title: Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Unit of Muscular and Neurodegenerative Diseases, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
authors.affiliation: Unit of Muscular and Neurodegenerative Diseases, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Verrigni
authors.affiliation: Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway.
authors.forename: Magnhild
authors.initials: M
authors.lastname: Rasmussen
authors.affiliation: Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: de Coo
authors.affiliation: Servicio de Neurología Infantil, Hospital Universitario Austral, Buenos Aires, Argentina.
authors.forename: Hernan
authors.initials: H
authors.lastname: Amartino
authors.affiliation: Unit of Muscular and Neurodegenerative Diseases, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Bianchi
authors.affiliation: Department of Medical Genetics, Montreal Children's Hospital, Montréal, Quebéc, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Buhas
authors.affiliation: Biochemistry, CHU de Bordeaux, Bordeaux, France.
authors.forename: Samir
authors.initials: S
authors.lastname: Mesli
authors.affiliation: Department of Laboratory Medicine and Centre for Inherited Metabolic Diseases, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Naess
authors.affiliation: Department of Pediatrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Alfred Peter
authors.initials: AP
authors.lastname: Born
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
authors.forename: Berit
authors.initials: B
authors.lastname: Woldseth
authors.affiliation: Centro di Riferimento Regionale di Genetica Medica, Azienda Ospedaliera di Perugia, CREO, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Prontera
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Batbayli
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Ravn
authors.affiliation: Department of Pediatrics, National Hospital of the Faroe Islands, Tórshavn, Faroe Islands.
authors.forename: Fróði
authors.initials: F
authors.lastname: Joensen
authors.affiliation: U.O. Neuropsichiatria Infantile - Franzoni, Policlinico S. Orsola Malpighi, Bologna, Italy.
authors.forename: Duccio M
authors.initials: DM
authors.lastname: Cordelli
authors.affiliation: Neurogenetics, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Filippo Maria
authors.initials: FM
authors.lastname: Santorelli
authors.affiliation: Department of Pediatrics, University of Gothenburg, The Queen Silvia's Children Hospital, Gothenburg, Sweden.
authors.forename: Mar
authors.initials: M
authors.lastname: Tulinius
authors.affiliation: Department of Pediatrics, University of Gothenburg, The Queen Silvia's Children Hospital, Gothenburg, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Duno
authors.affiliation: Neonatal and Pediatric Intensive Care Unit, Children's Hospital, Bordeaux, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jouvencel
authors.affiliation: Division of Inherited Metabolic Diseases, Department of Pediatrics, University Hospital of Padua, Padua, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Burlina
authors.affiliation: Centro di Riferimento Regionale di Genetica Medica, Azienda Ospedaliera di Perugia, CREO, Perugia, Italy.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Stangoni
authors.affiliation: Unit of Muscular and Neurodegenerative Diseases, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Biochemistry, CHU de Bordeaux, Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Redonnet-Vernhet
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Wibrand
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.affiliation: Institute of Clinical Medicine/Department of Paediatrics, Finland and Medical Research Center, University of Oulu, Oulu University Hospital, Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Uusimaa
authors.affiliation: Institute of Clinical Medicine/Department of Paediatrics, Finland and Medical Research Center, University of Oulu, Oulu University Hospital, Oulu, Finland.
authors.forename: Paivi
authors.initials: P
authors.lastname: Vieira
authors.affiliation: Unidad de patología neuromuscular, Servicio de Neurología, Hospital Sant Joan de Déu. Hospital Sant Joan de Déu and CIBERER, ISCIII, Barcelona, Spain.
authors.forename: Andrés Nascimento
authors.initials: AN
authors.lastname: Osorio
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Department of Clinical Chemistry, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Holme
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. elsebet.ostergaard@dadlnet.dk.
authors.forename: Elsebet
authors.initials: E
authors.lastname: Ostergaard
mesh_terms: D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008764:Methylmalonic Acid / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics*; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D013389:Succinate-CoA Ligases / Q000235:genetics*; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D004272:DNA, Mitochondrial; D008764:Methylmalonic Acid; C000611245:SUCLG1 protein, human; D013389:Succinate-CoA Ligases; C518788:SUCLA2 protein, human