Sirs: Mitochondrial diseases are an important cause of progressive ataxic syndromes due to mutations to either mitochondrial (mt) or nuclear DNA. mtDNA replication and repair are under the control of the DNA polymerase γ (POLG), until now the only mitochondrial DNA polymerase found in mammalian cells. POLG is a heterotrimer consisting of two accessory subunits and one catalytic subunit encoded by the nuclear gene POLG1 (MIM 174763). Dominant and recessive POLG1 mutations are responsible for an extraordinary spectrum of clinical phenotypes varying in onset, from infancy to adulthood, and in severity from fulminant hepatocerebral syndrome (Alpers’ syndrome) to slowly progressive external ophthalmoplegia (PEO) and/or ataxia. In particular, the mutations c.1399G > A (A467T), and c.2243G > C (W748S) are associated with a mitochondrial recessive ataxic syndrome (MIRAS) [3, 8]. MIRAS is a neurodegenerative disorder with usually early onset (range from 5 to 50 years) characterized beside ataxia, by epilepsy, headache, neuropathy, and myoclonus. Ophthalmoplegia may be present as a late event. To evaluate the prevalence of these two mutations in a Southern Italian population, we conducted a genetic analysis of 66 ataxic patients with ataxia and clinical (decreased or absent ankle reflexes and decreased vibration sense) or neurophysiologic signs of peripheral neuropathy from a larger series of Italian ataxic patients with onset below 50 years. Forty-eight patients were sporadic and 18 were index cases from families compatible with a recessive transmission. Pathologic GAA expansions in the Friedreich ataxia gene were excluded in all and mutations in Aptx and Setx were absent in the 38 studied patients. After informed consent, A467T and W748S were detected by a combination of denaturing high performance liquid chromatography (dHPLC) and direct sequencing analysis. Mean age at onset was 21 ± 15 years (range 2–50 years). All patients had ataxia and peripheral neuropathy, 28 had ataxia plus features frequent in MIRAS or in other mitochondrial diseases (myoclonus, epilepsy, hypogonadism, ophthalmoplegia). Ataxia was associated with myoclonus in 17 (6 of them had also epilepsy), with hypogonadism or premature menopause in 6, and with ophthalmoplegia in 5 patients. None of the 66 patients carried the studied mutations neither in homozygous nor in heterozygous state. Over the last 6 years, it has become clear that mutations of POLG are a major cause of human disease. A467T and W748S are mainly responsible for MIRAS. Both A467T and W748S occur in the linker region between N-terminal proofreading domain and the C-terminal polymerase domain of POLG. Both mutations are pathogenic, because the impaired activity of the mutant proteins has been evaluated by biochemical tests. The A465T mutant enzyme possesses only 4 % of wildtype POLG activity and fails to interact with the accessory subunit. W748S POLG exhibited low DNA polymerase activity, low processivity and a severe DNA-binding defect [1]. A467T is the most common mutation in POLG1. This amino acid change occurred with an allele frequency of 0.6 % in the Belgian [7] and 0.69 % in the British population providing a reservoir for recessive diseases. In contrast A467T was found in < 0.2 % in the Finnish population [5], in 0.19 % in the German and in 0.16 % in the Italian population [4, 6]. Up to now, in Italy A467T has been only found in patients with Alpers’ syndrome [2]. W748S has been reported as the most common genetic cause of ataxia in Finland with a carrier frequency in the general population of 0.8 %. MIRAS patients with W748S have been also reported in Norway, the United Kingdom, and Belgium [3]. Haplotype analysis revealed that the ‘ataxic’ W748S allele is of European origin, having descended from a common founder. In Italy W748S has been identified in 2 of 271 Italian controls [6]. The only two Italian patients with W748S have Alpers’ syndrome [2]. Our study is the first POLG1 screening conducted on ataxic patients from a southern European country. According to our analysis A467T and W748S are not a frequent cause of ataxia in Southern Italy. Nevertheless, the identification of healthy subjects and Alpers’ patients with both these mutations in Italy suggests LETTER TO THE EDITORS