A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.

Evaluation of (99m)Tc-TRODAT-1 SPECT in the diagnosis of Parkinson's disease versus other progressive movement disorders.

OBJECTIVE: Parkinson disease (PD), parkinsonian syndromes (PS) and essential tremor (ET) are different types of movement disorders which share some symptoms resulting in a difficulty of certain diagnosis. This study was conducted to determine the value of (99m)Tc-TRODAT-1 scan to differentiate PD from ET and other PS cases. METHODS: Totally, 75 patients were studied including 29 PD, 6 possible PD, 22 ET and 18 PS cases. A dual-head SPECT-CT was used to perform basal ganglia (BG) imaging following administration of (99m)Tc-TRODAT-1. The BG uptake values were normalized to whole brain and occipital activity. All patients were followed for 2-22 months to reach a certain diagnosis. RESULTS: Patients with ET and drug-induced parkinsonism show significantly higher normalized BG uptake as compared to the other subgroups; however, no significant difference was noted between PD and PS patients. The sensitivity and specificity of the findings for the differentiation between patients with the disease associated versus not associated with BG dysfunction were 80 and 83.3%, respectively. A predictive positive value of 82.6% was obtained using an additive scaling index defined as asymmetry and unevenness of uptake in putamen and/or caudate contralateral to the dominant side of current symptoms. CONCLUSIONS: (99m)Tc-TRODAT-1 scan is an appropriate method to differentiate PD or PS versus ET. A combination of scan pattern including asymmetry of BG uptake and unevenness of activity in caudate and putamen along with the side of dominant symptoms may be valuable for the differentiation of Parkinson's disease from the other parkinsonian syndromes.

Assessment of nutritional status in patients with Parkinson's disease and its relationship with severity of the disease.

Background: Malnutrition, loss of body weight, muscle and fat mass wasting are common in patients with Parkinson's disease, and are associated with disability, longer length of hospital stay, impaired immune system and increased risk of mortality. The aim of this study was to assess the nutritional status in patients with Parkinson's disease and its relation to the severity of the disease. Methods: This cross- sectional study was conducted on 130 patients with Parkinson's disease, with a mean (SD) age of 59.1 (12.9) years in disease stages of 1 to 4. In this study, the Mini Nutritional Assessment (MNA) questionnaire was used along with anthropometric measurements (Body Mass Index (BMI), Mid-arm circumference (MAC), Calf Circumference (CC)) to evaluate the nutritional status, and they were applied by a trained nutritionist. Hoehn and Yahr Scale were used to determine the severity of the disease. One-way ANOVA test was used to assess the relationship between anthropometric indices, nutritional status and severity of disease. Assessment of the relationship between age, duration of disease and nutritional status was categorized according to MNA score, and was performed, using one-way ANOVA. Chi - Square test was utilized to assess the relationship between education level and nutritional status. SPSS Version 18 was used for data analysis. Results: In this study, 30% (n=39) of the participants were diagnosed with normal nutritional status, 58.5% (n=76) were at risk of malnutrition and 11.5% (n=15) were malnourished according to MNA. Reduction of weight, and muscle mass wasting was observed in different disease stages. Muscle mass wasting and worsening nutritional status, based on MNA score, showed a significant increase as the disease progressed, MAC (p=0.009), MNA score (p<0.001). After assessing the relationship between education level, age, duration of disease with nutritional status, the results revealed a significant relationship between age (p=0.008), education level (p<0.001) with nutritional status according to MNA score. Conclusion: Reduction of BMI, depletion of muscle mass, and worsening of nutritional status according to MNA, was observed in many patients along with an increase in the severity of the disease. Assessing nutritional status in those with Parkinson's disease to provide information to identify necessary nutritional intervention is highly recommended.

Detection of copy number changes in genes associated with Parkinson's disease in Iranian patients.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, after Alzheimer's disease. Genomic rearrangements are common mutations reported in PD patients. In this study, we investigated the prevalence of genomic rearrangements in a total of 232 Iranian PD patients, out of which 102 were sporadic early-onset (age-at-onset ≤ 45 years) and 51 had a family history. We used multiplex ligation-dependent probe amplification (MLPA) method to detect exon dosage changes. Two new improved probe kits, SALSA P051 and P052, were used and altogether α-synuclein, parkin, UCHL1, PINK1, DJ-1, LRRK2, GCH1, ATP13A2, CAV1, CAV2, LPA and TNFRSF9 genes were analyzed. Exon or whole-gene rearrangements were identified in 14 (13.7%) sporadic early-onset PD patients in parkin, α-synuclein and PINK1. Of familial PD patients 46 cases from 18 families (35.3%) showed exon or whole-gene rearrangements in parkin, α-synuclein, PINK1, DJ-1, and ATP13A2 genes. All changes were verified by quantitative PCR (qPCR). Novel mutations and unusual clinical features are reported in this study. Mutations in parkin were the predominant genetic cause in both early-onset and familial PD groups. Also the mutations observed in family PD group are more in number and diversity than the sporadic early-onset PD group.

Biased homozygous haplotypes across the human caveolin 1 upstream purine complex in Parkinson's disease.

The alpha-synuclein-caveolin 1 axis is suggested to be of role in the pathogenesis of Parkinson's disease in cell line models. The objective of this study was to analyze the homozygous haplotype compartment of the human caveolin 1 gene upstream purine complex in patients afflicted with Parkinson's disease. This complex was screened in patients with Parkinson's disease (n = 141) and compared with a group of controls (n = 760) using polymerase chain reaction and sequencing. The expression activity of the homozygous haplotypes was then examined using luciferase Dual-Glo system in human neuronal cell line, LAN-5. Six haplotypes were found to be homozygous in the patients, and not in the control pool (Fisher exact p < 1 × 10(-6)). Three of those haplotypes were specific to Parkinson's disease (Fisher exact p < 0.002), and the remaining three overlapped with homozygous haplotypes in Alzheimer's disease and multiple sclerosis (Fisher exact p < 0.002). The disease haplotypes contained motif lengths that were nonexistent in the control homozygous haplotype pool and significantly increased gene expression (p < 9 × 10(-6)). We conclude that skew in the caveolin 1 purine complex homozygous haplotype compartment and an additive effect of those haplotypes may be linked with Parkinson's disease.