Genetic factors in the etiology of idiopathic Parkinson's disease

Abstract

Overshadowed by a vigorous search for an environmentally-derived toxin that would be possibly relevant for the pathogenesis of idiopathic Parkinson's disease (PD), genetic factors have largely been neglected for this condition during the last two decades. Recent descriptions of kindreds over three or more generations with several family members affected have renewed the interest in genetics of PD. Concurring with this, diagnostic concepts and pathologic criteria for PD and for idiopathic Lewy-body (LB) disease have been reevaluated such that LB-proven parkinsonism is sufficiently differentiated from familial parkinsonism without LB pathology. Surveys on genetic epidemiology in PD have confirmed the 19th century's notion that 10 to 15% of PD index cases report a further family member with PD. These figures were, however, substantiated on a statistical basis only in single surveys when comparisons were made with the numbers of PD relatives in control index cases. Twin studies did not reveal a higher rate of concordance within monozygotic pairs than in dizygotic pairs. Tests of striatal 18-F-Dopa uptake in clinically unaffected mono- and dizygotic co-twins did not alter the ratio between the concordance rates. Though not excluded by the twin studies, multifactorial (or polygenic) inheritance as well as mitochondrial inheritance are at present less likely to cover most of the inheritance pattern in familial LB parkinsonism. Instead, autosomal dominant inheritance with reduced penetrance is the most probable inheritance pattern for most of the reported pedigrees. Molecular genetic investigations have to consider the biochemical basis of the age- and region-specific pathology of PD. The first analyses of linkage and allelic associations gave inconclusive results in sporadic and familial PD. The hunt for metabolic factors that link geno- and phenotype expression in PD will continue.

Environmental, medical, and family history risk factors for Parkinson's disease: A New England‐based case control study

“…Cases were consistently more likely than controls to have an affected family member: roughly three to four times more likely in birth cohort and sex adjusted analyses and six times more likely in birth cohort, sex, and other risk factoradjusted analyses (Table II). Many studies have found family history of PD [Alonso et al, 1986;Duvoisin et al, 1969;Lazzarini et al, 1994;Marder et al, 1996;Martilla and Rinne, 1976;Martin et al, 1973;Payami et al, 1994;Seidler et al, 1996;Semchuk et al, 1993;Vieregge and Heberlein, 1995;Wang et al, 1993] and family history of tremor [De Michele et al, 1996;Jankovic et al, 1995;Morano et al, 1994;Vieregge, 1994] to be major risk factors for PD and with odds ratios of *Second-and third-degree relatives (aunts, uncles, grandparents, cousins) similar magnitude. We find a similar risk to parents and siblings for PD, which is consistent with an autosomal dominant mode of inheritance with reduced penetrance.…”

Pathogenesis and preclinical course of Parkinson’s disease

“…In the absence of a clearly identifiable cause for IP, it is assumed that some degree of genetic predisposition to the disease must exist (reviews: Vieregge, 1994;Golbe, 1995;Duvoisin, 1996). However, despite intensive investigation of a number of candidate genes, the specification of this involvement remains problematic.…”

Génétique et maladie de Parkinson

“…La proportion des formes familiales de la maladie de Parkinson est difficile à estimer, mais les études basées sur l'anamnèse, qui comportent un biais systématique [72], rapportent une prévalence d'environ 10 à 15% de cas avec au moins un membre direct de la famille atteint [73]. Les formes monogéniques connues n'en constituent qu'une minorité, la plus fréquente étant PARK 2, retrouvée chez 49% des cas débutant avant 45 ans dans les familles à transmission autosomique récessive [41], responsable de 9 à 18% des parkinsonismes du sujet jeune, mais de moins de 1% de tous les cas de la maladie de Parkinson.…”