Editorials

A gene for Parkinson's disease?

In the early 1980s medical opinion favoured an environmental cause for Parkinson's disease. This viewpoint was founded partly on a small study of twins¹ and the evidence that drug addicts inadvertently exposed to methylphenyltetrahydropyridine (MPTP) developed an illness very similar to the sporadic form of the disease. Ten years later, the pendulum had swung toward genetic factors. The twin data were reanalysed and deemed inconclusive,² and several families were identified with apparent autosomal dominant inheritance.

The most convincing family is described by Golbe and others, who identified 41 affected people in four generations.³ The cases were slightly atypical, with young age of onset (mean 46.5 years), predominance of the rigid form of Parkinson's disease, and a rapid course (average 9.7 years to death). However, the patients responded to levodopa, and necropsies of two patients showed changes typical of Parkinson's disease.

There seems no doubt that on occasion the disease may be inherited, but it must not be forgotten that a gene may confer susceptibility to an environmental agent such as a chemical or virus. Furthermore, prion diseases, for example, are both inheritable and infectious so that it is no longer wise to think of aetiology purely in terms of all genetic or all environmental.

Despite many case-control studies, epidemiological evidence has been inconclusive. There seems to be a link between not smoking and Parkinson's disease,⁴ but this may be an epiphenomenon because many patients with the disease tend to be shy and, as a result, less likely to smoke.⁵ Probably the most convincing association has been with exposure to pesticides on the basis of a retrospective case-control study.⁶

Family studies have been fraught with methodological difficulties. Based on more accurate estimates from large controlled studies, the prevalence in first degree relatives is 1.3-2.1%, which equates to about double that expected.^{7 8} Twin studies, while capable in principle of indicating the level of genetic input, have been contentious, although the results of a large American study based on military servicemen is awaited with interest.

Last week the discovery of a highly penetrant genetic locus linked to Parkinson's disease came as a welcome breath of fresh air in the current sea of confusion. Polymeropoulos and colleagues performed a genome scan of the large Italian kindred with autosomal dominant inheritance mentioned above.⁹ Genetic markers on chromosome 4q21-q23 were linked to the Parkinson's disease phenotype in this family. There are at least 30 genes known in this region, none of which immediately infers a likely mechanism of disease.⁹ The discovery is nonetheless of major importance: it suggests that a single gene is capable of producing all the features of Parkinson's disease, and although the evidence is only at the stage of linkage it is probably only a matter of time before the responsible gene is found--at least for this family.

Assuming, as is likely, that a mutation is found for familial Parkinson's disease, what then? The vast majority of patients with Parkinson's disease (98% or more) have no family history. For them there may be no important genetic contribution or several genes may be responsible. We are in a similar position to that five years ago when a mutation in superoxide dismutase 1 was found for familial motor neuron disease.¹⁰ In this condition about 6% of patients have an affected first degree relative.¹¹ While this observation has stimulated many theories and treatment strategies, the role of genes in the sporadic form of motor neurone disease is still far from clear.

The discovery of genetic linkage of Parkinson's disease to chromosome 4q is a major step forward in our knowledge of the mechanism of this condition. Taking a conservative view, the observation may relate to just one family. More likely it will uncover fundamental information on the mechanism of this disabling condition.

Neurologist Department of Neurology, Leeds General Infirmary, Leeds LS1 3EX

Christopher Hawkes 

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