Letterio Morgante

Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2.

Headache attacks and autonomic dysfunctions characterize migraine, a very common, disabling disorder with a prevalence of 12% in the general population of Western countries. About 20% of individuals affected with migraine experience aura, a visual or sensory-motor neurological dysfunction that usually precedes or accompanies the headache. Although the mode of transmission is controversial, population-based and twin studies have implicated genetic factors, especially in migraine with aura. Familial hemiplegic migraine is a hereditary form of migraine characterized by aura and some hemiparesis. Here we show that mutations in the gene ATP1A2 that encodes the α2 subunit of the Na+/K+ pump are associated with familial hemiplegic migraine type 2 (FHM2) linked to chromosome 1q23 (OMIM 602481). Functional data indicate that the putative pathogenetic mechanism is triggered by a loss of function of a single allele of ATP1A2. This is the first report associating mutations of Na+K+ pump subunits to genetic diseases.

Prevalence of Parkinson's disease and other types of parkinsonism A door‐to‐door survey in three Sicilian municipalities

We investigated the prevalence of Parkinsons disease and other types of parkinsonism in a Sicilian population using a door-to-door two-phase approach. This design called for the administration of a brief screening instrument to all subjects who, on November 1, 1987, were residents of Terrasini (Palermo Province), Santa Teresa di Riva (Messina Province), and Riposto (Catania Province), Sicily (N = 24,496). Study neurologists using specified diagnostic criteria extensively investigated those subjects who screened positive. We found 63 subjects affected by Parkinsons disease, 21 with secondary parkinsonism, and seven with unspecified parkinsonism. The crude prevalence per 100,000 population was 371.5 for all types of parkinsonism and 257.2 for Parkinsons disease; for both entities, prevalence increased steeply with age and showed an inconsistent sex pattern. Our prevalence figures for Parkinsons disease are higher than those previously reported in Italy or elsewhere, which may be due, in part, to more complete case-ascertainment.

Pramipexole versus sertraline in the treatment of depression in Parkinson's disease: a national multicenter parallel-group randomized study.

In addition to treating the motor symptoms of Parkinson’s disease, the dopamine agonist pramipexole has shown an antidepressant effect. The trials, however, included patients with motor complications, raising the question of whether the antidepressant benefit represented only a treatment–related motor improvement. To address this issue, we have conducted a 14–week randomized trial comparing pramipexole with an established antidepressant in patients without motor complications. At seven Italian centers, 67 Parkinsonian outpatients with major depression but no history of motor fluctuations and/or dyskinesia received open–label pramipexole (at 1.5 to 4.5 mg/day) or sertraline (at 50 mg/day). In both groups, the Hamilton Depression Rating Scale (HAM–D) score decreased throughout 12 weeks of treatment, but in the pramipexole group the proportion of patients who recovered, as defined by a final HAM–D score ≤ 8,was significantly higher, at 60.6% versus 27.3% (p = 0.006). Patients’ self–ratings improved in both groups. All adverse events were mild or moderate, but five patients (14.7%) withdrew from the sertraline group. Despite the absence of motor complications, the pramipexole recipients showed improvement on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscore. We conclude that dopamine agonists may be an alternative to antidepressants in Parkinson’s disease.

Quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis.

ObjectiveThis study aimed to compare the efficacy and safety of quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis in a randomized, open-label, blinded-rater, parallel group trial. MethodsForty-five patients with Parkinson disease (PD) and psychosis induced by antiparkinsonian drugs were randomly assigned to receive either quetiapine or clozapine. The duration of the trial was 12 weeks. Forty patients, 20 in each treatment group, completed the study. The final dose of quetiapine (mean ± SD) was 91 ± 47 mg/d and that of clozapine 26 ± 12 mg/d. The severity of psychosis was assessed using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Scale–Severity Subscale (CGI-S). The Unified Parkinson’s Disease Rating Scale (UPDRS) III was used to assess motor conditions during the study period. The Abnormal Involuntary Movement Scale (AIMS) was performed to evaluate dyskinesias. ResultsForty patients, 20 on clozapine and 20 on quetiapine, completed the study. The psychopathologic state improved significantly (P < 0.001) from baseline in both treatment groups. No differences were found between clozapine and quetiapine at any assessment time. Motor conditions remained unchanged after clozapine and quetiapine. Dyskinesias decreased significantly (P < 0.05) in both groups. Side effects were mild, generally transient, and well tolerated. ConclusionsQuetiapine and clozapine appear equally efficacious for treatment of dopaminergic psychosis in patients with PD.

Risk of Parkinson disease in women Effect of reproductive characteristics

Objective: To investigate the association between some fertile life characteristics and Parkinson disease (PD) in women. Methods: Women affected by PD and control subjects were matched one to one by age (±2 years). One hundred thirty-one women with idiopathic PD and 131 matched control subjects were interviewed. Controls were randomly selected from the resident list of the same municipality of residence of cases. All subjects had a Mini-Mental State Examination score of ≥24. Cumulative length of pregnancies, age at menarche, age and type of menopause, and estrogen use before and after menopause were investigated in cases and controls through a structured questionnaire. Models of matched pair univariate analysis and conditional logistic regression analyses were used to calculate adjusted odds ratio (OR), 95% CI, and two-tailed p values for the investigated variables. Results: PD was significantly associated with a fertile life length shorter than 36 years (OR 2.07; 95% CI 1.00 to 4.30) and a cumulative length of pregnancies longer than 30 months (OR 2.19; 95% CI 1.22 to 3.91). An inverse association between PD and surgical menopause (adjusted OR 0.30; 95% CI 0.13 to 0.77) was also found. Conclusions: An association between factors reducing estrogen stimulation during life and PD was found. These results support the hypothesis that endogenous estrogens play a role in the development of PD.

Clinical and neuropsychological follow up at 12 months in patients with complicated Parkinson’s disease treated with subcutaneous apomorphine infusion or deep brain stimulation of the subthalamic nucleus

Background: The clinical condition of advanced Parkinson’s disease (PD) patients is often complicated by motor fluctuations and dyskinesias which are difficult to control with available oral medications. Objective: To compare clinical and neuropsychological 12 month outcome following subcutaneous apomorphine infusion (APO) and chronic deep brain stimulation of the subthalamic nucleus (STN-DBS) in advanced PD patients. Methods: Patients with advanced PD and medically untreatable fluctuations underwent either APO (13 patients) or STN-DBS (12 patients). All patients were clinically (UPDRS-III, AIMS, 12 h on-off daily) and neuropsychologically (MMSE, Hamilton-17 depression, NPI) evaluated at baseline and at 12 months. APO was discontinued at night. Results: At 12 months APO treatment (74.78±24.42 mg/day) resulted in significant reduction in off time (−51%) and no change in AIMS. Levodopa equivalent medication doses were reduced from 665.98±215 mg/day at baseline to 470±229 mg/day. MMSE, NPI, and Hamilton depression scores were unchanged. At 12 months STN-DBS resulted in significant clinical improvement in terms of reduction in daily off time (−76%) and AIMS (−81%) as well as levodopa equivalent medication doses (980±835 to 374±284 mg/day). Four out of 12 patients had stopped oral medications. MMSE was unchanged (from 28.6±0.3 to 28.4±0.6). Hamilton depression was also unchanged, but NPI showed significant worsening (from 6.58±9.8 to 18.16±10.2; p<0.02). Category fluency also declined. Conclusions: Both APO and STN-DBS resulted in significant clinical improvement in complicated PD. STN-DBS resulted in greater reduction in dopaminergic medications and provided 24 h motor benefit. However, STN-DBS, unlike APO, appears to be associated with significant worsening on NPI resulting from long term behavioral problems in some patients.

Prevalence of essential tremor A door‐to‐door survey in Terrasini, Sicily

As part of a door-to-door neuroepidemiologic survey, we investigated the frequency and distribution of essential tremor (ET) in a Sicilian municipality. During phase 1, we administered a screening instrument for tremor to 7,653 persons residing in Terrasini (Palermo province). During phase 2, neurologists evaluated those subjects who had screened positive. The diagnoses, based on specified clinical criteria, were reviewed to increase reliability across neurologists. We found 31 subjects affected by ET (17 men, 14 women); 11 patients (35.5%) reported a familial aggregation. The prevalence of ET as of November 1, 1987, was 405.1 per 100,000 for the total population, and 1,074.9 per 100,000 for those 40 years old or older. The prevalence increased with advancing age for both sexes and was slightly but consistently higher in men. Comparison with other studies suggests striking geographic variation, which may reflect genetic differences.

Prevalence of cervical spondylotic radiculopathy: a door‐to‐door survey in a Sicilian municipality

Introduction— Because of the limited information on cervical spondylotic radiculopathy, we conducted a door‐to‐door two‐phase survey in a Sicilian municipality. Material and methods ‐ We first screened for cervical spondylotic radiculopathy among the inhabitants of the municipality: (N= 7653, as of the prevalence day, November 1, 1987). Study neurologists then investigated those subjects suspected to have had a cervical spondylotic radiculopathy. Diagnoses were based on specified criteria. Results— We found 27 subjects affected by CSR (17 definite, 10 possible). Prevalence (cases per 1000 population) was 3.5 in the total population; it increased to a peak at age 50–59 years and decreased thereafter. The age‐specific prevalence was consistently higher in women. Conclusions— Comparison with other prevalence studies shows similar age‐specific patterns, but different magnitudes, which may partly reflect methodologic differences across studies.

Long-term survival of Parkinson's disease: a population-based study.

AbstractIn a set of a population– based study, long–term survival of 59 prevalent PD patients was compared with that of individuals free of neurological diseases matched 1:2 by sex and age of enrolment. PD individuals, compared with reference subjects, showed a two–fold increased risk of death (OR 2.1; 95 % CI 1.4, 3.1). Among causes of death, pneumonia and cachexia were significantly more frequent among PD patients than among individuals free of neurological diseases. We confirmed in a long–term follow–up study an increased mortality among PD individuals compared with that of the general population.

Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23.

Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder characterized by episodes of transient hemiparesis followed by headache. Two chromosomal loci are associated to FHM: FHM1 on chromosome 19 and FHM2 on chromosome 1q21‐23. Mutations of the α‐1A subunit of the voltage gated calcium channel (CACNA1A) are responsible for FHM1. FHM2 critical region spans 28cM, hence hampering the identification of the responsible gene. Here, we report the FHM2 locus refining by linkage analysis on two large Italian families affected by pure FHM. The new critical region covers a small area of 0.9Mb in 1q23 and renders feasible a positional candidate approach. By mutation analysis, we excluded the calsequestrin and two potassium channel genes mapping within the narrowed FHM2 locus. Ann Neurol 2003