Damiano Branca

Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD.

OBJECTIVE To investigate whether polymorphisms in the genes for dopamine receptors D1 and D2 are associated with the risk of developing peak-dose dyskinesias in PD. BACKGROUND Peak-dose dyskinesias are the most common side effects of levodopa therapy for PD. The identified predictors may only partially account for the risk of developing peak-dose dyskinesias because a substantial proportion of patients never develop peak-dose dyskinesias. Genetic factors could play a role in determining the occurrence of peak-dose dyskinesias. METHODS A case-control study of 136 subjects with sporadic PD and 224 population control subjects. We studied three polymorphisms involving the dopamine receptor D1 gene and one intronic short tandem repeat polymorphism of the dopamine receptor D2 gene. RESULTS The polymorphisms of the dopamine receptor D1 gene were not associated with the risk of developing PD or peak-dose dyskinesias. The 15 allele of the polymorphism of the dopamine receptor D2 gene was more frequent in parkinsonian subjects than in control subjects. More important, the frequency of both the 13 allele and the 14 allele of the dopamine receptor D2 gene polymorphism was higher in nondyskinetic than in the dyskinetic PD subjects. The risk reduction of developing peak-dose dyskinesias for PD subjects carrying at least 1 of the 13 or 14 alleles was 72% with respect to the PD subjects who did not carry these alleles. CONCLUSIONS Certain alleles of the short tandem repeat polymorphism of the dopamine receptor D2 gene reduce the risk of developing peak-dose dyskinesias and could contribute to varying susceptibility to develop peak-dose dyskinesias during levodopa therapy.

The dopamine D2 receptor gene is a susceptibility locus for Parkinson's disease

The dopamine D2 receptor (DRD2) gene has been proposed as a candidate gene underlying several psychiatric and neurologic disorders. The aim of the present study was to examine if selected polymorphisms in the DRD2 gene are associated with Parkinsons disease (PD). We determined the allelic frequencies for four polymorphisms located in the DRD2 gene in a sample of 135 patients with PD and 202 normal control subjects. No significant difference was observed in the allelic frequencies between patients with PD and control subjects with regard to the ‐141C Ins/Del and the Ser311/Cys311 variants. On the contrary, the A1 allele of the TaqIA polymorphism and the B1 allele of the TaqIB polymorphism were more frequent in patients with PD than in control subjects (control subjects: TaqIA A1 = 14.6%, TaqIB B1 = 10.6%; patients with PD: TaqIA A1 = 20.7%, TaqIB B1 = 17.4%). Patients carrying the A1 allele or the B1 allele had an increased risk of developing PD (TaqIA, odds ratio: 1.71, 95% confidence intervals: 1.08–2.73; TaqIB, odds ratio: 1.83, 95% confidence intervals: 1.12–3.02). The TaqIA and TaqIB polymorphisms were in strong linkage disequilibrium, suggesting that these two polymorphisms convey the same information about the risk of presenting with PD. Genetic variation in the DRD2 gene may influence the risk of developing PD, thus confirming that the DRD2 gene is a susceptibility locus for PD.

The long-duration response to L-dopa in the treatment of early PD.

Objective: To investigate the long-duration response (LDR) to l-dopa resulting from different regimens of l-dopa. Background: In clinical practice, l-dopa is usually administered without considering the LDR due to the drug. Moreover, it has not been established whether in early PD a multiple daily intake of small doses of l-dopa may induce a sustained LDR. Methods: Twenty-four patients with early PD underwent a double-blind, crossover trial, comparing three different 15-day treatment periods with l-dopa: treatment A (250 mg every 24 hours); treatment B (250 mg every 8 hours); and treatment C (125 mg every 8 hours). After completion, 20 patients underwent a subsequent open-label randomized trial with prolonged treatments (250 mg every 24 hours or 125 mg every 8 hours) up to 3 months. LDR was measured at the end of each treatment. Results: All patients achieved a sustained LDR after treatments A and B, whereas only 17% of patients reached a sustained LDR after treatment C. Overall, the LDRs resulting from treatments A and B had similar magnitude and were larger than the LDR deriving from treatment C. After 3 months of prolonged treatments, only three of 10 patients treated with 125 mg every 8 hours increased their LDR, whereas all 10 patients treated with 250 mg every 24 hours had a maximal and stable LDR. Conclusions: Sustained LDR to l-dopa is dependent on the amount of the single doses of the drug. A regimen scheduling small, divided doses during the day, as done in clinical practice, is a questionable therapy for the achievement of a sustained LDR.

Pharmacodynamics of the long-duration response to levodopa in PD

Objective: To determine the latency, magnitude, and duration of the long-duration response (LDR) to levodopa in PD in relationship to the administration of levodopa at different interdose intervals. Methods: In six patients with PD, two different 15-day treatment regimens were used in which the drug was administered with interdose intervals of 24 or 8 hours. Results: The LDR built up within a few days with either regimen, but a faster rate of administering levodopa shortened the latency to the appearance of a sustained LDR. Once a sustained response had been reached, the magnitude of the LDR showed a stable ceiling effect that was independent of the levodopa schedule. After discontinuation of treatment, the decay of the LDR was similar for both regimens. Conclusions: The system underlying the LDR to levodopa may be completely saturated when a sustained response has been fully developed. The intervals between doses of levodopa shorter than the interval effective to reach a sustained LDR should not be used in the clinical management of patients with PD because the antiparkinsonian benefit deriving from the LDR is already maximal and briefer intervals do not provide a greater benefit.

Chorea induced by non-ketotic hyperglycaemia: a case report.

We describe an 81-year-old woman presenting with sudden onset of generalised chorea. She was unaware of suffering from diabetes. Laboratory screening revealed non-ketotic hyperglycaemia. Brain magnetic resonance imaging (MRI) failed to show basal ganglia abnormalities. Monotherapy with subcutaneous regular insulin induced a progressive normalisation of glycaemia as well as a parallel improvement of the abnormal involuntary movement scale on a nine-day sequential observation. This correlation strongly supports the hypothesis that non-ketotic hyperglycaemia itself might play a major pathogenetic role in chorea associated with non-ketotic hyperglycaemia. Diabetes mellitus should be suspected in patients who develop sudden onset of chorea even in the absence of putaminal abnormalities on MRI.

Apolipoprotein E polymorphisms and Parkinson's disease.

The apolipoprotein E (APOE) gene polymorphism has been studied in Parkinsons disease (PD) with conflicting results. Recently, a newly described functional polymorphism in the regulatory region of the APOE gene, (-491 A/T), has been associated with late-onset Alzheimers disease. We studied the association between these two polymorphisms of the APOE gene with PD in a sample of 126 PD patients and in 119 controls from the same geographic background. Allelic and genotypic frequencies were not different between PD cases and population controls for either the APOE or -491 A/T polymorphism. The age at onset of the disease was not different according to the specific genotypes of the two polymorphisms of the APOE gene.

Rating scale for psychogenic nonepileptic seizures: Scale development and clinimetric testing

Our aim was to develop a clinimetric scale evaluating motor phenomena, associated features, and severity of psychogenic nonepileptic seizures (PNES). Sixty video/EEG-recorded PNES induced by suggestion maneuvers were evaluated. We examined the relationship between results from this scale and results from the Clinical Global Impression (CGI) scale to validate this technique. Interrater reliabilities of the PNES scale for three raters were analyzed using the AC1 statistic, Kendalls coefficient of concordance (KCC), and intraclass correlation coefficients (ICCs). The relationship between the CGI and PNES scales was evaluated with Spearman correlations. The AC1 statistic demonstrated good interrater reliability for each phenomenon analyzed (tremor/oscillation, tonic; clonic/jerking, hypermotor/agitation, atonic/akinetic, automatisms, associated features). KCC and the ICC showed moderate interrater agreement for phenomenology, associated phenomena, and total PNES scores. Spearmans correlation of mean CGI score with mean total PNES score was 0.69 (P<0.001). The scale described here accurately evaluates the phenomenology of PNES and could be used to assess and compare subgroups of patients with PNES.

Non-paraneoplastic limbic encephalitis characterized by mesio-temporal seizures and extratemporal lesions: a case report.

Limbic encephalitis (LE) can be either paraneoplastic or a non-paraneoplastic autoimmune disorder. Magnetic resonance imaging (MRI) of the brain on T2-weighted fluid-attenuated inversion recovery (FLAIR) classically shows hyperintensities of the temporal structures, but multifocal involvement of extratemporal cortex has also been described in paraneoplastic LE. Here we describe a 27-year-old woman whose idiopathic autoimmune (glutamic acid decarboxylase-antibody positive) LE debuted with multiple daily mesio-temporal seizures, amnesia and multifocal extratemporal cortical MRI abnormalities. Mesio-temporal MRI signal increase was found after 20 days. This case report highlights that early diagnosis of non-paraneoplastic LE may be considered in patients with multiple daily mesio-temporal seizures and amnesia even in the absence of early typical MRI abnormalities.

Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia.

Spastic paraplegia type 4 is caused by mutations in the gene that encodes spastin (SPG4), a member of the AAA protein family. A cohort of 34 unrelated Italian patients with pure spastic paraplegia, of which 18 displayed autosomal dominant inheritance and 16 were apparently sporadic, were screened for mutations in the SPG4 gene by denaturing high performance liquid chromatography. We identified a previously reported mutation in a sporadic patient with pure hereditary spastic paraplegia. We also identified eight unrelated patients with pure autosomal dominant hereditary spastic paraplegia carrying five novel mutations in the SPG4 gene (one missense mutation, c.1304 C>T; one nonsense mutation, c.807C>A; two frameshift mutations, c.1281dupT, c.1514_1515insATA; and one splicing mutation, c.1322-2A>C). The frequency for SPG4 mutations detected in autosomal dominant hereditary spastic paraplegia was 44.4%. This study contributes to expand the spectrum of SPG4 mutations in Italian population.

Usefulness of rectal biopsy for the diagnosis of Kufs disease: a controlled study and review of the literature

Rectal biopsy is usually performed for in vivo diagnosis of Kufs disease (KD). We evaluated the usefulness of rectal biopsy in the diagnosis of such condition by comparing ultrastructural data of patients with suspicion of KD with those of control subjects. Furthermore, we reviewed literature data concerning the value of such a diagnostic procedure in the diagnosis of KD.