including the gene were identified by WES (whole exome sequencing), uncovering the genetic diagnosis clinically hypothesized for 15 years. We also report the long-term follow-up of this patient, showing a comparison with classical LS or other Leigh-like pictures.

KEYWORDS:

ECHS1 gene; Exome analysis; Leigh disease