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

Abstract

Mutations in the short‐chain enoyl‐CoA hydratase (SCEH) gene, ECHS1, cause a rare autosomal recessive disorder of valine catabolism. Patients usually present with developmental delay, regression, dystonia, feeding difficulties, and abnormal MRI with bilateral basal ganglia involvement. We present clinical, biochemical, molecular, and functional data for four affected patients from two unrelated families of Samoan descent with identical novel compound heterozygous mutations. Family 1 has three affected boys while Family 2 has an affected daughter, all with clinical and MRI findings of Leigh syndrome and intermittent episodes of acidosis and ketosis. WES identified a single heterozygous variant in ECHS1 at position c.832G > A (p.Ala278Thr). However, western blot revealed significantly reduced ECHS1 protein for all affected family members. Decreased SCEH activity in fibroblasts and a mild increase in marker metabolites in urine further supported ECHS1 as the underlying gene defect. Additional investigations at the DNA (aCGH, WGS) and RNA (qPCR, RT‐PCR, RNA‐Seq, RNA‐Array) level identified a silent, common variant at position c.489G > A (p.Pro163=) as the second mutation. This substitution, present at high frequency in the Samoan population, is associated with decreased levels of normally spliced mRNA. To our understanding, this is the first report of a novel, hypomorphic allele c.489G > A (p.Pro163=), associated with SCEH deficiency.

Whole‐exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees

“…The studies have revealed that variants in NARS2 can affect protein expression and dimerization, which may result in a decreased level of charged tRNA Asn and total tRNA Asn , thereby influencing the synthesis and activity of mitochondrial complexes except complex II (Mizuguchi et al, 2017;Ognjenovic & Simonovic, 2018;Seaver et al, 2018;Simon et al, 2015;Vanlander et al, 2015). In our study, the variant c. Mutairi et al, 2017;Aretini et al, 2018;Carlston et al, 2019;Ferdinandusse et al, 2015;Fitzsimons et al, 2018;Haack et al, 2015;Nair et al, 2016;Olgiati et al, 2016;Pajares et al, 2020;Peters et al, 2014;Ronchi et al, 2020;Sakai et al, 2015;Sharpe & McKenzie, 2018;Simon et al, 2021;Tetreault et al, 2015;Uchino et al, 2019;Wu et al, 2020;Yang & Yu, 2020). protein (Sakai et al, 2015).…”

Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review

“…Quality of life in these patients and their caregivers are influenced by progressive evolution. Prognosis is poor, with a short survival rate of about 70 months, but cases with neonatal deaths or adulthood survival up to 32 years have also been reported [ 41 , 42 ].…”

Terminal 10q26.12 deletion is associated with neonatal asymmetric crying facies syndrome: a case report and literature review

“…Previous studies delineate that haploinsufficiency of EBF3 is a critical contributor to developmental delay, intellectual disability, and particular facial dysmorphisms in patients bearing point mutations and indels in this gene [ 29 , 30 ]. Mutations in ECHS1 cause rare autosomal recessive disorders mainly presenting with developmental delay, dystonia, feeding difficulties, and abnormal neuroimaging with bilateral basal ganglia involvement [ 31 ]. ECHS1 deficiency is also linked with the occurrence of pachygyria, microcephaly and dysmorphic facies.…”

“…Mutations in ECHS1 cause rare autosomal recessive disorders mainly presenting with developmental delay, dystonia, feeding difficulties, and abnormal neuroimaging with bilateral basal ganglia involvement [31]. ECHS1 deficiency is also linked with the occurrence of pachygyria, microcephaly and dysmorphic facies.…”