Screening for the C9ORF72 expansion in Greek Huntington Disease phenocopies and controls and meta-analysis of current data.

Background: Several European studies examined the role of C9orf72 repeat expansion in patients with Huntington-disease like phenotypes (HD-L). The scope of our study is to investigate the expansion frequency in a Greek HD-L cohort and the meta-analysis of all published cases. This will be of use in genetic counseling of these cases. Methods: A cohort of 74 patients with HD-L and 67 healthy controls were screened for the C9orf72 expansion status. Case-controls comparison was assessed with the Pearson's chi-square statistic for a 2 × 2 table.A systematic database search was conducted and seven studies, including the current study, were considered eligible for inclusion in a meta-analysis considering a total of 812 patients with HD phenocopies. Pooled mutation frequency was calculated using a Random Effects model or the Mantel-Haezsel fixed effects model, depending on the observed heterogeneity. Results: In our cohort, one patient was found to have a pathologic expansion of C9orf72, and none from the control group (chi-square: 0.91, p-value: 0.34). Pooled mutation frequency was found at 2% (CI: 1-3%) with low heterogeneity (I2:15%). Discussion: Based on this meta-analysis the recommendation for genetic testing for C9orf72 expansions is further solidified.

Psychological distress, personality traits and functional disability in patients with osteonecrosis of the femoral head.

BACKGROUND: The aim of the present study was to investigate personality traits, psychological distress and functional disability in patients with non-traumatic osteonecrosis of the femoral head (ONFH). METHODS: Sixty-seven patients participated in the study, 48 males and 19 females. The mean age was 37.6 years (SD: 10.92, range: 15 - 61). Seventy-five healthy individuals, age and sex matched, served as controls. Socio-demographic information and clinical data were collected. The following instruments were used: the General Health Questionnaire (GHQ-28), the Defence Style Questionnaire (DSQ) and the World Health Organization Disability Assessment Schedule II (WHO-DAS II). RESULTS: Patients suffering from ONFH presented higher scores at the GHQ-28 compared to healthy controls (P < 0.001). Duration of disease (P < 0.047) and age (P < 0.023) were the main factors associated with psychological distress (P < 0.003). Personality traits such as image distorting (P < 0.025) and self-sacrificing (P < 0.029) were identified in patients with ONFH compared to healthy controls. Functional disability was associated with high scores at GHQ-28 scale (P < 0.001). The "adaptive personality structure", as measured by DSQ was negatively associated with functional impairment (P < 0.022). CONCLUSIONS: Patients with ONFH more commonly present symptoms of psychological distress associated with distinct functional clinical parameters. The present study also reveals the role of personality traits. Further investigation could specify the possible influence of psychopathology and personality traits or coping strategies on the course of disease.

Randomized trials of dopamine agonists in restless legs syndrome: a systematic review, quality assessment, and meta-analysis.

BACKGROUND: The use of dopamine agonists (DAs) for the treatment of restless legs syndrome (RLS) has been assessed in numerous randomized clinical trials (RCTs). OBJECTIVES: The aims of this study were to assess the reporting quality of published RCTs according to the Consolidated Standards of Reporting Trials (CONSORT) statement and to synthesize the study results in terms of efficacy and tolerability to inform the clinical management of RLS. METHODS: PubMed and Cochrane Controlled Trials Register were searched for English-language RCTs that assessed the effects of DAs in RLS. Quality of reporting was measured using the proportion of 17 CONSORT checklist items included in each study. The 2 primary outcomes were pooled mean change from baseline in International RLS (IRLS) Study Group rating scale score (Deltamu) (95% CI) and relative risk (RR) (95% CI) of response based on the Clinical Global Impression-Improvement (CGI-I) scale score. The pooled proportions of adverse events (PAEs) (95% CI) were also estimated. RESULTS: Eighteen RCTs (N = 2848 patients) were included. Two of the 17 CONSORT checklist items were reported in 7 studies (39%) and 9 of the 17 items were reported in all 18 studies (100%). The differences in the IRLS scores and RR for CGI-I were significantly greater with pramipexole, ropinirole, rotigotine, and cabergoline compared with placebo. Results for heterogeneity were nonsignificant. The difference in Deltamu (95% CI) was significant with pramipexole (-6.63 [-9.15 to -4.10]) versus ropinirole (-3.64 [-4.76 to 2.51]) (P = 0.04). The difference between pramipexole and rotigotine was nonsignificant. The pooled PAEs (95% CI) for pramipexole, ropinirole, and rotigotine were 4.8% (2.0% to 8.7%), 10.2% (2.6% to 22.1%), and 7.6% (1.3% to 18.5%), respectively. In the trial of sumanirole, the PAE value was 2% (0% to 5.4%). CONCLUSION: Based on the findings from the meta-analysis, DAs were significantly more efficacious in the treatment of RLS compared with placebo.

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset.

Parkinson's disease (PD), a common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and their terminations in the basal ganglia, is thought to be related to genetic and environmental factors. Although the pathophysiology of PD neurodegeneration remains unclear, protein misfolding, mitochondrial abnormalities, glutamate dysfunction and/or oxidative stress have been implicated. In this study, we report that a rare T1492G variant in GLUD2, an X-linked gene encoding a glutamate dehydrogenase (a mitochondrial enzyme central to glutamate metabolism) that is expressed in brain (hGDH2), interacted significantly with age at PD onset in Caucasian populations. Individuals hemizygous for this GLUD2 coding change that results in substitution of Ala for Ser445 in the regulatory domain of hGDH2 developed PD 6-13 years earlier than did subjects with other genotypes in two independent Greek PD groups and one North American PD cohort. However, this effect was not present in female PD patients who were heterozygous for the DNA change. The variant enzyme, obtained by substitution of Ala for Ser445, showed an enhanced basal activity that was resistant to GTP inhibition but markedly sensitive to modification by estrogens. Thus, a gain-of-function rare polymorphism in hGDH2 hastens the onset of PD in hemizygous subjects, probably by damaging nigral cells through enhanced glutamate oxidative dehydrogenation. The lack of effect in female heterozygous PD patients could be related to a modification of the overactive variant enzyme by estrogens.

Lack of evidence for a genetic association between FGF20 and Parkinson's disease in Finnish and Greek patients.

BACKGROUND: Fibroblast growth factor 20 (FGF20) is a neurotrophic factor preferentially expressed in the substantia nigra of rat brain and could be involved in dopaminergic neurons survival. Recently, a strong genetic association has been found between FGF20 gene and the risk of suffering from Parkinson's disease (PD). Our aim was to replicate this association in two independent populations. METHODS: Allelic, genotypic, and haplotype frequencies of four biallelic polymorphisms were assessed in 151 sporadic PD cases and 186 controls from Greece, and 144 sporadic PD patients and 135 controls from Finland. RESULTS: No association was found in any of the populations studied. CONCLUSION: Taken together, these findings suggest that common genetic variants in FGF20 are not a risk factor for PD in, at least, some European populations.

Depressive symptoms in Alzheimer's disease: natural course and temporal relation to function and cognitive status.

OBJECTIVES: To examine the natural course of depressive symptoms in patients with probable Alzheimer's disease (AD), specifically, the temporal relationship between depressive symptoms, function, and cognitive status. DESIGN: Multicenter cohort study with follow-up of up to 14 years. SETTING: Patients from the two Multicenter Study of Predictors of Disease Course in Alzheimer's Disease (Predictors Study) cohorts were recruited at five sites in the United States and Europe. PARTICIPANTS: Patients diagnosed with probable AD (n=536) enrolled in a longitudinal study (Predictors Study). MEASUREMENTS: Depressive symptoms were evaluated at 6-month intervals using the Columbia Scale for Psychopathology in Alzheimer's Disease. The Modified Mini-Mental State (3MS) and Blessed Dementia Rating Scale (BDRS) were used to assess cognitive status and functional activity, respectively. RESULTS: The prevalence of depressive symptoms was stable over the first 3 years of follow-up, at approximately 40%. There was a significant drop to 28% and 24% in the fourth and fifth years of follow-up, respectively. Time-dependent Cox analysis revealed that functional activity (BDRS) but not cognitive status (3MS) was a significant predictor of the first episode of depressive symptoms during follow-up. Generalized estimating equation analyses showed that AD duration and functional activity but not cognitive status were significantly related to depressive symptoms over the entire follow-up period. CONCLUSION: Depressive symptoms are common in AD, but their prevalence decreases over time. Examination of the temporal relationship between depressive symptoms and risk factors suggests that decline in function but not in cognition precedes the first episode of depressive symptoms in patients with probable AD.

A new mitochondrial DNA mutation in ND3 gene causing severe Leigh syndrome with early lethality.

We describe a new mitochondrial DNA mutation in a male infant who presented clinical and magnetic resonance imaging features of Leigh syndrome and died at the age of 9 mo. The patient's development was reportedly normal in the first months of life. At the age of 5 mo, he presented severe generalized hypotonia, nystagmus, and absent eye contact. Laboratory examination showed increased lactate and pyruvate in both serum and cerebrospinal fluid. Brain magnetic resonance imaging revealed multiple necrotic lesions in the basal ganglia, brain stem, and thalamus. Muscle histopathology was unremarkable, whereas respiratory chain enzyme analysis revealed a severe complex I deficiency. The patient died after an acidotic coma at age 9 mo. Sequence analysis of the entire mtDNA disclosed a new T10158C mutation with variable tissue heteroplasm (muscle: 83%; blood: 48%). The mutation was undetectable in the blood of his unaffected mother. The transition changes a serine residue into a proline, in a highly conserved region of the NADH dehydrogenase subunit 3 (ND3). This is the first description of a mitochondrial ND3 gene in Leigh syndrome with early lethality.