Familial Parkinsonism

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While most parkinsonian disorders are sporadic, rare familial forms have been described and mutations have been found or genetic linkage analyses have suggested a strong genetic factor in their etiology (58). Perhaps the most common cause of early onset familial PD is autosomal recessive juvenile PD (ARJP). The clinical features are somewhat atypical in that dystonia is common in ARJP (59). The pathology of ARJP is based upon only a few autopsy reports. Initial studies emphasized severe neuronal loss in the substantia nigra with no Lewy bodies, but a more recent report of an individual who died prematurely of an automobile accident had Lewy bodies in the substantia nigra and other vulnerable regions (60,61). Even in sporadic PD there is an inverse relationship between the disease duration and the number of Lewy bodies in the sub-stantia nigra. When the disease is very severe, there are very few residual neurons. Since Lewy bodies are intraneuronal inclusions that are phagocytosed after the neuron dies, it is not surprising that there are few Lewy bodies in cases of long duration.

Less common than ARJP are autosomal dominant forms of early onset PD. The best characterized is the Contursi kindred, a familial PD due to a mutation in the a-synuclein gene (62). The pathology of the Contursi kindred is typical Lewy body PD; however, given the young age of onset, by the time the individual dies, Lewy body pathology is typically widespread in the brain. Lewy neurites are also prominent in many cortical areas. Some young onset autosomal dominant PD kindreds, such as the Iowa kindred, have atypical clinical presentations and include family members with dementia and psychosis. The Iowa kindred has a multiplication of the a-synuclein gene (63). Families with duplications have a milder phenotype than those with a triplication of the a-synuclein gene, suggesting a role for overexpression of a-synuclein in the pathogenesis of even sporadic PD (64). The pathology in cases with gene triplication is associated with severe Lewy body-related pathology in the cortex, hippocampus, and amygdala, in addition to the substantia nigra and other brainstem nuclei and, in some cases, glial inclusions similar to those found in MSA are present (65) (Fig. 6). Late onset familial PD, such as Family C, has clinical characteristics and pathology that is virtually indistinguishable from sporadic PD (66). This kindred is linked to chromosome 2, but the gene has yet to be discovered.

FIGURE 6 Familial Parkinson's disease (PD): Many Lewy bodies are detected in early onset familial cases and some of the inclusions have unusual morphologies (A, B). Like multiple system atrophy, synuclein-immunoreactive glial inclusions are also detected in some cases of familial early onset PD.

The most common cause of autosomal dominant late onset PD is mutation in the LRRK2 gene on chromosome 12 (67,68). The pathology in most cases is characterized by Lewy bodies (69), but in some individuals, other types of pathology, including neurofibrillary pathology or ubiquitin immunoreactive inclusions, are detected (67,70). The genetic influence of LRRK2 to seemingly sporadic PD continues to expand (71-73), with problems in interpretation of genetic results related to the incomplete penetrance of the mutations, reaching more than 80% only after 70 years of age (74).

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