Clinical, metabolic, and genetic characteristics of 42 children with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency in China

Abstract

Objective: To summarize clinical characteristics of the largest Chinese cohort of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) and analyze the genotype-phenotype correlations.

Methods: This retrospective study enrolled 42 children with genetically diagnosed ECHS1D within the China Mitochondrial Disease Network. Patients were classified into severe infantile (SI), slowly progressive infantile (SPI), and late-onset phenotype (LP) based on onset age, disease progression rate, and gross motor impairment severity. Prognosis was assessed using the Modified Rankin Scale(mRS).

Results: Forty-two patients (25 male) were included, with a median onset age of 13.5 months (range 3-60). Paroxysmal dystonia (PD, 33.3 %) was the most common initial symptoms, followed by developmental delay(28.6 %) and regression(21.4 %). All patients had globus pallidus involvement and were diagnosed with Leigh syndrome (SI, n = 18; SPI, n = 13; LP, n = 11). SI cases all started with non-paroxysmal dystonia, and showed more frequent putamen (77.8 %) and caudate nucleus (72.2 %) involvement. In SPI and LP cases, PD was more common at onset, with milder symptoms and often isolated globus pallidus involvement. The proportions of elevated urinary metabolic markers 2,3-dihydroxy-2-methylbutyrate (2,3DH2MB) and S-(2-carboxypropyl) cysteamine (SCPCM) were 89.7 % and 93.1 % respectively, and the degree of their elevation was significantly correlated with phenotype severity. Regarding overall prognosis, 52.4 % of patients could walk independently (mRS < 4), with three fatalities. SI cases had the worst prognosis, followed by SPI, while LP cases showed the best outcomes (p < 0.05). In terms of genetics, all patients were compound heterozygous variants in the ECHS1 gene, with 21 novel variants identified. The most common variant was the c.489G > A (p.Pro163=) variant, which was found in 18 patients, accounting for as high as 42.8 % (allele frequency 0.214). And patients carrying this synonymous variant exhibited later onset age, longer diagnostic duration, milder phenotypes.

Conclusions: This study provides a comprehensive overview of ECHS1D, summarizing its clinical and genetic spectrum, and indicating that the c.489G > A variant is a potential hotspot in the Chinese population. As findings from single-center studies may not be generalizable to a broader population, multi-center prospective studies are warranted.

Keywords: ECHS1 gene; Leigh syndrome; Prognosis; Synonymous variant; Urinary metabolite.