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Scientific Reports Sep 2023Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca-release channel of the sarcoplasmic reticulum....
Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca-release channel of the sarcoplasmic reticulum. Some mutations impair the gating and thus cause muscle disease. The RyR1 mutation T4706M is linked to a myopathy characterized by muscle weakness. Although, low expression of the T4706M RyR1 protein can explain in part the symptoms, little is known about the function RyR1 channels with this mutation. In order to learn whether this mutation alters channel function in a manner that can account for the observed symptoms, we examined RyR1 channels isolated from mice homozygous for the T4709M (TM) mutation at the single channel level. Ligands, including Ca, ATP, Mg and the RyR inhibitor dantrolene were tested. The full conductance of the TM channel was the same as that of wild type (wt) channels and a population of partial open (subconductive) states were not observed. However, two unique sub-populations of TM RyRs were identified. One half of the TM channels exhibited high open probability at low (100 nM) and high (50 μM) cytoplasmic [Ca], resulting in Ca-insensitive, constitutively high P channels. The rest of the TM channels exhibited significantly lower activity within the physiologically relevant range of cytoplasmic [Ca], compared to wt. TM channels retained normal Mg block, modulation by ATP, and inhibition by dantrolene. Together, these results suggest that the TM mutation results in a combination of primary and secondary RyR1 dysfunctions that contribute to disease pathogenesis.
Topics: Animals; Mice; Ryanodine Receptor Calcium Release Channel; Dantrolene; Muscular Diseases; Cytoplasm; Myotonia Congenita; Adenosine Triphosphate
PubMed: 37670077
DOI: 10.1038/s41598-023-41801-2 -
The Journal of Clinical Investigation Aug 2023BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.
Topics: Adult; Animals; Child; Humans; Fragile X Syndrome; Single-Blind Method; Learning; Language; Cleft Palate; Indoles; Malignant Hyperthermia; Myotonia Congenita
PubMed: 37651202
DOI: 10.1172/JCI171723 -
Handbook of Clinical Neurology 2023Muscle channelopathies encompass a wide range of mainly episodic conditions that are characterized by muscle stiffness and weakness. The myotonic conditions,... (Review)
Review
Muscle channelopathies encompass a wide range of mainly episodic conditions that are characterized by muscle stiffness and weakness. The myotonic conditions, characterized predominantly by stiffness, include myotonia congenita, paramyotonia congenita, and sodium channel myotonia. The periodic paralysis conditions include hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil syndrome. Clinical history is key, and diagnosis is confirmed by next-generation genetic sequencing of a panel of known genes but can also be supplemented by neurophysiology studies and MRI. As genetic testing expands, so have the spectrum of phenotypes seen including pediatric presentations and congenital myopathies. Management of these conditions requires a multidisciplinary approach with extra support needed when patients require anesthetics or when pregnant. Patients with Andersen-Tawil syndrome will also need cardiac input. Diagnosis is important as symptomatic treatment is available for all of these conditions but need to be tailored to the gene and variant of the patient.
Topics: Humans; Andersen Syndrome; Channelopathies; Paralysis, Hyperkalemic Periodic; Myotonic Disorders; Muscle, Skeletal; Paralysis; Mutation
PubMed: 37562884
DOI: 10.1016/B978-0-323-98818-6.00006-6 -
Genes Jun 2023Congenital myopathies are a group of clinically, genetically, and histologically heterogeneous diseases caused by mutations in a large group of genes. One of these is ,... (Review)
Review
BACKGROUND
Congenital myopathies are a group of clinically, genetically, and histologically heterogeneous diseases caused by mutations in a large group of genes. One of these is , which is recognized as the cause of Dihydropyridine Receptor Congenital Myopathy.
METHODS
To better characterize the phenotypic spectrum of myopathy, we conducted a systematic review of cases in the literature through three electronic databases following the PRISMA guidelines. We selected nine articles describing 23 patients with heterozygous, homozygous, or compound heterozygous mutations in and we added one patient with a compound heterozygous mutation in (c.1394-2A>G; c.1724T>C, p.L575P) followed at our Institute. We collected clinical and genetic data, muscle biopsies, and muscle MRIs when available.
RESULTS
The phenotype of this myopathy is heterogeneous, ranging from more severe forms with a lethal early onset and mild-moderate forms with a better clinical course.
CONCLUSIONS
Our patient presented a phenotype compatible with the mild-moderate form, although she presented peculiar features such as a short stature, myopia, mild sensorineural hearing loss, psychiatric symptoms, and posterior-anterior impairment gradient on thigh muscle MRI.
Topics: Female; Humans; Calcium Channels, L-Type; Muscular Diseases; Mutation; Muscle, Skeletal; Phenotype; Myotonia Congenita
PubMed: 37510268
DOI: 10.3390/genes14071363 -
Experimental and Clinical... Jun 2023Czechoslovakia was created after the First World War in 1918 as a common state of Czechs, Moravians, and Slovaks. After several transformations, 2 separate republics...
Czechoslovakia was created after the First World War in 1918 as a common state of Czechs, Moravians, and Slovaks. After several transformations, 2 separate republics were established from Czechoslovakia in 1993: the Czech Republic and the Slovak Republic. The objective of this article was to analyze the Prague Spring (1968), the period after the invasion into Czechoslovakia by Warsaw Pact Troops (1968), the period of cruel normalization (1968-1989), and the influence of Soviet domination in the Czechoslovak Republic on people with higher education. The invasion of the Warsaw Pact Troops into Czechoslovakia and the period of normalization had a highly negative impact on the life and work of the Czechoslovak people. Many eminent scientists left the Republic. The reason for this was persecution for their attitude to the situation behind the Iron Curtain. Professor Jan Brod, a world-renowned nephrologist and cardiologist, one of the signatories of the Two Thousand Words Manifesto, emigrated to the Federal Republic of Germany in 1968. Professor William Ganz, a world-renowned cardiologist of Slovak origin, emigrated to the United States in 1966. With Jeremy Swan, he was a coinventor of the Swan-Ganz balloon flotation catheter. Primary reasons for the emigration of scientists from Czechoslovakia was the suppression of the nascent democracy (the Prague Spring in 1968 by the invasion of Warsaw Pact Troops and the continuation of Soviet rule).
Topics: Male; Humans; United States; Czechoslovakia; Emigration and Immigration; Slovakia; Interpersonal Relations; Myotonia Congenita
PubMed: 37496349
DOI: 10.6002/ect.IAHNCongress.17 -
Cureus Jun 2023Non-dystrophic myotonia (NDM) is a group of rare mono-genetic muscle disorders caused by skeletal muscle sodium or chloride channelopathies. These disorders are...
Non-dystrophic myotonia (NDM) is a group of rare mono-genetic muscle disorders caused by skeletal muscle sodium or chloride channelopathies. These disorders are characterized by high muscle tone and the inability of the muscles to relax spontaneously after voluntary contraction. Myotonia congenita refers to a form of NDM that typically manifests during the later stages of childhood. It occurs as a result of genetic mutations affecting the chloride channels found in the sarcolemma membrane of skeletal muscles. Here, we present a case series of two male siblings born out of third-degree consanguineous union ages 10 and eight years, respectively, who presented with proximal muscle weakness and the characteristic "Herculean body" appearance. They demonstrated characteristic clinical diagnostic signs of myotonia. The diagnosis of myotonia congenita was confirmed through distinctive electromyography (EMG) findings, which were further supported by genetic testing revealing a homozygous mutation c.1445G>A in exon 13 of the CLCN1 gene, indicating autosomal recessive inheritance. This uncommon condition exhibits characteristic clinical manifestations and classical EMG findings, which are difficult to disregard once encountered. Genetic tests serve as a valuable tool to validate the diagnosis.
PubMed: 37489215
DOI: 10.7759/cureus.40869 -
Journal of Neuromuscular Diseases 2023Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride...
BACKGROUND
Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride channel of skeletal muscle.
OBJECTIVE
The study aimed to describe the clinical and genetic spectrum of Myotonia congenita in a large pediatric cohort.
METHODS
Demographic, genetic, and clinical data of the patients aged under 18 years at time of first clinical attendance from 11 centers in different geographical regions of Türkiye were retrospectively investigated.
RESULTS
Fifty-four patients (mean age:15.2 years (±5.5), 76% males, with 85% Becker, 15% Thomsen form) from 40 families were included. Consanguineous marriage rate was 67%. 70.5% of patients had a family member with Myotonia congenita. The mean age of disease onset was 5.7 (±4.9) years. Overall 23 different mutations (2/23 were novel) were detected in 52 patients, and large exon deletions were identified in two siblings. Thomsen and Becker forms were observed concomitantly in one family. Carbamazepine (46.3%), mexiletine (27.8%), phenytoin (9.3%) were preferred for treatment.
CONCLUSIONS
The clinical and genetic heterogeneity, as well as the limited response to current treatment options, constitutes an ongoing challenge. In our cohort, recessive Myotonia congenita was more frequent and novel mutations will contribute to the literature.
Topics: Male; Humans; Child; Adolescent; Aged; Infant; Child, Preschool; Female; Myotonia Congenita; Retrospective Studies; Chloride Channels; Mutation; Muscle, Skeletal
PubMed: 37355912
DOI: 10.3233/JND-230046 -
Journal of Veterinary Diagnostic... Jul 2023Hereditary myotonia (HM) is characterized by delayed muscle relaxation after contraction as a result of a mutation in the gene. We describe here a complex variant in a...
Hereditary myotonia (HM) is characterized by delayed muscle relaxation after contraction as a result of a mutation in the gene. We describe here a complex variant in a mixed-breed dog with clinical and electromyographic signs of HM. Blood samples from the myotonic dog, as well as from his male littermate and parents, were analyzed via amplification of the 23 exons encoding . After sequencing the gene, a complex variant was found in exon 6 c.[705T>G; 708del; 712_732del], resulting in a premature stop codon in exon 7 and a protein that was 717 amino acids shorter than the normal CLC protein. The myotonic dog was identified as homozygous recessive for the complex variant; its parents were heterozygous, and its male littermate was homozygous wild-type. Knowledge of the mutations responsible for the development of hereditary myotonia allows greater clarification of this condition.
Topics: Animals; Dogs; Male; Chloride Channels; Dog Diseases; Exons; Mutation; Myotonia; Myotonia Congenita
PubMed: 37212506
DOI: 10.1177/10406387231176736 -
Breastfeeding Medicine : the Official... Jun 2023Mexiletine is a class 1B antiarrhythmic agent, used to treat ventricular arrhythmias, and noncardiac-related problems such as myotonia. Limited safety data are...
Mexiletine is a class 1B antiarrhythmic agent, used to treat ventricular arrhythmias, and noncardiac-related problems such as myotonia. Limited safety data are available on the transfer of this drug into breast milk. We report the case of a woman diagnosed with myotonia congenita who breastfed two children after two consecutive pregnancies. During the breastfeeding of the first and the second infant, she collected, respectively, five and seven samples at 0, 2, 4, 6, and 8 hours and 0, 1, 2, 3, 4, 6, and 8 hours after taking 200 mg of mexiletine thrice daily for seven doses. One week after the collection, samples were analyzed with a validated liquid chromatography tandem mass spectrometry method. No side effect was observed in either child according to the mother. Using the mean milk concentrations, it is estimated that an exclusively breastfed infant would receive a maximum of 5.14% of the initial pediatric mexiletine dosage. We calculated a maximum of 2.67% for the first infant in our case, considering a nonexclusive breastfeeding. Maximal concentrations were observed 1-2 hours after the dose of mexiletine. Results seem to be in accordance with the two cases previously published. Mexiletine transfers into breast milk in low levels. However, results are obtained from only one woman. Therefore, caution should be used when mexiletine is prescribed to breastfeeding women. More cases are needed to evaluate the interindividual variability and to guide women regarding breastfeeding with mexiletine.
Topics: Infant; Pregnancy; Female; Child; Humans; Milk, Human; Breast Feeding; Mexiletine; Mothers
PubMed: 37184533
DOI: 10.1089/bfm.2023.0042