Deficiency of the ADP-Forming Succinyl-CoA Synthase Activity Is Associated with Encephalomyopathy and Mitochondrial DNA Depletion

Abstract

The mitochondrial DNA (mtDNA) depletion syndrome is a quantitative defect of mtDNA resulting from dysfunction of one of several nuclear-encoded factors responsible for maintenance of mitochondrial deoxyribonucleoside triphosphate (dNTP) pools or replication of mtDNA. Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion. Succinyl-CoA synthetase is invariably in a complex with mitochondrial nucleotide diphosphate kinase; hence, we propose that a defect in the last step of mitochondrial dNTP salvage is a novel cause of the mtDNA depletion syndrome.

Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion

“…The patients, who were examined, had a respiratory chain SUCLA2 point mutation and 13q14 deletion S Matilainen et al defect and depletion of mtDNA. [6][7][8][9][10] Our two Finnish patients became symptomatic at the age of 5-6 months, similar to other reported patients, but showed clearly slower progression of the disease: at the current age of 9 and 20, they are able to walk with a walker, go to school and, despite a hearing deficit and inability to speak, are able to communicate using signs and gestures. The MRI findings of patient 1 have not progressed between the age of 2 and a half years and 7 years of age.…”

“…Two Israeli patients carried a deletion causing skipping of exon 6 and part of exon 7 ( Figure 3a); however, the RNA was expressed in the patients' cells. 6 Protein without this fragment is predicted to be unstable and incapable of ADP phosphorylation. All Faroese patients carried the mutation c.534 þ 1G4A in intron 4, 7,8 which led to multiple exon skipping, resulting in complete absence of functional protein.…”

“…4,5 Patients with SUCLA2 mutations typically have progressive childhood-onset Leigh-like encephalomyopathy associated with dystonia, hypotonia, sensorineural hearing deficit, lesions of the basal ganglia, depletion of mtDNA and methylmalonic aciduria. 3,6 Over 20 patients and five different mutations in SUCLA2 have been described. [6][7][8][9][10] We report here molecular basis of mitochondrial encephalomyopathy, also combined with bilateral retinoblastoma, in patients with clinical symptoms or signs previously described in association with SUCLA2 mutations: encephalomyopathy with hearing deficit and methylmalonic aciduria.…”

“…3,6 Over 20 patients and five different mutations in SUCLA2 have been described. [6][7][8][9][10] We report here molecular basis of mitochondrial encephalomyopathy, also combined with bilateral retinoblastoma, in patients with clinical symptoms or signs previously described in association with SUCLA2 mutations: encephalomyopathy with hearing deficit and methylmalonic aciduria.…”

Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes

“…Patient 1 manifested with a severe progressive metabolic encephalomyopathy and the brain MRI of Patient 1 disclosed white matter degeneration as well as basal ganglia and thalamic lesions resembling Leigh syndrome. Similar encephalopathic phenotypes have been described in MDDS caused by several mtDNA maintenance genes including in SUCLA2 and SUCLG1 (Ostergaard et al 2007a, b;Carrozzo et al 2007;Elpeleg et al 2005), DGUOK (Mandel et al 2001;Dimmock et al 2008) and RRM2B (Bornstein et al 2008;Acham-Roschitz et al 2009;Kollberg et al 2009). Patient 1 was also found with generalized aminoaciduria that has previously been described in MDDS patients (Uusimaa et al 2014).…”