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

Abstract

Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affects the catabolism of various amino acids, particularly valine. We describe a case compound heterozygous for ECHS1 mutations c.836T>C (novel) and c.8C>A identified by whole exome sequencing of proband and parents. SCEH deficiency was confirmed with very low SCEH activity in fibroblasts and nearly absent immunoreactivity of SCEH. The patient had a severe neonatal course with elevated blood and CSF lactate and pyruvate concentrations, high plasma alanine and slightly low plasma cystine. 2-Methyl-2,3-dihydroxybutyric acid was markedly elevated as were metabolites of the three branched-chain ketoacids on urine organic acids analysis. These urine metabolites notably decreased when lactic acidosis decreased in blood. Lymphocyte pyruvate dehydrogenase complex (PDC) activity was deficient, but PDC and α-ketoglutarate dehydrogenase complex activities in cultured fibroblasts were normal. Oxidative phosphorylation analysis on intact digitonin-permeabilized fibroblasts was suggestive of slightly reduced PDC activity relative to control range in mitochondria. We reviewed 16 other cases with mutations in ECHS1 where PDC activity was also assayed in order to determine how common and generalized secondary PDC deficiency is associated with primary SCEH deficiency. For reasons that remain unexplained, we find that about half of cases with primary SCEH deficiency also exhibit secondary PDC deficiency. The patient died on day-of-life 39, prior to establishing his diagnosis, highlighting the importance of early and rapid neonatal diagnosis because of possible adverse effects of certain therapeutic interventions, such as administration of ketogenic diet, in this disorder. There is a need for better understanding of the pathogenic mechanisms and phenotypic variability in this relatively recently discovered disorder.

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

“…Evidence is emerging that metabolite levels may correlate with disease severity, being subtle or normal for some metabolites in clinically milder cases (Haack et al, 2015; Yamada et al, 2015) and retrospective analysis of S ‐(2‐carboxypropyl)cysteamine, S ‐(2‐carboxypropyl)cysteine, and N ‐acetyl‐ S ‐(2‐carboxypropyl) cysteine can be a diagnostic clue in the disease spectrum of ECHS1 deficiency (A Mutairi et al, 2017). SCEH activity in cultured fibroblasts was markedly reduced but not completely deficient, which is in agreement with a milder clinical phenotype considering the age of death when compared to some other published cases (Bedoyan et al, 2017; Haack et al, 2015; Peters et al, 2014). Ferdinandusse et al investigated the role of SCEH in fatty acid and branched‐chain amino acid metabolism in four patients with mutations in ECHS1 and results from their enzyme activity measurements and immunoblot analysis strongly suggest that there is a correlation between the residual SCEH enzyme activity and the severity of the clinical symptoms (Ferdinandusse et al, 2015).…”

“…Only Patient 1 and Patient 3 had muscle biopsies performed, showing a mild secondary PDH deficiency in Patient 1 while Patient 3 had reduced complex III activity, which would support published data (Bedoyan et al, 2017; Ferdinandusse et al, 2013; Sakai et al, 2015). …”

“…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). …”

Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency

“…Investigations into the molecular etiology of about a third of genetically- unresolved PDC-deficient subjects have identified categories of several other “PDC-associated” genes (an all-inclusive term that includes the PDC-specific genes as well as other genes noted below) whose products are involved with branched-chain amino acid [BCAA] catabolism or other 2-ketoacid dehydrogenase complexes ( DLD ), thiamine-pyrophosphate cofactor synthesis ( TPK ), synthesis of lipoate ( LIAS , LIPT1 , and LIPT2 ), and iron-sulfur cluster complexes ( BOLA3 , NFU1 , GLRX5 , and IBA57 ), as well as with secondary PDC deficiencies, including fatty acid β-oxidation ( ECHS1 and HIBCH ) and tricarboxylic acid cycle ( SUCLA2 ) defects where the mechanism of decreased activity is not yet known. [4–7]. …”