Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes.

OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism. METHODS: The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases. RESULTS: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later. CONCLUSIONS: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.

Long-duration effect and the postsynaptic compartment: study using a dopamine agonist with a short half-life.

A possible reason why levodopa induces a sustained, stable motor benefit during the first months to years of therapy may be its long duration of action. This long-duration effect may be due either to a presynaptic storage mechanism or to postsynaptic pharmacodynamic changes. We previously reported that the dopamine agonist ropinirole induced a long-duration response (LDR) in levodopa-naive patients with Parkinson's disease. In this study, we investigated motor responses to the short half-life dopamine agonist lisuride in a group of levodopa naive parkinsonian patients. Once lisuride reached its maximum effect, it was substituted, in randomized order, with placebo. Neither investigators nor patients knew when the active drug was switched to placebo. When patients were switched from lisuride to placebo, their Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and tapping test and screw scores declined to baseline values within a mean 9.0 +/- 1.9 days. The results confirmed that, like ropinirole and levodopa, the short-acting dopamine agonist lisuride induces a long-duration response, probably due to postsynaptic changes.

Alterations of thermoregulation in Parkinson's disease.

Sweating and superficial vasodilator responses were studied in 22 patients suffering from Parkinson's disease in order to evaluate the thermoregulatory function. Sweating was evaluated on different areas of the body with a colorimetric method (Minor's method). The superficial vasodilatation at the level of the face was assessed after oral intake of nitroglycerin by means of telethermography. Sweating and superficial vasodilatation were reduced in parkinsonian patients compared with control subjects. Asymmetries in sweating and superficial vasodilator responses were also observed between the left and right sides of the body in the patients. The decreased heat elimination was more apparent on the symptomatic side in patients with hemiparkinsonism. No relationship was found between the alterations of the thermoregulation and the other clinical features of Parkinson's disease.