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Mutations in the Grb10-interacting GYF protein 2 (GIGYF2) gene, within the PARK11 locus, have been nominated as a cause of Parkinson's disease in Italian and French populations. By sequencing the whole GIGYF2 coding region in forty-six probands (thirty-seven Italians) with familial Parkinson's disease compatible with an autosomal dominant inheritance, we identified no mutations. Our data add to a growing body of evidence suggesting that GIGYF2 mutations are not a frequent cause of PD.

Objective: To determine whether pain is more frequent among people with Parkinson disease (PD) than among age-matched controls., Design: Case-control study., Patients and Methods: Logistic regression models taking into account type of pain, time between pain and PD onset, and possible confounders were used to compare 402 PD patients with 317 age-matched healthy control subjects., Results: The overall frequency of pain was significantly greater in PD patients than in controls (281 [69.9%] vs 199 [62.8%]; P = .04), mainly because the healthy control group lacked dystonic pain. Conversely, the frequency of nondystonic pain was similar among PD patients and controls (267 [66.4%] vs 199 [62.8%]; P = .28). Nevertheless, we observed a significant association between PD and nondystonic pain, beginning after the onset of parkinsonian symptoms (odds ratio, 2.1; 95% confidence interval, 1.4-2.9). Cramping and central neuropathic pain were more frequent among PD patients than controls. About one-quarter of patients who experienced pain reported pain onset before starting antiparkinsonian therapy., Conclusion: These data support the hypothesis that pain begins at clinical onset of PD or thereafter as a nonmotor feature of PD.

Since a number of patients with Parkinson's Disease (PD) complain of painful sensations, we studied whether the central processing of nociceptive inputs is abnormal in PD. To test this hypothesis, we recorded scalp CO(2) laser evoked potentials (LEPs) to hand skin stimulation in 18 pain-free PD patients with unilateral bradykinetic-rigid syndrome (hemiparkinson) during the off state and in 18 healthy subjects. This technique allows us to explore non-invasively the functional status of some cerebral structures involved in nociceptive input processing. In both PD patients and control subjects, CO(2) laser stimulation gave rise to a main negative N2 potential followed by a positive P2 response at vertex peaking at a latency of about 200 and 300ms, respectively. These potentials are thought to originate from several brain structures devoted to nociceptive input processing, including the cingulate gyrus and insula. PD patients and normal subjects showed comparable N2 and P2 latencies, whereas the N2/P2 peak-to-peak amplitude was significantly lower in PD patients (regardless of the clinically affected body side) than in controls. LEPs were even recorded after acute L-dopa administration in 7 additional PD patients. L-dopa administration yielded no significant change in N2/P2 amplitude as compared to the off state. These results suggest an abnormal nociceptive input processing in pain-free PD patients which appears to be independent of clinical expression of parkinsonian motor signs and is not affected by dopaminergic stimulation.

Objective: To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset <21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD)., Methods: We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA., Results: A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state., Conclusions: We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.

We used qualitative visual assessment and semiquantitative measures of striatal DAT binding using [(123)I]FP-CIT-SPET in 85 patients with Parkinson's disease (PD). We compared these two assessments and their correlation with PD clinical progression. SPET imaging was visually classified by a nuclear medicine physician as normal or abnormal pattern grade I, II and III, in relation to a different degree of radioligand reduction uptake. Nineteen patients presented abnormal grade I (group 1), 53 grade II (group 2) and 13 grade III (group 3). The UPDRS III motor score, the H-Y score, the rigidity and bradykinesia subscores were significantly different among the three groups. Post hoc analysis showed that all values of these clinical parameters were higher in group 3 than in 2 and 1. All clinical indices were also significantly higher in group 2 than in group 1. This means that groups 3 and 2 were clinically more severely affected. No significant differences among the 3 groups were observed for age or duration of disease. Values of the mean striatum uptake were also significantly different among the three groups. Post hoc analysis revealed significantly lower values of the mean striatum uptake in group 3 with respect to groups 2 and 1; values were also significantly lower in group 2 than in group 1. We conclude that our findings of good consistency between visual and semi-quantitative assessment may help simplify the evaluation of striatal DAT binding in PD in a clinical routine setting.

Aims: To study the association of pain with motor complications in 117 patients with Parkinson's disease., Methods: Patients were asked to refer any pain they experienced at the time of study and lasting since at least 2 months. Basic parkinsonian signs and motor complications (including motor fluctuations and dyskinesia) were assessed and Unified Parkinson's Disease Rating Scale (UPDRS) motor score part III (during on) and part IV were calculated. Information on age, sex, duration of disease, use of dopamine agonists and levodopa, years of levodopa treatment and current levodopa dosage, medical conditions possibly associated with pain, and depression were collected. Single and multiple explanatory variable logistic regression models were used to check the association of pain with the investigated variables., Results: Pain was described by 47 patients (40%) and could be classified into dystonic (n.19) and non dystonic pain (n.16); in 12 patients both types coexisted. Multiple explanatory variable logistic regression models indicated a significant association of pain with motor complications (adjusted OR, 5.7; 95% CI, 2 to 16.5; p = 0.001). No association was found between pain, dystonic or non dystonic, and the other investigated variables including medical conditions known to be associated to pain in the general population. There was a significant correlation (r = 0.31, p<0.05) between severity of pain (measured on a Visual Analogue Scale) and severity of motor complications (UPDRS part IV)., Conclusions: Pain may be a representative feature of Parkinson's disease frequently associated with motor complications. The association is independent of a number of potentially relevant demographic and clinical variables.

Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

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.

A multiethnic series of patients with early-onset Parkinson's disease (EOP) was studied to assess the frequency and nature of parkin/PARK2 gene mutations and to investigate phenotype-genotype relationships. Forty-six EOP probands with an onset age of < 45 years, and 14 affected relatives were ascertained from Italy, Brazil, Cuba, and Turkey. The genetic screening included direct sequencing and exon dosage using a new, cost-effective, real-time polymerase chain reaction method. Mutations were found in 33% of the indexes overall, and in 53% of those with family history compatible with autosomal recessive inheritance. Fifteen parkin alterations (10 exon deletions and five point mutations) were identified, including four novel mutations: Arg402Cys, Cys418Arg, IVS11-3C > G, and exon 8-9-10 deletion. Homozygous mutations, two heterozygous mutations, and a single heterozygous mutation were found in 8, 6, and 1 patient, respectively. Heterozygous exon deletions represented 28% of the mutant alleles. The patients with parkin mutations showed significantly earlier onset, longer disease duration, more frequently symmetric onset, and slower disease progression than the patients without mutations, in agreement with previous studies. This study confirms the frequent involvement of parkin and the importance of genetic testing in the diagnostic work-up of EOP., (Copyright 2004 Movement Disorder Society.)

We investigated the prevalence of dementia and the apolipoprotein E (APOE) genotype distribution in the elderly of Buttapietra, a village near Verona, Italy. All residents over the age of 74 (n = 238), including those who were institutionalized, were studied using a direct-contact, single-phase design. The overall prevalence of dementia, clinically defined by DSM-III-R criteria, was 15.8 cases per 100 population, with age-specific figures increasing steeply with advancing age in both sexes. Alzheimer's disease (AD) was the most frequent dementing disorder (43%). APOE genotyping was determined after DNA amplification by restriction isotyping. We found that the epsilon4 allele and the epsilon3/epsilon4 genotype were associated with all types of dementia, although only the association of epsilon3/epsilon4 with AD reached statistical significance (odds ratio 4.5, 95% confidence interval 1.3-16.1). However, as reported in other Mediterranean countries, the frequency of the epsilon4 allele in our population was low (8.9%), suggesting that the population-attributable risk for AD, at least for elderly individuals (> or =75 years), could be small., (Copyright 2002 S. Karger AG, Basel)

Muscle cramps may be caused by fluid and salt loss induced by diffuse or focal hyperhidrosis. Recent reports have described the efficacy of botulinum, toxin in the treatment of primary focal hyperhidrosis. Botulinum toxin inhibits sweating by blocking exocytosis of acetylcholine from presynaptic cholinergic nerve terminals. We report the case of a patient who complained of frequent muscle cramps associated with unusually severe axillary hyperhidrosis. We used botulinum toxin to treat the excessive focal sweating presuming that it would also reduce the muscle cramps. A total dose of 200 MU of botulinum A toxin (Dysport) per axilla markedly reduced sweating and cramps. The beneficial effect started four days after the injection and it was still present five months later. Treatment was repeated in the sixth month with analogous results. No side-effects were observed and no compensatory sweating occurred.

Simultaneous bilateral plantar sympathetic skin response (SSR) was studied in 25 patients with early stage idiopathic Parkinson's disease (IPD), characterized by monolateral motor involvement (Hoehn and Yahr, stage <2) and without clinical evidence of autonomic dysfunctions. Thirteen (mean age: 68.69 +/- 7.70, range 55-76) had extrapyramidal clinical signs only at the left body side, 12 (mean age 66.60 +/- 7.43, range 51-73) at the right body side. A group of 25 healthy, age-matched, subjects were also evaluated. To evoke the responses, trains of 10 electrical pulses were applied at different intensities and frequencies. Only intensities of stimulation > or = 5 times the sensory electrical threshold always assured bilateral plantar responses in all the examined subjects. Amplitude asymmetry between left and right responses was found only in the IPD patients (P < 0.05). The amplitude reduction corresponded to the motor affected side. No analogue latency variation was observed in any group. Independently from the peripheral or central origins of such phenomena, these findings suggest that simultaneous bilateral SSR amplitude evaluation could be useful, in early IPD patients, to demonstrate and to monitor the sympathetic cholinergic dysfunction, despite the lack of autonomic symptoms.

Botulinum toxin is now widely used in the treatment of several hyperkinetic movement disorders. To evaluate its efficacy in treating muscle cramping syndromes, we studied clinical and neurophysiological variables before and after botulinum toxin injections into calf muscles and small flexor muscles of the foot in patients with an inherited benign cramp-fasciculation syndrome. At each assessment the clinical severity of cramp was scored and the cramp threshold frequency was measured with repetitive electrical peripheral nerve stimulation. Botulinum toxin injection significantly lowered our patients' clinical cramp severity scores (mean +/- SD: before, 3.80 +/- 0.44; after, 1.40 +/- 0.54), left muscle strength unchanged and significantly increased their cramp threshold frequencies (before, 4.22 +/- 2.26 Hz; after, 10.0 +/- 3.74 Hz). The clinical benefit induced by botulinum toxin lasted about 3 months. Botulinum toxin injections also significantly reduced fasciculation potentials in relaxed muscles (before, 0.86 +/- 0.19 fasciculations/sec; after, 0.45 +/- 0.11 fasciculations/sec). These findings show that local intramuscular injections of botulinum toxin provide effective, safe, and long-lasting relief of cramps possibly by reducing presynaptic cholinergic stimulation of motor nerve terminals and by impairing the input/output function of intrafusal and extrafusal motor end plates.

This case of subacute encephalomyelitis with a hyperekplexia type syndrome was characterized histologically by marked lymphomonocytic infiltrates, nodules of microglia, evidence of neuronophagia. These findings suggested a viral infection. The clinical peculiarities of this encephalomyelitis are explained by the elective site of the lesions in the grey substance of the spinal cord, of the tegmentum of the medulla oblongata and pons and of some nuclei of the extrapyramidal system.