DLB is a disorder mainly characterized by dementia and parkinsonism, but with other distinguishing features. The question of whether PD-D and DLB are different entities or different demonstrations of the same pathological spectrum has been extensively discussed (including elsewhere in this book); however, it is important to stress that even fully penetrant, autosomal dominant mutations may lead to different clinical phenotypes across the spectrum of PD-D, DLB, and beyond. Families with mutations in SNCA emphasize this premise: (1) the family described by Zarranz et al. [12] includes individuals carrying the same mutation (p.E46K) but with PD-D and DLB phenotypes within the same cohort; (2) multiplications of the SNCA locus may lead to either PD-D or DLB [15, 16, 30]. Neuropathological examination of brain tissue from dominantly inherited forms of AD and from Down’s syndrome patients frequently reveals Lewy body pathology. Mutations in LRRK2 may lead to a-synuclein, tau, or ubiquitin pathology with or without Lewy bodies. Clearly there are multiple genetic factors that can trigger the formation of Lewy bodies, irrespective of the disease phenotype, and this implicitly links the underlying molecular aetiology of these diseases to that of PD.

Multiple system atrophy (MSA) is the second most common parkinsonian syndrome after idiopathic PD, presenting clinically with various combinations of parkinsonism, cerebellar ataxia, and autonomic failure. Even though cognitive dysfunction appears to be minimal, the majority of patients have frontal system impairment and some develop dementia late in the course of the disease. Pathologically, it is characterized by glial cytoplasmic inclusions mainly composed of a-synuclein. MSA is usually a sporadic disease, but the fact that several MSA patients have relatives with PD led to the study of various genes. Clearly, from the point of view of molecular pathology, the most plausible gene responsible for the pathogenesis of MSA is SNCA. Several genetic analyses of SNCA in MSA cases have been conducted, but they have largely failed to identify any pathogenic mutations, particularly when only pathologically confirmed cases were screened [64, 65]. More recently, an individual with a SNCA multiplication mutation was reported with a clinical syndrome reminiscent of MSA [31]. Common genetic variability at this locus may also confer risk for MSA in White populations [66-68].

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