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Source: Askthedoctor-mailinglist Date: 13 januari 2002 Orig. source: Neurology, volume 58, pages 79-84 Orig. date: 9 januari 2002 The following article appeared in Neurology, the official journal of the American Academy of Neurology. The article was modified to make it more readable for lay people with PD. Epidemiologic Study of 203 sibling pairs with Parkinson’s disease The GenePD Study N.E. Maher, MPH Abstract Objective: To examine patterns of familial aggregation and factors influencing onset age in a sample of siblings with PD. Methods: Sibling pairs (n=203) with PD were collected as part of the GenePD study. Standardized family history, medical history, and risk factor data were collected and analyzed. Results: The mean age at onset was 61.4 years and did not differ according to sex, exposure to coffee, alcohol, or pesticides. Head trauma was associated with younger onset and multivitamin use with later onset Age at onset correlation between sibling pairs was significant and was larger than the correlation in year of onset. The mean difference in onset age between siblings was 8.7 years (range, 0 to 30 years). Female sex was associated with increased frequency of relatives with PD. The frequency of affected parents (7.0%) and siblings (5.1%) was increased when compared with frequency in spouses (2.0%). Conclusions: The greater similarity for age at onset than for year of onset in sibling pairs with PD, together with increased risk for biological relatives over spouses of cases, supports a genetic component for PD. Additional data suggest that factors influencing penetrance (why one person with a genetic predisposition develops the disease while another with a similar genetic predisposition does not develop the disease) are critical to the understanding of this disease. The risk for PD is associated with advancing age, but onset may occur as early as the teenage years. The average age at onset is approximately 60 years and an estimated 1% of the US and European populations aged >60 have PD. PD appears to have a multifactorial cause, with combined genetic and environmental causes, although controversy persists over their relative contribution to the disease. Past epidemiologic studies have reported an increased risk for PD associated with farming, rural living, drinking well water, pesticide and herbicide exposures, head trauma, and industrial pollutants. Studies of familial aggregation in PD find that a family history of PD is among the strongest and most consistent risk factors for the disease. First-degree relatives of patients with PD are from 1.5 - 9.5 times more likely to develop PD than first-degree relatives of controls. 16%-27% of patients with PD report having a relative with PD and 6.8-16% of patients with PD report having an affected parent or sibling. Twin studies of PD have yielded conflicting results regarding the inheritance of PD. Although a few monozygotic twins with young-onset PD showed increased concordance, a recent study of twins with PD found little evidence for increased concordance of monozygotic twins (identical twins) compared with dizygotic twins (non identical twins). However, one study reported abnormal PET scans, indicative of preclinical PD, in discordant monozygotic (one twin had PD the other did not have PD) but not discordant dizygotic twin pairs. A prolonged preclinical phase of PD, combined with widely disparate onset ages between twins, may contribute to low concordance in monozygotic twins. The identification of genetic forms of PD attributable to the alpha-synuclein and Parkin genes supports a role for genetics in PD. However, these mutations are rare and appear to account for only a small fraction of patients with PD with a family history. Although weak associations have been reported, the genes that lend risk to commonly occurring PD have not been identified. We examined the patterns of disease expression and familial aggregation in a rigorously evaluated sample of 203 sibling pairs with PD. We assessed commonly reported risk factors for PD to gain insight into their relationship to patterns of disease expression. We report patterns of familial aggregation, disease expression, and risk factor exposure for a highly selected sample of 203 siblings with PD. In comparison with randomly ascertained PD case series, this unique set of sibling pairs is similar in onset age (mean, 61.4 years), proportion of male (57.8%) and female (42.2%) affected members, and frequency with which spouses (2.0%) have PD. Although the frequency of siblings with PD (5.1%) was greater than the 3% seen in random samples, this sample appears otherwise similar to random samples of PD. Based on these results, the etiologic risk factors identified in this unique sample appear to resemble those for PD in general. The role of genetics has been the subject of much controversy. The recent report that the concordance rate for monozygotic twins is not remarkably different from that of dizygotic twins has lessened the enthusiasm for a genetic component in PD. Nevertheless, the presence of a family history for PD has been found to be a strong risk factor for the disease. Furthermore, in this series, as in others, the risk to parents and siblings is 2.3 -3.5 times that for spouses. This suggests that PD aggregates among biological relatives more frequently than in married couples. Although intrauterine or early life exposures cannot be ruled out, the hypothesis that common residential exposures in adult life, such as fumigation, pesticide exposure, or well water consumption, play a significant role in causing PD is not consistent with the absence of increased risk to spouses. We found that siblings showed significant similarity for age at onset and modest evidence suggesting concordance for parental lineage in disease transmission in that when a mother is affected, other affected relatives tended to be of maternal lineage as well. These patterns are consistent with a genetic component for PD risk. The finding that nearly twice as many of the other relatives with PD were of maternal lineage as of paternal lineage may implicate a mitochondrial role for a subset of these families (a disorder that can be passed on only through the mother). However, the finding of more affected fathers (n = 16) than mothers (n = 11) and more affected grandfathers (n = 5) than grandmothers (n = 1) detracts from a mitochondrial hypothesis. We noted that female siblings, and in particular female/female sibling pairs, more frequently reported having other relatives with PD than male siblings. Increased risk to relatives of affected women has been previously noted and suggests that women may be more likely to have a stronger genetic component to their disease. Such a pattern may be seen when there is sex-dependent penetrance for the disease. In sex-dependent penetrance, there is increased risk to the relatives of the less frequently affected sex. Such a pattern could suggest that sex-associated risk factors may be protective for PD. Estrogen is one possible sex-associated protective factor for PD, although prior studies found no support for it as a protective agent. We also explored evidence for environmental factors in PD. As measured, there was no relationship of pesticide exposure to age at onset. Head trauma was associated with a 3.3-year younger age at onset. Studies have implicated head trauma as a risk factor for PD. One caveat of past studies is that patients with PD may have differential recall of head trauma events compared with normal control subjects. For this study, all siblings are PD affected and thus the younger age at onset for patients with head trauma is unlikely due to differential recall. Multivitamin use was found to be related to a 3.2-year later age at onset. Many of those taking multivitamins also reported taking vitamin E, vitamin C, and -carotene and we were not able to discern an affect for any single vitamin supplement. These supplements may be related to the potential antioxidant effects of certain vitamins that may delay onset of PD. Thus although vitamin intake has not been found to be protective for PD, it may be related to delayed onset. However, the delayed onset cannot be firmly attributed to multivitamin use, as these may be a marker for other health factors such as exercise, diet, socioeconomic status, or other drug use. The protective effects of cigarette smoking are widely recognized for PD. Within this sample, pack-years of smoking was significantly related to a later age at onset. Although the role of nicotine has been examined in PD, the mechanism for a protective effect of smoking in PD has not been resolved. This unique sample of sibling pairs with PD has been ascertained as part of a genetic linkage study to identify chromosomal loci that may contain genes that confer risk for PD. Although the sample may not be representative of PD in general, it is likely representative of patients with a family history of PD. The sample also offers the potential to explore gene-environment interactions for PD. The finding that onset age among these siblings is similar to that of patients with PD in general suggests that a genetic component is not limited to early-onset forms of PD. Although risk to parents and siblings has consistently been found to be about three times that seen in controls, only a small fraction of first-degree relatives of patients with PD develop the disease. The results from this study further support the role of factors, either genetic or environmental, that influence penetrance in PD. The identification of these factors will be critical to understanding the pathogenesis of the disease. ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn