Identification of mutations in the PARK2 gene in Serbian patients with Parkinson's disease.

Mutations in the PARK2 (PRKN) gene are the most common cause of autosomal-recessive (AR) juvenile parkinsonism and young-onset Parkinson's disease (YOPD). >100 different variants have been reported, including point mutations, small indels and single or multiple exon copy number variations. Mutation screening of PARK2 was performed in 225 Serbian PD patients (143 males and 82 females) with disease onset before 50 years and/or positive family history with apparent AR inheritance. All coding regions and their flanking intronic sequences were amplified and directly sequenced. Whole exon multiplications or deletions were detected using Multiple Ligation Probe Amplification (MLPA) method. We identified 12 PD patients with PARK2 mutations (5.3%). Five patients (2.2%) had biallelic mutations and seven (3.1%) were single mutation carriers. Patients with compound heterozygous mutations had earlier onset of the disease compared to non-carriers (p = 0.005) or heterozygotes (p = 0.001). Other clinical features in mutation carriers were not different compared to non-carriers. In our cohort, sequence and dosage variants were equally represented in patients, inducing their first symptoms mainly before the age of 30. For efficient genetic testing strategy, patients with early, especially juvenile onset of PD were strong candidates for both dosage and sequence variants screening of PARK2 gene.

Glucocerebrosidase mutations in a Serbian Parkinson's disease population.

BACKGROUND AND PURPOSE: To screen for glucocerebrosidase (GBA) mutations in a Serbian Parkinson's disease (PD) population. METHODS: Glucocerebrosidase exons 8-11 harbouring the most common mutations were sequenced in 360 patients with PD and 348 controls from Serbia. Haplotype analysis was performed for the N370S mutation and compared with German and Ashkenazi Jewish carriers. RESULTS: Glucocerebrosidase mutations were significantly more frequent in patients with PD (21/360; 5.8%) vs. controls (5/348; 1.4%; OR = 4.25; CI, 1.58-11.40; P = 0.0041). Two patients with PD carried homozygous or compound heterozygous mutations in GBA. The N370S mutation accounted for about half of the mutated alleles in patients (10/23) but was absent amongst controls. Three novel variants were detected including two non-synonymous variants (D380V, N392S) in the patient group and one synonymous change (V459V) in a control. Carriers of the D409H mutation were also sequenced for H255Q, and all were found to carry the [D409H; H255Q] double-mutant allele. Genotyping suggested a common haplotype for all N370S carriers. CONCLUSION: Glucocerebrosidase mutations represent a PD risk factor in the Serbian population.

History of exposure to dopaminergic medication does not affect motor cortex plasticity and excitability in Parkinson's disease.

OBJECTIVE: Little is known whether and how chronic exposure to dopaminergic treatment alters physiological mechanisms in Parkinson's disease (PD). METHODS: Two clinically similar groups of PD patients, one consisting of drug-naïve patients and another of patients already on chronic dopaminergic medication (when off medication), were compared to each other and to a control group. Plasticity and excitability of the hand primary motor cortex of the more affected side were evaluated using transcranial magnetic stimulation (TMS) techniques. RESULTS: There was little difference between two patient groups, and both groups showed similar differences in comparison to controls: decreased facilitatory sensory-motor plasticity (as measured by paired associative stimulation [PAS] protocol), impaired short-interval intracortical inhibition (SICI), and diminished slope of input-output curves at higher TMS intensities. The exception was that 30 min after PAS, intracortical facilitation (ICF) was significantly reduced in drug-naïve patients, whereas it changed much less in other two groups. CONCLUSIONS: Chronic exposure to dopaminergic drugs does not affect substantially the features of motor cortex excitability and plasticity in PD. There is little interaction between plasticity and excitability features of motor cortex in PD. SIGNIFICANCE: Reduced response to facilitatory PAS protocol, reduced SICI, and reduced slope of the input-output curve at higher TMS pulse intensities, seem to be physiological markers for the presence of the pathological disease process in PD. Long term treatment does not seem to change the underlying physiology of the disease.

Long-term outcome in Serbian patients with Wilson disease.

BACKGROUND AND PURPOSE: To investigate survival rates, prognostic factors, and causes of death in Wilson disease (WD). METHODS: In the years 1980-2007, a cohort of 142 patients with WD was prospectively registered (54 presented with neurologic symptoms, 49 with hepatic symptoms, 33 had mixed form, and data were missing for six patients). The duration of follow-up for patients alive was 11.1 +/- 8.8 years. RESULTS: After initiation of treatment (d-penicillamine and zinc salts), 79% of patients had a stable or improved course of disease. Despite early diagnosis and appropriate therapy, 15 patients still had a relentlessly progressive course. Thirty patients died. The cumulative probability of survival in a 15-year period for the whole group was 76.7 +/- 4.9%. Better prognosis of WD was associated with male sex, younger age at onset, neurologic form of the disease, and treatment continuity. Causes of death were predominantly related to hepatic failure (16 patients), but also suicide (four patients) and cancer (three patients). CONCLUSION: Despite the relatively early diagnosis and treatment of our patients with WD, mortality was still considerably high.