Showing papers by "Giovanni Fabbrini published in 2006"

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.

Abstract: 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.

A comparative study of primary and secondary hemifacial spasm

Abstract: Background Hemifacial spasm (HFS) is a common movement disorder. Objective To evaluate possible differences in the demographic and clinical features between primary and secondary HFS. Design In-person interview using a standardized questionnaire to collect demographic and clinical data. Setting A multicenter study that included patients with HFS attending 3 Italian academic centers. Patients Two hundred fourteen patients with HFS. Main Outcome Measure A complete neurological examination assessed the current muscle distribution of spasm and the presence of synkinetic movements between upper and lower facial muscles. Results The study sample comprised 214 patients with HFS, 81 men and 133 women, having a mean ± SD age of 65.9 ± 12.3 years; 164 patients were classified as having primary HFS and 50 patients (48 postparalytic and 2 symptomatic cases) were classified as having secondary HFS. Patients with primary and those with secondary HFS had similar mean ± SD ages at onset (54.9 ± 13.5 vs 57.0 ± 12.8 years), male-female ratios (63:101 vs 18:32), right-sided–left-sided HFS (77:86 [1 bilateral] vs 21:28 [1 bilateral]), and frequencies of familial cases (2.9% vs 2.0%), respectively. Most patients (65.0%) with primary HFS had initial symptoms of periocular muscle contractions alone and had subsequent involvement of the lower facial muscles. Most patients (72.0%) with secondary HFS reported initial involvement of the upper and lower facial muscles simultaneously. Signs of synkinesis were present in primary (43.3%) and secondary (58.0%) HFS. Conclusions Patients with primary and those with secondary HFS share common demographic and clinical features, including sex distribution, age at onset, affected side of HFS, synkinesis, and rarity of familial cases. Signs of synkinesis were present in significant proportions of patients with primary or secondary HFS. The 2 forms differed in clinical presentation.

Head trauma in primary cranial dystonias: a multicentre case–control study

Abstract: Background: The relationship between prior trauma and primary adult-onset dystonia is not well understood. Previous uncontrolled observations and exploratory case–control studies have yielded contradictory results. Objective: To analyse the association between cranial dystonia and prior head trauma. Methods: An ad hoc multicentre case–control study was performed using a semistructured interview to collect detailed information on the history of head trauma before disease onset in five Italian tertiary referral centres for movement disorders. The presence of a history of head trauma and of post-traumatic sequelae (loss of consciousness, bone fractures, scalp/facial wounds) before disease onset was recorded from 177 patients with primary adult-onset cranial dystonia and from 217 controls with primary hemifacial spasm matched by age strata and sex. Differences between groups were assessed by Mann–Whitney U test and Fisher’s exact test, and the relationship between prior head trauma and case/control status was analysed by multivariate logistic regression models. Results: No association was found between vault/maxillofacial trauma and cranial dystonia. Most reported traumas occurred several years before disease onset. None of the main post-traumatic sequelae altered the chance of developing cranial dystonia compared with patients with primary hemifacial spasm, nor did head trauma modify the age at onset of cranial dystonia. Conclusions: These results do not support prior head trauma as a possible environmental factor modifying the risk of developing late-onset cranial dystonia. The lack of association may have pathogenetic and medical–forensic implications.

No clinical or neurophysiological evidence of botulinum toxin diffusion to non-injected muscles in patients with hemifacial spasm.

Abstract: Botulinum toxin injected into a muscle may diffuse to nearby muscles thus producing unwanted effects. In patients with hemifacial spasm, we evaluated clinically and neurophysiologically, whether botulinum toxin type A (BoNT-A) diffuses from the injection site (orbicularis oculi) to untreated muscles (orbicularis oris, the affected side; and orbicularis oculi and oris; the unaffected side). We studied 38 patients with idiopathic hemifacial spasm. Botulinum toxin was injected into the affected orbicularis oculi muscle alone (at 3 standardized sites) at a clinically effective dose. Patients were studied before (T0) and 3-4 weeks after treatment (T1). We evaluated the clinical effects of botulinum toxin and muscle strength in the affected and unaffected muscles. We also assessed the peak-to-peak amplitude compound muscle action potential (CMAP) recorded from the orbicularis oculi and orbicularis oris muscles on both sides after supramaximal electrical stimulation of the facial nerve at the stylomastoid foramen. In all patients, botulinum toxin treatment reduced muscle spasms in the injected orbicularis oculi muscle and induced no muscle weakness in the other facial muscles. The CMAP amplitude significantly decreased in the injected orbicularis oculi muscle, but remained unchanged in the other facial muscles (orbicularis oris muscle on the affected side and contra-lateral unaffected muscles). In conclusion, in patients with hemifacial spasm, botulinum toxin, at a clinically effective dose, induces no clinical signs of diffusion and does not reduce the CMAP size in the nearby untreated orbicularis oris or contralateral facial muscles.

Drug Insight: new drugs in development for Parkinson's disease.

Abstract: For many years, levodopa has given most patients with Parkinson's disease excellent symptomatic benefit. This agent does not slow down the progression of the disease, however, and it can induce motor fluctuations and dyskinesias in the long term. The other available antiparkinsonian agents also have drawbacks, and as a consequence research into antiparkinsonian drugs is expected to take new and different directions in the coming years. The most promising approaches include the development of 'neuroprotective' drugs that are capable of blocking or at least slowing down the degenerative process that is responsible for cellular death; 'restorative' strategies intended to restore normal brain function; more-effective agents for replacing dopamine loss; and symptomatic and antidyskinetic drugs that act on neurotransmitters other than dopamine or target brain areas other than the striatum. In this Review, we discuss the numerous drugs in development that target the primary motor disorder in Parkinson's disease.