Search

BACKGROUND Differences have been noted in the clinical presentation and mutational spectrum of CADASIL among various geographical areas. The aim of the present study was to investigate the mode of clinical presentation and genetic mutations reported in Greece. METHODS After a systematic literature search, we performed a pooled analysis of all published CADASIL cases from Greece. RESULTS We identified 14 studies that reported data from 14 families comprising 54 patients. Migraine with aura was reported in 39%, ischemic cerebrovascular diseases in 68%, behavioral-psychiatric symptoms in 47% and cognitive decline in 60% of the patients. The mean (±SD) age of onset for migraine with aura, ischemic cerebrovascular diseases, behavioral-psychiatric symptoms and cognitive decline was 26.2 ± 8.7, 49.3 ± 14.6, 47.9 ± 9.4 and 42.9 ± 10.3, respectively; the mean age at disease onset and death was 34.6 ± 12.1 and 60.2 ± 11.2 years. With respect to reported mutations, mutations in exon 4 were the most frequently reported (61.5% of all families), with the R169C mutation being the most common (30.8% of all families and 50% of exon 4 mutations), followed by R182C mutation (15.4% of all families and 25% of exon 4 mutations). CONCLUSIONS The clinical presentation of CADASIL in Greece is in accordance with the phenotype encountered in Caucasian populations, but differs from the Asian phenotype, which is characterized by a lower prevalence of migraine and psychiatric symptoms. The genotype of Greek CADASIL pedigrees is similar to that of British pedigrees, exhibiting a high prevalence of exon 4 mutations, but differs from Italian and Asian populations, where mutations in exon 11 are frequently encountered.

BACKGROUND A decrease in glutathione (GSH) levels is considered one of the earliest biochemical changes in Parkinson's disease (PD). OBJECTIVE The authors explored the potential role of plasma GSH as a risk/susceptibility biomarker for prodromal PD (pPD) by examining its longitudinal associations with pPD probability trajectories. METHODS A total of 405 community-dwelling participants (median age [interquartile range] = 73.2 [7.41] years) without clinical features of parkinsonism were followed for a mean (standard deviation) of 3.0 (0.9) years. RESULTS A 1 μmol/L increase in plasma GSH was associated with 0.4% (95% confidence interval [CI], 0.1%-0.7%; P = 0.017) less increase in pPD probability for 1 year of follow-up. Compared with participants in the lowest GSH tertile, participants in the highest GSH tertile had a 12.9% (95% CI, 22.4%-2.2%; P = 0.020) slower rate of increase of pPD probability for 1 year of follow-up. CONCLUSION Plasma GSH was associated with pPD probability trajectories; therefore, it might assist in the identification of individuals who are likely to reach the threshold for pPD diagnosis more rapidly. © 2021 International Parkinson and Movement Disorder Society.

Background Small vessel disease (SVD), and most specifically hereditary forms like CADASIL and cerebral amyloid angiopathy (hCAA), are conditions of increasing clinical importance. We report a rare case of hCAA in a Greek family that presented with a CADASIL clinical and neuroimaging phenotype. Methods A 65-year-old man was admitted with recurrent transient episodes of right leg numbness. The patient's medical history started at the age of 50 years with depression and behavioral disorders. His family history was positive for stroke (father), dementia (father and brother), migraine (daughter) and depression (father and daughter). Results Neurological examination disclosed anomic aphasia with severely impaired cognitive status, and brisk reflexes. Brain computed tomography and magnetic resonance imaging showed CADASIL-like leukoencephalopathy (hyperintense lesions in bilateral temporopolar area, external capsule, thalami, centrum semiovale and superior frontal regions) with occipital calcifications and cerebral microbleeds. Screen for variants in NOTCH3 gene was negative. Exome sequencing revealed a novel pathogenic mutation for hCAA. Conclusions We report a novel amyloid precursor protein mutation which results in a CADASIL-like clinical phenotype (progressive cognitive and motor decline, stroke, migraine and behavioral disorders) and CADASIL-leukoencephalopathy coupled with occipital calcifications. Earlier recognition and swift hCAA diagnosis may prompt rational preventive and potential disease-modifying interventions.

BackgroundMortality due to Parkinson's disease (PD) and its long-term trends worldwide in recent decades remain unknown. No previous studies have simultaneously studied age- and sex-specific mortality trends at a population level worldwide. Insights gained from this study can help identify high-risk populations and inform healthcare service requirements for managing Parkinson's disease globally.ObjectivesThe aim of the study was to examine trends in mortality from Parkinson's disease by age-group and sex across countries all over the world. In this study, we used worldwide registry data to examine the temporal trends in PD mortality across most counties of the world from 1994 to 2019 using joinpoint regression.ResultsIn data from vital registration systems, huge variations in the patterns of deaths due to Parkinson's disease were observed both over time and between countries. Between 1994 and 2019, there was a significant increase in mortality rates globally in both men and women. In more detail, the mortality rate (per 100,000) in 1994 was 1.76 and reached 5.67 in 2019. Greater increases in mortality were seen in men than in women; and in older than in younger people.ConclusionsThere has been a striking rising trend in Parkinson's disease mortality globally. Persistent age and sex disparities are found in Parkinson's disease mortality trends. Our findings may have important implications for future research, healthcare planning, and provision.

White matter hyperintensities (WMHs) may be observed on Magnetic Resonance Imaging (MRI) in patients with Parkinson disease with or without vascular risk factors. Whether WMHs may influence motor and non-motor aspects of Parkinson disease is a subject of debate. The aim of this study is to evaluate the impact of WMH severity on various aspects of Parkinson disease in combination to the estimation of the impact of cerebrovascular risk factors. We included a cohort of patients with Parkinson’s disease who underwent MRI examination. The Fazekas visual rating scale was used to assess the severity and location of WMHs, and patient clinical characteristics were correlated with MRI data. All vascular risk factors were associated with higher Fazekas score in both periventricular and deep white matter. Periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) were associated with lower scores in the ACE-R cognitive assessment scale (p < 0.001). Furthermore, PWMHs and DWMHs severity was associated with higher UPDRS motor score (p < 0.001), while the Postural Instability Gait Difficulty (PIGD) phenotype was correlated with higher burden of WMHs. Comorbid WMHs may contribute to multi-dimension dysfunction in patients with Parkinson disease and consequently the management of vascular risk factors may be crucial to maintain motor and non-motor functions in PD.

A total of 178 consecutive patients with definite sALS without frontotemporal dementia (FTD) were enrolled in this study, after complete clinical evaluation. A Repeat-Primed Polymerase Chain Reacti...

Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson’s disease and Parkinson’s disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.G379W) variant in SORL1 which segregated with the disease in the family. Mutation screening in sporadic Greek PD cases identified one additional individual with the mutation, sharing the same 12.8Mb haplotype. Our findings provide support for SORL1 mutations resulting in a broad range of additional phenotypes and warrants further studies in neurodegenerative diseases beyond AD.

Introduction Some case series have suggested that psychotic features could occur even before the onset of motor symptoms of Parkinson's Disease (PD). Our aim was to investigate a possible association between psychotic symptoms and prodromal Parkinson's disease in a population-based cohort, the Hellenic Longitudinal Investigation of Aging and Diet study. Methods This cross-sectional study included participants aged ≥65 years without dementia or PD. We defined psychotic symptoms as the presence of at least one new hallucinatory or delusional feature, assessed with the Neuropsychiatric Inventory scale and the Columbia University Scale for Psychopathology in Alzheimer's Disease, exhibited only at follow-up and not present at baseline visit. We calculated the probability of prodromal PD (pPD) for every participant, according to the 2019 International Parkinson and Movement Disorders Society research criteria for prodromal PD. Results Participants who developed psychotic manifestations over a three-year follow up (20 of 914) had 1.3 times higher probability of pPD score (β [95%CI]: 1.3 [0.9-1.5], p=0.006) compared to non-psychotic subjects. This association was driven mostly by depressive symptoms, constipation and subthreshold parkinsonism (p Conclusion Our data indicate that emerging psychotic features evolve in parallel with the probability of pPD. This is the first study that provides evidence for the presence of psychotic experiences in pPD. The association detected needs to be confirmed in longitudinal studies.

Guillain-Barre syndrome (GBS) is the most common cause of acute flaccid paralysis and its incidence increases with age, although all age groups can be affected. The cranial subtypes of GBS account for approximately 5% of cases. Posterior reversible encephalopathy syndrome (PRES) is an acute neurological disorder, mostly reversible but with increased morbidity with permanent neurological sequelae in severe cases. The coexistence of these two syndromes is very rare and underdiagnosed. To the best of our knowledge, there are several dozen cases reported in the literature including ours with the coexistence of these two syndromes in adult patients. We present a rare case of oculopharyngeal type of GBS followed by PRES syndrome. Based on the reviewed cases we discuss various pathogenic mechanisms that support the association between these two entities. This review illustrates the importance of detecting PRES syndrome in the context of acute inflammatory immune-mediated polyneuropathies especially when the patients present early dysautonomia. We also discuss the importance of early administration of immunoglobulin (IVIG) treatment but the possible risks that poses to the occurrence of PRES syndrome as well.

To present the new guidelines and therapeutic options regarding cerebrovascular complications of cancer, mainly ischemic stroke, cerebral venous thrombosis (CVT), and leptomeningeal carcinomatosis (LMC). A temporal trend study (2019) revealed that clinicians are still reluctant to apply thrombolysis to cancer patients, although two new studies (2018) reported no increased mortality. Several clinical trials on direct oral anticoagulants (DOACs) showed their superiority or, at least, non-inferiority compared with low molecular weight heparins in the treatment of venous thromboembolism (VTE) (2018–2019). These trials helped in formulating the new guidelines that are being published and the decisions made for cancer-associated thrombosis (CAT) as a whole. A new DOAC antidote was also officially released (US 2018, Europe 2019). Thrombolysis is safe in a malignancy setting, thus cancer per se should not be considered a contraindication for thrombolysis. Clinical trials assessing the newest DOACs for cancer-associated arterial thrombosis are scarce; however, based on data from VTE studies, the newest DOACs seem to be safe for CAT in patients that are not in high risk of bleeding or suffering from certain malignancies. The treatment should not be ceased after 6 months, but rather continued as long as the cancer remains active. Decompressive craniectomy should maintain its place in patients with CVST in risk of herniation. Last, the future also holds much promise on the role of novel compounds to be used in LMC.

Objective The objective of this study was to validate the recently updated research criteria for prodromal Parkinson's disease (pPD) proposed by the International Parkinson's Disease and Movement Disorders Society. Methods A total of 16 of 21 markers of pPD were ascertained in the Hellenic Longitudinal Investigation of Aging and Diet cohort composed of community-dwelling individuals aged ≥65 years. The probability of pPD was calculated for 961 individuals without Parkinson's disease (PD) or dementia with Lewy bodies at baseline who were followed-up for a median of 3 years. The ability of the criteria to predict conversion to PD/dementia with Lewy bodies was assessed by estimating their sensitivity and specificity, plotting receiver operating characteristics curves, and using logistic regression. These analyses were repeated using the original criteria. Results No incident PD/dementia with Lewy bodies case had probable pPD at baseline (ie, ≥80% pPD probability). At cut-offs of 10%, 30%, and 50% probability of pPD, the sensitivity and specificity of the criteria ranged from 4.5% to 27.3%, and 85.7% to 98.3% respectively. The area under the receiver operating characteristics curve was 0.691 (95% confidence intervals, 0.605-0.777). In logistic regression models, the criteria-derived posttest odds of pPD were a significant predictor of conversion at follow-up. The updated criteria performed similarly to the original but showed a slight increase in sensitivity. Conclusions The new criteria demonstrated suboptimal sensitivity in our random sample of community-dwelling individuals. The absence of specialized assessments with high likelihood ratios in our cohort could be hindering the demonstration of higher sensitivities. Such assessments should be a part of future validation attempts. © 2020 International Parkinson and Movement Disorder Society.

A 67-year-old male photographer who used traditional cameras that necessitated monocular focusing developed intermittent blepharospasms, evident only during and shortly after the voluntary contraction of the left eyelids while using the camera, a form of a task-specific blepharospasm. The spasms gradually progressed to involve the entire hemiface resulting in a task-specific hemifacial spasm that eventually evolved into a persistent hemifacial spasm. Our case report highlights the fact that focal dystonia may also develop in the facial muscles following chronic and repetitive muscle contractions, such as those performed by an older photographer who used traditional cameras that necessitated monocular focusing. To our knowledge, hemifacial spasm has not yet been recognized as a form of focal, task-specific dystonia. Moreover, occupational, focal dystonia has not been described in photographers.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

A pathologic expansion of a noncoding GGGGCC hexanucleotide repeat of the C9orf72 gene has been strongly associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) cases predominantly in Caucasian populations. In the last decade, scientific interest had been drawn to this gene and many studies conducted have shown a possible correlation with other neurodegenerative diseases as well. We performed an extensive literature search for C9orf72 mutation and its frequency in various neurological and psychiatric diseases. In addition, we performed a meta-analysis of the data related to ALS and familial ALS. An online cloud-based database and an interactive map were developed. The overall mutation frequency of C9orf72 is 20% for familial FTD, 16% for familial ALS and around 6%–8% for sporadic ALS and FTD. The updated meta-analysis that we performed showed that the pooled frequency of C9orf72 repeat expansion in patients with familial ALS was 23% (CI: 18%–28%) and in patients with sporadic ALS 3% (CI: 3%–4%). The subgroup analysis regarding the origin of the population revealed significant differences between Caucasian and Asian patients. Our analysis supports the direct causal relation of the C9orf72 expansion in ALS and FTD. On the contrary, the role of C9orf72 in other neurodegenerative disorders remains controversial. The system that we developed—the online database and the interactive map—is hopefully a stepping stone for an ever-growing platform that will aid scientists from all over the world in contributing to the meta-analysis of C9orf72-related publications.

Introduction Fahr’s syndrome due to hypoparathyroidism refers to bilateral basal ganglia (BG) calcifications and manifests with movement disorders, seizures, cognitive and behavioral symptoms. Case presentation We report a case of a 74-year-old woman, who presented with parkinsonism due to post-surgical hypoparathyroidism and normal DaT scan, despite extensive calcifications of the BG, periventricular white matter, and cerebellum. Methods A comprehensive literature review of all reported cases of Fahr’s syndrome due to hypoparathyroidism was conducted in the electronic databases PubMed and Web of science. Moreover, demographic and clinical characteristics of the patients overall were calculated and associated with radiological findings. Results We reviewed a total of 223 cases with Fahr’s syndrome due to hypoparathyroidism (124 female, 99 male). Mean age on presentation was 44.6 ± 17.7 years. Thirty nine percent of patients had idiopathic hypoparathyroidism, 35.4 % acquired and 25.6 % pseudohypoparathyroidism. Almost half of the patients had tetany, seizures or a movement disorder and approximately 40 % neuropsychiatric symptoms. The patients with a movement disorder had a 2.23 likelihood of having neuropsychiatric symptoms as well (OR 2.23, 95 % CI 1.29–3.87). Moreover, there was a statistically significant association between the phenotype severity (i.e. the presence of more than one symptom) and the extent of brain calcifications (χ2 = 32.383, p = 0.009). Conclusion Fahr’s syndrome is a rare disorder, which nonetheless manifests with several neurological symptoms. A head CT should be considered for patients with hypoparathyroidism and neurological symptoms. More studies using DaT scan are needed to elucidate the effects of calcifications on the dopaminergic function of the BG.

It is critical that Randomized Controlled Trials(RCTs) present complete and transparent reporting. The present study aims to determine the reporting quality of double-blind RCTs for medicinal interventions in patients with ischemic stroke, based on the 2010 CONSORT-statement.MEDLINE was comprehensively searched. The CONSORT period was demarcated between 2000 and 2019, while compliance ≥75 was defined as good-adequate. Possible determinants were univariately and multivariately examined for associations.Overall, 197 articles were considered eligible, 143 published after and 54 before 2000. CONSORT compliance was 68.11% ± 11.56% (standard deviation) and 55.65% ± 11.57% respectively. Among retrieved articles 56/143(39.16%) and 1/54(1.85%) were rated as of good reporting quality correspondingly [p .001, OR = 34.115, 95%CI = (4.586, 253.762)]. McNemar's test was indicative of consistency regarding the adequately/inadequately reported items before and after the 2010 CONSORT-revision (p = 1.00). Univariate analysis revealed two significant associations with the reporting quality: high impact factor(IF) [high vs. moderate; p = .007, OR = 3.521, 95%CI = (1.396, 8.879), high vs. low; p .001, OR = 7.583, 95%CI = (3.063, 18.762), moderate vs. low; p = .078, OR = 2.154, 95%CI = (0.911, 5.093)] and sample size [p .001, OR = 4.297, 95%CI = (2.081, 8.874)]. Publication period (p = .742) and funding (p = .280) were not significantly associated. Multivariate analysis attenuated the impact of sample size providing insignificant results, whereas the effect of high IF remained significant [moderate vs. high; p = .029, OR = 0.337, 95%CI = (0.127, 0.895), low vs. high; p = .012, OR = 0.199, 95%CI = (0.057, 0.699)]. An exploratory analysis demonstrated significant, weak to moderate, positive linear correlation between reporting quality and IF [Pearson's r = 0.418, p .001].Adherence to the CONSORT-statement needs to be further endorsed and incorporated in every journal's instructions-to-authors.

ObjectiveThe aim of this study was to evaluate the correlation between the various NOTCH3 mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient.MethodsHere, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed an extensive literature research for NOTCH3 mutations published since the identification of the gene and performed a systematic review of all published cases with NOTCH3 mutations. We evaluated the mutation pathogenicity in a great number of patients with detailed clinical and genetic evaluation and investigated the possible phenotype-genotype correlations.ResultsOur patient harbored a novel mutation in the NOTCH3 gene, the c.3084 G > C, corresponding to the aminoacidic substitution p.Trp1028Cys, presenting with seizures as the first neurologic manifestation. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age at onset of CADASIL. Significant differences were also identified between men and women regarding the phenotype severity.ConclusionsThe collection and analysis of these scarce data published since the identification of NOTCH3 qualitatively by means of a systematic review and quantitatively regarding genetic profile and pathogenicity scores, highlight the significance of the ongoing trend of investigating phenotypic genotypic correlations.

Background Thyrotoxic periodic paralysis (TPP) is an uncommon complication of Graves' disease, characterized by the triad of acute hypokalemia without total body potassium deficit, episodic muscle paralysis, and thyrotoxicosis. Graves' encephalopathy is an extremely rare form of encephalopathy associated with autoimmune thyroid disease (EAATD), characterized by neuropsychiatric symptoms, increased antithyroid antibodies and cerebrospinal fluid protein concentration, nonspecific electroencephalogram abnormalities, and cortico-responsiveness. Coexistence of both these complications in the same patient has not been reported before. Case report We herein present a 48-year-old white male patient with TPP and encephalopathy as initial presentations of Graves' disease. Flaccid tetraparesis was reversed a few hours after potassium level correction and the patient did not suffer any relapse with the successful pharmaceutical management of the thyroid function. One month later, the patient presented with dizziness and behavioral symptoms, such as inappropriate laughter and anger. Brain magnetic resonance imaging revealed meningeal enhancement and cerebrospinal fluid analysis showed a mild protein increase, with a blood-brain barrier disruption. With the suspicion of EAATD, the patient was treated with high doses of corticosteroids and improved dramatically. Conclusions To our knowledge this is the first reported coexistence of potentially treatable TPP and EAATD as initial neurological manifestations of Graves' disease, thereby underscoring the necessity of suspicion of possible underlying Graves' disease in patients with acute paralysis and encephalopathy of unclear origin.

The syndrome of deafness-dystonia is rare and refers to the association of hearing impairment and dystonia when these are dominant features of a disease. Known genetic causes include Mohr-Tranebjaerg syndrome, Woodhouse-Sakati syndrome, and mitochondrial disorders, but the cause frequently remains unidentified. The aim of the current study was to better characterize etiological and clinical aspects of deafness-dystonia syndrome. We evaluated 20 patients with deafness-dystonia syndrome who were seen during the period between 1994 and 2011. The cause was identified in only 7 patients and included methylmalonic aciduria, meningoencephalitis, perinatal hypoxic-ischemic injury, large genomic deletion on chromosome 7q21, translocase of inner mitochondrial membrane 8 homolog A (TIMM8A) mutation (Mohr-Tranebjaerg syndrome), and chromosome 2 open reading frame 37 (C2orf37) mutation (Woodhouse-Sakati syndrome). The age of onset and clinical characteristics in these patients varied, depending on the etiology. In 13 patients, the cause remained unexplained despite extensive work-up. In the group of patients who had unknown etiology, a family history for deafness and/or dystonia was present the majority of patients, suggesting a strong genetic component. Sensory-neural deafness always preceded dystonia. Two clinical patterns of deafness-dystonia syndrome were observed: patients who had an onset in childhood had generalized dystonia (10 of 13 patients) with frequent bulbar involvement, whereas patients who had a dystonia onset in adulthood had segmental dystonia (3 of 13 patients) with the invariable presence of laryngeal dystonia. Deafness-dystonia syndrome is etiologically and clinically heterogeneous, and most patients have an unknown cause. The different age at onset and variable family history suggest a heterogeneous genetic background, possibly including currently unidentified genetic conditions.

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted. (C) 2016 Elsevier Inc. All rights reserved.

THAP1 mutations have been shown to be the cause of DYT6. A number of different mutation types and locations in the THAP1 gene have been associated with a range of severity and dystonia phenotypes, but, as yet, it has been difficult to identify clear genotype phenotype patterns. Here, we screened the THAP1 gene in a further series of dystonia cases and evaluated the mutation pathogenicity in this series as well as previously reported mutations to investigate possible phenotype-genotype correlations. THAP1 mutations have been identified throughout the coding region of the gene, with the greatest concentration of variants localized to the THAP1 domain. In the additional cases analyzed here, a further two mutations were found. No obvious, indisputable genotype-phenotype correlation emerged from these data. However, we managed to find a correlation between the pathogenicity of mutations, distribution, and age of onset of dystonia. THAP1 mutations are an important cause of dystonia, but, as yet, no clear genotype-phenotype correlations have been identified. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various THAP1 mutations. © 2012 Movement Disorder Society.

We present a 70-year-old male patient of Greek origin with choreatic movements of the tongue and face, lower limb muscle weakness, peripheral neuropathy, elevated creatinephosphokinase (CPK), acanthocytosis and haemolysis in the absence of Kell RBC antigens with an additional Factor IX-deficiency. Genetic testing for mutations in the three exons of the XK gene revealed a previously unreported hemizygous single base-pair frameshift deletion at exon 1 (c.229delC, p.Leu80fs). In conclusion, we hereby describe a rare phenotype of a patient with McLeod syndrome which was discovered coincidentally during routine blood group testing and consecutively genetically confirmed., Highlights • McLeod syndrome with chorea, muscle wasting, and peripheral neuropathy • Acanthocytosis and haemolysis in the absence of Kell RBC antigens • McLeod syndrome with an additional Factor IX deficiency • Novel hemizygous single base-pair frameshift deletion in the XK gene

Phenotype of patients with the aprataxin gene mutation varies and according to previous studies, screening of aprataxin gene could be useful, once frataxin gene mutation is excluded in patients with normal GAA expansion in frataxin gene. In the present study, we sought to determine possible causative mutations in aprataxin gene (all exons and flanking intronic sequences) in 14 Greek patients with sporadic cerebellar ataxia all but one without GAA expansion in frataxin gene (1 patient was heterozygous). No detectable point mutation or deletion was found in the aprataxin gene of all the patients. Our results do not confirm the previous studies. This difference may be attributed to the different populations studied and possible different genetic background. It is still questionable whether the screening for aprataxin mutation in Greek patients' Friedreich ataxia phenotype is of clinical importance; larger, multicenter studies are necessary to clarify this issue.

We investigated the association of specific polymorphisms of the interleukin IL-1b (AvaI -511 and TaqI +3,953) and IL-1 receptor antagonist (IL-1RN) (a variable number of tandem repeats; VNTR) genes with both the susceptibility to and the clinical characteristics in Greek multiple sclerosis (MS) patients cohort with bout-onset. Genotypes were determined from 351 patients with clinically definite MS and 375 age- and sex-matched healthy controls. Our results showed no significant differences in the distribution of these polymorphisms between MS patients and controls. Furthermore, stratification for clinical characteristics, such as age at disease onset, clinical course, sex, and severity did not provide significant differences between patients and controls. Together, our findings suggest that IL-1B and IL-1RN gene polymorphisms may not be relevant to the susceptibility to MS or the clinical characteristics of Greek MS patients.

Mutations in SNCA and LRRK2 genes, encoding alpha-synuclein and leucine-rich repeat kinase 2, respectively, cause autosomal dominant Parkinson's disease (AdPD). The LRRK2 G2019S (c.6055G > A) and R1441G (c.4321C > G) mutations have also been identified in sporadic PD (sPD). We studied 55 unrelated patients with AdPD, 235 patients with sPD, and 235 healthy age- and gender-matched controls all of Greek origin. Patients with AdPD were screened for SNCA and LRRK2 mutations by direct sequencing. SNCA gene dosage analysis was also performed for AdPD using quantitative duplex polymerase chain reaction of genomic DNA. In addition, we investigated the frequency of the LRRK2 G2019S mutation in sPD. We found no missense mutations or multiplications in the SNCA gene. Here we report two novel variants, A211V (c.632C > T) and K544E (c.1630A > G) in LRRK2 gene in two patients with AdPD that was not present in controls. We identified only one patient with sPD (1/235; 0.4%) carrying the G2019S mutation. LRRK2 mutations are present in AdPD and sPD patients of Greek origin.

Rapid progress in genetics has meant that there are now five genes identified for 'Parkinson's disease'. The detailed phenotypes vary, but generally the dominant genes cause a Lewy body disease spectrum whereas recessive genes cause a milder parkinsonism with variable inclusion body pathology. The subject of this review is to highlight these discoveries and to discuss their relationships to idiopathic Parkinson's disease.In January 2004, mutations in PINK1, coding for a mitochondrial kinase, were found to be causal for recessive parkinsonism. Subsequently, several studies have found additional mutations associated with early onset parkinsonism. Some cases have been described with a phenotype much closer to idiopathic Parkinson's disease, but it does not appear that PINK1 is a major risk factor for the sporadic disease. Later in the same year, the LRRK2 gene was shown to cause a dominant disease with a broader phenotype. The protein product was named dardarin and contains GTPase and kinase domains. Lewy bodies have been reported in LRRK2 cases, potentially linking this gene with sporadic Parkinson's disease. One mutation, G2019S, is found in a significant percentage of cases, including sporadic Parkinson's disease.Mutations in these two genes, along with previously described Mendelian variants, are beginning to yield important information about loss of specific neuronal groups or to protein inclusion pathology. How this relates to sporadic Parkinson's disease, however, is not yet fully defined. There are clear phenotypic overlaps with genetic and sporadic Parkinson's disease, especially for the dominant genes, suggesting that common facets of pathogenesis may exist.

Nasu-hakola disease (NHD) is a rare disease characterized by bone cysts and fractures, frontal lobe syndrome, and progressive presenile dementia. NHD may be the prototype of primary microglial disorders of the CNS or, as they have been coined, "microgliopathies". Mutations in TREM2 and TYROBP genes are known to cause NHD. Interestingly, recent evidence-associated rare genetic variants of TREM2 gene with increased risk of Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease. Here, we report a 33-year-old Greek female with phenotype suggestive of NHD. Full gene sequencing of the TREM2 and TYROBP genes revealed a novel mutation in exon 2 of TREM2 gene, namely c.244G>T (p.W50C) and heterozygosity in the parents and her brother. This report extends the range of TREM2 mutations that cause NHD phenotype. In addition, we provide a comprehensive review of all reported in the literature TREM2 gene mutations and the respective wide spectrum of clinical manifestations that highlights the importance of considering TREM2 gene mutations in a variety of neurodegenerative phenotypes.

Analysis of concordancy rates in monozygotic and dizygotic twins with Parkinson's disease (PD) has been an important subject for research into the disorder1 and discordancy between twins has traditionally been interpreted as evidence against a genetic etiology of disease. Discordancy in late-onset diseases such as PD is complicated by the possibility that the disease onset may vary considerably between twins, and cases with up to 20 years of discordance have been reported.2 Leucine-rich repeat-kinase type 2 (LRRK2) mutations are the most common Mendelian cause of PD,3, 4 with the G2109S mutation occurring in 1% to 2% of idiopathic cases in the UK.5 Here we report the identification of a pair of identical twins with this mutation who are discordant by more than 10 years.

High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium.GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3. kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants.The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I2 estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest.This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide. © 2009 Elsevier Inc.

Lysosomal protein 2 (LIMP2), the product of the scavenger receptor class B member 2 (SCARB2) gene, is a ubiquitously expressed transmembrane protein that is the mannose-6-phosphate–independent receptor for glucocerebrosidase (β-GCase); a deficiency in this protein causes Gaucher disease. Several studies have shown a link between mutations in the β-GCase gene and diseases characterized clinically by Parkinsonism and by the presence of Lewy body–related pathology. We hypothesized that genetic variants in the SCARB2 gene could be risk factors for Parkinson's disease (PD). A candidate-gene study of 347 Greek patients with sporadic PD and 329 healthy controls was conducted to investigate the association between 5 polymorphisms in the SCARB2 gene (rs6824953, rs6825004, rs4241591, rs9991821, and rs17234715) and the development of PD. The single-locus analysis for the 5 polymorphisms revealed an association only for the rs6825004 polymorphism: the generalized odds ratio (ORG) was 0.68 (95% confidence interval [CI], 0.51–0.90), and the OR for the allelic test was OR = 0.71 (95% CI, 0.56–0.90). Haplotype analysis showed an association for the GCGGT haplotype (P < .01). Our study supports a genetic contribution of the SCARB2 locus to PD; future studies in larger cohorts are necessary to verify this finding. © 2012 Movement Disorder Society

Over the past few years, considerable progress has been made in understanding the molecular mechanisms of Parkinson disease (PD). Mutations in certain genes are found to cause monogenic forms of the disorder, with autosomal dominant or autosomal recessive inheritance. These genes include alpha-synuclein, parkin, PINK1, DJ-1, LRRK2, and ATP13A2. The monogenic variants are important tools in identifying cellular pathways that shed light on the pathogenesis of this disease. Certain common genetic variants are also likely to modulate the risk of PD. International collaborative studies and meta-analyses have identified common variants as genetic susceptibility risk/protective factors for sporadic PD.

Traumatic brain injury (TBI) constitutes a major cause of mortality and disability worldwide, especially among young individuals. It is estimated that despite all the recent advances in the management of TBI, approximately half of the patients suffering head injuries still have unfavorable outcomes, which represents a substantial health care, social, and economic burden to societies. Considerable variability exists in the clinical outcome after TBI, which is only partially explained by known factors. Accumulating evidence has implicated various genetic elements in the pathophysiology of brain trauma. The extent of brain injury after TBI seems to be modulated to some degree by genetic variants. The authors' current review focuses on the up-to-date state of knowledge regarding genetic association studies in patients sustaining TBI, with particular emphasis on the mechanisms underlying the implication of genes in the pathophysiology of TBI.

The thalami of the human brain obtain their blood supply from many perforating arteries, which exhibit complex distribution and many variations. One rare variation is the artery of Percheron that supplies the paramedian thalami bilaterally. This artery arises from the first segment of the posterior cerebral artery and gives rise to bilateral medial thalamic perforants. Occlusion of the artery of Percheron none rarely results in bilateral thalamic and mesencephalic infarctions. We describe the case of a 38-year-old male patient with a presumed occlusion of this artery in which MR imaging revealed characteristic symmetrical bilateral paramedian thalamic infarctions. The unique characteristics of this case are based on the young age of the patient, the absence of any risk factors or other diseases and even more on the rare clinical manifestations consisted of hypophonia, memory dysfunction, time disorientation and apathy.

Restless legs syndrome (RLS) is a sensorimotor disorder with a general population prevalence of 3-10%. A single, previous epidemiological study performed in south-east Europe reported the lowest prevalence rate amongst European countries. We conducted a population-based survey of RLS in central Greece. A total of 4200 subjects were randomly recruited. We used the international RLS study group criteria for diagnosis and the severity scale for severity assessment in subjects with RLS. We also included questions to assess the level of awareness of RLS in our region. A total of 3033 subjects were screened. The overall lifetime prevalence was 3.9% with a female-to-male ratio of 2.6:1. Nearly half of RLS patients reported moderate to severe intensity of symptoms. After adjustment for multiple comparisons we found no association of RLS with education level, smoking, alcohol intake, caffeine consumption, shift work, professional pesticide use or comorbid illness. Our study revealed a low level of awareness amongst the population and physicians in our region and sub-optimal management. We provide further evidence for low prevalence of RLS in south-east Europe and a low level of awareness of RLS in our region. Eur J Neurol

Genome-wide association studies (GWAS) have been shown to be a powerful approach to identify risk loci for neurodegenerative diseases. Recent GWAS in Parkinson's disease (PD) have been successful in identifying numerous risk variants pointing to novel pathways potentially implicated in the pathogenesis of PD. Contributing to these GWAS efforts, we performed genotyping of previously identified risk alleles in PD patients and control subjects from Greece. We showed that previously published risk profiles for Northern European and American populations are also applicable to the Greek population. In addition, although our study was largely underpowered to detect individual associations, we replicated 5 of 32 previously published risk variants with nominal p values

Leucine-rich repeat kinase 2 (LRRK2) mutation is the most common cause of genetic-related parkinsonism and is usually associated with Lewy body pathology; however, tau, α-synuclein, and ubiquitin pathologies have also been reported. We report the case of a patient carrying the LRRK2 G2019S mutation and a novel heterozygous variant c.370C>G, p.Q124E in exon 4 of the microtubule-associated protein tau (MAPT). The patient developed parkinsonism with good levodopa response in her 70s. Neuropathological analysis revealed nigral degeneration and Alzheimer-type tau pathology without Lewy bodies. Immunohistochemical staining using phospho-TDP-43 antibodies identified occasional TDP-43 pathology in the hippocampus, temporal neocortex, striatum, and substantia nigra. However, TDP-43 pathology was not identified in another 4 archival LRRK2 G2019S cases with Lewy body pathology available in the Queen Square Brain Bank. Among other published cases of patients carrying LRRK2 G2019S mutation, only 3 were reportedly evaluated for TDP-43 pathology, and the results were negative. The role of the MAPT variant in the clinical and pathological manifestation in LRRK2 cases remains to be determined.

Microtubule-associated protein tau (MAPT) mutations have been shown to underlie frontotemporal dementia and a variety of additional sporadic tauopathies. We identified a rare p.A152T variant in MAPT exon 7 in two (of eight) patients with clinical presentation of parkinsonism and postmortem finding of neurofibrillary tangle pathology. Two siblings of one patient also carried the p.A152T variant, and both have progressive cognitive impairment. Further screening identified the variant in two other cases: one with pathologically confirmed corticobasal degeneration and another with the diagnosis of Parkinson's disease with dementia. The balance of evidence suggests this variant is associated with disease, but the very varied phenotype of the cases with the mutation is not consistent with it being a fully penetrant pathogenic mutation. Interestingly, this variation results in the creation of a new phosphorylation site that could cause reduced microtubule binding. We suggest that the A152T variant is a risk factor associated with the development of atypical neurodegenerative conditions with abnormal tau accumulation.

Primary intracerebral haemorrhage (PICH) originates from the spontaneous rupture of cerebral arteries as a result of chronic degenerative alterations. Although the aetiology of PICH has not been fully elucidated, it may be the result of an interaction between genetic and environmental risk factors. Several genetic association studies have been conducted in patients with PICH with both positive and negative results. Most of them investigated the role of mutations in genes affecting the lipid metabolism, the coagulation processes, the inflammation and the regulation of blood pressure. In this article we briefly discuss the majority of these studies reporting the susceptibility genes that have been implicated in PICH.