Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). Results: Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific diseaseassociated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. Conclusions: To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

Background: Pathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia. Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse. Results: We delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5-/- mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/-, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5-/- mice. In contrast, Gnb5-/- mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients. Conclusions: Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5-/- mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants.

Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1-/- mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy

Genetic association study in genes related to stroke

Background and Purpose: There is accumulating evidence that genetic elements contribute to the pathogenesis of primary intracerebral hemorrhage (PICH). Alpha-1 antichymotrypsin (ACT), angiotensin converting enzyme (ACE) and interleukins (IL) 1a, 1b and 1Ra are implicated in vascular pathology and coagulation processes. TT genotype of the ACT A/T signal peptide polymorphism and DD genotype of ACE I/D polymorphism have been reported to confer susceptibility for PICH. We conducted a prospective study to test possible association between ACT A/T signal peptide, ACE I/D, IL-1a (-899), IL-1b (-511) and IL-1Ra (VNTR) polymorphisms and PICH in a Greek cohort. Methods: 178 patients with PICH were prospectively recruited in the study. ACT A/T signal peptide, ACE I/D, IL-1a (-899), IL-1b (-511) and IL-1Ra (VNTR) genotypes were determined in patients and 206 healthy, age and sex matched control subjects collected from Neurology outpatient Clinic using polymerase chain reaction restriction fragment length polymorphism method. Initial neurological status of patients was assessed by means of the Glasgow Coma Score, while we defined patients’ six-month outcome using the modified Rankin Scale. Epidemiological risk factors as well as location and volume of the hemorrhage were also recorded. Possible associations were examined using the t-test, the Fisher’s exact test and the χ2 test. Odds ratios with the corresponding 95% confidence intervals were calculated using logistic regression analysis. Results: No statistically significant difference was found in allele and genotype frequencies of all polymorphisms between patients and normal controls. (ACT polymorphism [OR(95% C.I.)]=1.14(0.64-2.01), ACE=1.08(0.58-1.82), IL-1α(-899)=1.03 (0.55-2.02), IL-1β(-511)=0.66(0.51-1.53), IL-1ra (VNTR)=1.27(0.62-2.54). However, our study showed an association [OR (95%C.I.)=2.57 (1.02-6.51), p=0.05] between ACT TT genotype and normotensive PICH patients. Conclusions: Our data confirm the previously reported association between ACT A/T signal peptide polymorphism and normotensive PICH patients. In the non-hypertensive patients, although they represent a heterogenic group, it is possible, that the absence of hypertension unmask the relatively minor effects of ACT A/T signal peptide polymorphism on cerebral vasculature making it more susceptible to hemorrhage. However, further studies should be conducted to confirm and evaluate this association.Εισαγωγή και σκοπός: Στην παθογένεση της πρωτοπαθούς ενδοεγκεφαλικής αιμορραγίας (ΠΕΑ) εμπλέκονται τόσο γενετικοί όσο και επιδημιολογικοί παράγοντες κινδύνου. Η Α1-αντιχυμοθρυψίνη (ACT), το μετατρεπτικό ένζυμο της αγγειοτενσίνης (ACE) και οι ιντερλευκίνες (IL) 1α, 1β και 1Ra έχει βρεθεί ότι εμπλέκονται στην παθολογία του αγγειακού τοιχώματος και τους μηχανισμούς πήξης. Μελέτες έχουν δείξει ότι ο ΤΤ γονότυπος του Α/Τ πολυμορφισμού του πεπτιδίου συνθήματος της ACT και ο DD γονότυπος του I/D πολυμορφισμού του ACE αυξάνουν τον κίνδυνο εμφάνισης ΠΕΑ. Σκοπός της παρούσας προοπτικής μελέτης είναι η διερεύνηση πιθανής συσχέτισης μεταξύ των ACT A/T, ACE I/D, IL-1α (-899), IL-1β (-511) και IL-1Ra (VNTR) γενετικών πολυμορφισμών και Ελλήνων ασθενών με ΠΕΑ. Μέθοδος: Η μελέτη διενεργήθηκε σε 178 ασθενείς με ΠΕΑ και 206 φυσιολογικούς μάρτυρες σε αντιστοιχία με τους ασθενείς ως προς την ηλικία και το φύλο. Κατά την καταγραφή των ασθενών μεταξύ των στοιχείων που συλλέχθηκαν αξιολογήθηκαν τα εξής: ηλικία, φύλο, επιδημιολογικοί παράγοντες κινδύνου, εντόπιση και όγκος της αιμορραγίας, κλίμακα κώματος Γλασκώβης κατά την είσοδο του ασθενούς και 6μηνη έκβαση σύμφωνα με την τροποποιημένη κλίμακα του Rankin. Η ταυτοποίηση των γονοτύπων της ACT (-15 A/T), του ACE I/D, της IL-1α (-899), της IL-1β(-511C/T) και της IL-1ra (VNTR) έγιναν με γνωστές PCR/RFLP μεθόδους. Πιθανές συσχετίσεις εξετάσθηκαν με τη χρήση του Fisher’s exact test, του t-test και του χ2 test και οι αναλογίες πιθανοτήτων με τα αντίστοιχα 95% διαστήματα εμπιστοσύνης υπολογίστηκαν με βάση την ανάλυση με λογιστική παλινδρόμηση. Αποτελέσματα: Από τη μελέτη δεν προέκυψε κάποια στατιστικώς σημαντική διαφορά στις συχνότητες των γονοτύπων και των αλληλομόρφων μεταξύ των ασθενών και των φυσιολογικών μαρτύρων στους εξετασθέντες πολυμορφισμούς (για τον πολυμορφισμό της ACT [OR(95% C.I.)]=1.14(0.64-2.01), ACE=1.08(0.58-1.82), IL-1α(-899)=1.03(0.55-2.02), IL-1β(-511)=0.66(0.51-1.53), IL-1ra (VNTR)=1.27(0.62-2.54). Στη μελέτη μας όμως διαπιστώθηκε ότι ο γονότυπος ΤΤ της ACT σχετίζεται με αυξημένο κίνδυνο πρόκλησης ΠΕΑ στους μη υπερτασικούς ασθενείς OR (95% C.I.)=2.57 (1.02-6.51) p=0.05. Συμπεράσματα: Η μελέτη μας επιβεβαιώνει τα θετικά αποτελέσματα που έχουν αναφερθεί στους μη υπερτασικούς ασθενείς με ΠΕΑ. Η απουσία υπέρτασης, που αποτελεί τον κύριο παράγοντα κιν­δύ­νου για την εκδήλωση της ΠΕΑ, πιθανόν να καθιστά φανερή την επίδραση του ACT πολυμορφισμού στο αγγειακό δίκτυο του εγκεφάλου αυξάνοντας την ευαισθησία για αιμορραγία. Ωστόσο, απαιτείται περαιτέρω έρευνα για την επιβεβαίωση των παραπάνω συσχετίσεων και την εξακρίβωση των υποκείμενων παθογενετικών μηχανισμώ

From Broca and Wernicke to the Neuromodulation Era: Insights of Brain Language Networks for Neurorehabilitation

Communication in humans activates almost every part of the brain. Of course, the use of language predominates, but other cognitive functions such as attention, memory, emotion, and executive processes are also involved. However, in order to explain how our brain “understands,” “speaks,” and “writes,” and in order to rehabilitate aphasic disorders, neuroscience has faced the challenge for years to reveal the responsible neural networks. Broca and Wernicke (and Lichtheim and many others), during the 19th century, when brain research was mainly observational and autopsy driven, offered fundamental knowledge about the brain and language, so the Wernicke-Geschwind model appeared and aphasiology during the 20th century was based on it. This model is still useful for a first approach into the classical categorization of aphasic syndromes, but it is outdated, because it does not adequately describe the neural networks relevant for language, and it offers a modular perspective, focusing mainly on cortical structures. During the last three decades, neuroscience conquered new imaging, recording, and manipulation techniques for brain research, and a new model of the functional neuroanatomy of language was developed, the dual stream model, consisting of two interacting networks (“streams”), one ventral, bilaterally organized, for language comprehension, and one dorsal, left hemisphere dominant, for production. This new model also has its limitations but helps us to understand, among others, why patients with different brain lesions can have similar language impairments. Furthermore, interesting aspects arise from studying language functions in aging brains (and also in young, developing brains) and in cognitively impaired patients and neuromodulation effects on reorganization of brain networks subserving language. In this selective review, we discuss methods for coupling new knowledge regarding the functional reorganization of the brain with sophisticated techniques capable of activating the available supportive networks in order to provide improved neurorehabilitation strategies for people suffering from neurogenic communication disorders

The Role of the T2–FLAIR Mismatch Sign as an Imaging Marker of IDH Status in a Mixed Population of Low- and High-Grade Gliomas

Our study evaluated the role of the T2–fluid-attenuated inversion recovery (FLAIR) mismatch sign in detecting isocitrate dehydrogenase (IDH) mutations based on a mixed sample of 24 patients with low- and high- grade gliomas. The association between the two was realized using univariate and multivariate logistic regression analysis. There was a substantial agreement between the two raters for the detection of the T2–FLAIR mismatch sign (Cohen’s kappa coefficient was 0.647). The T2–FLAIR mismatch sign when co-registered with the degree of tumor homogeneity were significant predictors of the IDH status (OR 29.642; 95% CI 1.73–509.15, p = 0.019). The probability of being IDH mutant in the presence of T2–FLAIR mismatch sign was as high as 92.9% (95% CI 63–99%). The sensitivity and specificity of T2–FLAIR mismatch sign in the detection of the IDH mutation was 88.9% and 86.7%, respectively. The T2–FLAIR mismatch sign may be an easy to use and helpful tool in recognizing IDH mutant patients, particularly if formal IDH testing is not available. We suggest that the adoption of a protocol based on imaging and histological data for optimal glioma characterization could be very helpful

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5-10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important because it improves their therapeutic efficacy. Current diagnosis is based on clinical assessment and requires approximately 12 months, leading to a significant delay in drug administration. Therefore, new methods are required for the earlier diagnosis of ALS. Screening for pathogenic variants in known ALS-associated genes is already exploited as a diagnostic tool in ALS but cannot be applied for population-based screening. New circulating biomarkers (proteins or small molecules) are needed for initial screening, whereas specific diagnostic methods can be applied to confirm the presence of pathogenic variants in the selected population subgroup. Lipids appear as promising biomarkers for population-based screening and for monitoring disease progression. Genetic analysis can also assist in the prediction of disease progression by analyzing disease-modifying genes, for example, EPHA4 and CHGB. Furthermore, molecular diagnosis will aid the stratification of ALS patients for improved pharmacological approaches. Here, we discuss current and novel diagnostic strategies and how they can be applied to revolutionize the field of ALS molecular diagnosis

Primary Sjogren's syndrome (pSS)-related cerebellar ataxia: a systematic review and meta-analysis

Background Primary Sjogren’s syndrome (pSS) is a chronic autoimmune disorder characterized by lymphocytic infiltrates of the exocrine glands, particularly the salivary and lacrimal glands, resulting in oral and ocular dryness. pSS has been linked to various neurological manifestations, including cerebellar dysfunction. We aimed to provide a comprehensive analysis of the currently available evidence regarding pSS-related cerebellar ataxia. Methods A systematic literature search in the PubMed database was performed and 19 papers were eligible to be included in this paper. Results The pooled prevalence of cerebellar ataxia in pSS is estimated to be 1.5% (95% CI 0.3-6.8%). pSS patients with cerebellar involvement have a female-to-male ratio of 6:1. Although most of the patients are adults in their fifth decade of life when diagnosed, cases of children with pSS and cerebellar involvement have been reported. Typical cerebellar ataxia related to pSS manifests with vermian dysfunction, namely gait ataxia and/or cerebellar speech. Cerebellar ataxia due to pSS may also mimic degenerative cerebellar ataxia, especially when the onset is progressive. Conclusions The diagnostic approach to a patient with cerebellar ataxia of unknown etiology should include evaluation for an underlying pSS. A thorough history and clinical examination, antibody testing, brain MRI imaging and/or MRS of the cerebellum will assist in establishing the diagnosis. Setting up a joint neuro-rheumatology clinic can be valuable given that rheumatic and neurological diseases share comorbidities