Phenotype Of Parkinrelated Parkinsons Disease Clinical Features

The most typical features of Parkinson's disease caused by PARKIN mutations are early-onset typical parkinsonism with a slow clinical course, good or excellent response to low doses of levodopa, frequent treatment-induced dyskinesias and the absence of dementia (47,99). Other frequent signs, that occur in less than 50% of the cases, however, are foot dystonia, brisk reflexes, sleep benefit, and psychiatric or behavioral disorders (Table 1).

Two studies (47,90) have compared the frequency of clinical signs in Parkinson's disease patients with and without PARKIN mutations, recruited according to the same clinical criteria. Although the range of ages at onset was similar in both groups of patients, the mean age at onset was significantly earlier in patients with mutations (31.4 ± 11.9 vs. 38.1 ± 11.2; p < 0.001), and dystonia, symmetry at onset and

TABLE 1 Phenotype of PARKIN-Related Parkinson's disease

Major features of PARKIN carriers Early- or juvenile-onset

Excellent and sustained response to low doses of L-Dopa

Slow progression

Absence of dementia

Typical parkinsonism

Foot dystonia

Levodopa induced dyskinesias No reduced olfaction Atypical or rare additional features Late-onset (IPD-like) (29,43,47,67) DRD-like (99)

Leg tremor in orthostatism (34) Focal dystonia (105) Mild cerebellar signs (33,59,103) Pyramidal tract dysfunction (59) Peripheral neuropathy (6,84,90) White matter abnormalities on brain MRI (90) Psychiatric or behavioral manifestations Psychosis (99,106) Panic attacks (90) Depression (6,90,99) Disturbed sexual behavioral (90,99) Obsessive-compulsive behaviors (90,105)

Abbreviations: DRD, dopa-responsive dystonia; IPD, idiopathic Parkinson's disease; MRI, magnetic resonance imaging.

brisk reflexes were significantly more frequent. In addition, despite longer treatment, the daily dose of levodopa was significantly lower in the group with mutations. However, there was no individual sign or symptom that distinguished PARKIN mutation carriers from noncarriers with early-onset parkinsonism, and there was no effect of gender on the phenotype.

Interestingly, dystonia at onset was not specific to PARKIN carriers, but was associated with young-onset parkinsonism regardless of the cause. Freezing, festi-nation, retropulsion, instability, and falls, which are usually considered to be late features in patients with idiopathic Parkinson's disease and often assumed to be extranigral or nondopaminergic in origin, can be early or presenting features in some patients with PARKIN mutations who have in principle no nondopaminergic lesions (99). Reduced olfaction, which is a frequent early frequent finding in idiopathic Parkinson's disease, is not associated with PARKIN mutations (100), but rapid eye movement sleep behavior disorder is frequent in both (101).

Atypical presentations or additional signs are observed as well, including onset as late as age 72 (29,43,47,67), pyramidal tract dysfunction (59) peripheral neuropathy (6,84,90,102), cerebellar ataxia (33,59,103), tremor mainly during orthos-tatism (34), and white matter abnormalities on brain MRI (90). One study found corticospinal dysfunction in PARKIN carriers suggesting extended involvment of the central nervous system in Parkinson's disease (104). Some phenotypes resemble dopa-responsive dystonia (99,105) or hemiparkinsonism-hemiatrophy (69).

Cognitive function remains normal in the majority of patients with PARKIN mutations (47,90,99), even after 45 years of evolution (99), but behavioral disorders have been reported, included anxiety, psychosis, panic attacks, depression, disturbed sexual behavioral, and obsessive-compulsive behaviors (6,90,99,106,107). However, since psychiatric manifestations are frequent in the general population and delirium and hypersexuality can be triggered by antiparkinsonism drugs, it cannot yet be concluded whether they are part of the phenotype or if they occurred by chance in some of the patients.

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