Genetic assessment of familial and early-onset Parkinson's disease in a Greek population.

BACKGROUND AND PURPOSE: Although the first mutation associated with Parkinson's disease (PD) was identified several years ago in the alpha-synuclein (SNCA) gene in families of Greek and Italian ancestry, a more systematic study of this and other known PD mutations has not been performed in the Greek population. METHODS: A genetic analysis in 111 familial or sporadic with early-onset (≤50 years, EO) PD patients was performed for the presence of the A53T SNCA mutation. In separate subgroups of these patients, further mutations in the SNCA, LRRK2, Parkin, PINK1 and DJ-1 genes were searched for. Additionally, a subgroup of familial cases was analysed for mutations in the glucocerebrosidase (GBA) gene. RESULTS: In total, five patients (4.5% of our whole population) were identified with the A53T SNCA mutation, two with a heterozygote dosage mutation and one with a heterozygote point mutation in the Parkin gene, and seven patients (10.3% of our familial cohort) with GBA gene mutations. CONCLUSIONS: The A53T mutation in the SNCA gene, although uncommon, does represent a cause of PD in the Greek population, especially of familial EOPD with autosomal dominant inheritance. GBA mutations in the familial cohort tested here were as common as in a cohort of sporadic cases previously examined from the same centres. For the remainder of the genes, genetic defects that could definitively account for the disease were not identified. These results suggest that further Mendelian traits that lead to PD in the Greek population remain to be identified.

Transcranial alternating current stimulation reduces symptoms in intractable idiopathic cervical dystonia: a case study.

Idiopathic cervical dystonia (ICD) is a movement disorder often resulting in profound disability and pain. Treatment options include oral medications or other invasive procedures, whereas intractable ICD has been shown to respond to invasive (deep) brain stimulation. In the present blinded, placebo-controlled case study, transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) has been applied to a 54-year old patient with intractable ICD. Results showed that 15 Hz tACS had both immediate and cumulative effects in dystonic symptom reduction, with a 54% reduction in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score, and a 75% in the TWSTRS Pain Scale. These effects were persistent at 30-days follow-up. This is the first report to demonstrate a significant and lasting therapeutic effect of non-invasive electrical brain stimulation in dystonia.

Current concepts on the mechanisms of dystonia and the beneficial effects of deep brain stimulation.

The application of lesioning procedures in the basal ganglia and, more recently, of deep brain stimulation (DBS) has revolutionalized dystonia treatment. However, our understanding of the mechanism of action of DBS is only minimal. This is largely due to a rudimentary understanding of dystonia pathophysiology itself, which in turn reflects an insufficient understanding of the functional significance of the cortico-striato-pallido-thalamocortical loops. The initial dystonia pathophysiology concept was one of changes in oscillation rate. Soon, it was realized that not only rate but also the pattern of basal ganglia activity is crucial in the etiology of the disease. The observations of altered somatosensory responsiveness and cortical neuroplasticity, along with the vast array of clinical phenotypes, imply the need for a wholistic neuronal pathophysiology model; one in which an underlying defect of basal ganglia function results in increased cortical excitability, misprocessing of sensory feedback, aberrant cortical plasticity, and ultimately clinical dystonia. This unified dystonia pathophysiology model, although simplistic, may provide the scaffold on which all incoming research and clinical data becomes united in a meaningful and practical way. In light of this model, the dramatic response of some forms of dystonia to pallidal stimulation, the time latency for the beneficial effect and even the presence of non-responders may be explained. Additionally, it may help in developing a rationale for more efficacious DBS programming, better selection of the timing of surgery, and more successful identification of those candidates that are most likely to respond to DBS.