Ophthalmic manifestations of short-chain enoyl-CoA hydratase deficiency associated with a hypomorphic founder allele in ECHS1 inthe Pacific peoples population

Abstract

Purpose : To describe the Ophthalmic manifestations occurring in association with Short-chain enoyl-coA hydratase (SCEH) deficiency due to biallelic ECHS1 variants. This was first reported in 2014 in association with Leigh syndrome (LS) and increased S-(2-carboxypropyl)cysteine excretion. Recently, Simon et al described four Samoan children harbouring a hypomorphic allele c.489G>A, p.(Pro163=) associated with reduced levels of normally-spliced mRNA. This synonymous variant, overlooked on standard genomic testing, is prevalent in the Samoan population with a minor-allele frequency of 0.17.

Methods : Patients with LS and one ECHS1 variant were identified in NZ and Australian genomic and clinical databases. ECHS1 sequence data were interrogated for c.489G>A p.(Pro163=), and clinical data were reviewed. Ophthalmic investigation included eye movements, serial visual acuity, and retinal and optic nerve imaging.

Results : Thirteen patients from ten families were identified; all had Pacific ancestry including Cook Island, Tokelau and Māori. All were heterozygous for the c.489G>A allele, in conjunction with a pathogenic or likely pathogenic allele.
Optic atrophy leading to progressive decline in visual acuity occurred in nine, and was first detected at 3-9 years of age. Eye movement abnormalities, present in 9, and the first symptom in 3, included oscillopsia, nystagmus ( horizontal and rotary), end-point nystagmus, and saccadic overshoots. Visual acuity declined rapidly with the majority of patient’s vision reaching logMAR 2.0 between 15-20 years of age, secondary to progressive optic atrophy.

Conclusions : SCEH deficiency was an unrecognised entity in the Pacific peoples population, but the ocular manifestations start at an early age, in particular the ocular motility disorders, and paediatric ophthalmologists need to consider this association in their differential. As this is potentially treatable with a valine-restricted, high-energy diet and emergency regimen, early diagnosis and appropriate dietary intervention may modulate the course of the significant progression of optic atrophy which untreated results in significant and irreversible visual impairment.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.