Succinyl-CoA synthetase ( SUCLA2 ) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion

Abstract

Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. We developed a new LC-MS/MS based enzyme assay to demonstrate the decreased SCS activity in the siblings with this unique genotype. Both siblings shared bilateral progressive hearing loss, encephalopathy, global developmental delay, generalized myopathy, and dystonia with choreoathetosis. Prior to diagnosis and because of lactic acidosis and low activity of muscle pyruvate dehydrogenase complex (PDC), sibling 1 (S1) was placed on dichloroacetate, while sibling 2 (S2) was on a ketogenic diet. S1 developed severe cyclic vomiting refractory to therapy, while S2 developed Leigh syndrome, severe GI dysmotility, intermittent anemia, hypogammaglobulinemia and eventually succumbed to his disorder. The mitochondrial DNA contents in skeletal muscle (SM) were normal in both siblings. Pyruvate dehydrogenase complex, ketoglutarate dehydrogenase complex, and several mitochondrial electron transport chain (ETC) complexes activities were low or at the low end of the reference range in frozen SM from S1 and/or S2. In contrast, activities of PDC, other mitochondrial enzymes of pyruvate metabolism, ETC and, integrated oxidative phosphorylation, in skin fibroblasts were not significantly impaired. Although we show that propionyl-CoA inhibits PDC, it does not appear to account for decreased PDC activity in SM. A better understanding of the mechanisms of phenotypic variability and the etiology for tissue-specific secondary deficiencies of mitochondrial enzymes of oxidative metabolism, and independently mitochondrial DNA depletion (common in other cases of A-SCS deficiency), is needed given the implications for control of lactic acidosis and possible clinical management.

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

“…Initiation of a therapeutic intervention on the basis of only functional PDC deficiency without follow up genetic resolution of the etiology is not recommended and could be harmful [4,5,11]. Likewise terminating a PDC deficiency work-up following a normal PDC activity assay result in one cell/tissue type without pursuing additional molecular and/or enzymatic testing using another cell/tissue type is ill advised, because of the observed significant cell/tissue type-specific variability in assay outcome irrespective of the underlying genetic etiology of the PDC deficiency (Results 3.1.4).…”

“…Subjects who were determined to be PDC enzyme deficient first at CIDEM but without a known genetic etiology were enrolled in the IRB-approved studies for molecular confirmation by either 1) Sanger sequencing for the common PDC genes ( DLAT, DLD, PDHA1, PDHB, PDHX, and PDP1 performed at CIDEM on a research or clinical basis at UHCMC Center for Human Genetics Laboratory (CHGL), 2) next-generation sequencing (NGS) of 23 genes associated with pyruvate metabolism (i.e., targeted gene panel; TGP) including BOLA3, DLAT, DLD, LIAS, LIPT1, LIPT2, NFU1, PDHA1, PDHB, PDHX, PDK1, PDK2, PDK3, PDK4, PDP1, PDP2, PC, PCK1, PCK2, SLC19A2, SLC19A3, SLC25A19 and TPK1 (performed at UHCMC CHGL), or 3) whole exome sequencing (WES; performed at the Genomics Core Facility of CWRU) [4,5]. …”

“…The efficacy of this therapeutic intervention appears to depend on the disease phenotype and the attainment and maintenance of ketosis [8]. However, administration of a ketogenic diet may not be completely effective and may be harmful (or even lethal) in cases where PDC deficiency is associated with more general impairment of formation of acetyl-CoA (e.g., fatty acid β-oxidation [FAO] or BCAA metabolism defects) or oxidation (e.g., TCA cycle defects or other mitochondrial dysfunction) of acetyl-CoA [4,5,11]. Therefore, prompt and correct diagnosis of this disorder is critical for the long-term positive outcome of a child affected with a specific PDC deficiency.…”

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

“…This led to performance of trio WES analysis using DNA from parents and proband. The WES pipeline used was described before [18], except for using updated Omicia Opal version 4.23.2 and Omicia VAAST Trio Report algorithm in this case.…”

Phenotypic heterogeneity of a compound heterozygous SUCLA2 mutation

“…With interest we read the article by Huang et al about two siblings carrying both the same compound heterozygous SUCLA2 mutation, which manifested phenotypically with a progressive multisystem syndrome, resulting in severe disability (patient-1) or death (patient-2) [1]. We have the following comments and concerns.…”