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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 -
Pediatric Neurology Mar 2020Congenital myopathy is a heterogeneous group of muscle disorders characterized by muscle weakness and hypotonia. This condition is associated with a range of skeletal,... (Review)
Review
Congenital myopathy is a heterogeneous group of muscle disorders characterized by muscle weakness and hypotonia. This condition is associated with a range of skeletal, respiratory, and ophthalmologic complications and requires a multidisciplinary therapeutic approach aimed at maximizing the function and independence of patients. One promising direction for therapeutic intervention is physical exercise rehabilitation, given its demonstrated ability to promote muscle and bone health of patients with a variety of neuromuscular conditions. However, there are few data to assist health care professionals identify the optimal physical activity levels and exercise type, including the intensity, frequency, and duration. This lack of empirical evidence is particularly problematic given the fact that inappropriate exercise modes can potentially cause muscle damage in patients with congenital myopathy. In this article, we discuss the rationale behind the incorporation of two types of physical exercises, strength and aerobic training, into the clinical care of patients with congenital myopathy. Given the paucity of literature on the management of congenital myopathy, we review the results of published research on the treatment of both congenital myopathy and other neuromuscular diseases that could provide helpful insights into the physical rehabilitation of patients with congenital myopathy. We also discuss the potential benefits of vibration therapy, which has been studied in patients with other neuromuscular disorders over the last two decades. We conclude by proposing directions for future research on physical rehabilitation of patients with congenital myopathy.
Topics: Exercise Therapy; Humans; Myotonia Congenita; Vibration
PubMed: 31926608
DOI: 10.1016/j.pediatrneurol.2019.10.008 -
Neuromuscular Disorders : NMD Sep 2021Skeletal muscle sodium channelopathies due to SCN4A gene mutations have a broad clinical spectrum. However, each phenotype has been reported in few cases of Chinese...
Skeletal muscle sodium channelopathies due to SCN4A gene mutations have a broad clinical spectrum. However, each phenotype has been reported in few cases of Chinese origin. We present detailed phenotype and genotype data from a cohort of 40 cases with SCN4A gene mutations seen in neuromuscular diagnostic service in Huashan hospital, Fudan University. Cases were referred from 6 independent provinces from 2010 to 2018. A questionnaire covering demographics, precipitating factors, episodes of paralysis and myotonia was designed to collect the clinical information. Electrodiagnostic studies and muscle MRI were retrospectively analyzed. The clinical spectrum of patients included: 6 Hyperkalemic periodic paralysis (15%), 18 Hypokalemic periodic paralysis (45%), 7 sodium channel myotonia (17.5%), 4 paramyotonia congenita (10%) and 5 heterozygous asymptomatic mutation carriers (12.5%). Review of clinical information highlights a significant delay to diagnosis (median 15 years), reports of pain and myalgia in the majority of patients, male predominance, circadian rhythm and common precipitating factors. Electrodiagnostic studies revealed subclinical myotonic discharges and a positive long exercise test in asymptomatic carriers. Muscle MRI identified edema and fatty infiltration in gastrocnemius and soleus. A total of 13 reported and 2 novel SCN4A mutations were identified with most variants distributed in the transmembrane helix S4 to S6, with a hotspot mutation p.Arg675Gln accounting for 32.5% (13/40) of the cohort. Our study revealed a higher proportion of periodic paralysis in SCN4A-mutated patients compared with cohorts from England and the Netherlands. It also highlights the importance of electrodiagnostic studies in diagnosis and segregation studies.
Topics: Adult; Asian People; Channelopathies; China; Cohort Studies; Electromyography; Female; Genotype; Humans; Male; Mutation; Myotonia; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel; Paralyses, Familial Periodic; Pedigree; Phenotype; Retrospective Studies; Surveys and Questionnaires; Young Adult
PubMed: 33965302
DOI: 10.1016/j.nmd.2021.03.014 -
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 -
Journal of Neurology May 2021Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in...
INTRODUCTION
Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in a large German cohort.
METHODS
We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy.
RESULTS
70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient's perceived efficacy were mexiletine and lamotrigine.
CONCLUSION
This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge.
Topics: Adult; Chloride Channels; Female; Humans; Male; Mutation; Myotonia; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Retrospective Studies
PubMed: 33263785
DOI: 10.1007/s00415-020-10328-1 -
Frontiers in Neurology 2020Inherited myotonic disorders are genetically heterogeneous and associated with overlapping clinical features of muscle stiffness, weakness, and pain. Data on...
Inherited myotonic disorders are genetically heterogeneous and associated with overlapping clinical features of muscle stiffness, weakness, and pain. Data on genotype-phenotype correlations are limited. In this study, clinical features and treatment patterns in genetically characterized myotonic disorders were compared. A retrospective chart review was completed in patients with genetic variants in , and to document clinical signs and symptoms, clinical testing, and antimyotonia medication use. A total of 142 patients (27 , 15 , 89 , and 11 ) were reviewed. The frequency of reported symptoms (stiffness, weakness, and pain) and electromyographic spontaneous activity were remarkably similar across genotypes. Most patients were not treated with antimyotonia agents, but those with non-dystrophic disorders were more likely to be on a treatment. Among the features reviewed, we did not identify clinical or electrophysiological differences to distinguish - and -related myotonia. Weakness and pain were more prevalent in non-dystrophic disorders than previously identified. In addition, our results suggest that medical treatments in myotonic disorders may be under-utilized.
PubMed: 32670189
DOI: 10.3389/fneur.2020.00593 -
Neuromuscular Disorders : NMD Nov 2021The MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
The MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients with myotonia congenita (MC) and paramyotonia congenita (PC). The primary endpoint was the self-reported score of stiffness severity on a 100 mm visual analogic scale (VAS). Mexiletine treatment started at 200 mg/day and was up-titrated by 200 mg increment each three days to reach a maximum dose of 600 mg/day for total treatment duration of 18 days for each cross-over period. The modified intent-to-treat population included 25 patients (13 with MC and 12 with PC; mean age, 43.0 years; male, 68.0%). The median VAS score for mexiletine was 71.0 at baseline and decreased to 16.0 at the end of the treatment while the score did not change for placebo (81.0 at baseline vs. 78.0 at end of treatment). A mixed effects linear model analysis on ranked absolute changes showed a significant effect of treatment (p < 0.001). The overall score of the Individualized Neuromuscular Quality of Life questionnaire (INQoL) was significantly improved (p < 0.001). No clinically significant adverse events were reported. In conclusion, mexiletine improved stiffness and quality of life in patients with nondystrophic myotonia and was well tolerated.
Topics: Adult; Aged; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Mexiletine; Middle Aged; Myotonia; Myotonia Congenita; Myotonic Disorders; Quality of Life; Treatment Outcome
PubMed: 34702654
DOI: 10.1016/j.nmd.2021.06.010 -
Neuromuscular Disorders : NMD Jul 2020Non-dystrophic myotonias are a group of rare neuromuscular diseases linked to SCN4A or CLCN1. Among the subtypes, myotonia permanens, associated with the Gly1306Glu...
Non-dystrophic myotonias are a group of rare neuromuscular diseases linked to SCN4A or CLCN1. Among the subtypes, myotonia permanens, associated with the Gly1306Glu variant of SCN4A, is a relatively less frequent but more severe form. Most reports of non-dystrophic myotonias describe European populations. Therefore, to expand the genetic and phenotypic spectrum of this disorder, we evaluated 30 Chilean patients with non-dystrophic myotonias for associated variants and clinical characteristics. SCN4A variants were observed in 28 (93%) of patients, including 25 (83%) with myotonia permanens due to the Gly1306Glu variant. Myotonia permanens was inherited in 24 (96%) patients; the mean age of onset was 6 months, and the initial symptoms were orbicularis oculi myotonia in 17 (74%) patients and larynx myotonia in 12 (52%) patients. The extraocular muscles were involved in 11 (44%) patients, upper limbs in 20 (80%), and lower limbs in 21 (84%). Thirteen (52%) patients experienced recurrent pain and 10 (40%) patients reported limitations in daily life activities. Carbamazepine reduced myotonia in eight treated patients. The high frequency of the Gly1306Glu variant in SCN4A in Chilean patients suggests a founder effect and expands its phenotypic spectrum.
Topics: Adolescent; Adult; Child; Chile; Cohort Studies; Female; Founder Effect; Humans; Infant; Male; Mutation; Myotonia; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel; Young Adult
PubMed: 32593548
DOI: 10.1016/j.nmd.2020.04.006 -
Neuromuscular Disorders : NMD Jul 2020The skeletal muscle channelopathies are a group of rare diseases and include non-dystrophic myotonia and periodic paralysis. Given their rarity, little has been...
The skeletal muscle channelopathies are a group of rare diseases and include non-dystrophic myotonia and periodic paralysis. Given their rarity, little has been published on the management of anaesthesia and pregnancy in this cohort despite being important aspects of care. We have conducted a large study of over 70 patients who underwent anaesthesia and 87 pregnancies to investigate the problems encountered following anaesthesia or during pregnancy. This was performed via patient surveys sent out to genetically confirmed channelopathy patients seen at the National Hospital for Neurology and Neurosurgery. Most significantly in our cohort, patients frequently experienced a worsening or precipitation of symptoms during pregnancy (75%) or following anaesthetic (31%). None of our patients developed malignant hyperthermia, although there are confirmed reports of this in patients with periodic paralysis and mutations in RYR1. There was a significantly higher number of miscarriages compared to the normal population. There was no significant difference in antenatal or delivery complications compared to the general population. However, three neonates did have complications, all of whom were found to carry mutations in SCN4A. This study highlights the importance of counselling patients and clinicians for the possibility of worsening symptoms during pregnancy or anaesthesia and the careful management of neonates following delivery.
Topics: Anesthetics; Channelopathies; Female; Humans; Infant, Newborn; Male; Middle Aged; Muscle, Skeletal; Myotonia; Pregnancy; Pregnancy Complications; Surveys and Questionnaires
PubMed: 32622512
DOI: 10.1016/j.nmd.2020.05.007 -
Genes Nov 2021Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to...
Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible -related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes.
Topics: Animals; Cattle; Cattle Diseases; Channelopathies; Inbreeding; Mutation; Myotonia Congenita; Phenotype; Potassium Channels, Voltage-Gated
PubMed: 34828398
DOI: 10.3390/genes12111792