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.

Transcranial sonography in dopa-responsive dystonia.

BACKGROUND AND PURPOSE: Mutations in the GCH1 gene, encoding GTP cyclohydrolase 1, the enzyme critically important for dopamine production in nigrostriatal neurons, are the most common cause of dopa-responsive dystonia (DRD), characterized predominantly by limb dystonia, although parkinsonian features may also be present. It has been suggested that DRD is a neurochemical rather than neurodegenerative disorder. METHODS: Transcranial brain sonography, which might be a risk marker for nigral injury, was obtained from 141 subjects divided into four groups: (i) 11 patients with genetically confirmed DRD; (ii) 55 consecutive patients with Parkinson's disease (PD); (iii) 30 patients diagnosed as isolated adult-onset focal dystonia; and (iv) 45 healthy controls (HCs). RESULTS: Substantia nigra hyperechogenicity was present in 63.6% of patients with DRD, which was significantly different in comparison to patients with dystonia (20%) and HCs (6.7%), but not in comparison to the PD group (87.3%). Also, values of the maximal areas of substantia nigra hyperechogenicity in patients with DRD were higher in comparison to HCs, but significantly lower than among the PD group. CONCLUSIONS: We suggested that the observed transcranial brain sonography features in patients with DRD might primarily be risk markers for particular clinical features (parkinsonism, dystonia) occurring in the specific genetic context (i.e. GCH1 mutations), or might reflect compensated neurodegenerative processes triggered by the long-lasting dopamine deficiency due to the profound delay in levodopa treatment in our patients with DRD.

Five-year study of quality of life in myotonic dystrophy.

Background - Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. There is a complete lack of studies that assessed quality of life (QoL) trajectory during time in DM1 cohorts. Aim - To analyze changes of QoL in patients with DM1 during a 5-year follow-up period and to assess responsiveness of the SF-36 questionnaire. Patients and Method - At the baseline, this study comprised 84 DM1 patients, of whom 62 were retested after the mean period of 64.2 ± 3.9 months. Severity of muscular weakness was assessed using the Muscular Impairment Rating Scale (MIRS). Patients completed Serbian version of the SF-36 questionnaire as a measure of health-related QoL. Results - After 5 years, MIRS score of our DM1 patients showed significant progression of 0.5 grade (P < 0.01). All mental subdomains, role physical, and total SF-36 scores significantly improved after 5 years (P < 0.01). Unexpectedly, worsening of muscular weakness from mild to severe was in association with improvement of QoL. Conclusion - QoL improved in our cohort of DM1 patients during a 5-year period despite the progression of the disease. SF-36 should be used with caution as a patient-reported outcome measure in DM1 clinical trials.

Comparison of temporal and stride characteristics in myotonic dystrophies type 1 and 2 during dual-task walking.

OBJECTIVE: We analyzed temporal and stride characteristics in patients with myotonic dystrophy type 1 (DM1) and type 2 (DM2) while performing dual mental and motor tasks, and investigated correlations between gait parameters and cognitive impairments. METHOD: Dual-task walking was performed by 37 patients (20 DM1 and 17 DM2) and 48 healthy subjects divided into two groups, age- and gender-matched control group for DM1 (HC1) and age- and gender-matched control group for DM2 (HC2). The subjects performed a basic walking task, dual-motor task, dual-mental task, and combined motor and mental task. RESULTS: DM1 and DM2 patients differed significantly in temporal and stride characteristics compared to HC. Main differences in DM1 were slower gait and shorter stride length, while both DM1 and DM2 patients had a higher degree of variation of the swing time during dual-task gait, a parameter that reflects posture and balance. Impact of the cognitive dual task on gait pattern changes was also observed. Visuospatial ability correlated with gait changes in DM1, while executive functions had stronger influence in DM2 (p<0.01). Both patient groups had leg muscle weakness. CONCLUSION: Gait pattern was impaired in both patient groups concerning temporal and stride characteristics. Dual-task walking paradigm may discover mild initial gait changes and could provide early identification of fall risks and predict possible falls in DM patients.

Significant impact of behavioral and cognitive impairment on quality of life in patients with myotonic dystrophy type 1.

OBJECTIVE: To assess an impact of cognitive and behavioral impairment on QoL in a larger cohort of patients with DM1. METHODS: Sixty six genetically confirmed DM1 patients (22 with juvenile (jDM1) and 44 with adult form (aDM1) of the disease) were recruited. Following behavioral tests were used: Hamilton scales for depression and anxiety (HamD and HamA), Daytime Sleepiness Scale (DSS), and Krupp's Fatigue Severity Scale (FSS). Patients also underwent detailed classic neuropsychological investigation and Cambridge Neuropsychological Test Automated Battery (CANTAB). Individualized Neuromuscular Quality of Life questionnaire (INQoL) was used as a measure of QoL. RESULTS: Patients with jDM1 scored lower than aDM1 patients regarding total INQoL score and all INQoL subdomains, except for myotonia. Significant predictors of total INQoL score in patients with jDM1 were severity of fatigue (ß=+0.60, p<0.01) and percentage of correct responses on Spatial Recognition Memory test from CANTAB that measures visuospatial abilities (ß=-0.38, p<0.05). The most important predictors of total INQoL score in patients with aDM1 were severity of fatigue (ß=+0.36, p<0.05) and level of education (ß=-0.29, p<0.05). CONCLUSION: Our results showed clear influence of different central manifestations on QoL in patients with both aDM1 and jDM1.

A novel Notch3 Gly89Cys mutation in a Serbian CADASIL family.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. We present a family from Serbia presenting with stroke and depression in the lack of vascular risk factors, with brain MRI indicating CADASIL. A novel NOTCH3 Gly89Cys mutation was located in exon 3. This report illustrates that in the setting of a positive family history with typical clinical and MRI features, even with an atypical form of pedigree, a high suspicion of CADASIL should lead to genetic testing.

HD phenocopies--possible role of Saitohin gene.

Saitohin (STH) is located in the intron of the human gene for microtubule-associated protein tau. Q7R polymorphism has been identified in the STH gene. Some neurodegenerative disorders were found to be associated with the presence of certain STH allele. This study genotyped 37 subjects with diagnosis of Huntington's disease, but lacking mutations in HD, PRNP, JPH-3, and FTL genes for STH polymorphism. It was determined that Q allele of STH gene was over-represented in a tested group of patients (P > Pt). Over-representation of Q allele in a group of patients might be considered as genetic risk factor for HD like diseases.

MECP2 mutations in Serbian Rett syndrome patients.

BACKGROUND: Rett syndrome is a severe neurodevelopmental X-linked dominant disorder affecting 1/15,000 girls worldwide. Eight years ago, the MECP2 gene was associated with the devastating clinical features observed in Rett syndrome patients. OBJECTIVES: To investigate the spectrum and the frequency of MECP2 mutations in Serbian Rett syndrome patients. PATIENTS AND METHODS: We screened the MECP2 coding region by conventional mutational screening (single-strand conformation polymorphism/sequencing) in 24 patients of Serbian origin and in their 41 unaffected family members. In search for gene dosage alterations in seemingly mutation-negative girls, we developed a new, specific quantitative PCR method. RESULTS: Nineteen patients (79%) carried MECP2 mutations, five of which were novel (one nonsense mutation, one duplication and three deletions). Fourteen previously described disease-causing sequence changes and one polymorphism were also detected. Detailed case reports are given for the carriers of the novel mutations. Large MECP2 rearrangements cause Rett syndrome in a significant number of girls without 'classic' mutations in this gene. Therefore, we developed a specific quantitative PCR method, covering MECP2 exons 3 and 4, which previously has not been used for screening. No dosage alterations of the two exons were found in the four tested mutation-negative girls. CONCLUSIONS: This is the first genetic study of Rett syndrome in Serbian patients describing the MECP2 mutational and phenotypic spectrum in this population. Detailed clinical descriptions of this ethnically homogeneous patient population add to our knowledge of genotype/phenotype correlations in this severe condition.