Episodic memory effects of gamma frequency precuneus transcranial magnetic stimulation in Alzheimer's disease: A randomized multiple baseline study.

Episodic memory decline is the prominent neuropsychological feature of typical Alzheimer's Disease (AD), for which current treatments have a limited clinical response. Recently, gamma entrainment therapy has been used as a non-invasive treatment in AD, providing evidence that it may have the potential to alleviate brain pathology and improve cognitive function in AD patients. At the same time, the precuneus (PC) has been recognized as a key area involved in AD related memory deficits and as a key node of the Default Mode Network. This study aimed to investigate the effectiveness of a 40 Hz Transcranial Magnetic Stimulation (TMS) intervention, delivered bilaterally to the precuneus for 10 days, in improving the patients' episodic memory performance. Secondary outcome variables investigated included general cognitive function, semantic and spatial memory, as well as attention and executive function. A concurrent multiple baseline design across five cases was employed. Four patients completed the study. Visual analysis combined with effect size indices were used to evaluate changes across phases. An increase in the average level of immediate recalled words was observed in three out of four patients. Effect size indices indicated significant improvement of attention skills in two patients. No treatment effect was observed for semantic and visual memory, or for executive function. An immediate treatment effect was observed in all patients' general cognitive function as assessed with the Alzheimer's Disease Assessment Scale (mean reduction of 5 points), which was maintained and improved further three months post-treatment. The neuropsychological evaluations indicated improved performance three months post-treatment in immediate and delayed recall, attention, phonological verbal fluency, anxiety, and neuropsychiatric symptoms. This study provides preliminary evidence for the efficacy of a novel non-pharmacological treatment using gamma-band TMS in addressing cognitive dysfunction in AD.

Genetic Study of Early Onset Parkinson's Disease in Cyprus.

Parkinson's Disease (PD) is a multifactorial neurodegenerative disease characterized by motor and non-motor symptoms. The etiology of PD remains unclear. However, several studies have demonstrated the interplay of genetic, epigenetic, and environmental factors in PD. Early-onset PD (EOPD) is a subgroup of PD diagnosed between the ages of 21 and 50. Population genetic studies have demonstrated great genetic variability amongst EOPD patients. Hence, this study aimed to obtain a genetic landscape of EOPD in the Cypriot population. Greek-Cypriot EOPD patients (n = 48) were screened for variants in the six most common EOPD-associated genes (PINK1, PRKN, FBXO7, SNCA, PLA2G6, and DJ-1). This included DNA sequencing and Multiplex ligation-dependent probe amplification (MLPA). One previously described frameshift variant in PINK1 (NM_032409.3:c.889del) was detected in five patients (10.4%)-the largest number to be detected to date. Copy number variations in the PRKN gene were identified in one homozygous and 3 compound heterozygous patients (8.3%). To date, the pathogenic variants identified in this study have explained the PD phenotype for 18.8% of the EOPD cases. The results of this study may contribute to the genetic screening of EOPD in Cyprus.

Mechanisms of change in acceptance and commitment therapy for primary headaches.

BACKGROUND: Despite the demonstrated effectiveness of behavioural headache interventions, it is not yet known which intervention processes account for treatment responses. Acceptance and commitment therapy (ACT), an emerging behavioural intervention for headaches, proposes psychological flexibility (PF) processes as the mechanisms via which intervention change occurs. This is the first study examining these processes of change variables on headache-related disability and quality of life (treatment outcome). METHODS: Data originated from a Randomized Clinical Trial evaluating the efficacy of ACT for primary headaches. Ninety-four individuals with primary headaches (M = 43 y; 84% females; M headache frequency/month = 9.30) were randomized to either an ACT-based or a Wait-list control group (N = 47 in each). Participants completed questionnaires related to their headache experiences and PF processes at pre- (T1), post-treatment (T2), and 3-month follow-up (T3). RESULTS: Following a bootstrapped cross product of coefficients approach, results demonstrated mediating effects of headache acceptance, cognitive defusion, avoidance of headache, and mindfulness in the ACT group compared to control on parameters of headache-related disability and quality of life at post and 3-month follow-ups. CONCLUSIONS: These findings demonstrate that changes in certain PF processes lower disability and improve quality of life in headache sufferers, supporting that ACT works via its proposed mechanisms of change. Interventions for headache management may be optimized if they target increases in headache acceptance, defusion from thoughts, and mindfulness. SIGNIFICANCE: Psychological flexibility (PF) guides the ACT approach, an emerging behavioral headache intervention that focuses on optimizing head pain adjustment via flexible responses to pain. It targets at increasing daily functioning rather than preventing or controlling headache episodes. Pain acceptance, cognitive defusion, and mindfulness act as processes of functional change in ACT, lowering disability and increasing daily functioning and quality of life. These components can upgrade the established effectiveness of behavioral headache interventions with personalized, modularized therapeutic targets that can help headache sufferers re-establish optimal daily functioning even in fluctuating and persistent headache episodes. TRIAL REGISTRATION: clinical trials.gov registry (NCT02734992).

Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date. METHODS: We performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders. RESULTS: We confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10-13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders. DISCUSSION: Our gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms.

A Novel CLN6 Variant Associated With Juvenile Neuronal Ceroid Lipofuscinosis in Patients With Absence of Visual Loss as a Presenting Feature.

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive lysosomal storage disorders that are characterized by neurodegeneration, progressive cognitive decline, motor impairment, ataxia, loss of vision, seizures, and premature death. To date, pathogenic variants in more than 13 genes have been associated with NCLs. CLN6 encodes an endoplasmic reticulum non-glycosylated transmembrane protein, which is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile juvenile NCL (JNCL) adult-onset NCL, and Kufs disease. Members from two available families with JNCL were clinically evaluated, and samples were collected from consenting individuals. The molecular investigation was performed by whole-exome sequencing, Sanger sequencing, and family segregation analysis. Furthermore, in silico prediction analysis and structural modeling of the identified CLN6 variants were performed. We report clinical and genetic findings of three patients from two Greek-Cypriot families (families 915 and 926) with JNCL. All patients were males, and the first symptoms appeared at the age of 6 years. The proband of family 926 presented with loss of motor abilities, ataxia, spasticity, seizure, and epilepsy. The proband of family 915 had ataxia, spasticity, dysarthria, dystonia, and intellectual disability. Both probands did not show initial signs of vision and/or hearing loss. Molecular analysis of family 926 revealed two CLN6 biallelic variants: the novel, de novo p.Tyr295Cys and the known p.Arg136His variants. In family 915, both patients were homozygous for the p.Arg136His CLN6 variant. Prediction analysis of the two CLN6 variants characterized them as probably damaging and disease-causing. Structural modeling of the variants predicted that they probably cause protein structural differentiation. In conclusion, we describe two unrelated Cypriot families with JNCL. Both families had variants in the CLN6 gene; however, they presented with slightly different symptoms, and notably none of the patients has loss of vision. In silico prediction and structural analyses indicate that both variants are most likely pathogenic.

Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty.

Background: Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3, DLK1, KISS1, and KISS1R genes were investigated in patients with CPP. Methods: Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children found negative (n = 44) for the MKRN3 gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was designed. Results: Three previously described pathogenic MKRN3 variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic MKRN3 variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP. Conclusion: The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP.

Prediction of Parkinson's Disease Risk Based on Genetic Profile and Established Risk Factors.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder, and literature suggests that genetics and lifestyle/environmental factors may play a key role in the triggering of the disease. This study aimed to evaluate the predictive performance of a 12-Single Nucleotide Polymorphisms (SNPs) polygenic risk score (PRS) in combination with already established PD-environmental/lifestyle factors. METHODS: Genotypic and lifestyle/environmental data on 235 PD-patients and 464 controls were obtained from a previous study carried out in the Cypriot population. A PRS was calculated for each individual. Univariate logistic-regression analysis was used to assess the association of PRS and each risk factor with PD-status. Stepwise-regression analysis was used to select the best predictive model for PD combining genetic and lifestyle/environmental factors. RESULTS: The 12-SNPs PRS was significantly increased in PD-cases compared to controls. Furthermore, univariate analyses showed that age, head injury, family history, depression, and Body Mass Index (BMI) were significantly associated with PD-status. Stepwise-regression suggested that a model which includes PRS and seven other independent lifestyle/environmental factors is the most predictive of PD in our population. CONCLUSIONS: These results suggest an association between both genetic and environmental factors and PD, and highlight the potential for the use of PRS in combination with the classical risk factors for risk prediction of PD.

A Novel SPG7 Gene Pathogenic Variant in a Cypriot Family With Autosomal Recessive Spastic Ataxia.

The SPG7 gene encodes the paraplegin protein, an inner mitochondrial membrane-localized protease. It was initially linked to pure and complicated hereditary spastic paraplegia with cerebellar atrophy, and now represents a frequent cause of undiagnosed cerebellar ataxia and spastic ataxia. We hereby report the molecular characterization and the clinical features of a large Cypriot family with five affected individuals presenting with spastic ataxia in an autosomal recessive transmission mode, due to a novel SPG7 homozygous missense variant. Detailed clinical histories of the patients were obtained, followed by neurological and neurophysiological examinations. Whole exome sequencing (WES) of the proband, in silico gene panel analysis, variant filtering and family segregation analysis of the candidate variants with Sanger sequencing were performed. RNA and protein expression as well as in vitro protein localization studies and mitochondria morphology evaluation were carried out towards functional characterization of the identified variant. The patients presented with typical spastic ataxia features while some intrafamilial phenotypic variation was noted. WES analysis revealed a novel homozygous missense variant in the SPG7 gene (c.1763C > T, p. Thr588Met), characterized as pathogenic by more than 20 in silico prediction tools. Functional studies showed that the variant does not affect neither the RNA or protein expression, nor the protein localization. However, aberrant mitochondrial morphology has been observed thus indicating mitochondrial dysfunction and further demonstrating the pathogenicity of the identified variant. Our study is the first report of an SPG7 pathogenic variant in the Cypriot population and broadens the spectrum of SPG7 pathogenic variants.

Acceptance and Commitment Therapy for Primary Headache Sufferers: A Randomized Controlled Trial of Efficacy.

Prevention of headaches via avoidance of triggers remains the main behavioral treatment suggestion for headache management despite trigger avoidance resulting in increases in potency, lifestyle restrictions, internal locus of control decreases, pain exacerbation and maintenance. New approaches, such as Acceptance and Commitment Therapy (ACT), instead emphasize acceptance and valued living as alternatives to avoidance. Though ACT is an empirically supported treatment for chronic pain, there is limited evidence for headache management while preliminary outcome studies are afflicted with methodological limitations. This study compared an ACT-based group headache-specific intervention to wait-list control, in a randomized clinical trial, on disability, distress, medical utilization, functioning, and quality of life. Ninety-four individuals with primary headache (84% women; Mage = 43 years; 87.35% migraine diagnosis) were randomized into 2 groups (47 in each). Assessments occurred: before, immediately after, and at 3 months following treatment end. Only the ACT group was additionally assessed at 6- and 12-month follow-up. Results (intent to treat analyses corroborated by linear mixed model analyses) showed substantial improvements in favor of ACT compared to control, on disability, quality of life, functional status, and depression at 3-, 6-, and 12-month follow-up. Improvements were maintained in the ACT group at 6- and 12-month follow-up. At 3-month follow-up, clinical improvement occurred in headache-related disability (63%) and 65% in quality of life in ACT versus 37% and 35% in control. These findings offer new evidence for the utility and efficacy of ACT in localized pain conditions and yields evidence for both statistical and clinical improvements over a years' period. PERSPECTIVE: An Acceptance and Commitment Therapy approach focusing on acceptance and values-based activities was found to improve disability, functioning, and quality of life among patients with primary headaches.

Risk factors for breast cancer brain metastases: a systematic review.

BACKGROUND: Brain metastasis (BM) is an increasingly common and devastating complication of breast cancer (BC). METHODS: A systematic literature search of EMBASE and MEDLINE was conducted to elucidate the current state of knowledge on known and novel prognostic factors associated with 1) the risk for BCBM and 2) the time to brain metastases (TTBM). RESULTS: A total of 96 studies involving institutional records from 28 countries were identified. Of these, 69 studies reported risk factors of BCBM, 46 factors associated with the TTBM and twenty studies examined variables for both outcomes. Young age, estrogen receptor negativity (ER-), overexpression of human epidermal factor (HER2+), and higher presenting stage, histological grade, tumor size, Ki67 labeling index and nodal involvement were consistently found to be independent risk factors of BCBM. Of these, triple-negative BC (TNBC) subtype, ER-, higher presenting histological grade, tumor size, and nodal involvement were also reported to associate with shorter TTBM. In contrast, young age, hormone receptor negative (HR-) status, higher presenting stage, nodal involvement and development of liver metastasis were the most important risk factors for BM in HER2-positive patients. CONCLUSIONS: The study provides a comprehensive and individual evaluation of the risk factors that could support the design of screening tools and interventional trials for early detection of BCBM.

Genetic and Environmental Factors Contributing to Parkinson's Disease: A Case-Control Study in the Cypriot Population.

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder affecting a substantial proportion of the elderly Cypriot population. The objective of this study was to evaluate PD risk variants that have been identified previously in Genome Wide Association Studies (GWAS) and to find environmental factors that are predictors for PD onset in the Cypriot population. Methods: A case-control study was conducted with a total of 235 PD patients and 464 healthy controls of Greek-Cypriot ethnicity. Demographic and lifestyle characteristics, exposure to PD risk factors and clinical data were collected. Moreover, 13 previously GWAS-identified PD risk variants were genotyped. Univariate and multivariate regression analyses examined the association between a number of environmental and genetic factors and PD. Results: Multivariable regression analysis revealed that exposure to both pesticides and other toxic substances (P = 0.03), severe head injury accompanied with fainting (P = 0.001), nuts consumption (P = 0.004), red meat consumption (P = 0.02), and soft drinks consumption (P = 0.008) were increasing the risk for PD, whereas cumulative smoking (P = 0.02), and fish consumption (P = 0.02) were decreasing the risk for PD. Five out of the 13 tested SNPs (rs12185268, rs6599389, rs356220, rs13312, and rs17649553) were confirmed to be nominally significantly associated (P < 0.05) with PD risk in the Cypriot population. Conclusions: Collectively, this case-control study has shed some light on the nature of PD epidemiology in Cyprus, by demonstrating a number of genetic and environmental determinants of PD in the Cypriot population.

Prevalence of Anti-JC Virus (JCV) Antibodies in the Multiple Sclerosis (MS) Population in Cyprus: A Retrospective Study.

BACKGROUND AND PURPOSE: Progressive multifocal leukoencephalopathy (PML) is a debilitating disease of the central nervous system caused by the ubiquitous polyomavirus JC (JCV) in immunocompromised hosts. In recent years, a new subpopulation of patients at risk for PML has emerged, due to the growing use of immunomodulatory or immunosuppressive therapies in autoimmune diseases such as multiple sclerosis (MS). The anti-JCV antibody index is used as a stratification tool in assessing the risk of developing PML. The objective of this study was to retrospectively describe the prevalence of anti-JCV antibodies in the MS population in Cyprus. METHODS: We retrospectively collected the demographics of 214 MS patients in Cyprus who were screened for anti-JCV antibodies using the STRATIFY JCV™ assay between September 2011 and June 2018. Logistic regression analysis was used to examine the effect of demographic variables on seropositivity, and bivariate tests were used to assess the association between demographic characteristics and JCV AI index. RESULTS: A total of 214 MS patients in Cyprus were tested. Overall anti-JCV antibody prevalence was 45.8% (95% confidence interval 37.2%-55.8%). We could not establish a significant association between seropositivity and increasing age or sex. In the subgroup analysis of natalizumab-treated patients, the annual seroconversion rate was 4.5%. CONCLUSIONS: Overall seroprevalence of anti-JCV antibodies in MS patients in Cyprus using the STRATIFY JCV assay was lower than the worldwide reported mean. Although previously reported, in our study, the anti-JCV antibody seropositivity was not associated with increasing age or sex.

Retrospective longitudinal study of ALS in Cyprus: Clinical characteristics, management and survival.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disease. There is heterogeneity of clinical phenotypes while a clinical characterization of ALS in Cyprus is still lacking. The aim of this 30-year retrospective study of ALS in Cyprus is to determine the demographic characteristics of patients, the clinical features of the disease, the uptake of supportive therapies and factors influencing survival. METHODS: All ALS patients seen at the Cyprus Institute of Neurology and Genetics from January 1985 until July 2015 were included. Medical records of eligible patients were used for data extraction and compilation of an ALS database. Clinical features were compared between gender categories using univariate tests, while survival was assessed using Kaplan-Meier curves. Cox proportional hazards models were used to identify prognostic factors for survival. RESULTS: One hundred and seventy-nine ALS patients were included in the study, of whom 7 had a positive family history. Most clinical characteristics of ALS did not differ from what is observed in other European countries. However, some clinical characteristics were unique to our population, such as an increased acceptability and utilisation of supportive treatments such as gastrostomy. CONCLUSIONS: Overall, clinical characteristics of patients with ALS in the Republic of Cyprus do not differ from other European counties. Our study demonstrates a high acceptance and utilisation of supportive interventions enhancing survival, in the context of a multidisciplinary approach offered in the single tertiary centre that services the whole Cypriot ALS population. The findings of this paper are of value to the health professionals treating ALS in Cyprus.

A retrospective observational study of rituximab treatment in multiple sclerosis patients in Cyprus.

Objective: The objective of this study was to evaluate the efficacy and safety of rituximab (RTX) treatment given off-label to Cypriot patients with multiple sclerosis (MS). Methods: Clinical data from 30 MS patients ever treated with off-label RTX until mid-2018 at the Cyprus Institute of Neurology and Genetics were retrospectively collected and reviewed. The heterogeneous patient cohort included patients with relapsing-remitting MS (RRMS), primary progressive MS (PPMS) and secondary progressive MS (SPMS). Outcome data (relapse rate and EDSS progression) as well as adverse effects for patients with a follow-up period of >12 months (n = 13) were recorded. Results: Following RTX administration, all patients with RRMS remained relapse free and had a stable or slightly improved EDSS score (mean EDSS before treatment = 6, mean EDSS at 12 months = 4.75). Patients with SPMS had a significant reduction in their relapse rate and a stabilization or slight improvement of their EDSS scores (mean EDSS before treatment = 6.25, mean EDSS at 12 months = 5.5). Only one of the patients with PPMS had a follow-up period of >12 months and his EDSS score remained unchanged. Rituximab infusions were generally well tolerated; there were only seven grade 3 or 4 adverse events recorded. Conclusion: Our results are in agreement with larger retrospective studies in which it was demonstrated that RTX was well tolerated and effective in treating RRMS and SPMS patients by reducing relapse rate and stabilizing disease.

Mitochondrial superclusters influence age of onset of Parkinson's disease in a gender specific manner in the Cypriot population: A case-control study.

BACKGROUND: Despite evidence supporting an involvement of mitochondrial dysfunction in the pathogenesis of some neurodegenerative disorders, there are inconsistent findings concerning mitochondrial haplogroups and their association to neurodegenerative disorders, including idiopathic Parkinson's disease (PD). METHODS: To test this hypothesis for the Greek-Cypriot population, a cohort of 230 PD patients and 457 healthy matched controls were recruited. Mitochondrial haplogroup distributions for cases and controls were determined. Association tests were carried out between mitochondrial haplogroups and PD. RESULTS: Mitochondrial haplogroup U was associated with a reduced PD risk in the Cypriot population. After pooling mitochondrial haplogroups together into haplogroup clusters and superclusters, association tests demonstrated a significantly protective effect of mitochondrial haplogroup cluster N (xR) and supercluster LMN for PD risk only in females. In addition, for female PD cases belonging to UKJT and R (xH, xUKJT) haplogroup, the odds of having a later age of onset of PD were 13 and 15 times respectively higher than the odds for female cases with an H haplogroup. CONCLUSION: Statistically significant associations regarding PD risk and PD age of onset were mostly detected for females thus suggesting that gender is a risk modifier between mitochondrial haplogroups and PD status / PD age of onset. The biological mechanisms behind this gender specificity remain to be determined.

Open-Label Fosmetpantotenate, a Phosphopantothenate Replacement Therapy in a Single Patient with Atypical PKAN.

Objective. Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder with variable onset, rate of progression, and phenotypic expression. Later-onset, more slowly progressive PKAN often presents with neuropsychiatric as well as motor manifestations that include speech difficulties, progressive dystonia, rigidity, and parkinsonism. PKAN is caused by biallelic PANK2 mutations, a gene that encodes pantothenate kinase 2, a regulatory enzyme in coenzyme A biosynthesis. Current therapeutic strategies rely on symptomatic relief. We describe the treatment of the first, later-onset PKAN patient with oral fosmetpantotenate (previously known as RE-024), a novel replacement therapy developed to bypass the enzymatic defect. Methods. This was an open-label, uncontrolled, 12-month treatment with fosmetpantotenate of a single patient with a later-onset, moderately severe, and slowly progressive form of PKAN. Results. The patient showed improvement in all clinical parameters including the Unified Parkinson's Disease Rating Scale (UPDRS), Barry-Albright Dystonia Scale, the EuroQol five-dimensional three-level (EQ-5D-3L) scale, timed 25-foot walk test, and electroglottographic speech analysis. Fosmetpantotenate was well-tolerated with only transient liver enzyme elevation which normalized after dose reduction and did not recur after subsequent dose increases. Conclusions. Fosmetpantotenate showed promising results in a single PKAN patient and should be further studied in controlled trials.

Identification of exosomal muscle-specific miRNAs in serum of myotonic dystrophy patients relating to muscle disease progress.

Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy, which is characterised by progressive muscle wasting and the discovery of reliable blood-based biomarkers could be useful for the disease progress monitoring. There have been some reports showing that the presence of specific miRNAs in blood correlates with DM1. In one of these, our group identified four muscle-specific miRNAs, miR-1, miR-133a, miR-133b and miR-206, which correlated with the progression of muscle wasting observed in DM1 patients. The levels of the four muscle-specific miRNAs were elevated in the serum of DM1 patients compared to healthy participants and were also elevated in the serum of progressive muscle wasting DM1 patients compared to disease-stable DM1 patients. The aim of this work was to characterise the ontology of these four muscle-specific miRNAs in the blood circulation of DM1 patients. Here we show that the four muscle-specific miRNAs are encapsulated within exosomes isolated from DM1 patients. Our results show for the first time, the presence of miRNAs encapsulated within exosomes in blood circulation of DM1 patients. More interestingly, the levels of the four exosomal muscle-specific miRNAs are associated with the progression of muscle wasting in DM1 patients. We propose that exosomal muscle-specific miRNAs may be useful molecular biomarkers for monitoring the progress of muscle wasting in DM1 patients. There has been a growing interest regarding the clinical applications of exosomes and their role in prognosis and therapy of various diseases and the above results contribute towards this way.

A quantitative method for the assessment of dysarthrophonia in myasthenia gravis.

Speech and voice symptomatology (dysarthrophonia) are often reported by patients with myasthenia gravis (MG). However, they have been poorly investigated despite their significant impact on quality of life. Quantitative methods for the assessment of dysarthrοphonia could facilitate the evaluation of these common MG symptoms. The goal of this study was to investigate the phonatory (sustained phonation and reading) and speech (diadochokinesis) function in MG patients using quantitative measures. The voice/speech of 12 MG patients (7 with anti-AchR and 5 with anti-MuSK antibodies) and 24 age-matched healthy controls was recorded and analyzed using electroglottography (EGG) and speech acoustics. For the analysis of voice, the variables that were found to distinguish MG patients compared to healthy controls were a higher average fundamental frequency (P<0.05), a higher standard deviation of the average fundamental frequency (P<0.001), a higher mean fundamental frequency of the vibrating vocal folds (P<0.005) and a higher fundamental frequency range (P<0.005). The analysis of diadochokinesis showed that MG patients had a higher mean duration of the silent interval between a series of repetitive /pa/ syllables (P<0.05), of the sound /t/ (P=0.05) and of the silent interval between a series of repetitive /ka/syllables (P<0.05). No statistical differences were found in any of these variables between the MG subgroups with anti-AchR or anti-MuSK antibodies. This study demonstrates that non-invasive physiological methods (EGG and speech acoustics) offer essential tools for the assessment of dysarthrophonia in MG patients.

Epidemiology of Amyotrophic Lateral Sclerosis in the Republic of Cyprus: A 25-Year Retrospective Study.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare, rapidly progressive neurodegenerative disease. Despite wide variability in the incidence and prevalence of ALS, there is evidence of positive temporal trends and an increase in incidence with age. The aim of this study was to conduct a detailed epidemiological investigation of ALS in Cyprus. METHODS: All registered Cypriot ALS patients in the Republic of Cyprus from January 1985 until December 2014 were included. Socio-demographic information was extracted from patient files. RESULTS: The study identified 179 ALS patients, of whom 7 had a positive family history. The mean age at onset was 58.6 years and a slight male predominance was observed. Average annual crude incidence was 1.26 cases/100,000 person-years and at the beginning of 2015, prevalence of ALS was 7.9 cases/100,000 population. Both incidence and prevalence displayed an increasing trend, even after age-standardization of incidence rates. CONCLUSIONS: Incidence, prevalence and main socio-demographic characteristics of ALS in Cyprus were similar to those of other European countries, without any geographic clustering of the disease. Additionally, an increased incidence through the years was confirmed. However, observations such as a higher male prevalence and a younger mean age of onset compared to published literature require further investigation.

Quality of Life of Cypriot Patients Suffering with Huntington's Disease.

INTRODUCTION: Huntington's disease (HD) has profound motor, behavioural and cognitive symptoms. Despite the enormous burden of this disease on the quality of life (QoL) of patients and their families, there is very limited evidence on this topic. Considering the severity of HD patients, and the high prevalence in Cyprus more studies are needed to assess QoL among Cypriot patients, in order to improve our knowledge about their living conditions and to assist the management of this condition. Project Aim: The aim of this cross-sectional study is to assess QoL among Cypriot patients with HD, using a standardized health-related QoL questionnaire. MATERIALS AND METHODS: A generic QoL questionnaire was used, namely EQ-5D, which is a standardised instrument for use as a measure of health outcomes and is applicable to a wide range of health conditions. The study was conducted with 34 patients, which represented 46% of the Cypriot HD patient population. RESULTS: Ability of patients to care for themselves and to carry out usual activities were reported to be most severely affected (37.5% and 40.6% replying "Severe Problems" respectively). Mobility and psychosocial well-being were also affected to a lesser extent (25.0% and 15.6% replying "Severe Problems"). Interestingly, in the anxiety/depression scale, 77.8% of asymptomatic patients reported "Some Problems". Half of the patients did not experience pain or discomfort but 40.6% reported "Some Problems" and 6.3% reported "Severe Problems". The Health Status as perceived by the patients was found to be moderately to severely affected.  In multivariate ordinal regression analyses, age at onset and disease duration significantly impacted on self-care. In addition, disease duration was significantly associated with mobility, self-care and usual activities scales. No significant determinants were evidenced for Pain/Discomfort and Anxiety/Depression. Lastly, age of onset was found to be the only significant determinant of the cumulative QoL score (Range=5-15). CONCLUSIONS: Age at onset and disease duration were found to severely affect the QoL of Cypriot HD patients, and more specifically their mobility, ability to self-care and perform usual activities. The percentage of patients reporting "Some Problems" in the Pain/Discomfort category can be explained by the direct translation of the word as presented in the questionnaire, indicating the need for language specific instruments. Perhaps more noteworthy is the phychosocial burden on even asymptomatic patients, which needs to be acknowledged and managed to improve their quality of life.