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Background: Numerous cross-sectional studies report cognitive impairment in multiple sclerosis (MS), but longitudinal studies with sufficiently long-term follow-up are scarce., Objective: We aimed to investigate the cognitive 10-year course of a cohort of MS patients., Methods: 59 patients with clinically isolated syndrome (CIS) or relapsing-remitting (RR) MS were evaluated with Rao's Brief Repeatable Battery of Neuropsychological Tests at baseline and follow-up (at least 10 years later). They constituted 47.2% of 124 consecutive CIS and RRMS patients originally evaluated at baseline. Patients assessed at follow-up were well matched for baseline clinical characteristics with dropouts., Results: The proportion of MS patients with overall cognitive impairment was increased by 10% within the 10-year period. When grouped on the basis of impairment in specific cognitive domains at baseline, patients originally impaired showed improvement at follow-up, while the opposite trend was observed for patients non-impaired at first assessment. A detailed case-by-case investigation revealed mixed evolution patterns, several patients fail in fewer domains at follow-up compared to baseline or failing at different domains at follow-up compared to baseline., Conclusions: This study suggests a more fluid picture for the evolution of cognitive function in a subgroup of MS patients and contradicts the concept of an inevitable, progressively evolving "dementia".

Recent evidence suggests a potential role for mixed proteinopathies in the development of clinical manifestations in patients with Huntington's disease (HD). A possible cross-talk between mutant huntingtin and α-synuclein aggregates has been postulated. Serum α-synuclein has been evaluated as a potential biomarker in patients with Parkinson's disease (PD). We presently sought to investigate serum α-synuclein levels in 38 HD patients (34 symptomatic and 4 premanifest) and compare them to 36 controls. We found that α-synuclein was elevated in HD patients vs. controls (2.49 ± 1.47 vs. 1.40 ± 1.16, p = 0.001). There was no difference in α-synuclein levels between symptomatic vs. premanifest HD, nor between HD patients receiving medication vs. treatment-naïve. Furthermore, α-synuclein levels showed no correlation with CAG2, Unified HD Rating Scale (UHDRS) motor score, age, disease duration or disease burden score. Our results provide evidence for elevated serum α-synuclein in HD and lend support to further investigating the role of α-synuclein in this disorder., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

IgG antibodies to myelin oligodendrocyte glycoprotein (MOG) detected by cell based assays (CBA) have been identified in a constantly expanding spectrum of CNS demyelinating disorders. However, a universally accepted CBA has not been adopted yet. We aimed to analyze the clinical and radiological features of patients with anti-MOG IgG1-antibodies detected with a live-cell CBA and to compare the three most popular MOG-CBAs. We screened sera from 1300 Greek patients (including 426 patients referred by our 8 clinics) suspected for anti-MOG syndrome, and 120 controls with the live-cell MOG-CBA for IgG1-antibodies. 41 patients, versus 0 controls were seropositive. Clinical, serological and radiological data were available and analyzed for the 21 seropositive patients out of the 426 patients of our clinics. Their phenotypes were: 8 optic neuritis, 3 myelitis, 3 neuromyelitis optica, 2 encephalomyelitis, 2 autoimmune encephalitis and 3 atypical MS. We then retested all sera of our 426 patients with the other two most popular MOG-CBAs for total IgG (a live-cell and a commercial fixed-cell CBAs). Seven IgG1-seropositive patients were seronegative for one or both IgG-CBAs. Yet, all 21 patients had clinical and radiological findings previously described in MOG-antibody associated demyelination disease supporting the high specificity of the IgG1-CBA. In addition, all IgG1-CBA-negative sera were also negative by the IgG-CBAs. Also, all controls were negative by all three assays, except one serum found positive by the live IgG-CBA. Overall, our findings support the wide spectrum of anti-MOG associated demyelinating disorders and the superiority of the MOG-IgG1 CBA over other MOG-CBAs., Competing Interests: Declaration of Competing Interest J.S.T. and S.T. have shares in the research and diagnostic laboratory Tzartos NeuroDiagnostics, Athens. G.K. reports grants from Teva Pharmaceuticals and Genesis Pharma; personal fees from Novartis, Genesis Pharma, Sanofi-Genzyme and Teva Pharmaceuticals; non-financial support from Merck, Sanofi-Genzyme and Genesis Pharma. M.E.E. has received travel grants and consulting fees from Biogen, Novartis, Teva, Genzyme and Merk. C.K. received research grants from Biogen, Novartis, Teva, and Merck-Serono. All other authors declare no relevant to this work conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: X-linked Charcot-Marie-Tooth disease (CMTX) is an hereditary neuropathy caused by mutations in GJB1 coding for connexin-32, found in Schwann cells, but also expressed in oligodendrocytes. Reports have identified CNS involvement in CMTX, but no systematic study of cognitive function has been published., Methods: We assessed 24 CMTX patients (13 males; 9GJB1 mutations) with a comprehensive neuropsychological battery, including tests of memory, language, and executive functions., Results: No differences in cognitive performance were observed between males and females. A case-by-case investigation revealed selective deficits in individual patients. One subgroup (29%) demonstrated executive abnormalities; and a non-overlapping subgroup (29%), prominent reading (decoding) abnormalities., Conclusions: The present data provide evidence for cognitive deficits in CMTX. Emerging neuropsychological patterns are also discussed.

IgG4-related disease (IgG4-RD) is a disorder with various clinical manifestations. Central nervous system (CNS) involvement is well recognized, with hypertrophic pachymeningitis and hypophysitis being the most common manifestations. Spinal cord involvement is an extremely rare manifestation. We present the first case of an IgG4-RD patient with spinal cord parenchymal disease and concurrent hypophysitis. We review also the current literature about CNS parenchymal involvement in the context of IgG4-RD. A young female presented with clinical symptoms of myelitis. Cervical spinal cord magnetic resonance imaging (MRI) displayed features of longitudinally extensive transverse myelitis (LETM). Brain MRI showed a small number of high-intensity lesions in the deep white matter and enlargement of hypophysis with homogeneous gadolinium enhancement (asymptomatic hypophysitis). Diagnostic workup revealed elevated IgG4 serum levels (146 mg/dL). Our patient fulfilled the organ-specific diagnostic criteria of IgG4-hypophysitis. Treatment with intravenous glucocorticoids led to rapid clinical response, and to the substantial resolution of imaging findings. Azathioprine was used as a maintenance treatment. One relapse occurred 2 years after the initial diagnosis and patient was re-treated with glucocorticoids. Three years after relapse, patient is in remission with azathioprine. We present the first case of myelitis with radiological features of LETM associated with increased IgG4 serum levels and the simultaneous presence of asymptomatic IgG4-related hypophysitis.

Background: Multiple Sclerosis is a multifactorial autoimmune disease of the central nervous system, characterized by focal inflammation, demyelination and secondary axonal injury. TREM2 is a signaling protein which participates in the innate immune system by implication to inflammation, proliferation and phagocytosis. The R47H (rs75392628) rare variant of the TREM2 gene has been related to various neurological diseases and leads to impaired signaling, lipoprotein binding, lipoprotein uptake and surface uptake., Aim: To assess the role of TREM2 rs75932628 on MS risk through a genetic candidate gene association case-control study in a Greek population., Methods: 1246 MS cases and 398 controls were genotyped for this variant., Results: No MS or healthy subjects carried the variant., Conclusion: This variant does not seem to play a determining role in the pathogenesis of MS, although further studies examining the presence of TREM2 mutations in other, phylogenetically different populations and the epigenetic regulation of this gene are needed in order to thoroughly investigate its role in MS., (Copyright © 2019. Published by Elsevier B.V.)

MOG-antibody associated demyelinating disease is a new emerging diagnostic entity. Recently, international recommendations for testing of anti-MOG antibodies were published. Herein, we describe a case of anti-MOG antibody-associated demyelinating disease initially diagnosed as typical MS, and, at presentation, not fulfilling the proposed recommendations. This case highlights the expanding spectrum of anti-MOG antibody-associated demyelinating disease, illustrating the distinct and overlapping features of MS and MOG-antibody associated demyelinating disease, providing evidence that on rare occasions these recommendations may prove too restrictive., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a rare, X-linked hereditary lower motor neuron disease, characterized by progressive muscular weakness. An expanded trinucleotide repeat (CAG > 37) in the androgen receptor gene (AR), encoding glutamine, is the mutation responsible for Kennedy's disease. Toxicity of this mutant protein affects both motor neurons and muscles. In this review, we provide a comprehensive, clinically oriented overview of the current literature regarding Kennedy's disease, highlighting gaps in our knowledge that remain to be addressed in further research. Kennedy's disease mimics are also discussed, as are ongoing and recently completed therapeutic endeavours.

Charcot-Marie-Tooth disease type 4 C (CMT4C) is an autosomal recessive form of demyelinating peripheral neuropathy caused by mutations in SH3TC2, characterized by early onset, spine deformities, and cranial nerve involvement. We screened SH3TC2 in 50 unrelated Greek patients with suspected demyelinating Charcot-Marie-Tooth disease and pedigree compatible with recessive inheritance. All patients had been previously screened for PMP22, GJB1, and MPZ mutations. We found five previously identified pathogenic mutations in SH3TC2 distributed among 13 patients in homozygosity or compound heterozygosity (p. Arg954Stop, Arg1109Stop, Gln892Stop, Ala878Asp, and Arg648Trp). Although most cases had early onset and spine deformities were almost omnipresent, a wide phenotypic spectrum was observed. Particularly notable were two siblings with Roussy-Lévy syndrome and one patient with young-onset trigeminal neuralgia. In conclusion, mutations in SH3TC2 are responsible for 26% of Greek patients with suspected CMT4, identifying CMT4C as the most common recessive demyelinating neuropathy in the Greek population, in accordance with other Mediterranean cohorts., (© 2019 Peripheral Nerve Society.)

Objectives: To validate in an ethnically homogeneous Greek multiple sclerosis (MS) cohort, genetic risk factors for the disease, identified through a number of previous multi-ethnic genome-wide association studies (GWAS)., Methods: A total of 1228 MS cases and 1014 controls were recruited in the study, from 3 MS centers in Greece. We genotyped 35 susceptibility SNPs that emerged from previous GWAS or meta-analyses of GWAS. Allele and genotype single locus regression analysis, adjusted for gender and site, was performed. Permutation testing was applied to all analyses., Results: Six polymorphisms reached statistical significance (permutation p value < 0.05). In particular, rs2760524 of LOC105371664, near RGS1 (permutation p value 0.001), rs3129889 of HLA-DRA, near HLA-DRB1 (permutation p value < 1.00e-04), rs1738074 of TAGAP (permutation p value 0.007), rs703842 of METTL1/CYP27B1 (permutation p value 0.008), rs9596270 of DLEU1 (permutation p value < 1.00e-04), and rs17445836 of LincRNA, near IRF8 (permutation p value 0.001) were identified as susceptibility risk factors in our group., Conclusion: The current study replicated a number of GWAS susceptibility SNPs, which implies that some similarities between the examined Greek population and the MS genetic architecture of the GWAS populations do exist.

Objective: X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary neuropathy caused by mutations in GJB1 coding for connexin-32, a gap junction protein expressed in Schwann cells, but also found in oligodendrocytes. Four patients with CMTX developing central nervous system (CNS) demyelination compatible with multiple sclerosis (MS) have been individually published. We presently sought to systematically investigate the relationship between CMTX and MS., Methods: Over 20 years, 70 consecutive patients (36 men) with GJB1 mutations were identified at our Neurogenetics Unit, Athens, Greece, and assessed for clinical features suggestive of MS. Additionally, 18 patients with CMTX without CNS symptoms and 18 matched controls underwent brain MRI to investigate incidental findings. Serum from patients with CMTX and MS was tested for CNS immunoreactivity., Results: We identified three patients with CMTX who developed clinical features suggestive of inflammatory CNS demyelination fulfilling MS diagnostic criteria. The resulting 20-year MS incidence (4.3%) differed significantly from the highest background 20-year MS incidence ever reported from Greece (p=0.00039). The search for incidental brain MRI findings identified two CMTX cases (11%) with lesions suggestive of focal demyelination compared with 0 control. Moreover, 10 cases in the CMTX cohort had hyperintensity in the splenium of the corpus callosum compared with 0 control (p=0.0002). No specific CNS-reactive humoral factors were identified in patients with CMTX and MS., Conclusions: We have demonstrated a higher than expected frequency of MS in patients with CMTX and identified incidental focal demyelinating lesions on brain MRI in patients with CMTX without CNS symptoms. This provides circumstantial evidence for GJB1 mutations acting as a possible MS risk factor., Competing Interests: Competing interests: GK reports grants from Teva Pharmaceuticals and Genesis Pharma; personal fees from Novartis, Genesis Pharma, Sanofi-Genzyme and Teva Pharmaceuticals; non-financial support from Merck, Sanofi-Genzyme and Genesis Pharma; MB reports no disclosures; GV reports no disclosures; JT reports shares in a diagnostic laboratory (Tzartos Neurodiagnostics) in Athens; DK reports no disclosures; CK reports no disclosures; EK reports no disclosures; DT reports no disclosures; MA reports research grants from Biogen, Merck-Serono, Novartis, Teva, Bayer and Genzyme, as well as lecture-fees from Novartis, Teva, Biogen and Genzyme; EA reports research grants from Biogen, Merck-Serono, Novartis, and Sanofi-Aventis, as well as lecture-fees from Teva; M-EE reports consultation services and honoraria from Novartis, Biogen and Teva; CK reports research grants from Biogen, Novartis, Teva, and Merck-Serono; CP reports no disclosures; MP reports no disclosures; GK reports no disclosures., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

A 13-year-old girl presented with a 5-day history of oscillopsia. On examination, ocular flutter and mild cerebellar signs were found. Brain magnetic resonance imaging (MRI) revealed four periventricular and subcortical non-enhancing lesions. Cerebrospinal fluid (CSF) oligoclonal bands were negative. Neuroblastoma or other malignancies were not found. She responded well to a corticosteroid-intravenous immunoglobulin (IVIG) combination and remained symptom-free for 3 years until presenting again with isolated ocular flutter. Brain MRI at this time remained atypical for classic multiple sclerosis (MS) with a predominance of juxtacortical demyelinating lesions. CSF was positive for oligoclonal bands. Serum myelin oligodendrocyte glycoprotein (MOG) antibodies were present. Ocular flutter can be the presenting feature of MOG antibody-associated pediatric demyelination.

Despite recent advances in genetics, in most cases of Amyotrophic Lateral Sclerosis (ALS) no etiological factor can be identified. Cerebral Arteriovenous Malformations (AVMs) have been associated with ALS development in a few studies, but the nature of this connection is unclear. We report here 3 additional cases of young adults, who had undergone repeated embolizations for complex AVMs, and who then developed, after many years, ALS symptoms and signs. In two of these cases Vascular Endothelial Growth Factor (VEGF) levels were found to be extremely high, in contrast to previous reports. Our 3 cases, together with the previously reported ones, suggest that a subgroup of patients with AVMs, with a particular profile of a complex nidus with repeated embolization procedures, are at increased risk of developing ALS. The reason for this association is unclear, but may relate to dysregulation of secreted vascular factors, as suggested by our VEGF results, or more broadly to the neurovascular hypothesis of ALS. Alternatively, a transneuronal type of neurodegeneration may be involved., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The p. A53T mutation in the alpha-synuclein (SNCA) gene is a rare cause of autosomal dominant Parkinson's disease (PD). Although generally rare, it is particularly common in the Greek population due to a founder effect. A53T-positive PD patients often develop dementia during disease course and may very rarely present with dementia., Methods: We screened for the p. A53T SNCA mutation a total of 347 cases of Greek origin with parkinsonism and/or dementia, collected over 15 years at the Neurogenetics Unit, Eginition Hospital, University of Athens. Cases were classified into: "pure parkinsonism", "pure dementia" and "parkinsonism plus dementia"., Results: In total, 4 p. A53T SNCA mutation carriers were identified. All had autosomal dominant family history and early onset. Screening of the "pure parkinsonism" category revealed 2 cases with typical PD. The other two mutation carriers were identified in the "parkinsonism plus dementia" category. One had a diagnosis of PD dementia and the other of behavioral variant frontotemporal dementia. Screening of patients with "pure dementia" failed to identify any further A53T-positive cases., Conclusions: Our results confirm that the p. A53T SNCA mutation is relatively common in Greek patients with PD or PD plus dementia, particularly in cases with early onset and/or autosomal dominant family history., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The C9orf72 repeat expansion is a common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in European populations. A previous study has reported a high frequency of the expansion in Greek ALS. However, no data have been reported on the frequency of the expansion in Greek FTD. Currently, we investigated the frequency of the C9orfF72 expansion in a well-characterized cohort of 64 Greek FTD patients. We detected the C9orf72 repeat expansion in 9.3% of cases. Overall, 27.7% of familial and 2.2% of sporadic cases were expansion-positive. Five out of 6 cases had a diagnosis of behavioral variant FTD. All expansion-positive cases had fairly typical FTD presentations. Clinical features included motor neuron disease, Parkinsonism and hallucinations. We conclude that the overall frequency of C9orf72-positive cases in Greek FTD is high, comparable to Greek ALS, similar to some Western European, but significantly higher than some Mediterranean FTD populations.

Background: Spastic paretic hemifacial contracture (SPHC) is characterized by sustained unilateral contraction of the facial muscles associated with mild ipsilateral facial paresis. Rarely described in the context of multiple sclerosis (MS), it has never been reported as presenting symptom of MS., Case Reports: Two patients developed SPHC within the context of a clinically isolated syndrome suggestive of MS. EMG revealed continuous resting activity of irregularly firing motor unit potentials, associated with impaired recruitment upon voluntary contraction. SPHC remitted fully in both patients., Conclusions: SPHC, a rare but distinct clinical and EMG entity, can occasionally be the presenting feature of MS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: The p.A53T point mutation in SNCA, the alpha-synuclein gene, has been linked to a rare dominant form of Parkinson's disease (PD)., Methods: Here, we describe two apparently unrelated cases of p.A53T (G209A) SNCA mutation carriers with an atypical initial manifestation and disease course. Moreover, cerebrospinal fluid (CSF) levels of tau, p-tau and amyloid Aβ42 were measured in these patients and in an additional cohort of 5 symptomatic and 2 asymptomatic p.A53T carriers without an initial manifestation of dementia., Results: Both patients exhibited an early onset frontal-dysexecutive dysfunction with apathy and emotional blunting resembling frontotemporal dementia (FTD). Motor symptoms typical of Parkinson's disease appeared only later in the disease course and were less prominent than cognitive ones, which included language impairment. Autonomic dysfunction and myoclonus also emerged in a more advanced disease stage. In both patients, Brain Magnetic Resonance Imaging showed fronto-temporo-parietal atrophy, and CSF analysis showed elevated tau protein levels. In contrast, tau protein levels were normal in a cohort of 7 other p.A53T mutation carriers (5 symptomatic/2 asymptomatic). A screen of Greek patients presenting with frontotemporal dementia failed to identify any additional subjects with the p.A53T SNCA mutation., Conclusion: Although cognitive decline has been recognized as a feature of the full-blown clinical picture of p.A53T related parkinsonism, a predominant frontotemporal dementia-like phenotype at presentation has not been previously described. This may represent a subtype of this disorder, with distinctive clinical, imaging and CSF biochemical characteristics, in which additional genetic or epigenetic factors may play a role., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: Bladder dysfunction is frequent during the course of multiple sclerosis (MS), observed in up to 75% of patients. Urinary symptomatology can be a feature of the first episode of MS in a minority of cases, and most often shows characteristics of an overactive bladder (OAB), with voiding symptoms seen less frequently, often in combination with OAB. The neural control of micturition is complex, involving systems located in the brain, spinal cord, and periphery, and implicating central noradrenergic, serotonergic, and dopaminergic activities. Urinary disorders are also linked to anxiety and depression, conditions connected to hypothalamus-pituitary-adrenal axis activity. In this study we aimed to investigate neurochemical and neuroendocrine correlates of bladder dysfunction in early MS., Methods: We included 101 patients at first demyelinating episode suggestive of MS that were drug-free at assessment. We evaluated the presence of urinary symptomatology and estimated CSF levels of the main metabolites of noradrenaline, serotonin, and dopamine, as well CSF-ACTH and serum cortisol., Results: In total, 15 patients (15%) reported urinary dysfunction suggestive of OAB. Four of these had coexistent voiding symptomatology. The serotonin metabolite 5-HIAA was significantly reduced (P = 0.017) in patients with OAB syndrome, while there were no differences in the metabolites of noradrenaline (MHPG) and of dopamine (HVA). Additionally, significantly lower serum cortisol (P = 0.009) and borderline lower CSF-ACTH (P = 0.08) were found in patients with OAB., Conclusions: MS patients with OAB syndrome at the first demyelinating episode show reductions in central serotonergic activity and stress hormones. Whether the same changes persist at later disease stages remains to be investigated. Neurourol. Urodynam. 35:955-958, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Objective: To integrate neurophysiological findings with clinical and imaging data in a consecutive series of multiple sclerosis (MS) patients developing facial numbness during the course of an MS attack., Methods: Nine consecutive patients with MS and recent-onset facial numbness were studied clinically, imaged with routine MRI, and assessed neurophysiologically with trigeminal somatosensory evoked potential (TSEP), blink reflex (BR), masseter reflex (MR), facial nerve conduction, facial muscle and masseter EMG studies., Results: All patients had unilateral facial hypoesthesia on examination and lesions in the ipsilateral pontine tegmentum on MRI. All patients had abnormal TSEPs upon stimulation of the affected side, excepting one that was tested following remission of numbness. BR was the second most sensitive neurophysiological method with 6/9 examinations exhibiting an abnormal R1 component. The MR was abnormal in 3/6 patients, always on the affected side. Facial conduction and EMG studies were normal in all patients but one., Conclusions: Facial numbness was always related to abnormal TSEPs. A concomitant R1 abnormality on BR allowed localization of the responsible pontine lesion, which closely corresponded with MRI findings. We conclude that neurophysiological assessment of MS patients with facial numbness is a sensitive tool, which complements MRI, and can improve lesion localization., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Hereditary Spastic Paraplegia (HSP) is a syndrome characterised by lower limb spasticity, occurring alone or in association with other neurological manifestations, such as cognitive impairment, seizures, ataxia or neuropathy. HSP occurs worldwide, with different populations having different frequencies of causative genes. The Greek population has not yet been characterised. The purpose of this study was to describe the clinical presentation and molecular epidemiology of the largest cohort of HSP in Greece, comprising 54 patients from 40 families. We used a targeted next-generation sequencing (NGS) approach to genetically assess a proband from each family. We made a genetic diagnosis in >50% of cases and identified 11 novel variants. Variants in SPAST and KIF5A were the most common causes of autosomal dominant HSP, whereas SPG11 and CYP7B1 were the most common cause of autosomal recessive HSP. We identified a novel variant in SPG11, which led to disease with later onset and may be unique to the Greek population and report the first nonsense mutation in KIF5A. Interestingly, the frequency of HSP mutations in the Greek population, which is relatively isolated, was very similar to other European populations. We confirm that NGS approaches are an efficient diagnostic tool and should be employed early in the assessment of HSP patients.

Objective: The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome-wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases., Methods: We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single-nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study., Results: In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10(-5) ). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10(-5) ) and all SCAs (p = 2.22 × 10(-4) ) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10(-5) ), all in the same direction as in the HD GWAS., Interpretation: We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983-990., (© 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Objectives: To present a Greek family in which 5 male and 2 female members developed progressive spastic paraplegia. Plasma very long chain fatty acids (VLCFA) were reportedly normal at first testing in an affected male and for over 30 years the presumed diagnosis was hereditary spastic paraplegia (HSP). Targeted next generation sequencing (NGS) was used as a further diagnostic tool., Methods: Targeted exome sequencing in the proband, followed by Sanger sequencing confirmation; mutation segregation testing in multiple family members and plasma VLCFA measurement in the proband., Results: NGS of the proband revealed a novel frameshift mutation in ABCD1 (c.1174&#95;1178del, p.Leu392Serfs*7), bringing an end to diagnostic uncertainty by establishing the diagnosis of adrenomyeloneuropathy (AMN), the myelopathic phenotype of X-linked adrenoleukodystrophy (ALD). The mutation segregated in all family members and the diagnosis of AMN/ALD was confirmed by plasma VLCFA measurement. Confounding factors that delayed the diagnosis are presented., Conclusions: This report highlights the diagnostic utility of NGS in patients with undiagnosed spastic paraplegia, establishing a molecular diagnosis of AMN, allowing proper genetic counseling and management, and overcoming the diagnostic delay that can be rarely caused by false negative VLCFA analysis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

There has been limited information from population studies regarding the overall frequency of the common 1.5-Mb 17p11.2 deletion and even scarcer data regarding the overall frequency of PMP22 micromutations in patients with a clinical suspicion of hereditary neuropathy with liability to pressure palsies (HNPP). We have analysed 100 consecutive Greek patients referred for HNPP genetic testing over a 15-year period to our Neurogenetics Unit in Athens, a reference centre for all regions of Greece. All patients were screened for the 1.5-Mb deletion and a selected subgroup of deletion-negative patients for PMP22 micromutations. Mutation-positive and mutation-negative patients were compared for various clinical parameters. In total, 54 mutation-positive patients were identified. In index cases, the deletion frequency was 47.8%, and the PMP22 micromutation frequency was 2.2%. Within mutation-positive patients, the common deletion represented 95.7% and PMP22 micromutations 4.3% of cases. Two previously reported PMP22 micromutations (c.364&#95;365delCC and c.79-2A>G) were detected. HNPP index cases had a 2.8-1 male-to-female ratio, similar to mutation-negative patients. A typical phenotype (recurrent or isolated palsies) was present in 82.4% of symptomatic HNPP cases, significantly higher than mutation-negative patients. Sensitivity of proposed electrophysiological diagnostic criteria for HNPP was calculated at 95.7% and specificity at 80.5%. In conclusion, the common HNPP deletion accounts for ∼50% and PMP22 micromutations for ∼2% of cases in a large consecutive cohort of patients with suspected HNPP. The mutational and phenotypic spectrum of HNPP is similar in the Greek population compared with other populations. Proposed electrophysiological diagnostic criteria perform satisfactorily in everyday clinical practice., (© 2015 Peripheral Nerve Society.)

We report a patient with relapsing remitting multiple sclerosis (MS) and X-linked Charcot-Marie-Tooth disease (CMTX), carrying a GJB1 mutation affecting connexin-32 (c.191G>A, p. Cys64Tyr) which was recently reported by our group. This is the third case report of a patient with CMTX developing MS, but it is unique in the fact that other family members carrying the same mutation were found to have asymptomatic central nervous system (CNS) involvement (diffuse white matter hyperintensity on brain MRI and extensor plantars). Although this may be a chance association, the increasing number of cases with CMTX and MS, especially with mutations involving the CNS, may imply some causative effect and provide insights into MS pathogenesis.

An expanded hexanucleotide repeat in C9ORF72 has been identified as the most common genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia in many populations, including the Greek. Recently, C9ORF72 expansions were reported as the most common genetic cause of Huntington disease (HD) phenocopies in a UK population. In the present study, we screened a selected cohort of 40 Greek patients with HD phenocopies for C9ORF72 hexanucleotide repeat expansions using repeat-primed polymerase chain reaction. We identified 2 patients (5%) with pathologic expansions. The first patient had chorea, behavioral-psychiatric disturbance, cognitive impairment, and a positive family history, fulfilling the strictest criteria for HD phenocopy. The second patient was sporadic and had parkinsonism, behavioral-psychiatric disturbance, and cognitive impairment, corresponding to a broader definition of HD phenocopy. These findings identify C9ORF72 expansions as a frequent cause of HD phenocopies in the Greek population, confirming recent findings in other populations and supporting proposed diagnostic testing for C9ORF72 expansions in patients with HD-like syndromes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To address diagnostic and prognostic issues in patients with late-onset Huntington's disease (HD)., Methods: We analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20-59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale., Results: Late-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046)., Conclusions: A positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Charcot-Marie-Tooth (CMT) disease, the most common hereditary neuropathy, is clinically and genetically heterogeneous. X-linked CMT (CMTX) is usually caused by mutations in the gap junction protein b 1 gene (GJB1) coding for connexin 32 (Cx32). The clinical manifestations of CMTX are characterized by significant variability, with some patients exhibiting central nervous system (CNS) involvement. We report four novel mutations in GJB1, c.191G>A (p.Cys64Tyr), c.508G>T (p.Val170Phe), c.778A>G (p.Lys260Glu) and c.300C>G (p.His100Gln) identified in four unrelated Greek families. These mutations were characterized by variable phenotypic expression, including a family with the Roussy-Lévy syndrome, and three of them were associated with mild clinical CNS manifestations., (Copyright © 2014. Published by Elsevier B.V.)

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 <0.05. Genome-wide complex trait analysis revealed that known risk loci explain disease risk in 1.27% of Greek PD patients. Collectively, these results indicate that there is likely a substantial genetic component to PD in Greece, similarly to other worldwide populations, that remains to be discovered., (Published by Elsevier Inc.)

Limited data exist on the spectrum of heredoataxias in Greece, including the prevalence and phenotype of Friedreich's ataxia (FRDA) and the prevalence and subtypes of dominant spinocerebellar ataxias (SCAs). We analyzed clinically and investigated genetically for FRDA and triplet-repeat expansion SCAs a consecutive series of 186 patients with suspected heredoataxia referred to Athens over 18 years. For prevalence estimates we included patients with molecular diagnosis from Cyprus that were absent from the Athens cohort. The minimum prevalence of FRDA was ~0.9/100,000, with clusters of high prevalence in Aegean islands. FRDA was diagnosed in 73 probands. The genotypic and phenotypic spectrum of FRDA was similar to other populations, with one patient compound heterozygote for a known point mutation in FXN (Asn146Lys). Undiagnosed recessive ataxias included FRDA-like and spastic ataxias. The minimum prevalence of dominant SCAs was ~0.7/100,000. SCA1 (4), SCA7 (4), SCA2, SCA6, and SCA17 (1 each) probands were identified. A molecular diagnosis was reached in 31% of dominant cases. Undiagnosed dominant patients included a majority of type III autosomal dominant cerebellar ataxias. FRDA is the commonest heredoataxia in the Greek population with prevalence towards the lower end of other European populations. Dominant SCAs are almost as prevalent. SCA1, SCA2, SCA6, SCA7 and SCA17 patients complete the spectrum of cases with a specific molecular diagnosis., (© 2013.)

Several studies have investigated leptin levels in patients with multiple sclerosis (MS) with somewhat conflicting results. They have all focused on patients with established relapsing-remitting (RR) MS but have not specifically looked at patients with clinically isolated syndrome (CIS) suggestive of MS, in the early stages of disease. In this study, serum leptin levels were measured in 89 treatment-naïve patients with CIS (53 patients) or RRMS (36 patients) and 73 controls searching for differences between the groups and for associations with several disease parameters. The expected significant sexual dimorphism in leptin levels (higher levels in females) was observed in both MS patients and controls. Increased leptin levels were found in female patients with RRMS compared to female controls (P = .003) and female CIS patients (P = .001). Female CIS patients had comparable levels to controls. Leptin levels correlated positively to disease duration, but not to EDSS, in female patients with RRMS. The results of the present study do not indicate involvement of leptin in the early stages of MS. Normal leptin levels in patients with CIS suggest that leptin does not have a pathogenic role. The ratio leptin/BMI increases during disease course in female MS patients in a time-dependent and disability-independent manner.

Introduction. Spinocerebellar ataxia 17 (SCA 17) is a rare autosomal dominant cerebellar ataxia (ADCA) caused by a CAG/CAA expansion in the TBP gene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD) phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed. Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms. Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family.

Background: In recent years, there has been increasing interest in the role of plasma homocysteine (Hcy) as a possible risk factor for several diseases of the central nervous system. The aim of this study was to determine the plasma levels of Hcy in a group of multiple sclerosis (MS) patients from a Greek population and the possible correlation with age, disability status, activity or duration of disease, sex, and treatment., Methods: The MS group that was studied consisted of 46 patients and a total of 42 healthy individuals served as a control group. Plasma Hcy levels were determined by means of high-performance liquid chromatography coupled with fluorescence detection, after precolumn derivatization with 4-Fluoro-7-aminosulfonylbenzofurazan (ABD-F)., Results: Statistical analysis revealed that, in the MS patients, Hcy levels were not significantly different as compared to those in the controls. Men presented with higher Hcy levels than women in the MS group; however, age, disease subtype, disease duration, relapse rate, and Expanded Disability Status Scale score/Multiple Sclerosis Severity Score did not significantly affect Hcy levels in MS patients., Conclusion: The preliminary data suggest that Hcy levels were not elevated in our sample of Greek MS patients, which does not support previous findings of a significant correlation between elevated serum Hcy levels and MS. Further studies to establish a possible association between MS and Hcy levels in the context of different ethnic groups with different habits are needed., (Copyright © 2013. Published by Elsevier B.V.)

Body weight and height of patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome suggesting MS (CIS) in the age range 18 to 60 years (154 males and 315 females) were compared with those of subjects (146 males and 212 females) free of any major neurological disease. In drug-free patients, CSF levels of the metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA), neurotransmitters involved in eating behavior, were estimated in searching for associations with body mass index (BMI). Statistical evaluations were done separately for males and females. Lower BMI was found in female MS patients compared to female controls, more pronounced in RRMS. BMI was not associated with duration of illness, smoking, present or previous drug treatment, or disability score. Body height showed a shift towards greater values in MS patients compared to controls. Patients in the lower BMI quartile (limits defined from control subjects) had lower 5-HIAA and HVA compared to patients in the upper quartile. The results provide evidence for weight reduction during disease process in MS, possibly related to deficits in serotoninergic and dopaminergic activities that develop during disease course, resulting in impairments in food reward capacity and in motivation to eat.

Spinocerebellar ataxias (SCA) are a genetically heterogeneous group of neurodegenerative diseases characterised by progressive cerebellar ataxia, dysarthria and oculomotor abnormalities. Recently the prodynorphin (PDYN) gene was identified as the cause of SCA23 in four Dutch families displaying progressive gait and limb ataxia. In this study we aimed to assess the frequency of PDYN gene defects and extend the phenotype of SCA23 patients in a UK ataxia series and also in patients from Greece, Egypt and India. We sequenced the coding and flanking intronic regions of the PDYN gene in a total of 852 ataxia patients, of which 356 were sporadic with no family history, 320 had a positive family history, and 176 probands had a positive family history and at least one family member had also been investigated. We also analysed 190 patients with multiple-system atrophy with cerebellar features (MSA-C), a phenocopy of SCA23. We identified a novel putative pathogenic heterozygous missense variant in the PDYN gene in an early onset SCA patient with an unknown family history. This variant was not present in 570 matched British controls. This is the first study to screen for SCA23 in UK patients and confirms that PDYN mutations are a very rare cause of spinocerebellar ataxia, accounting for ~ 0.1 % of ataxia cases but perhaps with a higher frequency in pure cerebellar ataxia. Given the rarity of PDYN mutations, front-line diagnostic evaluation of UK familial and early onset pure spinocerebellar ataxia patients should focus on other known ataxia genes.

MicroRNAs (miRNAs) are small non-coding RNAs approximately 22 nucleotides in length that play a pivotal role in post-transcriptional gene regulation by binding to complementary sites in the 3'-untranslated region of messenger RNAs. In the past decade, their role in several human diseases, from cancer to cardiovascular disease, has been established by a wealth of evidence. Stroke is responsible for 10% of deaths worldwide and is one of the leading causes of disability. MiRNAs are involved in stroke risk factors including hypertension, atherosclerosis, atrial fibrillation, diabetes and dyslipidemia. The role of miRNAs in the pathophysiology of stroke has been the subject of more recent investigations. Animal studies, which dominate the field, have demonstrated the differential expression of miRNAs in brain and blood following ischemic or hemorrhagic insult and the potential use of miRNA antagonists to reduce focal cerebral damage. In particular, antagomirs to miR-145, -497, -181a, -1 and let-7f have been found to be neuroprotective in vivo. The discovery of circulating miRNAs in peripheral blood, which are unexpectedly stable, has allowed the recent completion of several studies in human stroke patients that have confirmed the differential expression of specific miRNAs following stroke and have addressed their potential use as diagnostic and prognostic markers. With miRNA research in stroke still in its infancy, it is anticipated that in the next few years significant discoveries that may have important therapeutic implications will emerge.

In recent years two association studies investigating the HAP1 T441M (rs4523977) polymorphism as a potential modifying factor of the age at onset (AAO) of Huntington's disease (HD), have been reported. Initially evidence for association was found between the M441 risk allele and the AAO. Subsequently, a second study, although failing to replicate these findings, found evidence for association between the same risk allele and AAO of motor symptoms (mAAO). In the present study, the role of the HAP1 T441M polymorphism as a modifier of the AAO in HD was investigated in a cohort of 298 Greek HD patients. In this cohort the CAG repeat number accounted for 55% of the variance in AAO. No association was found between the HAP1 T441M polymorphism and the AAO of HD., (© 2012 Elsevier Ltd. All rights reserved.)

An intronic expansion of a hexanucleotide GGGGCC repeat in the C9ORF72 gene has recently been shown to be an important cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in familial and sporadic cases. The frequency has only been defined in a small number of populations where the highest sporadic rate was identified in Finland (21.1%) and the lowest in mainland Italy (4.1%). We examined the C9ORF72 expansion in a series of 146 Greek ALS cases, 10.95% (n = 16) of cases carried the pathological expansion defined as greater than 30 repeats. In the 10 familial ALS probands, 50% (n = 5) of them carried a pathologically large expansion. In the remaining 136 sporadic ALS cases, 11 were carriers (8.2%). None of the 228 Greek controls carried an expanded repeat. The phenotype of our cases was spinal (13/16) or bulbar (3/16) ALS, the familial cases were all spinal ALS and none of our cases had behavioral frontotemporal dementia. Expansions in the C9ORF72 gene therefore represent a common cause of ALS in Greece and this test will be diagnostically very important to implement in the Greek population. The frequency is higher than other populations with the exception of Finland and this may be due to Greece being a relatively isolated population., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The relative frequency of different autosomal dominant cerebellar ataxias, commonly referred to as spinocerebellar ataxias (SCAs), varies considerably among populations of different ethnic origin. No data exist at present on the frequency of different SCAs in the Greek population. In the present study we investigated the presence of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in a cohort of 83 Greek patients with slowly progressive cerebellar ataxia. Twenty patients came from autosomal dominant (AD) pedigrees, seven displayed recessive or unclear inheritance and 56 were sporadic. We found four patients with pathological SCA expansions, all from AD pedigrees. Two patients had SCA1, one SCA2 and one SCA7 (10.0, 5.0 and 5.0% of the AD group, respectively). The clinical features of these patients were within the expected spectrum. In total, a pathological expansion was detected in 20% of patients from AD pedigrees. Interestingly, no cases of SCA3 or SCA6 were detected in the AD group. No expansions were found in other familial cases or in sporadic patients. Overall, no cases of SCA3, SCA6, SCA12, SCA17 or DRPLA were identified in the Greek population. In conclusion, SCA1, SCA2 and SCA7 are present in Greek patients with AD cerebellar ataxia in frequencies similar to those observed in other populations. SCA3 and SCA6 appear however to be rare in Greece. The genetic cause for the majority of AD ataxias remains to be identified., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Crying as a response to emotionally-charged situations varies greatly among individuals, genders, and cultures. Information on the neural systems involved in crying behavior comes mainly from studies of pathological laughing and crying in patients after brain injury. The authors assessed crying proneness (CPR) as expressed by the score on the "crying easily" item of the SCL-90 questionnaire in 65 men and 105 women subjects in whom lumbar puncture was performed for diagnostic reasons. None of the subjects showed pathological laughing or crying. The authors estimated the levels of the main metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA) in CSF, and searched for associations to CPR score. Subjects with high CPR showed significantly lower MHPG levels than subjects with low CPR, and no differences in 5-HIAA or HVA levels. Higher frequencies of women were found in the subgroups with high CPR. The "crying easily" score was positively associated with the Interpersonal Sensitivity subscale of the SCL-90 questionnaire in female but not in male subjects, indicating the cultural dimension of crying behavior, while it was not associated with the Depression subscale score. It is suggested that central noradrenergic mechanisms control the threshold for tear production in normal crying behavior.

Introduction: Interleukin-15 (IL-15) is a proinflammatory cytokine. RANTES is a member of the beta chemokines subfamily with strong chemoattractant activity for T lymphocytes and monocytes., Materials and Methods: We measured by enzyme-like immunosorbent assay (ELISA) serum levels of IL-15 and RANTES in 24 patients with MS in relapse, 27 patients with stable MS and 21 healthy subjects. Serum levels of IL-15 and RANTES were also measured before, 5 days and 1 month after onset of treatment with methylprednisolone i.v., Results: IL-15 serum levels were higher in patients with relapse compared with patients in stable stage of the disease and healthy subjects (p=0.001 and p=0.008 respectively). RANTES serum levels were increased in patients with relapse and stable disease as compared to healthy subjects (p=0.01). IL-15 and RANTES levels were not decreased after treatment with corticosteroids., Conclusions: Our findings suggest a possible role of IL-15 and RANTES in MS. Treatment with methylprednisolone in relapse had no effect on serum IL-15 and RANTES levels.

Reduced central serotonergic activity and low total serum cholesterol have been related to increased aggression, violent behavior, and suicidality. Searching for a correlation between them, we estimated serum total cholesterol and CSF levels of the main serotonin metabolite 5-HIAA in medication free male and female subjects for whom diagnostic lumbar puncture was performed. To eliminate age influence, we included in the study subjects in the age range 26 to 45years. In a group of 62 subjects (30 males), found negative after diagnostic neurological examination, the correlation was not significant for the whole group, but after sex stratification, a significant positive correlation was revealed for males but not for females. These results were replicated in a second group of 76 subjects (31 males) with clinical and laboratory findings suggestive of multiple sclerosis (clinically isolated syndrome). The results link low cholesterol to low serotonergic activity only in males, predisposing them for violent and risky behaviors. This phenomenon could be seen as an evolutionary trait, possibly a result of the distinct role of males in a hunter-gatherer environment of evolutionary adaptedness, and may contribute to the understanding of the higher incidence of violent behavior observed in males., (Copyright 2010 Elsevier Inc. All rights reserved.)

Neuropsychiatric symptoms are common in multiple sclerosis (MS). They include two broad categories of disturbances: abnormalities in cognition, and abnormalities of mood, affect and behaviour. The present review deals with the epidemiology, clinical features, etiology and treatment of disturbances included in the second category, i.e., major depression, fatigue and sleep disorders, bipolar disorder, euphoria, pathological laughing and crying, anxiety, psychosis and personality changes. Major depression is one of the most common neuropsychiatric disorders in MS with an approximate 50% lifetime prevalence rate. Early recognition and management of depression in MS is of major importance because it is a key predictor of morbidity, mortality, quality of life, possibly physical outcome and disease exacerbations, adherence to immunomodulatory treatments and suicide risk in MS patients, as well as of the caregiver's distress and quality of life. The etiopathogenesis of neuropsychiatric disorders in MS has been incompletely investigated. It is postulated that a complex interplay of biological, disease-related, behavioural and psychosocial factors contribute to the pathophysiology of most of them. Management of neuropsychiatric symptoms in MS is often effective, although commonly based on evidence provided by case studies and uncontrolled trials. A comprehensive biopsychosocial neuropsychiatric approach is essential for the optimal care of patients with MS.