Evaluation Of Kindreds

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Kindreds with a parkinsonian phenotype have been reported in the world medical literature since the 19th century (27). In a 1926 literature review, Bell and Clark (28) described 10 families with "shaking palsy" believed to be hereditary. They also provided 20 references of earlier accounts of familial paralysis agitans. In 1937, Allen

(29) detailed an additional 25 families with inherited parkinsonism and speculated that the inheritance was autosomal dominant and probably the result of a single autosomal gene in about two-thirds of these kindreds. In 1949, Mjones (30) detailed eight pedigrees with inherited parkinsonism, some with atypical features such as myoclonic epilepsy. In the levodopa era (from the early 1960s to now), numerous reports described families with PD and parkinsonism-plus syndrome (31), including two large multigenerational kindreds known as the Contursi (32) and Family C (German-American) (33) kindreds. As molecular genetic techniques have improved, the importance of collecting data from parkinsonian families with PD has grown exponentially.

Eleven monogenetic PARK loci have been identified (Table 1). The PARK4 locus was reclassified because it shares the same gene (SNCA; a-synuclein) as the PARK1 locus (34). The PARK9 locus has been described in the Kufor-Rakeb kindred, with affected family members having atypical parkinsonism associated with dementia, spasticity, and supranuclear palsy (35). Mutations in six genes have been implicated in parkinsonism: SNCA (PARK1) in 1997 (34), parkin (PARK2) in 1998 (36), UCHL1 (PARK5) in 1998 (37), DJ-1 (PARK7) in 2001 (38), PINK (PARK6) in 2004 (39), and LRRK2 (PARK8) in 2004 (40,41).

LRRK2 G2019S has now become the most common cause of PD and may account for 1% to 1.6% of sporadic patients and 3% to 10% of familial patients in Europe, America, and Asia (41-52). However, the frequency is higher and the associated haplotype (60 kb[53]) is shorter in North African Arabs, for whom the mutation may be responsible for 40% of PD.

Additional PARK loci and contributing genes are likely to be identified through family studies, ultimately facilitating a molecular rather than a clinico-pathologic diagnosis. Mutations in genes implicated in parkinsonism have already been used to create in vivo models. These gene mutations can recapitulate the pathogenesis as well as the symptoms of disease, and they may provide powerful insight into neuronal degeneration. They facilitate validation of biomarkers of disease progression and neuroprotection strategies (54-56). Much as is the case with Alzheimer's disease, these new tools bring the hope of novel therapies for PD that are designed to address the causes rather than merely the symptoms of the disease (57).

The table summarizes the status of the current knowledge about the mendelian genetics of PD. It shows the types of inheritance and the location of known chromosomal loci and disease-linked mutations. The key references in the medical literature are also provided.

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