The A467T and W748S POLG substitutions are a rare cause of adult-onset ataxia in Europe

Abstract

In a recent edition of Brain , Tzoulis and colleagues (Tzoulis et al ., 2006) described the presentation and natural history of neurological disease due to the c.1399G → A/A467T and c.2243G → C/W748S mutations in POLG. POLG codes for mitochondrial DNA (mtDNA) polymerase ( pol γ), the only polymerase present within mitochondria (Kaguni, 2004). Pathogenic POLG mutations were first described in autosomal dominant and recessive progressive external ophthalmoplegia (PEO) (Van Goethem et al ., 2001), and more recently in recessive late-onset ataxia with peripheral neuropathy (Van Goethem et al ., 2003; Winterthun et al ., 2005), and the Alpers–Huttenlocher syndrome (Naviaux and Nguyen, 2004; Davidzon et al ., 2005; Ferrari et al ., 2005). Hakonen et al . (2005) recently reported the high carrier frequency of the W748S POLG substitution in control subjects in Finland (1 : 125 controls), explaining the high prevalence of mitochondrial recessive ataxia syndrome (MIRAS) in Scandinavia. Haplotype analysis revealed a common POLG haplotype in Finnish, Norwegian, Belgian and British subjects carrying W748S, raising the possibility that the same substitution is a common cause of late-onset ataxia throughout Europe (Hakonen et al ., 2005). In Norway, c.1491G → C/Q497H and A467T have also been …