Phenotype and genotype in 17 patients with succinate-CoA ligase deficiency caused by mutations in SUCLA2 and SUCLG1. E. Oestergaard1, M. Rasmussen2, H. Amartino3, IF. de Coo4, DC. Buhas5, S. Mesli6, K. Naess7, M. Tulinius8, N. Darin8, M. Duno1, P. Jouvencel9, I. Redonnet-Vernhet6, F. Wibrand1, E. Holme10 1) Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark; 2) Neuropediatric Department, Oslo University Hospital Rikshospitalet, Oslo, Norway; 3) Servicio de Neurología Infantil, Hospital Universitario Austral, Buenos Aires, Argentina; 4) Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands; 5) Department of Genetics, Sainte-Justine University Hospital, Montreal, QC, Canada; 6) Biochemistry, CHU de Bordeaux, Bordeaux, France; 7) Department of Laboratory Medicine and Centre for Inherited Metabolic Diseases, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; 8) Department of Pediatrics, University of Gothenburg, The Queen Silvia's Children Hospital, Gothenburg, Sweden; 9) Neonatal and Pediatric Intensive Care Unit, Children's Hospital, Bordeaux, France; 10) Department of Clinical Chemistry, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

   Background: The encephalomyopathic mtDNA depletion syndrome with methylmalonic acidura is associated with deficiency of the tricarboxylic acid cycle enzyme succinate-CoA ligase, and is caused by mutations in SUCLA2 or SUCLG1. Previously, 24 patients with SUCLA2 mutations have been reported, and 16 patients with SUCLG1 mutations. We here report the clinical and molecular genetic findings in 17 additional patients with succinate-CoA ligase deficiency. Patients and results: Of the 17 patients, 13 had SUCLA2 mutations and four had SUCLG1 mutations. In SUCLA2, we found seven mutations, of which six were novel. One was a whole gene deletion, one was a 1 bp duplication, and four were missense mutations. Three of four SUCLG1 mutations were novel, all missense. Onset of symptoms was from birth to 1-2 years of age. The presenting symptom in most patients was muscle hypotonia, with onset from birth to 5½ months of age. In one patient, onset of symptoms was at age 1-2 years with sensorineural hearing impairment. Most patients had dystonia, whereas only a few had epilepsy. Nearly all patients had severe hearing impairment; the age at diagnosis of hearing impairment was from 8 months to 4 years. In five of the patients, the disorder was associated with unusually long survival, beyond 20 years. No significant clinical differences between the patient groups with SUCLA2 and SUCLG1 mutations were identified. Brain MRI/CT was done in 11 patients; abnormal basal ganglia were found in nine. Five patients had central and cortical atrophy, and in three patients abnormalities of the white matter was found. Analysis of respiratory chain enzyme activity in muscle generally showed a combined deficiency of complexes I and IV, and in some cases also of complex II + III. One patient had normal enzyme activity in muscle. Urine organic acids showed elevated excretion of methylmalonic acid except in one patient, although this patient did have elevated methylcitrate. Conclusions: In the 17 patients with succinate-CoA ligase deficiency we found nine novel mutations in SUCLA2 and SUCLG1. Five patients had long survival, beyond 20 years, which has only been reported in a few patients previously. Normal respiratory chain enzyme activity in muscle or urine excretion of normal amounts of methylmalonic acid does not exclude a succinate-CoA ligase deficiency.

You may contact the first author (during and after the meeting) at