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Journal of Veterinary Internal Medicine Jul 2022A 10-month-old castrated male domestic longhair cat was evaluated for increasing frequency of episodic limb rigidity.
CASE DESCRIPTION
A 10-month-old castrated male domestic longhair cat was evaluated for increasing frequency of episodic limb rigidity.
CLINICAL FINDINGS
The cat presented for falling over and lying recumbent with its limbs in extension for several seconds when startled or excited. Upon examination, the cat had hypertrophied musculature, episodes of facial spasm, and a short-strided, stiff gait.
DIAGNOSTICS
Electromyography (EMG) identified spontaneous discharges that waxed and waned in amplitude and frequency, consistent with myotonic discharges. A high impact 8-base pair (bp) deletion across the end of exon 3 and intron 3 of the chloride voltage-gated channel 1 (CLCN1) gene was identified using whole genome sequencing.
TREATMENT AND OUTCOME
Phenytoin treatment was initiated at 3 mg/kg po q24 h and resulted in long-term improvement.
CLINICAL RELEVANCE
This novel mutation within the CLCN1 gene is a cause of myotonia congenita in cats and we report for the first time its successful treatment.
Topics: Animals; Cat Diseases; Cats; Chloride Channels; Electromyography; Exons; Male; Mutation; Myotonia Congenita
PubMed: 35815860
DOI: 10.1111/jvim.16471 -
Neurologia I Neurochirurgia Polska 2022In myotonia congenita (MC), activation with exercise or cooling can induce transient changes in compound motor action potential (CMAP) parameters, thus providing a guide...
INTRODUCTION
In myotonia congenita (MC), activation with exercise or cooling can induce transient changes in compound motor action potential (CMAP) parameters, thus providing a guide to genetic analysis.
MATERIAL AND METHODS
We performed the short exercise test (SET) and the short exercise test with cooling (SETC) in 30 patients with genetically confirmed Becker disease (BMC) to estimate their utility in the diagnosis of BMC.
RESULTS
Although we observed a significant decrease in CMAP amplitude immediately after maximal voluntary effort in both tests in the whole BMC group, in men this decline was significantly smaller than in women, especially in SET. Clinical implications/future directions: In men with a clinical suspicion of BMC, a small decrease in CMAP amplitude in SET together with a typical decline in SETC does not exclude the diagnosis of BMC. Our results show a sex-specific difference in chloride channel function in BMC, which needs further investigation.
Topics: Female; Humans; Male; Myotonia Congenita; Sex Characteristics; Electromyography; Action Potentials; Mutation
PubMed: 35792560
DOI: 10.5603/PJNNS.a2022.0051 -
Muscle & Nerve Aug 2022Consistency of differences between non-dystrophic myotonias over time measured by standardized clinical/patient-reported outcomes is lacking. Evaluation of longitudinal... (Observational Study)
Observational Study
INTRODUCTION/AIMS
Consistency of differences between non-dystrophic myotonias over time measured by standardized clinical/patient-reported outcomes is lacking. Evaluation of longitudinal data could establish clinically relevant endpoints for future research.
METHODS
Data from prospective observational study of 95 definite/clinically suspected non-dystrophic myotonia participants (six sites in the United States, United Kingdom, and Canada) between March 2006 and March 2009 were analyzed. Outcomes included: standardized symptom interview/exam, Short Form-36, Individualized Neuromuscular Quality of Life (INQoL), electrophysiological short/prolonged exercise tests, manual muscle testing, quantitative grip strength, modified get-up-and-go test. Patterns were assigned as described by Fournier et al. Comparisons were restricted to confirmed sodium channelopathies (SCN4A, baseline, year 1, year 2: n = 34, 19, 13), chloride channelopathies (CLCN1, n = 32, 26, 18), and myotonic dystrophy type 2 (DM2, n = 9, 6, 2).
RESULTS
Muscle stiffness was the most frequent symptom over time (54.7%-64.7%). Eyelid myotonia and paradoxical handgrip/eyelid myotonia were more frequent in SCN4A. Grip strength and combined manual muscle testing remained stable. Modified get-up-and-go showed less warm up in SCN4A but remained stable. Median post short exercise decrement was stable, except for SCN4A (baseline to year 2 decrement difference 16.6% [Q1, Q3: 9.5, 39.2]). Fournier patterns type 2 (CLCN1) and 1 (SCN4A) were most specific; 40.4% of participants had a change in pattern over time. INQoL showed higher impact for SCN4A and DM2 with scores stable over time.
DISCUSSION
Symptom frequency and clinical outcome assessments were stable with defined variability in myotonia measures supporting trial designs like cross over or combined n-of-1 as important for rare disorders.
Topics: Channelopathies; Chloride Channels; Hand Strength; Humans; Mutation; Myotonia; Myotonia Congenita; Myotonic Dystrophy; NAV1.4 Voltage-Gated Sodium Channel; Patient Reported Outcome Measures; Quality of Life
PubMed: 35644941
DOI: 10.1002/mus.27649 -
Frontiers in Neurology 2022Non-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by or mutations. This study aimed to describe the clinical, myopathological, and genetic...
INTRODUCTION
Non-dystrophic myotonias (NDMs) are skeletal muscle ion channelopathies caused by or mutations. This study aimed to describe the clinical, myopathological, and genetic analysis of NDM in a large Chinese cohort.
METHODS
We reviewed the clinical manifestations, laboratory results, electrocardiogram, electromyography, muscle biopsy, genetic analysis, treatment, and follow-up of 20 patients (from 18 families) with NDM.
RESULTS
Cases included myotonia congenita (MC, 17/20) and paramyotonia congenita (PMC, 3/20). Muscle stiffness and hypertrophy, grip and percussion myotonia, and the warm-up phenomenon were frequently observed in MC and PMC patients. Facial stiffness, eye closure myotonia, and cold sensitivity were more common in PMC patients and could be accompanied by permanent weakness. Nine MC patients and two PMC patients had cardiac abnormalities, mainly manifested as cardiac arrhythmia, and the father of one patient died of sudden cardiac arrest. Myotonic runs in electromyography were found in all patients, and seven MC patients had mild myopathic changes. There was no difference in muscle pathology between MC and PMC patients, most of whom had abnormal muscle fiber type distribution or selective muscle fiber atrophy. Nineteen variants were found in 17 MC patients, among which c.795T>G (p.D265E) was a new variant, and two variants were found in three PMC patients. The patients were treated with mexiletine and/or carbamazepine, and the symptoms of myotonia were partially improved.
CONCLUSIONS
MC and PMC have considerable phenotypic overlap. Genetic investigation contributes to identifying the subtype of NDM. The muscle pathology of NDM lacks specific changes.
PubMed: 35350395
DOI: 10.3389/fneur.2022.830707 -
Neuromuscular Disorders : NMD Apr 2022Mouse models of skeletal muscle channelopathies are not phenocopies of human disease. In some cases (e.g. Myotonia Congenita) the phenotype is much more severe, whilst...
Mouse models of skeletal muscle channelopathies are not phenocopies of human disease. In some cases (e.g. Myotonia Congenita) the phenotype is much more severe, whilst in others (e.g. Hypokalaemic periodic paralysis) rodent physiology is protective. This suggests a species' difference in muscle excitability properties. In humans these can be measured indirectly by the post-impulse changes in conduction velocity, using Muscle Velocity Recovery Cycles (MVRCs). We performed MVRCs in mice and compared their muscle excitability properties with humans. Mouse Tibialis Anterior MVRCs (n = 70) have only one phase of supernormality (increased conduction velocity), which is smaller in magnitude (p = 9 × 10), and shorter in duration (p = 3 × 10) than human (n = 26). This abbreviated supernormality is followed by a period of late subnormality (reduced velocity) in mice, which overlaps in time with the late supernormality seen in human MVRCs. The period of late subnormality suggests increased t-tubule Na/K-pump activity. The subnormal phase in mice was converted to supernormality by blocking ClC-1 chloride channels, suggesting relatively higher chloride conductance in skeletal muscle. Our findings help explain discrepancies in phenotype between mice and humans with skeletal muscle channelopathies and potentially other neuromuscular disorders. MVRCs are a valuable new tool to compare in vivo muscle membrane properties between species and will allow further dissection of the molecular mechanisms regulating muscle excitability.
Topics: Channelopathies; Humans; Hypokalemic Periodic Paralysis; Muscle Fibers, Skeletal; Muscle, Skeletal; Myotonia Congenita
PubMed: 35339342
DOI: 10.1016/j.nmd.2022.02.011 -
ELife Mar 2022To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of...
To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the ryanodine receptor 1 () gene; recessive mutations are accompanied by reduction of RyR1 expression and content in skeletal muscles and are associated with fiber hypotrophy and muscle weakness. Importantly, muscles of patients with recessive mutations exhibit increased content of class II histone deacetylases and of DNA genomic methylation. We recently created a mouse model knocked-in for the p.Q1970fsX16+ p.A4329D RyR1 mutations, which are isogenic to those carried by a severely affected child suffering from a recessive form of RyR1-related multi-mini core disease. The phenotype of the RyR1 mutant mice recapitulates many aspects of the clinical picture of patients carrying recessive mutations. We treated the compound heterozygous mice with a combination of two drugs targeting DNA methylases and class II histone deacetylases. Here, we show that treatment of the mutant mice with drugs targeting epigenetic enzymes improves muscle strength, RyR1 protein content, and muscle ultrastructure. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive mutations.
Topics: Animals; DNA; Disease Models, Animal; Histone Deacetylases; Humans; Methyltransferases; Mice; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Myotonia Congenita; Quality of Life; Ryanodine Receptor Calcium Release Channel
PubMed: 35238775
DOI: 10.7554/eLife.73718 -
Genes Feb 2022Congenital myopathy associated with pathogenic variants in the gene has long been considered native American myopathy (NAM). In 2017, the first case of a non-Amerindian...
Congenital myopathy associated with pathogenic variants in the gene has long been considered native American myopathy (NAM). In 2017, the first case of a non-Amerindian patient with this myopathy was described. Here, we report the first Russian patient with NAM. The patient is a 17-year-old female with compound-heterozygous single nucleotide variants in the gene: c.862A>T, p.(Lys288Ter) and c.93del, p.(Lys32ArgfsTer78). She has a milder phenotype than the earlier described patients. To our knowledge, this is the first case of a patient who had both nonsense and frameshift variants. It is assumed that the frameshift variant with premature stop codon lead to nonsense-mediated RNA decay. However, there are two additional coding isoforms of the gene, which are not affected by this frameshift variant. We can speculate that these isoforms may partially carry out the function, and possibly explain the milder phenotype of our patient.
Topics: Cleft Palate; Female; Humans; Malignant Hyperthermia; Muscular Diseases; Myotonia Congenita
PubMed: 35205385
DOI: 10.3390/genes13020341 -
Channels (Austin, Tex.) Dec 2022Myotonia congenita (MC) is a rare genetic disease caused by mutations in the skeletal muscle chloride channel gene (), encoding the voltage-gated chloride channel ClC-1... (Review)
Review
Myotonia congenita (MC) is a rare genetic disease caused by mutations in the skeletal muscle chloride channel gene (), encoding the voltage-gated chloride channel ClC-1 in skeletal muscle. Our study reported the clinical and molecular characteristics of six patients with MC and systematically review the literature on Chinese people. We retrospectively analyzed demographics, clinical features, family history, creatine kinase (CK), electromyography (EMG), treatment, and genotype data of our patients and reviewed the clinical data and mutations in literature. The median ages at examination and onset were 26.5 years (range 11-50 years) and 6.5 years (range 1.5-11 years), respectively, in our patients, and 21 years (range 3.5-65 years, n = 45) and 9 years (range 0.5-26 years, n = 50), respectively, in literature. Similar to previous reports, myotonia involved limb, lids, masticatory, and trunk muscles to varying degrees. Warm-up phenomenon (5/6), percussion myotonia (3/5), and grip myotonia (6/6) were common. Menstruation triggered myotonia in females, not observed in Chinese patients before. The proportion of abnormal CK levels (4/5) was higher than data from literature. Electromyography performed in six patients revealed myotonic changes (100%). Five novel mutations, including a splicing mutation (c.853 + 4A>G), a deletion mutation (c.2010_2014del), and three missense mutations (c.2527C>T, c.1727C>T, c.2017 G > C), were identified. The c.892 G > A (p.A298T) mutation was the most frequent mutation in the Chinese population. Our study expanded the clinical and genetic spectrum of patients with MC in the China. The MC phenotype in Chinese people is not different from that found in the West, while the genotype is different.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Chloride Channels; Female; Humans; Infant; Middle Aged; Mutation; Myotonia; Myotonia Congenita; Retrospective Studies; Young Adult
PubMed: 35170402
DOI: 10.1080/19336950.2022.2041292 -
European Journal of Medical Genetics Feb 2022Whole exome sequencing (WES) is a powerful tool for the cataloguing of population-specific genetic diseases. Within this proof-of-concept study we evaluated whether...
Whole exome sequencing (WES) is a powerful tool for the cataloguing of population-specific genetic diseases. Within this proof-of-concept study we evaluated whether analysis of a small number of individual exomes is capable of identifying recurrent pathogenic alleles. We considered 106 exomes of subjects of Russian origin and revealed 13 genetic variants, which occurred more than twice and fulfilled the criteria for pathogenicity. All these alleles turned out to be indeed recurrent, as revealed by the analysis of 1045 healthy Russian donors. Eight of these variants (NAGA c.973G>A, ACADM c.985A>C, MPO c.2031-2A>C, SLC3A1 c.1400T>C, LRP2 c.6160G>A, BCHE c.293A>G, MPO c.752T>C, FCN3 c.349delC) are non-Russian-specific, as their high prevalence was previously demonstrated in other European populations. The remaining five disease-associated alleles appear to be characteristic for subjects of Russian origin and include CLCN1 c.2680C>T (myotonia congenita), DHCR7 c.453G>A (Smith-Lemli-Opitz syndrome), NUP93 c.1162C>T (steroid-resistant nephrotic syndrome, type 12), SLC26A2 c.1957T>A (multiple epiphyseal dysplasia) and EIF3F c.694T>G (mental retardation). These recessive disease conditions may be of particular relevance for the Russian Federation and other countries with a significant Slavic population.
Topics: Adult; Amino Acid Transport Systems, Basic; Amino Acid Transport Systems, Neutral; Butyrylcholinesterase; Female; Gene Frequency; Genetic Diseases, Inborn; Humans; Lectins; Low Density Lipoprotein Receptor-Related Protein-2; Male; Peroxidase; Population; Russia; Exome Sequencing; alpha-N-Acetylgalactosaminidase
PubMed: 35026467
DOI: 10.1016/j.ejmg.2022.104426 -
The Journal of Pediatrics May 2022
Topics: Child; Humans; Male; Myotonia Congenita
PubMed: 34953819
DOI: 10.1016/j.jpeds.2021.12.039