Dysferlinopathy in Tunisia: clinical spectrum, genetic background and prognostic profile.

Dysferlinopathy is a rare group of hereditary muscular dystrophy with an autosomal recessive mode of inheritance caused by a mutation in the DYSF gene. It encodes for the dysferlin protein, which has a crucial role in multiple cellular processes, including muscle fiber membrane repair. This deficit has heterogeneous clinical presentations.

Orphan Drugs in Neurology-A Narrative Review.

Background And Aims: Orphan diseases, or rare diseases, are defined in Europe as diseases that affect less than 5 out of every 10,000 citizens. Given the small number of cases and the lack of profit potential, pharmaceutical companies have not invested much in the development of possible treatments. However, over the last few years, new therapies for rare diseases have emerged, giving physicians a chance to offer personalized treatment.

Clinical and functional characterization of a long survivor congenital titinopathy patient with a novel metatranscript-only titin variant.

Congenital titinopathies are an emerging group of a potentially severe form of congenital myopathies caused by biallelic mutations in titin, encoding the largest existing human protein involved in the formation and stability of sarcomeres. In this study we describe a patient with a congenital myopathy characterized by multiple contractures, a rigid spine, non progressive muscular weakness, and a novel homozygous TTN pathogenic variant in a metatranscript-only exon: the c.36400A > T, p.

Systemic light chain amyloidosis myopathy responsive to daratumumab monotherapy.

Background And Purpose: Amyloid myopathy is a rare and severe manifestation of systemic light chain (AL) amyloidosis. Early diagnosis and staging are mandatory for optimal therapy, given the rapid progression of muscle weakness. Despite the efficacy of bortezomib-based treatment regimens, there is a lack of therapeutic alternatives in non-responsive patients.

Obesity impairs skeletal muscle repair through NID-1 mediated extracellular matrix remodeling by mesenchymal progenitors.

Obesity triggers skeletal muscle physio-pathological alterations. However, the crosstalk between adipose tissue and myogenic cells remains poorly understood during obesity. We identified NID-1 among the adipose tissue secreted factors impairing myogenic potential of human myoblasts and murine muscle stem cells in vitro.

Systematic review and meta-analysis of cognitive impairment in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is commonly associated with cognitive complaints. To bring out the neuropsychological symptomatology inherent to ME/CFS, we conducted a systematic review according to PRISMA and MOOSE guidelines of the literature through the analysis of 764 studies published between 1988 and 2019 by using PubMed Central website and Clarivate analytics platform. We performed a meta-analysis to delineate an idea of the neuropsychological profile inherent in ME/CFS.

FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation.

Background And Objectives: To determine common clinical and biological traits in 2 individuals with variants in and , displaying severe and recurrent rhabdomyolyses and lactic acidosis.

Methods: We performed a clinical characterization of 2 distinct individuals with biallelic or variants from 2 separate families and a biological characterization with muscle and cells from those patients.

Results: The individual with variants was clinically more affected than the individual with variants.

Optimized Flow Cytometry Strategy for Phenotyping Intramuscular Leukocytes: Application to the Evaluation of Myopathological Processes.

Phenotyping intramuscular immune cells is essential for the characterization of dysimmune/inflammatory myopathies (DIM). Flow cytometry (FC) is the most reliable technique for analyzing leukocyte subpopulations and evaluating their activation levels. We developed a purely mechanical protocol for extracting cells from muscle tissue allowing us to preserve cell surface epitopes and determined its applicability to experimental pathology in mice and myopathological diagnosis in human.

A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course.

The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families.

European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe.

Designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)-COST action 15111-from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report our findings and make recommendations for clinical diagnosis, health services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS.

Novel splicing dysferlin mutation causing myopathy with intra-familial heterogeneity.

Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular disorders, caused by mutations in the dysferlin gene and characterized by a high degree of clinical variability even though within the same family. This study aims to describe three cases, belonging to a consanguineous Tunisian family, sharing a new splicing mutation in the dysferlin gene and presenting intra-familial variability of dysferlinopathies: Proximal-distal weakness and distal myopathy with anterior tibial onset. We performed the next generation sequencing for mutation screening and reverse transcriptase-PCR for gene expression analysis.

Immunolabelling Myofiber Degeneration in Muscle Biopsies.

The necrosis of muscle fibres (myonecrosis) plays a central role in the pathogenesis of several muscle conditions, including muscular dystrophies. Therapeutic options addressing the causes of muscular dystrophy pathogenesis are expected to alleviate muscle degeneration. Therefore, a method to assay and quantify the extent of cell death in muscle biopsies is needed.

Novel Missense CAPN3 Mutation Responsible for Adult-Onset Limb Girdle Muscular Dystrophy with Calves Hypertrophy.

CAPN3 gene encodes for calpain-3; this protein is a calcium-dependent intracellular protease. Deficiency of this enzyme leads to weakness of the proximal limb muscles and pelvic and shoulder girdles, the so-called limb-girdle muscular dystrophy type 2A (LGMD2A). Here, we reported the case of a Tunisian patient with LGMD2A associated with a novel missense mutation (c.

Macrophagic myofasciitis-associated dysfunctioning: An update of neuropsychological and neuroimaging features.

Macrophagic myofasciitis (MMF) syndrome is a subtype of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) or Shoenfeld's syndrome, characterized by the presence of stereotyped inflammatory lesions at muscle biopsy attesting the long-term persistence of aluminum hydroxide particles at the site of previous immunization. Most frequently reported symptoms are chronic arthromyalgias and fatigue and cognitive complaint. MMF-associated cognitive disorder (MACD) is characterized by the dysfunctioning of attention, executive functions, short-term term and long-term memory, and, in some instances, left ear extinction.

Automated image-analysis method for the quantification of fiber morphometry and fiber type population in human skeletal muscle.

Background: The quantitative analysis of muscle histomorphometry has been growing in importance in both research and clinical settings. Accurate and stringent assessment of myofibers' changes in size and number, and alterations in the proportion of oxidative (type I) and glycolytic (type II) fibers is essential for the appropriate study of aging and pathological muscle, as well as for diagnosis and follow-up of muscle diseases. Manual and semi-automated methods to assess muscle morphometry in sections are time-consuming, limited to a small field of analysis, and susceptible to bias, while most automated methods have been only tested in rodent muscle.

Distinct interferon signatures stratify inflammatory and dysimmune myopathies.

Objective: The role of interferons (IFN) in the pathophysiology of primary inflammatory and dysimmune myopathies (IDM) is increasingly investigated, notably because specific neutralisation approaches may constitute promising therapeutic tracks. In present work we analysed the muscular expression of specific IFNα/β and IFNγ-stimulated genes in patients with various types of IDM.

Methods: 39 patients with IDM with inclusion body myositis (IBM, n=9), dermatomyositis (DM, n=10), necrotising autoimmune myopathies (NAM, n=10) and antisynthetase myositis (ASM, n=10), and 10 controls were included.

Cognitive dysfunction associated with aluminum hydroxide-induced macrophagic myofasciitis: A reappraisal of neuropsychological profile.

Patients with macrophagic myofasciitis (MMF) present with diffuse arthromyalgias, chronic fatigue, and cognitive disorder. Representative features of MMF-associated cognitive dysfunction include attentional dysfunction, dysexecutive syndrome, visual memory deficit and left ear extinction. Our study aims to reevaluate the neuropsychological profile of MMF.

Fate and action of ricin in rat liver in vivo: translocation of endocytosed ricin into cytosol and induction of intrinsic apoptosis by ricin B-chain.

Cytotoxicity of many plant and bacterial toxins requires their endocytosis and retrograde transport from endosomes to the endoplasmic reticulum. Using cell fractionation and immunoblotting procedures, we have assessed the fate and action of the plant toxin ricin in rat liver in vivo, focusing on endosome-associated events and induction of apoptosis. Injected ricin rapidly accumulated in endosomes as an intact A/B heterodimer (5-90 min) and was later (15-90 min) partially translocated to cytosol as A- and B-chains.

Th2-M2 immunity in lesions of muscular sarcoidosis and macrophagic myofasciitis.

Objective: To analyse the paradox of a lack of giant cell formation and fibrosis in chronic lesions of macrophagic myofasciitis (MMF) in comparison with muscular sarcoidosis (MuS).

Methods: Inflammatory lesions and contiguous muscle regions from biopsy samples of 10 patients with MuS and 10 patients with MMF were cut out by laser microdissection. Mediators of the T helper cell (Th)1 inducing classical macrophage activation (e.

Biopersistence and brain translocation of aluminum adjuvants of vaccines.

Aluminum oxyhydroxide (alum) is a crystalline compound widely used as an immunological adjuvant of vaccines. Concerns linked to the use of alum particles emerged following recognition of their causative role in the so-called macrophagic myofasciitis (MMF) lesion detected in patients with myalgic encephalomyelitis/chronic fatigue/syndrome. MMF revealed an unexpectedly long-lasting biopersistence of alum within immune cells in presumably susceptible individuals, stressing the previous fundamental misconception of its biodisposition.

Clinical features in patients with long-lasting macrophagic myofasciitis.

Macrophagic myofasciitis (MMF) is an emerging condition characterized by specific muscle lesions assessing abnormal long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients usually are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and marked cognitive deficits, not related to pain, fatigue, or depression. Clinical features usually correspond to that observed in chronic fatigue syndrome/myalgic encephalomyelitis.

Myofiber HLA-DR expression is a distinctive biomarker for antisynthetase-associated myopathy.

Objectives: To assess the value of major histocompatibility complex (MHC) class II antigen (HLA-DR) expression to distinguish anti-synthetase myopathy (ASM) from dermatomyositis (DM).

Methods: Muscle biopsies from patients with ASM (n = 33), DM without anti-synthetase antibodies (ASAb) (n = 17), and normal muscle biopsy (n = 10) were first reviewed. ASAb included anti-Jo1 (26/33), anti-PL12 (4/33), anti-PL7 (2/33), and anti-EJ (1/33).