Succinyl-CoA Ligase Deficiency: A Mitochondrial Hepatoencephalomyopathy

Department of Pediatrics, University of Colorado Denver, Aurora, Colorado 80045, USA.
Pediatric Research (Impact Factor: 2.31). 05/2010; 68(2):159-64. DOI: 10.1203/PDR.0b013e3181e5c3a4
Source: PubMed


This patient presented on the first day of life with pronounced lactic acidosis with an elevated lactate/pyruvate ratio. Urine organic acids showed Krebs cycle metabolites and mildly elevated methylmalonate and methylcitrate. The acylcarnitine profile showed elevated propionylcarnitine and succinylcarnitine. Amino acids showed elevated glutamic acid, glutamine, proline, and alanine. From the age 2 of mo on, she had elevated transaminases and intermittent episodes of liver failure. Liver biopsy showed steatosis and a decrease of mitochondrial DNA to 50% of control. She had bilateral sensorineural hearing loss. Over the course of the first 2 y of life, she developed a progressively severe myopathy with pronounced muscle weakness eventually leading to respiratory failure, Leigh disease, and recurrent hepatic failure. The hepatic symptoms and the metabolic parameters temporarily improved on treatment with aspartate, but neither muscle symptoms nor brain lesions improved. Laboratory testing revealed a deficiency of succinyl-CoA ligase enzyme activity and protein in fibroblasts because of a novel homozygous mutation in the SUCLG1 gene: c.40A>T (p.M14L). Functional analysis suggests that this methionine is more likely to function as the translation initiator methionine, explaining the pathogenic nature of the mutation. Succinyl-CoA ligase deficiency due to an SUCLG1 mutation is a new cause for mitochondrial hepatoencephalomyopathy.

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    • "To date, at least a dozen patients have been described with mutations in SUCLG1. The clinical phenotype of these patients ranges from severe lactic acidosis and death during the first days of life [6] [8] to encephalomyopathy with mild methylmalonic acidemia and mtDNA depletion similar to SUCLA2 deficiency [3] [9]. The life expectancy is short, with death generally occurring prior to the age of three years, although one patient was reported to still be alive at the age of 20 [10]. "
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    ABSTRACT: Defects in two subunits of succinate-CoA ligase encoded by the genes SUCLG1 and SUCLA2 have been identified in mitochondrial DNA (mtDNA) depletion syndromes. Patients generally present with encephalomyopathy and mildmethylmalonicacidemia(MMA),howevermutationsinSUCLG1normallyappeartoresultinamoresevere clinical phenotype. In this report, we describe a patient with fatal infantile lactic acidosis and multiple congenital anomalies (MCAs) including renal and cardiac defects. Molecular studies showed a defective electron transport chain (ETC), mtDNA depletion, and a novel homozygous mutation in the SUCLG1 gene. Although our patient's clinical biochemical phenotype is consistent with a SUCLG1 mutation, it is unclear whether the MCAs observed in our patient are a result of the SUCLG1 mutation or alterations in a second gene. An increasing number of reports have described MCAs associated with mitochondrial disorders and SUCLG1 specifically. Additional studies such as whole exome sequencing will further define whether additional genes are responsible for the observed MCAs.
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    • "e l s e v i e r . c o m / l o c a t e / c l i n c h i m hypoacusis, Leigh disease, lactic acidosis, polyneuropathy, mild methylmalonic aciduria and mild elevation of C4DC-C [2] [3]. "
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