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In their recent article on the clinical phenotype in Greek patients with α-synuclein Parkinson's disease (α-sPD) Papapetropoulos et al1 reported male predominance (60%) in their patients. The authors concluded that the sex ratio in their families does not differ significantly from patients with sporadic idiopathic Parkinson's disease (3:2) or with autosomal dominant α-sPD in the Contursi kindred (3.7: 2) and in the Greek-American family H (2.7: 2). The sex ratio as computed by Papapetropoulos et al1 is somewhat misleading. These results suggest that men are more susceptible to PD, or women less. It would be better to compute the segregation ratio for men and women. The segregation ratio is the percentage of persons at risk who are affected. At risk is defined as having an affected parent or sibling. We computed the segregation ratios for the combined numbers of persons at risk in the Contursi kindred (data from Golbe et al),2 the updated pedigree of the Greek-American family H,3 and two Greek families.4 The families of Papapetropoulos et al1 are not included because the total number of persons at risk is not mentioned.
In these kindreds with α-sPD we counted 228 persons at risk: 132 men and 96 women. The total number of patients with α-sPD is 89, comprising 55 men with α-sPD and 34 women. These numbers yield a simple male/female patient ratio of 55/34=1.6, which is about the same as the ratio 60%/40%=1.5 in the patients with α-sPD reported by Papapetropoulos et al.1 However, the segregation ratio for male α-sPD in the kindreds mentioned above equals 55/13 =41%, for female α-sPD 34/96=35%. These segregation ratios do not differ significantly (p=0.21, χ2 test) suggesting that men and women are equally at risk of acquiring α-sPD, despite the greater number of male patients. There are just more men than women in these families! Furthermore, as far as the sex ratio in sporadic idiopathic PD is concerned, the largest epidemiological analysis we know—comprising 18 506 subjects of seven community surveys in Europe—found no difference in prevalence between the sexes either (men 1.74%; women 1.79%).5 This seems to confirm the conclusion about absence of sex difference in patients with α-sPD.
The only question that remains is why there are more men (n=132) than women (n=96) in these α-synuclein kindreds? If the number of men and women are equal in the general population, the male/female ratio 132/96=1.37 in the α-synuclein kindred is significantly abnormal (p=0.017; χ2 test). However, normally there are fewer men than women in the older age groups. If we take the ratio male/female=0.77 as computed for the whole population (patients plus controls) from the European Parkinson prevalence study mentioned above, which considers a very large similar age group in western and southern Europe,5 the difference from the α-synuclein kindred is even more remarkable (p=0.000; χ2 test). If this male preponderance is related to the abnormal α-synuclein gene, it could be speculated that the affected female fetus is less viable and more prone to fetal death. However, as it stands we are inclined to think that this notion is prompted by statistics rather than biological evidence. In transgenic mice and flies expressing mutant α-synuclein, numerous α-synuclein immunoreactive nerve cells, Lewy body-type inclusions, and loss of dopaminergic nerve cells have been described,6 but there were no sex related abnormalities or differences in sex. However, sex differences have probably not been examined specifically, so the actual cause of the male preponderance in α-synuclein kindreds remains to be elucidated.
As Horstink and Bloem suggest, the segregation ratio for men and women is indeed the most appropriate method to calculate the genetic risk for developing a disease. In our recent publication,1 the sex ratio was calculated from the sample of 15 patients with α-synuclein Parkinson's disease (α-synPD) included in the study. We now provide additional unpublished data to calculate the segregation ratios and to compare them with the other published series of patients with α-synPD.
In the 10 families examined in our study,1 198 members were at risk of developing α-synPD. Of the 103 male members at risk, 27 (26.2%) developed Parkinson's disease (PD), whereas of the 95 women at risk, 27 (28.4%) developed PD (p=0.73). When our data were combined with the data computed by Horstink and Bloem, the segregation ratio of all patients with α-synPD was 82/235 (34.9%) for men and 61/191 (31.9%) for women (p=0.52; table 1⇓).
Golbe et al2 had first noted the tendency of the Contursi kindred to have fewer female members at risk for developing α-synPD (male/female ratio 86/56=1.5). The male to female ratio of our subjects at risk was 103/95=1.08 (p=0.31 for the difference from 1:1 ratio and p=0.02 for the difference from 1:1.3 ratio, which is the male to female ratio of the whole population found in the European Parkinson prevalence study3). After excluding the Contursi kindred, the male to female ratio of all subjects of Greek origin combined,1,4,5 was 149/135=1.10 (p=0.22 for the difference from 1:1 ratio and p=0.002 for the difference from 1:1.3 ratio), whereas the male to female ratio of all known subjects at risk of developing α-synPD combined1,2,4,5 was 235/191=1.23 (p=0.02 for the difference from a 1:1 ratio and p<0.0001 for the difference from a 1:1.3 ratio)
Our data confirm the finding of Horstink and Bloem that men and women are equally at risk of acquiring α-synPD. The Contursi kindred data are skewing the male to female ratios towards a male predominance. The male to female ratio of our Greek families at risk of developing α-synPD, as well as the ratio of all Greek origin families, did not differ significantly from the 1:1 ratio. However, when the male to female ratios were compared with the expected 1:1.3 male to female ratio in the general population, a statistical significant male predominance was found. Whether this is due to statistical bias, recall bias, or to genetic or environmental factors remains unclear. The identification of larger numbers of families at risk of developing α-synPD may help to resolve the question.