Brain Advance Access originally published online on April 25, 2006
Brain 2006 129(7):1685-1692; doi:10.1093/brain/awl097
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The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases
1 Department of Neurology, Institute of Clinical Medicine, University of Bergen and Haukeland University Hospital Bergen 2 Førde Central Hospital Førde 3 St Olav's Hospital, Trondheim Norway 4 Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Neurological Institute ‘C. Besta’ Milan, Italy
Correspondence to: Prof. Laurence Bindoff, Department of Neurology, Institute of Clinical Medicine, University of Bergen, Haukeland University Hospital, 5021 Bergen, Norway; E-mail: laurence.bindoff{at}nevro.uib.no
We studied 26 patients belonging to 20 families with a disorder caused by mutations in the POLG gene. The patients were homozygous for 1399 G/A or 2243 G/C (giving the amino acid changes A467T and W748S, respectively) or compound heterozygotes for these two mutations. Irrespective of genotype, the patients exhibited a progressive neurological disorder usually starting in their teens and characterized by epilepsy, headache, ataxia, neuropathy, myoclonus and late onset ophthalmoplegia. However, major differences in survival were seen depending on genotype, with compound heterozygotes having a significantly shorter survival time than patients homozygous either for the A467T or W748S (P = 0.006). Epilepsy occurred in 22 of the 26 patients and in the majority of these there was an occipital EEG focus. Episodes of both generalized and focal motor status epilepticus were common and highly resistant to treatment, even with generalized anaesthesia. Status epilepticus was the recorded cause of death in 9 of 11 patients. Liver failure was the sole cause of death in two patients and evolved terminally in six others, all but one of whom were being treated with sodium valproate. Two patients underwent liver transplantation, but only one survived. Delayed psychomotor development and subsequent cognitive decline also occurs. This study demonstrates the clinical spectrum of a disorder that combines features of Alpers' syndrome and a later onset mitochondrial spinocerebellar ataxia with epilepsy and headache. Patients with this disorder are at high risk of death from status epilepticus and from liver failure, if exposed to sodium valproate. Each mutation appears capable of producing a disorder that is recessively inherited, although we also find evidence in one patient suggesting that heterozygotes may manifest. Compound heterozygotes have a significantly more severe phenotype raising the possibility of a dominant negative effect.
Key Words: mitochondrial; POLG; ataxia; hepatic; Alpers
Abbreviations: mtDNA, mitochondrial DNA; PEO, progressive external ophthalmoplegia
Received January 23, 2006. Revised March 22, 2006. Accepted March 23, 2006.
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