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Rosalba Carrozzo - One of the best experts on this subject based on the ideXlab platform.
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succinate coa ligase deficiency due to mutations in SUCLA2 and suclg1 phenotype and genotype correlations in 71 patients
Journal of Inherited Metabolic Disease, 2016Co-Authors: Rosalba Carrozzo, Daniela Verrigni, Magnhild Rasmussen, Hernan Amartino, Marzia Bianchi, Daniela Buhas, Samir Mesli, Karin Naess, Alfred Peter Born, Berit WoldsethAbstract:Background The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients.
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succinate coa ligase deficiency due to mutations in SUCLA2 and suclg1 phenotype and genotype correlations in 71 patients
Journal of Inherited Metabolic Disease, 2016Co-Authors: Rosalba Carrozzo, Daniela Verrigni, Magnhild Rasmussen, Hernan Amartino, Marzia Bianchi, Daniela Buhas, Samir Mesli, Karin Naess, Rene De Coo, Alfred Peter BornAbstract:The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported SUCLG1 patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients. Median survival was 20 years for SUCLA2 and 20 months for SUCLG1. Notable clinical differences between the two groups were hepatopathy, found in 38 % of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14 % of cases with SUCLG1 mutations. Long survival, to age 20 years or older, was reported in 12 % of SUCLA2 and in 10 % of SUCLG1 patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69 % of SUCLA2 and 80 % of SUCLG1 patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found. To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.
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Disorders of the Krebs Cycle
Physician's Guide to the Diagnosis Treatment and Follow-Up of Inherited Metabolic Diseases, 2014Co-Authors: Eva Morava, Rosalba CarrozzoAbstract:This chapter focuses on two classic Krebs cycle disorders (2-oxoglutaric aciduria and fumarase deficiency) and two recently discovered disorders of the Krebs cycle, severely affecting mitochondrial function and mitochondrial maintenance (succinyl-CoA synthetase –SCS – deficiencies, characterized by mutations in SUCLA2 and SUCLG1 genes). Fumarase deficiency and 2-oxoglutaric aciduria are rare disorders with global developmental delay and severe neurologic problems in infants. Patients with oxoglutaric aciduria have a variable severity of neurological involvement and metabolic acidosis and develop severe microcephaly and mental retardation. A special form (DOOR syndrome) occurs with sensorineural deafness and osteodystrophy. Patients with fumarase deficiency present with either a fulminant course associated with fatal outcome within the first 2 years of life or a subacute encephalopathy with profound speech delay without metabolic crises. SUCLA2 and SUCLG1 defects have the clinical presentation of mitochondrial depletion syndromes with profound hypotonia, progressive dystonia, and muscular atrophy, in addition to severe sensorineural hearing impairment, which has been specifically associated with SUCLA2 defect. The most important clues for the diagnosis in all these disorders rely in urine organic analysis. 2-oxoglutaric aciduria leads to chronic metabolic acidosis and variable urinary excretion of 2-oxoglutarate, while fumarase deficiency occurs with an increased excretion of fumarate associated with succinate and lactate excretion with eventual 2-oxoglutaric aciduria. A normal excretion of fumaric acid and a relative high fumarase residual activity do not rule out fumarase deficiency. In questionable cases mutation analysis is needed to confirm the diagnosis. In SCS defects mild methylmalonic aciduria with abnormal urine carnitine-ester profile is associated with only subtle abnormalities of the Krebs cycle intermediates. Due to the recognizable pattern of dystonia/±deafness syndrome and mild methylmalonic aciduria in SCS defects, direct genetic testing is a possible approach in the diagnosis of SUCLA2 and SUCLG1 defects. Carrier screening in fumarase deficiency is important due to the possible increased risk for certain malignancies.
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dystonia and deafness due to SUCLA2 defect clinical course and biochemical markers in 16 children
Mitochondrion, 2009Co-Authors: Eva Morava, Rosalba Carrozzo, Leo A J Kluijtmans, Carlo Dionisivici, Ulrike Steuerwald, Frodi Joensen, Rene Santer, Ron A. WeversAbstract:Patients with SUCLA2 gene defects characteristically develop the trias of early hypotonia, progressive dystonia and sensori-neural deafness. We describe the clinical course and biochemical phenotype in 16 children from the Faroe Islands with a homozygous SUCLA2 splice site mutation. Elevated urinary 3-hydroxyisovaleric acid is a novel biochemical feature in patients. Progressive hearing loss, in combination with a characteristic metabolite profile (increased lactate, methylmalonic acid, C4-dicarboxylic carnitine, 3-hydroxyisovaleric acid) should lead the clinician to the correct diagnosis even in patients with only intermittent lactic acidemia. Direct SUCLA2 sequence analysis is suggested instead of an invasive muscle biopsy to obtain the diagnosis. Nutritional intervention may be considered in SUCLA2 patients.
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SUCLA2 mutations are associated with mild methylmalonic aciduria leigh like encephalomyopathy dystonia and deafness
Brain, 2007Co-Authors: Rosalba Carrozzo, Leo A J Kluijtmans, Carlo Dionisivici, Ulrike Steuerwald, Simona Lucioli, Federica Deodato, Sivia Di Giandomenico, Enrico Bertini, Barbara Franke, Maria Chiara MeschiniAbstract:One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G --> A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1 : 2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.
Ann Saada - One of the best experts on this subject based on the ideXlab platform.
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the interplay between SUCLA2 suclg2 and mitochondrial dna depletion
Biochimica et Biophysica Acta, 2011Co-Authors: Chaya Miller, Elsebet Ostergaard, Liya Wang, Phyllis Dan, Ann SaadaAbstract:Abstract SUCLA2 -related mitochondrial DNA (mtDNA) depletion syndrome is a result of mutations in the β subunit of the ADP-dependent isoform of the Krebs cycle succinyl-CoA synthase (SCS). The mechanism of tissue specificity and mtDNA depletion is elusive but complementation by the GDP-dependent isoform encoded by SUCLG2 , and the association with mitochondrial nucleoside diphosphate kinase (NDPK), is a plausible link. We have investigated this relationship by studying SUCLA2 deficient fibroblasts derived from patients and detected normal mtDNA content and normal NDPK activity. However, knockdown of SUCLG2 by shRNA in both patient and control fibroblasts resulted in a significant decrease in mtDNA amount, decreased NDPK and cytochrome c oxidase activities, and a marked growth impairment. This suggests that, SUCLG2 , to a higher degree than SUCLA2 , is crucial for mtDNA maintenance and that mitochondrial NDPK is involved. Although results pertain to a cell culture system, the findings might explain the pathomechanism and tissue specificity in mtDNA depletion caused by defective SUCLA2 .
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Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion.
American journal of human genetics, 2005Co-Authors: Orly Elpeleg, Chaya Miller, Eli Hershkovitz, Maria Bitner-glindzicz, Gili Bondi-rubinstein, Shamima Rahman, Alistair T. Pagnamenta, Sharon Eshhar, Ann SaadaAbstract: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 β 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.
Elsebet Ostergaard - One of the best experts on this subject based on the ideXlab platform.
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Exclusive neuronal expression of SUCLA2 in the human brain
Brain Structure and Function, 2015Co-Authors: Arpád Dobolyi, Elsebet Ostergaard, Attila G. Bagó, Mária J. Molnár, Miklós Palkovits, Vera Adam-vizi, Tamás Dóczi, Christos ChinopoulosAbstract:SUCLA2 encodes the ATP-forming β subunit (A-SUCL-β) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here, we show that immunoreactivity of A-SUCL-β in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL-β immunoreactivity co-localized >99 % with that of the d subunit of the mitochondrial F_0–F_1 ATP synthase. Specificity of the anti-A-SUCL-β antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2 . A-SUCL-β immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming β subunit (G-SUCL-β) encoded by SUCLG2 , or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL-β immunoreactivity that was, however, not upregulated in samples obtained from diabetic versus non-diabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex.
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the interplay between SUCLA2 suclg2 and mitochondrial dna depletion
Biochimica et Biophysica Acta, 2011Co-Authors: Chaya Miller, Elsebet Ostergaard, Liya Wang, Phyllis Dan, Ann SaadaAbstract:Abstract SUCLA2 -related mitochondrial DNA (mtDNA) depletion syndrome is a result of mutations in the β subunit of the ADP-dependent isoform of the Krebs cycle succinyl-CoA synthase (SCS). The mechanism of tissue specificity and mtDNA depletion is elusive but complementation by the GDP-dependent isoform encoded by SUCLG2 , and the association with mitochondrial nucleoside diphosphate kinase (NDPK), is a plausible link. We have investigated this relationship by studying SUCLA2 deficient fibroblasts derived from patients and detected normal mtDNA content and normal NDPK activity. However, knockdown of SUCLG2 by shRNA in both patient and control fibroblasts resulted in a significant decrease in mtDNA amount, decreased NDPK and cytochrome c oxidase activities, and a marked growth impairment. This suggests that, SUCLG2 , to a higher degree than SUCLA2 , is crucial for mtDNA maintenance and that mitochondrial NDPK is involved. Although results pertain to a cell culture system, the findings might explain the pathomechanism and tissue specificity in mtDNA depletion caused by defective SUCLA2 .
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the severity of phenotype linked to suclg1 mutations could be correlated with residual amount of suclg1 protein
Journal of Medical Genetics, 2010Co-Authors: Cecile Rouzier, Le S Guedardmereuze, Valerie Serre, Sylvie Tufferygiraud, Sylvie Bannwarth, C Caruba, Jeanluc Miro, Konstantina Fragaki, Annabelle Chaussenot, Elsebet OstergaardAbstract:Background Succinate-CoA ligase deficiency is responsible for encephalomyopathy with mitochondrial DNA depletion and mild methylmalonic aciduria. Mutations in SUCLA2 , the gene encoding a β subunit of succinate-CoA ligase, have been reported in 17 patients until now. Mutations in SUCLG1 , encoding the α subunit of the enzyme, have been described in two pedigrees only. Methods and findings In this study, two unrelated patients harbouring three novel pathogenic mutations in SUCLG1 were reported. The first patient had a severe disease at birth. He was compound heterozygous for a missense mutation (p.Pro170Arg) and a c.97+3G>C mutation, which leads to the complete skipping of exon 1 in a minigene expression system. The involvement of SUCLG1 was confirmed by western blot analysis, which showed absence of SUCLG1 protein in fibroblasts. The second patient has a milder phenotype, similar to that of patients with SUCLA2 mutations, and is still alive at 12 years of age. Western blot analysis showed some residual SUCLG1 protein in patient9s fibroblasts. Conclusions Our results suggest that SUCLG1 mutations that lead to complete absence of SUCLG1 protein are responsible for a very severe disorder with antenatal manifestations, whereas a SUCLA2 -like phenotype is found in patients with residual SUCLG1 protein. Furthermore, it is shown that in the absence of SUCLG1 protein, no SUCLA2 protein is found in fibroblasts by western blot analysis. This result is consistent with a degradation of SUCLA2 when its heterodimer partner, SUCLG1, is absent.
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a novel missense mutation in suclg1 associated with mitochondrial dna depletion encephalomyopathic form with methylmalonic aciduria
European Journal of Pediatrics, 2010Co-Authors: Elsebet Ostergaard, Marianne Schwartz, Mustafa Batbayli, Ola Hjalmarson, Gittan Kollberg, E Christensen, Elisabeth HolmeAbstract:Mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria is associated with mutations in SUCLA2, the gene encoding a β subunit of succinate-CoA ligase, where 17 patients have been reported. Mutations in SUCLG1, encoding the α subunit of the enzyme, have been reported in only one family, where a homozygous 2 bp deletion was associated with fatal infantile lactic acidosis. We here report a patient with a novel homozygous missense mutation in SUCLG1, whose phenotype is similar to that of patients with SUCLA2 mutations.
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mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations
Brain, 2007Co-Authors: Elsebet Ostergaard, Flemming Juul Hansen, Nicolina Sorensen, Morten Duno, John Vissing, Pernille L Larsen, Oddmar Faeroe, Sigurdur Thorgrimsson, Flemming Wibrand, E ChristensenAbstract:We have identified 12 patients with autosomal recessive mitochondrial encephalomyopathy with elevated methylmalonic acid. The disorder has a high incidence of 1 in 1700 in the Faroe Islands due to a founder effect, and a carrier frequency of 1 in 33. The symptoms comprise hypotonia, muscle atrophy, hyperkinesia, severe hearing impairment and postnatal growth retardation. Neuroimaging showed demyelination and central and cortical atrophy, including atrophy of the basal ganglia, and some of the patients fulfilled the criteria for Leigh syndrome. Urine and plasma methylmalonic acid were elevated. Homozygosity mapping with the Affymetrix 10 K array revealed a homozygous region on chromosome 13q14 harbouring the SUCLA2 gene. Mutations in SUCLA2 were recently shown to cause a similar disorder in a small Israeli family. Mutation analysis identified a novel splice site mutation in SUCLA2, IVS4 + 1G --> A, leading to skipping of exon 4. The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. The hallmark of the condition, elevated methylmalonic acid, can be explained by an accumulation of the substrate of the enzyme, succinyl-CoA, which in turn leads to elevated methylmalonic acid, because the conversion of methylmalonyl-CoA to succinyl-CoA is inhibited.
Brett H Graham - One of the best experts on this subject based on the ideXlab platform.
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expanding the phenotypic spectrum of succinyl coa ligase deficiency through functional validation of a new suclg1 variant
Molecular Genetics and Metabolism, 2016Co-Authors: Taraka R Donti, Ruchi Masand, Daryl A Scott, William J Craigen, Brett H GrahamAbstract:Abstract Deficiency of the TCA cycle enzyme Succinyl-CoA Synthetase/Ligase (SCS), due to pathogenic variants in subunits encoded by SUCLG1 and SUCLA2, causes mitochondrial encephalomyopathy, methylmalonic acidemia, and mitochondrial DNA (mtDNA) depletion. In this study, we report an 11year old patient who presented with truncal ataxia, chorea, hypotonia, bilateral sensorineural hearing loss and preserved cognition. Whole exome sequencing identified a heterozygous known pathogenic variant and a heterozygous novel missense variant of uncertain clinical significance (VUS) in SUCLG1 . To validate the suspected pathogenicity of the novel VUS, molecular and biochemical analyses were performed using primary skin fibroblasts from the patient. The patient's cells lack the SUCLG1 protein, with significantly reduced levels of SUCLA2 and SUCLG2 protein. This leads to essentially undetectable SCS enzyme activity, mtDNA depletion, and cellular respiration defects. These abnormal phenotypes are rescued upon ectopic expression of wild-type SUCLG1 in the patient's fibroblasts, thus functionally confirming the pathogenic nature of the SUCLG1 VUS identified in this patient and expanding the phenotypic spectrum for SUCLG1 deficiency.
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depletion of mtdna with mma SUCLA2 and suclg1
2013Co-Authors: Nelson Hawkins, Brett H GrahamAbstract:Mitochondrial depletion syndromes (MDS) are a class of mitochondrial diseases characterized by reduction of mitochondrial DNA (mtDNA) content in muscle and/or liver as well as encephalomyopathy or hepatoencephalopathy. Mutations in SUCLG1 or SUCLA2, which encode the a and the ADP-specific b isoforms, respectively, of Succinyl-CoA Synthetase (SCS) and cause MDS associated with mild methylmalonic acidemia. SCS deficiency is speculated to cause mtDNA depletion through perturbation of mitochondrial nucleotide pools by disruption of its interaction with mitochondrial nucleotide diphosphate kinase (NDPK). Development and study of models of SCS deficiency are required to better understand the pathogenesis of SCS-dependent MDS and to develop novel therapeutic approaches.
Alfred Peter Born - One of the best experts on this subject based on the ideXlab platform.
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succinate coa ligase deficiency due to mutations in SUCLA2 and suclg1 phenotype and genotype correlations in 71 patients
Journal of Inherited Metabolic Disease, 2016Co-Authors: Rosalba Carrozzo, Daniela Verrigni, Magnhild Rasmussen, Hernan Amartino, Marzia Bianchi, Daniela Buhas, Samir Mesli, Karin Naess, Alfred Peter Born, Berit WoldsethAbstract:Background The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients.
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succinate coa ligase deficiency due to mutations in SUCLA2 and suclg1 phenotype and genotype correlations in 71 patients
Journal of Inherited Metabolic Disease, 2016Co-Authors: Rosalba Carrozzo, Daniela Verrigni, Magnhild Rasmussen, Hernan Amartino, Marzia Bianchi, Daniela Buhas, Samir Mesli, Karin Naess, Rene De Coo, Alfred Peter BornAbstract:The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported SUCLG1 patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients. Median survival was 20 years for SUCLA2 and 20 months for SUCLG1. Notable clinical differences between the two groups were hepatopathy, found in 38 % of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14 % of cases with SUCLG1 mutations. Long survival, to age 20 years or older, was reported in 12 % of SUCLA2 and in 10 % of SUCLG1 patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69 % of SUCLA2 and 80 % of SUCLG1 patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found. To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.
