Deficiency of the α Subunit of Succinate–Coenzyme A Ligase Causes Fatal Infantile Lactic Acidosis with Mitochondrial DNA Depletion

Abstract

Fatal infantile lactic acidosis is a severe metabolic disorder characterized by the onset of lactic acidosis within the 1st d of life and early death. We found a combined respiratory-chain enzyme deficiency associated with mitochondrial DNA (mtDNA) depletion in a small consanguineous family with this disorder. To identify the disease-causing gene, we performed single-nucleotide polymorphism homozygosity mapping and found homozygous regions on four chromosomes. DNA sequencing revealed a homozygous 2-bp deletion in SUCLG1, a gene that encodes the alpha subunit of the Krebs-cycle enzyme succinate-coenzyme A ligase (SUCL). The mtDNA depletion is likely explained by decreased mitochondrial nucleoside diphosphate kinase (NDPK) activity resulting from the inability of NDPK to form a complex with SUCL.

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).…”

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

“…Mutations in SUCLG1 have been reported less frequently with a similar phenotype to that observed in SUCLA2-related MDS [4,[24][25][26][27][28][29][30]. Affected infants present with hypotonia typically before the age of 6 months.…”

“…Quantitation of mtDNA shows a decreased mtDNA content in muscle. Prognosis is poor, with most affected children dying in childhood, most commonly from an intercurrent infection [24][25][26][27][28][29][30].…”

Flux variability analysis approach of autism related metabolism in stoichiometric model of mitochondria

“…Phenotype data for the haploinsufficiency of the gene is not available, however alpha subunit deficiency can cause severe lactic acidemia (Ostergaard et al, 2007).…”