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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    • "SUCLA2 is the β-subunit of succinyl CoA ligase which catalyzes the synthesis of succinate and ATP from succinyl-CoA and ADP in the TCA cycle. Mutations in the α-subunit of Succinyl CoA ligase, SUCLG1, also cause Leigh syndrome[158]. Patients with mutations in SUCLA2 or SUCLG1 present with mtDNA depletion[38]. "
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    ABSTRACT: Leigh syndrome is a progressive neurodegenerative disorder, affecting 1 in 40,000 live births. Most patients present with symptoms between the ages of three and twelve months, but adult onset Leigh syndrome has also been described. The disease course is characterized by a rapid deterioration of cognitive and motor functions, in most cases resulting in death due to respiratory failure. Despite the high genetic heterogeneity of Leigh syndrome, patients present with identical, symmetrical lesions in the basal ganglia or brainstem on MRI, while additional clinical manifestations and age of onset varies from case to case. To date, mutations in over 60 genes, both nuclear and mitochondrial DNA encoded, have been shown to cause Leigh syndrome, still explaining only half of all cases. In most patients, these mutations directly or indirectly affect the activity of the mitochondrial respiratory chain or pyruvate dehydrogenase complex. Exome sequencing has accelerated the discovery of new genes and pathways involved in Leigh syndrome, providing novel insights into the pathophysiological mechanisms. This is particularly important as no general curative treatment is available for this devastating disorder, although several recent studies imply that early treatment might be beneficial for some patients depending on the gene or process affected. Timely, gene-based personalized treatment may become an important strategy in rare, genetically heterogeneous disorders like Leigh syndrome, stressing the importance of early genetic diagnosis and identification of new genes/pathways. In this review, we provide a comprehensive overview of the most important clinical manifestations and genes/pathways involved in Leigh syndrome, and discuss the current state of therapeutic interventions in patients.
    No preview · Article · Dec 2015 · Molecular Genetics and Metabolism
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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.
    Full-text · Article · Dec 2014 · Molecular Genetics and Metabolism Reports
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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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    ABSTRACT: Methylmalonic aciduria (MMA) is one of the most frequent organic acidurias, a class of diseases caused by enzymatic defects mainly involved in the catabolism of branched-chain amino acids. Recently, mild MMA and C4-dicarboxylyl-carnitine (C4DC-C) accumulation have been reported in patients carrying mutation in genes encoding the α-subunit (SUCLG1) and the β-subunit (SUCLA2) of the ADP-forming succinyl-CoA synthetase (SCS). We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify in dried blood spot the two isobaric compounds of C4DC-C, succinyl-carnitine and methylmalonyl-carnitine, to allow the differential diagnosis between classical MMA and SCS-related defects. This method, with an easy liquid-phase extraction and derivatization procedure, has been validated to demonstrate the specificity, linearity, recovery, lowest limit of quantification (LLOQ), accuracy and precision for quantitative determination of blood succinyl-carnitine and methylmalonyl-carnitine. The assay was linear over a concentration range of 0.025-10 μmol/L and achieved the LLOQ of 0.025 μmol/L for both metabolites. The average slope, intercept, and coefficient of linear regression (r(2)) were respectively: 0.3389 (95% confidence interval 0.2888-0.3889), 0.0113 (95% confidence interval -0.0157-0.0384), 0.9995 (95% confidence interval 0.9990-1.0000) for succinyl-carnitine and 0.5699 (95% confidence interval 0.5263-0.6134), 0.0319 (95% confidence interval -0.0038-0.0677), 0.9997 (95% confidence interval 0.9995-1.0000) for methylmalonyl-carnitine. Within-day and between-day coefficients of variation (CV) were 1.94% and 3.19% for succinyl-carnitine and 3.21%, and 2.56 for methylmalonyl-carnitine. This method is accurate and provides a new tool to differentiate patients with classical methylmalonic acidemia from those with SCS-related defects.
    Full-text · Article · Nov 2013 · Clinica chimica acta; international journal of clinical chemistry
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