A novel compound heterozygous variant of ECHS1 identified in a Japanese patient with Leigh syndrome

Abstract

Leigh syndrome (LS) is a heterogeneous neurodegenerative disorder caused by mitochondrial dysfunction. Certain LS cases have mutations in ECHS1 , which encodes a short-chain enoyl-CoA hydratase involved in the metabolism of fatty acids and branched-chain amino acids in mitochondria. Using exome sequencing, we diagnosed a Japanese patient with LS and identified the patient as a compound heterozygote for a novel variant of ECHS1 , consisting of NM_004092.4:c.23T>C (p.Leu8Pro) and NM_004092.4:c.176A>G (p.Asn59Ser).

Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

“…All currently identified ECHS1D patients have mutations in both ECHS1 alleles, indicating autosomal recessive inheritance, with many different mutations identified (Table ). Patients who are homozygous for mutations in ECHS1 have all been offspring of consanguineous relationships, resulting in two copies of the same rare mutation .…”

“…These mutations can affect the mitochondrial targeting sequence, intro/exon boundaries, splice sites, potential protein–protein interaction sites or encode premature stop codons that lead to non‐sense‐mediated decay of the mRNA . Interestingly, two possible ECHS1 founder mutations have been identified; p.Asn59Ser, which is present in multiple patients of Japanese descent , and p.Thr180Ala, identified in an Irish traveller family and in French–Canadian patients . In addition, p.Gln159Arg has also been suggested as a founder mutation of Pakistani origin , although this mutation has also been identified in patients of German, Japanese and North American ancestry .…”

“…ECHS1 activity has found to be reduced whenever it has been measured in patients with confirmed pathogenic ECHS1 mutations . Interestingly, certain mutations appear to cause a more severe reduction in ECHS1 activity than others.…”

“…Short‐chain enoyl‐coA hydratase (ECHS1) is a key enzyme involved in mitochondrial fatty acid β‐oxidation (FAO). Since its initial identification in 2014, 46 patients have been described with ECHS1 deficiency (ECHS1D) . Almost all of these patients have been diagnosed with Leigh syndrome (LS), a lethal form of subacute necrotizing encephalomyelopathy.…”

ECHS1 disease in two unrelated families of Samoan descent: Common variant ‐ rare disorder

“…Most patients present with developmental delay, regression, dystonia, feeding difficulties, cardiomyopathy, and brain MRI changes consistent with Leigh syndrome. Since Sharpe et al, reviewed the mutational, clinical, and biochemical spectrum of 42 patients from 33 families with ECHS1 disease, an additional nine new cases have been reported, none of which are due to synonymous mutations (Aretini et al, 2018;Carlston, Ferdinandusse, Hobert, Mao, & Longo, 2019;Pajares et al, 2020;Ronchi et al, 2020;Sharpe & McKenzie, 2018;Uchino et al, 2019;Wu et al, 2020;Yang & Yu, 2020). Here we report clinical, biochemical, molecular, and functional data on four patients from two unrelated families, presenting with two novel mutations in ECHS1.…”