Reply
Department of Neurology, Institute of Clinical Medicine, Haukeland University Hospital, Bergen, Norway
Correspondence to: Prof. Laurence Bindoff, Department of Neurology, Institute of Clinical Medicine, Haukeland University Hospital, 5021, Bergen, Norway E-mail: laurence.bindoff{at}helse-bergen.no, laurence.bindoff{at}nevro.uib.no
Received January 11, 2007. Accepted January 11, 2007.
Sir, Craig and colleagues have investigated two cohorts of patients with ataxia, one from the UK and one from Italy, to ascertain whether the POLG mutations giving the A467T and W748S changes are common causes of adult-onset ataxia in these countries. The study is based on the recent findings showing that these mutations are common in Scandinavia and Finland with carrier frequencies of 1 : 100 for each in Norway (Winterthun et al., 2005
), 1 : 200 for the A467T in Sweden (Kollberg et al., 2006) and 1 : 125 for the W748S in Finland (Hakonen et al., 2005). The authors studied 192 patients from the UK and 96 from Italy; patients had been screened for a range of other genetic defects, although the conditions excluded differed between the two groups. In addition, we are told that the Italian patients comprised 70 individuals with sporadic disease, 16 with dominant and 8 with recessive transmission. The age distribution of patients in either group is not given.
The findings of this study suggest that these two mutations are rare causes of adult-onset ataxia in these two countries. Only one UK patient was heterozygous for the A467T otherwise no other patient in either cohort carried the A467T or W748S. The patient with the A467T also carried the c.2243G 
C giving the p.E1143G on the other allele. From earlier studies (Horvath et al., 2006), we know that the carrier frequency of the A467T in the UK is 0.69%. We also know that this mutation is found in Italy where it is reported as a cause of the Alpers’ phenotype (Ferrari et al., 2005). The W748S appears rare in Italy although it has been found in patients from the UK as well as several other European countries (Hakonen et al., 2005).
It is interesting that the A467T or W748S mutations are not found in these cohorts since this is telling us something about POLG and the causation of any type of ataxia. There are, however, several questions raised by this study and the first involves age of onset and phenotype. We are told that these patients have an adult-onset ataxia, but no further characterization is given. Patients with these two mutations can present both in adult life and earlier (Van Goethem et al., 2004; Tzoulis et al., 2006). In the study reported by Tzoulis et al., average age of onset was 14.5 years (95% CI 11.6, 17.5 years), meaning that many may already have been identified before the age of 18 years, if this is the limit for defining adult onset. Moreover, the ataxia that develops with the A467T and W748S typically has both cerebellar and peripheral features; in some it is predominantly sensory. Additionally, ophthalmoplegia is seen, albeit as a late feature, and epilepsy is common; 21/26 patients in the Norwegian material had epilepsy. This means that we have probably gathered sufficient clinical data to enable us to be more selective in our selection of patients for POLG testing.
The second question concerns inheritance. The A467T and W748S are associated, in most cases, with recessively inherited syndromes. Luoma and colleagues (Luoma et al., 2005) reported ptosis and ophthalmoplegia in patients having the A467T on only one allele. We reported a woman carrying only the W748S (mother of a patient with A467T/W748S), who developed epilepsy and signs of a peripheral neuropathy and parkinsonism (Tzoulis et al., 2006). Subsequently, we have identified one more patient apparently heterozygous for the W748S who has developed epilepsy and peripheral neuropathy (the mother of a patient with W748S/W748S). Final proof that these are indeed manifesting heterozygotes will require exhaustive sequencing and confirmation that we have examined the products of both alleles. Sixteen (23%) of the Italian cohort had documented dominant inheritance of their ataxia; details of the UK cohort are not given. While there are clear examples of dominantly inherited mutations in the POLG gene, we have yet to confirm that the A467T and W748S can act as dominant mutations.
The last question concerns the c.3248G C/p.E1143G and the increasing number of possible mutations found in the POLG gene. The human POLG mutation database currently registers 82 possible mutations. Some of these, such as the A467T and W748S, are definitely pathological and have been confirmed in multiple families in different countries. Others, such as the E1143G and Q497H, remain unproven. As discussed by Craig and colleagues, the E1143G affects a conserved amino acid and results in a change that should alter protein function. Interestingly, however, recent in vitro studies showed that the E1143G could partially rescue the phenotype caused by the W748S (Chan et al., 2006). The E1143G is found in around 4% of controls and we find that it is present, in cis, in all patients carrying the W748S. Moreover, we found that the mother and two sisters of a patient with W748S/W748S were themselves homozygous for the 3248G C/p.E1143G and heterozygous for the W748S (Winterthun et al., 2005). That these individuals were healthy, suggesting that the 3248G C is not pathological or at its most pathological under certain as yet undefined conditions, e.g. in combination with the A467T but not the W748S. We are unable currently to say whether the E1143G plays a protective role in the whole organism. In our material, the Q497H is found only in cis in patients carrying the W748S and there are no in vitro or clinical studies that confirm or refute its pathogenicity.
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Hakonen AH, Heiskanen S, Juvonen V, Lappalainen I, Luoma PT, Rantamaki M, et al. (2005) Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet 77:430–41.[CrossRef][Web of Science][Medline]
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