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Parkinson's disease (PD) is the second most common neurodegenerative disease, with some estimates suggesting over one million Americans suffering with symptoms. The pathological hallmark of PD that gives rise to the trademark motor complications is the loss of melanized tyrosine-hydroxylase-positive dopaminergic neurons in the substantia nigra pars compacta. The fundamental mechanisms underlying the loss of this indispensable nucleus of neurons remain largely a mystery. Additional lesions and cell loss likewise occur in many regions throughout the central and peripheral nervous system, probably responsible for the diverse and debilitating non-motor symptoms associated with the disease.1, 2

Phenotypes of Parkinsonism

PD is a complex disease with variable clinical presentation. Although an idea of what typical late-onset PD encompasses, both clinically and pathologically, has formed over the last century, it is likely that PD and related disorders encompass a number of distinct but overlapping etiologies.3 This spectrum includes many cases that can be said to suffer with parkinsonism but not necessarily PD. In most cases the approach used to separate these different phenotypes is clinical assessment, an imperfect tool at best. As this chapter delves into the molecular genetics of PD and closely related disorders, it is critically important to recognize that what is currently classified as “PD” may include diseases of different origins and causes. Ultimately, an accurate classification may demand identification of the specific cause(s) of disease, and genetic-based approaches are likely to play a central role in the development of better diagnostic approaches.

The goal of this chapter is to highlight advances in human genetic studies with the goal of placing each seminal study into a conceptual framework whereby appropriate future downstream studies, derived from criteria clearly justified from human genetic studies, can be designed for clarifying disease etiology and the development of a cure.

For much of the 20th century, PD was regarded as the archetypal neurodegenerative disorder with little or no genetic cause of disease. Indeed, most PD patients seen in modern movement disorder clinics do not report a family history of disease, in contrast to other rarer movement disorders such as Huntington's disease and frontal–temporal dementia. In James Parkinson's initial descriptions of the disease, a familial component was not mentioned, in line with Charcot's testament that “paralysis agitans is not a family disease.”4 Nevertheless, descriptions of families that pass disease from one generation to the next have been described since shortly after the recognition of PD as a distinct clinical entity.

Discoveries of PD Kindreds

PD kindreds were described by Gowers, and later Mjónes, among others, but these kindreds harbored a disease with comorbidities not usually associated with sporadic PD, and hence characterized as a “Parkinson's plus syndrome,” or other variable nomenclature that typically includes the term parkinsonism as opposed to PD (see Fig. 9–1). These families often pass a highly penetrant mutation compatible with Mendelian autosomal-dominant ...

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