The GAA repeat expansion is a major cause of ataxia in the Cypriot population.

Dominantly inherited intronic GAA repeat expansions in the fibroblast growth factor 14 gene have recently been shown to cause spinocerebellar ataxia 27B. Currently, the pathogenic threshold of (GAA) repeat units is considered highly penetrant, while (GAA) is likely pathogenic with reduced penetrance. This study investigated the frequency of the GAA repeat expansion and the phenotypic profile in a Cypriot cohort with unresolved late-onset cerebellar ataxia.

Genetic epidemiology of amyotrophic lateral sclerosis in Cyprus: a population-based study.

Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disease of motor neurons, presenting with relentlessly progressive muscle atrophy and weakness. More than fifty genes carrying causative or disease-modifying variants have been identified since the 1990s, when the first ALS-associated variant in the gene SOD1 was discovered. The most commonly mutated ALS genes in the European populations include the C9orf72, SOD1, TARDBP and FUS.

Glial Cells as Key Regulators in Neuroinflammatory Mechanisms Associated with Multiple Sclerosis.

Even though several highly effective treatments have been developed for multiple sclerosis (MS), the underlying pathological mechanisms and drivers of the disease have not been fully elucidated. In recent years, there has been a growing interest in studying neuroinflammation in the context of glial cell involvement as there is increasing evidence of their central role in disease progression. Although glial cell communication and proper function underlies brain homeostasis and maintenance, their multiple effects in an MS brain remain complex and controversial.

Lumbar Intrathecal Injection in Adult and Neonatal Mice.

This article describes a step-by-step process of lumbar intrathecal injection of Evans blue dye and AAV9-EGFP in adult (2-month-old) and neonatal (postnatal day 10) mice. Intrathecal injection is a clinically translatable technique that has already been extensively applied in humans. In mice, intrathecal injection is considered a challenging procedure that requires a trained and experienced researcher.

Repeat Distribution in the Cypriot Population: Study of a Large Cohort of Patients With Undiagnosed Ataxia and Non-Disease Controls.

Background And Objectives: The intronic biallelic AAGGG expansion in the replication factor C subunit 1 () gene was recently associated with a phenotype combining cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, as well as with late-onset ataxia. Following this discovery, studies in multiple populations extended the phenotypic and genotypic spectrum of this locus. Multiple benign and additional pathogenic configurations are currently known.

Highly Active Relapsing-Remitting Multiple Sclerosis with Neurofibromatosis Type 1: Radiological Aspects and Therapeutic Challenges - Case Report.

Introduction: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease which can rarely co-exist with neurofibromatosis 1 (NF1), a neurocutaneous inherited disorder that predisposes to oncogenesis. Patients who suffer from both conditions can be challenging cases for clinicians, as clinical symptoms and radiological findings may overlap, while MS immune-modifying treatments could further increase the risk of oncogenesis.

Case Presentation: In this study, we describe the case of a 27-year-old woman who presented with signs and symptoms of optic neuritis and was then diagnosed with both MS and NF1.

Gene replacement therapy in two Golgi-retained CMT1X mutants before and after the onset of demyelinating neuropathy.

X-linked Charcot-Marie-Tooth disease type 1 (CMT1X) is a demyelinating neuropathy resulting from loss-of-function mutations affecting the /connexin 32 (Cx32) gene. We previously showed functional and morphological improvement in -null mice following AAV9-mediated delivery of human Cx32 driven by the myelin protein zero (Mpz) promoter in Schwann cells. However, CMT1X mutants may interfere with virally delivered wild-type (WT) Cx32.

AAV9-mediated SH3TC2 gene replacement therapy targeted to Schwann cells for the treatment of CMT4C.

Type 4C Charcot-Marie-Tooth (CMT4C) demyelinating neuropathy is caused by autosomal recessive SH3TC2 gene mutations. SH3TC2 is highly expressed in myelinating Schwann cells. CMT4C is a childhood-onset progressive disease without effective treatment.

FUS-mediated blood-brain barrier disruption for delivering anti-Aβ antibodies in 5XFAD Alzheimer's disease mice.

Purpose: Amyloid-β (Aβ) peptides, the main component of amyloid plaques found in the Alzheimer's disease (AD) brain, are implicated in its pathogenesis, and are considered a key target in AD therapeutics. We herein propose a reliable strategy for non-invasively delivering a specific anti-Aβ antibody in a mouse model of AD by microbubbles-enhanced Focused Ultrasound (FUS)-mediated Blood-brain barrier disruption (BBBD), using a simple single stage MR-compatible positioning device.

Methods: The initial experimental work involved wild-type mice and was devoted to selecting the sonication protocol for efficient and safe BBBD.

Mitofusin 1 overexpression rescues the abnormal mitochondrial dynamics caused by the Mitofusin 2 K357T mutation in vitro.

Background And Aims: Mitofusin 1 (MFN1) and MFN2 are outer mitochondrial membrane fusogenic proteins regulating mitochondrial network morphology. MFN2 mutations cause Charcot-Marie-Tooth type 2A (CMT2A), an axonal neuropathy characterized by mitochondrial fusion defects, which in the case of a GTPase domain mutant, were rescued following wild-type MFN1/2 (MFN1/2 ) overexpression. In this study, we compared the therapeutic efficiency between MFN1 and MFN2 overexpression in correcting mitochondrial defects induced by the novel MFN2 mutation located in the highly conserved R3 region.

Charcot-Marie-Tooth neuropathies: Current gene therapy advances and the route toward translation.

Charcot-Marie-Tooth (CMT) neuropathies are a group of genetically and phenotypically heterogeneous disorders that predominantly affect the peripheral nervous system. Unraveling the genetic and molecular mechanisms, as well as the cellular effects of CMT mutations, has facilitated the development of promising gene therapy approaches. Proposed gene therapy treatments for CMTs include virally or non-virally mediated gene replacement, addition, silencing, modification, and editing of genetic material.

The phenotypic spectrum of pathogenic ATP1A1 variants expands: the novel p.P600R substitution causes demyelinating Charcot-Marie-Tooth disease.

Background: Charcot-Marie-Tooth disease (CMT) is a genetically and clinically heterogeneous group of inherited neuropathies. Monoallelic pathogenic variants in ATP1A1 were associated with axonal and intermediate CMT. ATP1A1 encodes for the catalytic α1 subunit of the Na/ K ATPase.

CMT1A current gene therapy approaches and promising biomarkers.

Charcot-Marie-Tooth neuropathies (CMT) constitute a group of common but highly heterogeneous, non-syndromic genetic disorders affecting predominantly the peripheral nervous system. CMT type 1A (CMT1A) is the most frequent type and accounts for almost ~50% of all diagnosed CMT cases. CMT1A results from the duplication of the peripheral myelin protein 22 (PMP22) gene.

Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer's Disease.

Gap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or motor dysfunction including Alzheimer's disease (AD). The aim of this study was to examine the alterations in astrocyte and related oligodendrocyte GJs in association with Aβ plaques in the spinal cord of the 5xFAD mouse model of AD.

Robotic device for transcranial focussed ultrasound applications in small animal models.

Background: Focussed Ultrasound (FUS) combined with microbubbles (MBs) was proven a promising modality for non-invasive blood brain barrier disruption (BBBD). Herein, two devices for FUS-mediated BBBD in rodents are presented.

Methods: A two-axes robotic device was manufactured for navigating a single element FUS transducer of 1 MHz relative to the brain of rodents.

A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice.

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Overexpression of WT PMP22 in Schwann cells destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course.

NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice.

Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. Here, we identify proteins in sera of patients and mouse models with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT.

Efficacy of AAV serotypes to target Schwann cells after intrathecal and intravenous delivery.

To optimize gene delivery to myelinating Schwann cells we compared clinically relevant AAV serotypes and injection routes. AAV9 and AAVrh10 vectors expressing either EGFP or the neuropathy-associated gene GJB1/Connexin32 (Cx32) under a myelin specific promoter were injected intrathecally or intravenously in wild type and Gjb1-null mice, respectively. Vector biodistribution in lumbar roots and sciatic nerves was higher in AAVrh10 injected mice while EGFP and Cx32 expression rates and levels were similar between the two serotypes.

Aberrant Mitochondrial Dynamics and Exacerbated Response to Neuroinflammation in a Novel Mouse Model of CMT2A.

Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common hereditary axonal neuropathy caused by mutations in encoding Mitofusin-2, a multifunctional protein located in the outer mitochondrial membrane. In order to study the effects of a novel mutation associated with early onset, autosomal dominant severe CMT2A, we generated a knock-in mouse model. While mouse pups were postnatally lethal, heterozygous mice were asymptomatic and had no histopathological changes in their sciatic nerves up to 10 months of age.

Variant transthyretin amyloidosis (ATTRv) polyneuropathy in Greece: a broad overview with a focus on non-endemic unexplored regions of the country.

Comprehensive data on variant transthyretin amyloidosis polyneuropathy (ATTRv-PN) in Greece are lacking. We presently provide an overview of ATTRv-PN in Greece, focusing on unexplored non-endemic regions of the country. In total, we identified 57 cases of ATTRv-PN diagnosed over the past 25 years, including 30 from the island of Crete, an apparent endemic region.

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

Background: Myasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date.

Methods: We performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls).