Video-Oculography Assessment in Neurodegenerative Ataxias and Niemann Pick Type C.

Introduction: Deceleration of vertical saccades, an early and characteristic finding of Niemann-Pick Type C (NP-C), may help diagnosis. Our aim in this study was to demonstrate the role of video-oculography (VOG), in the differential diagnosis of ataxia syndromes, particularly of NP-C, using this technique in the evaluation of saccadic velocity and smooth pursuit gain of ataxia patients. Methods: We recruited consecutive 50 ataxia patients and 50 healthy control subjects who were age and sex-matched with the patient group. Saccadic eye movements and smooth pursuit eye movements for different angles and different directions from patients and healthy subjects were recorded by using VOG. Results: Saccadic eye movement velocity and smooth pursuit gain values of the patients were significantly lower in all directions and at all angles as compared to healthy subjects. In the patient group, 3 cases out of 50 were selected as suspected NP-C, based on the dissociation between their markedly impaired vertical saccadic velocity and near normal to slightly impaired horizontal one and relatively intact smooth pursuit eye movements; the diagnoses in all 3 cases were confirmed with positive genetic testing, and thereupon Miglustat treatment was started. Conclusion: Our findings support that cerebellar pathology in degenerative ataxia patients is associated with both impaired saccadic velocity and smooth pursuit gain, whereas in NP-C, only the impaired vertical saccades as opposed to relatively preserved other eye movements are seemingly a diagnostic marker for the entity. We conclude that recording of eye movements could be useful for differential diagnosis and monitorization of the treatment of ataxia syndromes as an easy and objective method.

Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.

Autoimmune Encephalitis with Antibodies Against A-Amino-3hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor and γ-Aminobutyric Acid-Beta Receptor: Case Report.

Introduction: Limbic encephalitis is a rapidly progressing disease that presents with seizures, psychiatric symptoms, and recent memory loss. Detection of more than one autoantibody is a rare condition in this disease where an underlying autoantibody is frequently detected. Although different autoantibodies have been reported in the literature, no case has been reported regarding the association of anti-γ-aminobutyric acid-beta-receptor (anti-GABABR) and anti-α-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (anti-AMPAR). Case: In this presentation, a 46-year-old female patient with subacute development of short-term memory loss and behavioral symptoms will be described. Anti-GABABR and anti-AMPAR were positive in the anti-neuronal antibody panel sent from the cerebrospinal fluid and serum. Small cell lung cancer was detected as a result of malignancy screening tests. The patient's complaints and autoantibody positivity regressed after immunotherapy. Conclusion: In this case report, a case with coexistence of anti-GABABR and anti-AMPAR antibodies, which has not been previously reported in the literature, is described. As more cases with the coexistence of these two antibodies are detected, knowledge on clinical aspect, laboratory and treatment will increase.

Kappa/Lambda light-chain typing in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is a progressive neurodegenerative disorder characterized by memory loss and cognitive impairment. The diagnosis of Alzheimer's disease according to symptomatic events is still a puzzling task. Developing a biomarker-based, low-cost, and high-throughput test, readily applicable in clinical laboratories, dramatically impacts the rapid and reliable detection of the disease. OBJECTIVE: This study aimed to develop an accurate, sensitive, and reliable screening tool for diagnosing Alzheimer's disease, which can significantly reduce the cost and time of existing methods. METHODS: We have employed a MALDI-TOF-MS-based methodology combined with a microaffinity chromatography enrichment approach using affinity capture resins to determine serum kappa (κ) and lambda (λ) light chain levels in control and patients with AD. RESULTS: We observed a statistically significant difference in the kappa light chain over lambda light chain (κLC/λLC) ratios between patients with AD and controls (mean difference -0,409; % 95 CI:- 0.547 to -0.269; p<0.001). Our method demonstrated higher sensitivity (100.00%) and specificity (71.43%) for discrimination between AD and controls. CONCLUSION: We have developed a high-throughput screening test with a novel sample enrichment method for determining κLC/λLC ratios associated with AD diagnosis. Following further validation, we believe our test has the potential for clinical laboratories.

Frequency of frontotemporal dementia-related gene variants in Turkey.

Just as its clinical heterogeneity, genetic basis of Frontotemporal dementia (FTD) is also diverse and multiple molecular pathways are thought to be involved in disease pathogenesis. In the present study, FTD- related genes were evaluated in a Turkish cohort of 175 index FTD patients with a gene panel including GRN, MAPT, TARDBP, FUS, CHMP2B and VCP genes. Potential genetic associations were prospected in 16 patients (9.1%); five variants (p.(Gly35Glufs) and p.(Cys253Ter) in GRN; p.(Arg95Cys) in VCP; p.(Met405Val) in TARDBP and p.(Pro636Leu) in MAPT) were classified as pathogenic (P) or likely pathogenic (LP), in four familial and one sporadic patients. Three novel variants in MAPT, CHMP2B and FUS were also identified in familial cases. The most common pathogenic variants were observed in the GRN gene with a frequency of 1.14% (2/175) and this rate was 4.57% (8/175), including variants of uncertain significance (VUS). In this study with the largest cohort of Turkish FTD patients, GRN and MAPT variants were identified as the most common genetic associations; and rare causes like VCP, TARDBP, CHMP2B and FUS variants are recommended to be considered in patients with compatible clinical findings.

Inflammation and regulatory T cell genes are differentially expressed in peripheral blood mononuclear cells of Parkinson's disease patients.

Our aim was to identify the differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMC) of Parkinson's disease (PD) patients and healthy controls by microarray technology and analysis of related molecular pathways by functional annotation. Thirty PD patients and 30 controls were enrolled. Agilent Human 8X60 K Oligo Microarray was used for gene level expression identification. Gene ontology and pathway enrichment analyses were used for functional annotation of DEGs. Protein-protein interaction analyses were performed with STRING. Expression levels of randomly selected DEGs were quantified by real time quantitative polymerase chain reaction (RT-PCR) for validation. Flow cytometry was done to determine frequency of regulatory T cells (Tregs) in PBMC. A total of 361 DEGs (143 upregulated and 218 downregulated) were identified after GeneSpring analysis. DEGs were involved in 28 biological processes, 12 cellular components and 26 molecular functions. Pathway analyses demonstrated that upregulated genes mainly enriched in p53 (CASP3, TSC2, ATR, MDM4, CCNG1) and PI3K/Akt (IL2RA, IL4R, TSC2, VEGFA, PKN2, PIK3CA, ITGA4, BCL2L11) signaling pathways. TP53 and PIK3CA were identified as most significant hub proteins. Expression profiles obtained by RT-PCR were consistent with microarray findings. PD patients showed increased proportions of CD49d+ Tregs, which correlated with disability scores. Survival pathway genes were upregulated putatively to compensate neuronal degeneration. Bioinformatics analysis showed an association between survival and inflammation genes. Increased CD49d+ Treg ratios might signify the effort of the immune system to suppress ongoing neuroinflammation.

Small ubiquitin-related modifier (SUMO) 3 and SUMO4 gene polymorphisms in Parkinson's disease.

Objectives: The ubiquitin/proteasome system is one of the main axes of the pathogenesis of Parkinson's disease (PD). Small ubiquitin-related modifier (SUMO) proteins are involved in many biochemical events including regulation of transcriptional activity, modulation of signal transduction pathways, and response to cellular stress indicating a role for SUMO in the ubiquitin/proteasome system.Methods: In this study, our aim was to examine the prevalence of SUMO gene variants and their clinical associations in PD. Fifty-four consecutively recruited PD patients (34 male, 20 female) and 74 age-gender matched healthy controls (37 male, 37 female) were included. SUMO1, 2, 3 and 4 genes were screened by a next generation sequencing method using blood samples of participants. Single nucleotide polymorphisms (SNPs) with a significantly altered prevalence were determined by Bonferroni correction.Results: Two SNPs in the SUMO4 gene (rs237025 and rs237024) and two SNPs in the SUMO3 gene (rs180313 and rs235293) were found to have altered prevalence in PD. Although there was no association among these SNPs and clinical features of the patients, an increased family history of cancer was found in patients with SUMO3 gene variants.Discussion: Several SUMO SNPs were identified for the first time in PD patients suggesting that SUMO is involved in the pathophysiology of the disease. rs237025 has also been associated with diabetes mellitus indicating a pathogenic mechanism for SUMO that is shared with other degenerative disorders.

Smoking-responsive juvenile-onset Parkinsonism.

We describe a patient with juvenile levodopa-responsive Parkinsonism who reported a dramatic response to cigarette smoking with transient but marked improvement of motor symptoms associated with oculogyric crises and psychotic behavior. His beta-CIT single-photon emission computed tomography scan showed a complete absence of presynaptic dopaminergic nerve terminals.

Mitochondrial complex I, II/III, and IV activities in familial and sporadic Parkinson's disease.

A possible role of mitochondrial respiratory chain dysfunction in the pathogenesis of sporadic Parkinson's disease (PD) has been described. There are only a few reports concerning mitochondrial involvement in familial Parkinson's disease. The present study investigated mitochondrial complex I-IV activity in patients with sporadic and familial PD, compared to controls. Platelets were isolated from venous blood and platelet mitochondria were obtained through sonication and differential centrifugation. Complex I, II/III, and IV activities were measured in 17 patients with family history of Parkinson's disease (PDF), 15 patients with sporadic Parkinson disease (PDS), and 17 age-matched, healthy controls. The mitochondrial enzyme activities did not differ significantly between patient groups and controls. In addition, there was no correlation between mitochondrial complex activities and age, severity of disease, or age at onset of disease in the patient groups. In this study, the data indicate no significant differences in mitochondrial complex I-IV activities in PDF and PDS.