ECHS1 Deficiency as a Cause of Severe Neonatal Lactic Acidosis

Abstract

Mitochondrial short-chain enoyl-CoA hydratase deficiency (ECHS1D) is caused by mutations in ECHS1 (OMIM 602292) and is a recently identified inborn error of valine and fatty acid metabolism. This defect leads to secondary mitochondrial dysfunction. The majority of previously reported patients had the Leigh syndrome, with a median life expectancy of approximately 2 years. We report two siblings born 3 years apart with prenatal findings including facial dysmorphia, oligohydramnios, intrauterine growth restriction, and premature delivery. They had severe lactic acidosis with onset within the first hours of life, had congenital dilated cardiomyopathy, and died at 16 h of life and 2 days of life, respectively.Biochemical evaluation of these patients showed elevated butyryl-carnitine in the blood and elevated methylmalonyl/succinyl-CoA and decreased hydroxybutyryl-CoA in frozen liver of patient 2, confirming abnormal short-chain fatty acid metabolism. Elevated butyryl-carnitine has been reported only in a single previous case of ECHS1 deficiency, which also had neonatal onset. Pyruvate and lactate levels were both elevated with a normal pyruvate-lactate ratio. This supports the previous hypothesis that lactic acidosis in these patients results from secondary inhibition of the pyruvate dehydrogenase complex. The biomarker 2,3-dihydroxy-2-methylbutyric acid was detected in patient 2, but at lower levels than in previously reported cases.These cases extend our understanding of the severe end of the phenotypic spectrum of ECHS1 deficiency, clarify the range of biochemical abnormalities associated with this new disorder, and highlight the need to suspect this disease in patients presenting with comparable metabolic derangements and dysmorphic features.

Clinical, biochemical, and genetic features of four patients with short‐chain enoyl‐CoA hydratase (ECHS1) deficiency

“…All four patients had increased excretion of erythro ‐2,3‐dihydroxy‐2‐methylbutyrate; this metabolite derived from acryloyl‐CoA was originally described in SCEH deficiency in 2014 by Peters et al Latter patient reports document concentrations of varying magnitude (Bedoyan et al, 2017; Ferdinandusse et al, 2015; Peters et al, 2015) and that levels may be unreliable shortly after birth (Ganetzky et al, 2016) which was the case in Patient 4. Two out of four patients had increased methylmalonic acid which has been reported previously in a patient with SCEH deficiency (Tetreault et al, 2015).…”

“…Urine metabolite levels correlate with clinical severity and specific separation of isoC4OH and OH‐C4‐carnitine isomers can distinguish between SCEH and HIBCH deficiency (Al Mutairi et al, 2017; Bedoyan et al, 2017; Ganetzky et al, 2016; Haack et al, 2015; Nair et al, 2016). …”

Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency

“…The pathogenic c.836T>C mutation is novel, but the c.8C>A variant (in a compound heterozygous state with ECHS1 c.389T>A) was described in two siblings with severe lactic acidosis and congenital dilated cardiomyopathy with neonatal demise at ≤2 days of life, without functional studies of SCEH [13]. Although the Omicia score for the ECHS1 c.8C>A mutation was just below the range for a “potentially pathogenic” designation and could have been easily dismissed as not significant in our analysis, the markedly reduced SCEH activity and immunoreactivity supports that the c.8C>A mutation is indeed pathogenic.…”

“…Blood and cerebrospinal fluid (CSF) lactate and pyruvate are usually elevated and brain MRI may show white matter changes or a Leigh syndrome-like pattern affecting brainstem and basal ganglia resembling other inherited disorders of energy metabolism [5, 9–13]. A number of metabolites when present in the urine (and presumably blood) are important diagnostic markers for this disorder, including S-(2-carboxypropyl)-L-cysteine and S-(2-carboxypropyl)cysteamine (which are derived from methacrylyl-CoA), S-(2-carboxyethyl)-L-cysteine and S-(2-carboxyethylcysteamine (which are derived from acryloyl-CoA), and 2-methyl-2,3-dihydroxybutyric acid (MDHB) [5, 8, 14].…”

“…To date, almost half of cases diagnosed with this autosomal recessive disorder perish within the neonatal or infantile period, but survival into adulthood is reported. To date, at least 20 missense exonic, one nonsense, and a few splice site and frame shift mutations in ECHS1 have been reported associated with this relatively novel disorder [5, 8–13, 15–17]. …”