Case report: Multiple approach analysis in a case of clinically assessed myotonia congenita.

Myotonia congenita, both in a dominant (Thomsen disease) and recessive form (Becker disease), is caused by molecular defects in that encodes the major skeletal muscle chloride channel, ClC-1. This channel is important for the normal repolarization of muscle action potentials and consequent relaxation of the muscle, and its dysfunction leads to impaired muscle relaxation after voluntary or evoked contraction and muscle stiffness. More than 300 pathogenic variants have been found in association with congenital myotonia, inherited as recessive or dominant traits (with complete or incomplete penetrance).

Myotonic dystrophies: an update on clinical features, molecular mechanisms, management, and gene therapy.

Myotonic dystrophies (DM) encompass a group of complex genetic disorders characterized by progressive muscle weakness with myotonia and multisystemic involvement. The aim of our paper is to synthesize key findings and advancements in the understanding of DM, and to underline the multidisciplinary approach to DM, emphasizing the importance of genetic counseling, comprehensive clinical care, and symptom management. We discuss the genetic basis of DM, emphasizing the role of repeat expansions in disease pathogenesis, as well as cellular and animal models utilized for studying DM mechanisms and testing potential therapies.

Case report: Dihydropyridine receptor () congenital myopathy, a novel phenotype with early onset periodic paralysis.

Introduction: related congenital myopathy is an emerging recently described entity. In this report we describe 2 sisters with mutations in the gene and the novel phenotype of congenital myopathy and infantile onset episodic weakness.

Clinical Description: Both sisters had neonatal onset hypotonia, muscle weakness, and delayed walking.

Case report: Sodium and chloride muscle channelopathy coexistence: A complicated phenotype and a challenging diagnosis.

Non-dystrophic myotonias (NDM) encompass chloride and sodium channelopathy. Mutations in lead to either the autosomal dominant form or the recessive form of myotonia congenita (MC). The main symptom is stiffness worsening after rest and improving by physical exercise.

Co-occurrence of DMPK expansion and CLCN1 mutation in a patient with myotonia.

Introduction: Myotonic disorders are a group of diseases affecting the muscle, in different ways. Myotonic dystrophy type 1 (DM1) is related to (CTG)n expansion in the 3-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene and is the most frequent and disabling form, causing muscular, visibility, respiratory, and cardiac impairment. Non-dystrophic myotonias (NDMs) affect the skeletal muscle alone.

p.Asn1180Ile mutation of SCN4A gene in an Italian family with myopathy and myotonic syndrome.

Introduction: Mutations of the skeletal muscle sodium channel gene SCN4A are associated with several neuromuscular disorders including hyper/hypokaliemic periodic paralysis, paramyotonia congenita and sodium channel myotonia. These disorders are distinguished from dystrophic myotonias by the absence of progressive weakness and extramuscular systemic involvement.

Methods: We present an Italian family with 2 subjects carrying a p.

Sodium Channel Myotonia Due to Novel Mutations in Domain I of Na1.4.

Sodium channel myotonia is a form of muscle channelopathy due to mutations that affect the Na1.4 channel. We describe seven families with a series of symptoms ranging from asymptomatic to clearly myotonic signs that have in common two novel mutations, p.

Elucidating the role of Agl in bladder carcinogenesis by generation and characterization of genetically engineered mice.

Amylo-α-1,6-glucosidase,4-α-glucanotransferase (AGL) is an enzyme primarily responsible for glycogen debranching. Germline mutations lead to glycogen storage disease type III (GSDIII). We recently found AGL to be a tumor suppressor in xenograft models of human bladder cancer (BC) and low levels of AGL expression in BC are associated with poor patient prognosis.

Glucose-free/high-protein diet improves hepatomegaly and exercise intolerance in glycogen storage disease type III mice.

Glycogen disease type III (GSDIII), a rare incurable autosomal recessive disorder due to glycogen debranching enzyme deficiency, presents with liver, heart and skeletal muscle impairment, hepatomegaly and ketotic hypoglycemia. Muscle weakness usually worsens to fixed myopathy and cardiac involvement may present in about half of the patients during disease. Management relies on careful follow-up of symptoms and diet.

The analysis of myotonia congenita mutations discloses functional clusters of amino acids within the CBS2 domain and the C-terminal peptide of the ClC-1 channel.

Myotonia congenita (MC) is a skeletal-muscle hyperexcitability disorder caused by loss-of-function mutations in the ClC-1 chloride channel. Mutations are scattered over the entire sequence of the channel protein, with more than 30 mutations located in the poorly characterized cytosolic C-terminal domain. In this study, we characterized, through patch clamp, seven ClC-1 mutations identified in patients affected by MC of various severities and located in the C-terminal region.

Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression.

Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by a deficiency of glycogen-debranching enzyme (GDE), which results in profound liver metabolism impairment and muscle weakness. To date, no cure is available for GSDIII and current treatments are mostly based on diet. Here we describe the development of a mouse model of GSDIII, which faithfully recapitulates the main features of the human condition.

Neuromuscular excitability changes produced by sustained voluntary contraction and response to mexiletine in myotonia congenita.

Objective: To investigate the cause of transient weakness in myotonia congenita (MC) and the mechanism of action of mexiletine in reducing weakness.

Methods: The changes in neuromuscular excitability produced by 1min of maximal voluntary contractions (MVC) were measured on the amplitude of compound muscle action potentials (CMAP) in two patients with either recessive or dominant MC, compared to control values obtained in 20 healthy subjects. Measurements were performed again in MC patients after mexiletine therapy.

Translational approach to address therapy in myotonia permanens due to a new SCN4A mutation.

Objective: We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype.

Glycogen storage disease type III: A novel Agl knockout mouse model.

Glycogen storage disease type III is an autosomal recessive disease characterized by a deficiency in the glycogen debranching enzyme, encoded by AGL. Essential features of this disease are hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation. Progressive skeletal myopathy, neuropathy, and/or cardiomyopathy become prominent in adults.

In vitro analysis of splice site mutations in the CLCN1 gene using the minigene assay.

Mutations in the chloride channel gene CLCN1 cause the allelic disorders Thomsen (dominant) and Becker (recessive) myotonia congenita (MC). The encoded protein, ClC-1, is the primary channel that mediates chloride (Cl-) conductance in skeletal muscle. Mutations in CLCN1 lower the channel's threshold voltage, leading to spontaneous action potentials that are not coupled to neuromuscular transmission and resulting in myotonia.

Myotonia congenita: novel mutations in CLCN1 gene and functional characterizations in Italian patients.

Myotonia congenita is an autosomal dominantly or recessively inherited muscle disorder causing impaired muscle relaxation and variable degrees of permanent muscle weakness, abnormal currents linked to the chloride channel gene (CLCN1) encoding the chloride channel on skeletal muscle membrane. We describe 12 novel mutations: c.1606G>C (p.

Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients.

Limb girdle muscular dystrophies (LGMD) are characterized by genetic and clinical heterogeneity: seven autosomal dominant and 12 autosomal recessive loci have so far been identified. Aims of this study were to evaluate the relative proportion of the different types of LGMD in 181 predominantly Italian LGMD patients (representing 155 independent families), to describe the clinical pattern of the different forms, and to identify possible correlations between genotype, phenotype, and protein expression levels, as prognostic factors. Based on protein data, the majority of probands (n=72) presented calpain-3 deficiency; other defects were as follows: dysferlin (n=31), sarcoglycans (n=32), alpha-dystroglycan (n=4), and caveolin-3 (n=2).

Developmental and tissue-specific regulation of a novel dysferlin isoform.

Dysferlin plays an essential role in the muscle repair machinery, and its deficiency is associated with limb-girdle muscular dystrophy type 2B and with two different distal myopathies (Miyoshi myopathy and distal anterior compartment myopathy). Our aims were to characterize the pattern of dysferlin expression during myogenic cell differentiation and to assess possible differentially spliced isoforms of the DYSF gene. Human primary myogenic cells express a splice variant of dysferlin mRNA lacking exon 17 (Delta17), together with full-length dysferlin mRNA.