Do carriers of POLG mutation W748S have disease manifestations?

Mitochondrial recessive ataxia syndrome (MIRAS) is a common cause of autosomal recessive juvenile- or adult-onset ataxia, at least in Scandinavia. MIRAS patients are homozygous or compound heterozygous for POLG mutations W748S and A467T. Because many first-degree relatives of MIRAS patients in the studied families have reported neurological symptoms and some recent studies have suggested dominant negative effect of these mutations, a careful family study of heterozygotes was needed. We investigated all available members of the original large MIRAS family with W748S mutation. Neurological symptoms and signs were present in a number of carriers, but clearly defined neurological diseases did not segregate consistently with the mutation. Sensory polyneuropathy as a subclinical finding was observed in the majority of carriers examined. By positron emission tomography, cerebral glucose metabolism was moderately reduced in two out of four heterozygotes compared with severe reduction in one MIRAS patient. In conclusion, W748S heterozygotes showed no clinically manifesting phenotype.