To clarify the role of heredity and of some environment risk factors in the etiology of idiopathic Parkinson's disease, we performed a case-control study in two regions of southern Italy, Campania and Molise. We selected two controls for each parkinsonian patient, the patient's spouse and a sex- and age-matched neurological control. One hundred sixteen consecutive outpatients with Parkinson's disease (77 men, 39 women; mean age +/- SD = 62.5 +/- 9.9) and the same number of spouses and neurological controls were interviewed about five environmental risk factors (cigarette smoking, well-water drinking, head trauma with loss of consciousness, strict diets, general anesthesia) and two genetic risk factors (family history of Parkinson's disease or of essential tremor). Well-water drinking and family history of Parkinson's disease or essential tremor showed a positive association with Parkinson's disease; smoking showed a negative association. The most relevant risk factor was history of familial Parkinson's disease (odds ratio = 14.6; 95% confidence interval = 7.2 - 29.6); 33% of our patients had at least one affected relative. We also showed a unilateral distribution of ancestral secondary cases on the paternal or on the maternal side, which suggests a dominant inheritance. Clinical and epidemiologic features of cases with familial Parkinson's disease showed no peculiarity. The study suggests a strong role of the genetic factors in the etiology of Parkinson's disease.

We observed two families with a dominantly inherited complex neurological syndrome with onset in adulthood. Family F included 9 affected in four generations. One patient showed prominent anticipation of onset age. Onset was with cerebellar signs followed by dementia, psychiatric symptoms, seizures, and extrapyramidal features. Family M included 14 affected individuals in five generations. Presenting symptoms were either psychiatric and cognitive impairment or a cerebellar syndrome. Extrapyramidal features, dysphagia, incontinence, seizures, and myoclonus may occur. In both families magnetic resonance imaging showed marked atrophy of the brain and cerebellum. Molecular analyses demonstrated an expanded CAG/CAA repeat in the in the TATA box-binding protein (TBP) gene (SCA17).

The fact that the inverse association with smoking found previously in PD is shared by multiple system atrophy but not by progressive supranuclear palsy lends epidemiologic support to the notion that different smoking habits are associated with different groups of neurodegenerative disease.

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha-synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha-synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.

We report the results of a screen of 230 European familial index cases of Parkinson's disease for the recently described Ala53Thr mutation in the alpha-synuclein gene in an autosomal dominant Parkinson's disease kindred. No mutations were found from this broad white population, and we therefore conclude that although of great interest, this mutation is a very rare cause of familial Parkinson's disease.