Expanding the phenotype of SLC25A42-associated mitochondrial encephalomyopathy.

SLC25A42 gene encodes an inner mitochondrial membrane protein that imports Coenzyme A into the mitochondrial matrix. A mutation in this gene was recently reported in a subject born to consanguineous parents who presented with mitochondrial myopathy with muscle weakness and lactic acidosis. In this report, we present 12 additional individuals with the same founder mutation who presented with variable manifestations ranging from asymptomatic lactic acidosis to a severe phenotype characterized by developmental regression and epilepsy. Our report confirms the link between SLC25A42 and mitochondrial disease in humans, and suggests that pathogenic variants in SLC25A42 should be interpreted with the understanding that the associated phenotype may be highly variable.

A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency.

Short-chain enoyl-CoA hydratase (SCEH) is a mitochondrial enzyme involved in the oxidation of fatty acids and the catabolic pathway of valine and, to a lesser extent, isoleucine. Deficiency of this enzyme was recently shown to cause an early childhood Leigh syndrome phenotype. The few reported patients were compound heterozygotes for two missense or missense with truncating variants in ECHS1 that encodes SCEH. We describe two siblings with severe refractory lactic acidosis and death within the first 2 days of life. Following negative clinical whole-exome and whole-genome sequencing, we resorted to autozygome/exome analysis on research basis and identified a homozygous splice site mutation (c.88+5G>A) in the two cases. Analysis of cDNA confirmed complete replacement of the normal transcript with an aberrant transcript (r.88_89ins 88+1_88+11) predicting premature truncation of the protein [p.(Ala31Glufs*23)]. Furthermore, quantitative reverse transcriptase polymerase chain reaction (RTPCR) showed marked reduction in ECHS1, most likely nonsense-mediated decay (NMD)-mediated. This is the first report of homozygosity for a truncating mutation in ECHS1, which may explain the severe phenotype. Our report highlights the need to consider SCEH deficiency in patients with lethal neonatal lactic acidosis, and the potentially limited sensitivity of untargeted genomic sequencing towards non-canonical splicing mutations, which may explain at least some of the 'negative' cases on clinical exome/genome sequencing.