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

Abstract

ECHS1 gene mutations are known to cause mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, a neurodegenerative disorder characterized by psychomotor development delay, lactic acidosis, and basal ganglia lesions resembling Leigh syndrome. Short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency is a very rare and new disorder, with a wide phenotypic spectrum and different outcomes ranging from neonatal death to survival into adulthood. Since the identification of ECHS1 deficiency in 2014, almost 63 patients with pathogenic mutations in the ECHS1 gene have been described to date. This paper focuses on the clinical and molecular findings as well as the evolution of a Caucasian girl diagnosed with ECHS1 deficiency who carries a new compound heterozygous mutation in the ECHS1 gene. Polymorphic symptoms, namely failure to thrive, significant global developmental delay/regression, movement disorders, ocular abnormalities, hearing loss, seizure, and cardiac myopathy, may be a challenge in mitochondrial disorder suspicion. Early diagnosis, an appropriate diet with valine restriction, and trigger avoidance are essential, as there is no effective therapy for the disease. This disorder influences life quality in these patients and their caregivers, and it has the potential to be fatal.

A Novel Variant of the Short-Chain Enoyl-CoA Hydratase-1 Gene Presenting with a Mild Phenotype: The Second Case Report from India

“…1A >G (p.Met1? ), 3 the novel (p.Leu123Phe) change, 7 c.232G > T (p.Glu78Ter), 8 9 c.817A > G(p.Lys273Glu), 4 13 14 and c.394C > T (p.Ala132Thr) 17 were the other associated variations. However, till date the nonsense variation (chr10:g.133366045G > A) resulting in a stop codon that is identified in our patient has not yet been reported.…”

“…Korenke 14 described two unrelated girls, one with episodic opisthotonos and another with hemidystonia, both occurring in late afternoon after physical exertion. Muntean et al 4 described a girl with paroxysmal dystonia starting at 8 years of age. However, the combination of persistent dystonia with generalized choreoathetosis and alternating skew deviation with partial tonic OTR as in our case are hitherto unreported among patients with the milder phenotype, although choreoathetosis has been infrequently reported in patients with the Leigh-like syndrome.…”

“…Phenotypic heterogeneity exists for the same genotype, often making the diagnosis challenging. 4 action and later even persisted during rest. These twisting movements were minimally painful.…”

ECHS1 deficiency and its biochemical and clinical phenotype

“…Biochemical testing results were variable between reports. The most consistent biomarkers published were serum lactate, which was elevated in roughly 2/3 of the cases and 2‐methyl‐2,3‐dihydroxybutyrate, which was elevated in urine organic acid testing in approximately 1/3 of the patients (Bedoyan et al, 2017; Ferdinandusse et al, 2015; Fitzsimons et al, 2018; Haack et al, 2015; Marti‐Sanchez et al, 2020; Muntean et al, 2022; Peters et al, 2014; Yang & Yu, 2020). A recent study demonstrated differences in urine levels of some valine metabolites S‐(2‐carboxypropyl) cysteine/cysteamine, S‐(2‐carboxyethyl) cysteine/cysteamine between six patients and six controls (Kuwajima et al, 2021).…”

“…Among those with developmental delay, regression of skills was commonly reported (Carlston et al, 2018; Fitzsimons et al, 2018; Muntean et al, 2022; Tetreault et al, 2015; Yamada et al, 2015; Yang & Yu, 2020). Nystagmus and optic atrophy (Ferdinandusse et al, 2015; Fitzsimons et al, 2018; Haack et al, 2015; Huffnagel et al, 2018; Muntean et al, 2022; Peters et al, 2014; Sakai et al, 2015; Tetreault et al, 2015), dilated/hypertrophic cardiomyopathy (Ganetzky et al, 2016; Muntean et al, 2022; Peters et al, 2014), apneic spells (Bedoyan et al, 2017; Fitzsimons et al, 2018) were also reported albeit less frequently. Most of the reported patients had MRI findings of increased T2 and FLAIR signal in brainstem, basal ganglia and/or supratentorial white matter, regions characteristically involved in Leigh Syndrome (Balasubramaniam et al, 2017; Bedoyan et al, 2017; Carlston et al, 2018; Ferdinandusse et al, 2015; Fitzsimons et al, 2018; Haack et al, 2015; Huffnagel et al, 2018; Mahajan et al, 2017; Muntean et al, 2022; Olgiati et al, 2016; Peters et al, 2014; Sakai et al, 2015; Shayota et al, 2019; Tetreault et al, 2015; Uesugi et al, 2020; Yamada et al, 2015; Yang & Yu, 2020).…”