Μελέτη της προμηκονωτιαίας μυϊκής ατροφίας (νόσος Kennedy) στον ελληνικό πληθυσμό

Εισαγωγή Η προμηκονωτιαία μυϊκή ατροφία, γνωστή και ως νόσος του Kennedy, είναι μια σπάνια φυλοσύνδετη κληρονομική νόσος του κατώτερου κινητικού νευρώνα, με προεξάρχον κλινικό σύμπτωμα την προοδευτική μυϊκή αδυναμία. Σκοπός της παρούσας μελέτης ήταν η διερεύνηση της συχνότητας, της γεωγραφικής κατανομής και των χαρακτηριστικών της νόσου Kennedy στον ελληνικό πληθυσμό. Μέθοδος Στην παρούσα μελέτη συμπεριλήφθηκαν 234 ασθενείς με υποψία προμηκονωτιαίας ατροφίας που παραπέμφθηκαν στη Μονάδα Νευρογενετικής της Α΄ Νευρολογικής Κλινικής του Πανεπιστημίου Αθηνών, στο Αιγινήτειο Νοσοκομείο μέσα σε διάστημα 16 ετών. Πραγματοποιήθηκε απομόνωση DNA από περιφερικό αίμα και προσδιορισμός των επαναλήψεων CAG σε κάθε αλλήλιο του γονίδιου AR. Αποτελέσματα Από το 2001 έως το 2016 εντοπίστηκαν συνολικά 16 θετικοί ασθενείς για τη νόσο Kennedy και 10 γυναίκες-φορείς της μεταλλαγής της νόσου. Ο συνολικός αριθμός των θετικών Ελλήνων ασθενών για νόσο Kennedy ήταν μικρότερος από τον αναμενόμενο. Αυξημένη συχνότητα διαπιστώθηκε στα νησιά του Αιγαίου, με εστία υψηλής συχνότητας (cluster) στη Χίο. Το γονοτυπικό και το φαινοτυπικό φάσμα της νόσου Kennedy δεν διέφερε σημαντικά από άλλους πληθυσμούς. Συμπεράσματα H συχνότητα της νόσου Kennedy στην Ελλάδα είναι ενδεχομένως χαμηλότερη από την αναμενόμενη. Ωστόσο, δε μπορεί να αποκλειστεί το ενδεχόμενο η νόσος Kennedy να υποδιαγιγνώσκεται. Συνεπώς, ο κλινικός ιατρός πρέπει να διατηρεί υψηλή την υποψία της νόσου, ώστε να διενεργείται έγκαιρα ο μοριακός και ο προγεννητικός έλεγχος.Introduction Spinobulbar muscular atrophy, also known as Kennedy’s disease, is a rare, X-linked, hereditary lower motor neuron disease, with prominent clinical symptom progressive muscle weakness. The objective of this study was to investigate the frequency, geographical distribution and characteristics of Kennedy’s disease in the Greek population. Methods The study included 234 patients with suspected Kennedy’s disease referred to the Neurogenetics Unit of the Eginition Hospital in Athens, over a period of 16 years. DNA was isolated from peripheral blood and the CAG-repeat number was estimated in each allele of AR gene. Results From 2001 to 2016, a total of 16 patients were found positive for Kennedy’s disease and 10 women were mutation carriers. The number of Greek patients with Kennedy’s disease was lower than the expected. A higher prevalence was noted in the Aegean islands, with a cluster of high frequency in the island Chios. The genotypic and phenotypic spectrum of Kennedy’s disease was not significantly different from that documented in other populations. Conclusions The frequency of Kennedy’s disease in Greece is probably lower than the expected. However, we cannot exclude the possibility of underdiagnosis. Consequently, the clinicians must maintain a high index of suspicion for Kennedy’s disease, so as a molecular and prenatal genetic test will be promptly requested

Therapeutic Management: When and What

Migraine is a widespread brain disease that is classified as the second most disabling condition and has the third highest prevalence of all medical conditions. Despite its non-emergent or life-threatening nature, migraine can progress to chronic type, a subform associated with significant morbidity and drug overuse. In the management of migraine, it is important therefore to introduce early prophylactic treatment in order to limit migraine chronification. In this chapter, we will go through all the treatment options, both acute and preventive, pharmaceutical and non-pharmaceutical following this flowchart: 1. Introduction; 2. General principles; 2.1 Symptomatic therapy; 2.2 Prophylactic management; 3. Pharmaceutical therapies; 3.1 Symptomatic; 3.1.1 Disease-specific; 3.1.2 No disease-specific; 3.2 Prophylactic; 3.2.1 Disease-specific; 3.2.2 No disease-specific; 3.3 Non-Pharmaceutical therapies; 3.4 Neuromodulation; 3.4.1 Invasive; 3.4.5 Non-invasive; 3.5 Nutrient (nutraceuticals); 3.6 Dietary interventions; 3.7 Acupuncture; 3.8 Physical therapy; 4. Cognitive behavioral therapies; 5. Patient centricity and patient education

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

Βιολογικοί και απεικονιστικοί βιοδείκτες στη νόσο Huntington

Huntington’s Disease (HD) is a devastating, neurodegenerative disease with no cure available to date. Several clinical trials have failed and robust biomarkers are needed towards better study design. In this thesis, clinical, cognitive, imaging and biofluid (serum NfL and alpha-synuclein) known and potential markers were analyzed using a tailored framework, to characterize patients with manifest HD as well as pre-manifest HD, in comparison to controls. All biomarker data were compared between manifest and pre-manifest HD, as well as matched controls. Furthermore, data from clinical scales, such as the Unified Huntington Disease Rating Scale), neuropsychiatric scales, and an extensive neuropsychological battery were correlated to baseline neuroimaging findings (using whole-brain and region of interest analysis) and other biomarker data. Summarizing the most important findings, neuromelanin-MRI values, (a novel MRI sequence), were correlated in HD for the first time with finger-tapping, apathy scale and HD-QoL. In addition, a pilot study with measurements of serum a-synuclein levels in HD was conducted showing elevated levels in manifest HD patients. As an adjunct, genetic data from a recent GWAS in collaboration with UCL were used in parallel with other available DNA & RNA open databases to run computational analyses, with a view to provide further insight on the SNCA pathway and other specific pathways implicated in the pathophysiology of HD. In conclusion, the present thesis adds to the ongoing quest for biomarkers in HD hoping to lead to a better understanding of the disease as well as the prodromal phase of the disease, where upcoming treatments could be more efficient.Huntington’s Disease (HD) is a devastating, neurodegenerative disease with no cure available to date. Several clinical trials have failed and robust biomarkers are needed towards better study design. In this thesis, clinical, cognitive, imaging and biofluid (serum NfL and alpha-synuclein) known and potential markers were analyzed using a tailored framework, to characterize patients with manifest HD as well as pre-manifest HD, in comparison to controls. All biomarker data were compared between manifest and pre-manifest HD, as well as matched controls. Furthermore, data from clinical scales, such as the Unified Huntington Disease Rating Scale), neuropsychiatric scales, and an extensive neuropsychological battery were correlated to baseline neuroimaging findings (using whole-brain and region of interest analysis) and other biomarker data. Summarizing the most important findings, neuromelanin-MRI values, (a novel MRI sequence), were correlated in HD for the first time with finger-tapping, apathy scale and HD-QoL. In addition, a pilot study with measurements of serum a-synuclein levels in HD was conducted showing elevated levels in manifest HD patients. As an adjunct, genetic data from a recent GWAS in collaboration with UCL were used in parallel with other available DNA & RNA open databases to run computational analyses, with a view to provide further insight on the SNCA pathway and other specific pathways implicated in the pathophysiology of HD. In conclusion, the present thesis adds to the ongoing quest for biomarkers in HD hoping to lead to a better understanding of the disease as well as the prodromal phase of the disease, where upcoming treatments could be more efficient

Wide range of reduced penetrance alleles in spinal and bulbar muscular atrophy: a model-based approach

Background Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is an X-linked motor neuron disorder caused by an expanded CAG repeat in the gene coding for the androgen receptor (AR). The range and significance of reduced penetrance alleles in SBMA has not been fully determined to date. We presently sought to determine the range of reduced penetrance alleles in SBMA. Methods Through systematic literature review and meta-analysis, we collected and analysed data from 2576 patients with SBMA and compared the distributions of the CAG repeat number (CAG)(n) in the AR gene between patients and 112 248 control alleles of the general population. Results Our analysis revealed an unexpectedly high frequency of expanded SBMA-associated alleles, with (CAG)(n) >= 35 present in 107/100,000 and (CAG)(n) >= 38 present in 27/100,000 of the general population. Consequently, we suggest an updated model describing the distribution of expanded alleles in the general population. We argue against the established cut-off principle for the penetrance of SBMA and suggest that penetrance gradually increases from 35 to approximately 46 (CAG)(n), above which it reaches a plateau approaching maximum value. Conclusion Asymptomatic men of the general population with no/unknown SBMA family history are free of risk when carrying (CAG)(n) <= 34, are at intermediate but increasing risk for developing SBMA when carrying (CAG)(n) approximate to 35-46 and have close to 100% risk of developing the disease when carrying (CAG)(n) >= 47. The above observations should be helpful and clinically useful when providing genetic counselling to individuals and families bearing SBMA-associated alleles

FYN, SARS-CoV-2, and IFITM3 in the neurobiology of Alzheimer's disease

Introduction: (IFITM3) is an innate immune protein that has been identified as a novel γ-secretase (γs) modulator. FYN is a kinase that stabilizes IFITM3 on the membrane, primes APP for amyloidogenic γs processing and mediates tau oligomerization. The purpose of this study is to explore the role of FYN and IFITM3 in AD and COVID-19, expanding on previous research from our group. Methods: A 520 gene signature containing FYN and IFITM3 (termed Ia) was extracted from a previously published meta-analysis of Alzheimer's disease (AD) bulk- and single nuclei sequencing data. Exploratory analyses involved meta-analysis of bulk and single cell RNA data for IFITM3 and FYN differential expression per CNS site and cellular type. Confirmatory analyses, gene set enrichment analysis (GSEA) on Ia was performed to detect overlapping enriched biological networks between COVID-19 with AD. Results: Bulk RNA data analysis revealed that IFITM3 and FYN were overexpressed in two CNS regions in AD vs. Controls: the temporal cortex Wilcoxon p-value=1.3e-6) and the parahippocampal cortex Wilcoxon p-value=0.012). Correspondingly, single cell RNA analysis of IFITM3 and FYN revealed that it was differentially expressed in neurons, glial and endothelial cells donated b AD patients, when compared to controls. Discussion: IFITM3 and FYN were found as interactors within biological networks overlapping between AD and SARS-CoV-2 infection. Within the context of SARS-CoV-2 induced tau aggregation and interactions between tau and Ab1–42, the FYN – IFITM3 regulome may outline an important innate immunity element responsive to viral infection and IFN-I signaling in both AD and COVID-19

Monoclonal Antibodies Targeting CGRP: From Clinical Studies to Real-World Evidence—What Do We Know So Far?

Now more than ever is the time of monoclonal antibody use in neurology. In headaches, disease-specific and mechanism-based treatments existed only for symptomatic management of migraines (i.e., triptans), while the standard prophylactic anti-migraine treatments consist of non-specific and repurposed drugs that share limited safety profiles and high risk for interactions with other medications, resulting in rundown adherence rates. Recent advances in headache science have increased our understanding of the role of calcitonin gene relate peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) pathways in cephalic pain neurotransmission and peripheral or central sensitization, leading to the development of monoclonal antibodies (mAbs) or small molecules targeting these neuropeptides or their receptors. Large scale randomized clinical trials confirmed that inhibition of the CGRP system attenuates migraine, while the PACAP mediated nociception is still under scientific and clinical investigation. In this review, we provide the latest clinical evidence for the use of anti-CGRP in migraine prevention with emphasis on efficacy and safety outcomes from Phase III and real-world studies