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The Application of Clinical Genetics 2021Becker's type myotonia congenita is an autosomal recessive nondystrophic skeletal muscle disorder characterized by muscle stiffness and the inability of muscle...
BACKGROUND
Becker's type myotonia congenita is an autosomal recessive nondystrophic skeletal muscle disorder characterized by muscle stiffness and the inability of muscle relaxation after voluntary contraction. It is caused by mutations in the gene, which encodes for a chloride channel mainly expressed in the striated muscle. Most cases have been reported in the European population, and only mexiletine has demonstrated a randomized placebo-controlled, double-blinded effectiveness.
CASE PRESENTATION
We present two male siblings from Colombia with Latino ancestry, without parental consanguinity, with myotonia during voluntary movements, muscle hypertrophy of lower extremities, transient weakness, and severe muscle fatigue after exercise from three years of age. A genetic panel for dystrophic muscle disorders and a muscle biopsy were both negative. Genetic testing was performed in their second decade of life. Both patients' exomic sequencing test reported the mutation c.1129C >T (p.Arg377*) affecting exon 10 of the , generating a premature stop codon. This mutation was described as pathogenic and observed in only one other patient in the United Kingdom.
CONCLUSION
To our knowledge, these are the first cases of Becker's type myotonia congenita reported in Colombia. Increasing awareness of healthcare providers for this type of disease in the region could lead to the identification of undiagnosed patients. Limited availability of medical geneticists as well as genetic testing may be the cause of the lack of previous description of cases, in addition to the delay in the diagnosis of the patients. Further epidemiological studies can reveal underdiagnosed myotonias in the country and in the Latin-American region.
PubMed: 34938096
DOI: 10.2147/TACG.S323559 -
A&A Practice Dec 2021Native American Myopathy (NAM) is an inherited, malignant hyperthermia-susceptible myopathy associated with abnormal craniofacial development and neuromuscular...
Native American Myopathy (NAM) is an inherited, malignant hyperthermia-susceptible myopathy associated with abnormal craniofacial development and neuromuscular scoliosis. There is scant NAM anesthetic literature and, to our knowledge, no existing publications describing the anesthetic management of a NAM parturient. The constellation of symptoms of NAM in the parturient presents a number of challenges to the obstetric anesthesiologist, including difficult airway associated with craniofacial abnormalities and pregnancy, malignant hyperthermia susceptibility, and possible difficult neuraxial block. In this report, we present the anesthetic management of a parturient with NAM and previous extensive posterior spinal fusion undergoing cesarean delivery under general anesthesia.
Topics: Anesthesia, Obstetrical; Cesarean Section; Cleft Palate; Female; Humans; Malignant Hyperthermia; Myotonia Congenita; Pregnancy
PubMed: 34890372
DOI: 10.1213/XAA.0000000000001541 -
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 -
Genes Nov 2021Congenital myopathies are rare neuromuscular hereditary disorders that manifest at birth or during infancy and usually appear with muscle weakness and hypotonia. One of...
Congenital myopathies are rare neuromuscular hereditary disorders that manifest at birth or during infancy and usually appear with muscle weakness and hypotonia. One of such disorders, early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD, OMIM: 614399, MIM: 612453), is a rare autosomal recessive disorder caused by biallelic mutations (at homozygous or compound heterozygous status) in (multiple epidermal growth factor-like domains protein family). Here, we report two unrelated patients, who were born to consanguineous parents, having two novel deleterious variants. Interestingly, the presence of associated EMARDD has not been reported in Saudi Arabia, a highly consanguineous population. Moreover, both variants lead to a different phenotypic onset of mild and severe types. Our work expands phenotypic features of the disease and provides an opportunity for genetic counseling to the inflicted families.
Topics: Child, Preschool; Consanguinity; Humans; Infant; Male; Membrane Proteins; Myotonia Congenita; Pedigree; Phenotype
PubMed: 34828389
DOI: 10.3390/genes12111783 -
Frontiers in Pediatrics 2021-related myotonia congenita (MC) is one of the most common forms of non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked...
-related myotonia congenita (MC) is one of the most common forms of non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. However, there is limited data of clinical and molecular spectrum of MC patients in China. Five patients with myotonia congenita due to mutations in gene were enrolled, which were identified through trio-whole-exome sequencing or panel-based next-generation sequencing test. The clinical presentation, laboratory data, electrophysiological tests, muscular pathology feature, and genetic results were collected and reviewed. We also searched all previously reported cases of MC patients with genetic diagnosis in Chinese populations, and their data were reviewed. The median onset age of five patients was 3.0 years old, ranging from 1.0 to 5.0 years old, while the median age of admit was 5.0 years old, ranging from 3.5 to 8.8 years old. Five patients complained of muscle stiffness when rising from chairs or starting to climb stairs (5/5, 100.0%), four patients complained of delayed relaxation of their hands after forceful grip (4/5, 80.0%), all of which improved with exercise (warm-up phenomenon) (5/5, 100%). Electromyogram was conducted in five patients, which all revealed myotonic change (100%). Genetic tests revealed nine potential disease-causing variants in gene, including two novel variants: c.962T>A (p.V321E) and c.1250A>T (p.E417V). Literature review showed that 43 MC Chinese patients with genetic diagnosis have been reported till now (including our five patients). Forty-seven variants in gene were found, which consisted of 33 missense variants, 6 nonsense variants, 5 frame-shift variants, and 3 splicing variants. Variants in exon 8, 15, 12, and 16 were most prevalent, while the most common variants were c.892G>A (p.A298T) ( = 9), c.139C>T (p.R47W) ( = 3), c.1205C>T(p.A402V) ( = 3), c.1657A>T (p.I553F) ( = 3), c.1679T>C (p.M560T) ( = 3), c.350A>G (p.D117G) ( = 2), c.762C>G (p.C254W) ( = 2), c.782A>G (P.Y261C) ( = 2), and c.1277C>A (p.T426N) ( = 2). Our results reported five -related MC patients, which expanded the clinical and genetic spectrum of MC patients in China. Based on literature review, 43MC Chinese patients with genetic diagnosis have been reported till now, and variants in exon eight were most prevalent in Chinese MC patients while c.892G>A (p.A298T) was probably a founder mutation.
PubMed: 34790634
DOI: 10.3389/fped.2021.759505 -
Journal of the Neurological Sciences Dec 2021
Topics: Calcium Channels, L-Type; Humans; Muscle, Skeletal; Muscular Diseases; Mutation; Myopathies, Structural, Congenital; Myotonia Congenita
PubMed: 34763287
DOI: 10.1016/j.jns.2021.120047 -
Neuromuscular Disorders : NMD Nov 2021Congenital myopathies are a heterogeneous group of conditions diagnosed based on the clinical presentation, muscle histopathology and genetic defects. Recessive...
Congenital myopathies are a heterogeneous group of conditions diagnosed based on the clinical presentation, muscle histopathology and genetic defects. Recessive mutations in the SPEG gene have been described in recent years and are primarily associated with centronuclear myopathy with cardiomyopathy. In this report, we describe two Brazilian siblings, aged 13 and 6 years, with a novel homozygous mutation (c.8872 C>T:p.Arg2958Ter) in the SPEG gene leading to a congenital myopathy. In the older sibling, the muscle biopsy showed fiber size disproportion. The mean diameter of type 2 fibers (119 µm) was significantly higher than type 1 (57 µm) (P < 0,001) with a 72% prevalence of type 1 fibers. The patient also had progressive cardiomyopathy treated with heart transplantation. The present report expands the muscle histopathological findings related to mutations in the SPEG gene, including fiber size disproportion without central nuclei. Additionally, this report describes the first case of heart transplantation in a patient with SPEG mutations.
Topics: Adolescent; Brazil; Cardiomyopathy, Dilated; Child; Child, Preschool; Female; Heart Transplantation; Homozygote; Humans; Infant; Male; Muscle Proteins; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Myotonia Congenita; Protein Serine-Threonine Kinases
PubMed: 34742623
DOI: 10.1016/j.nmd.2021.09.005 -
Annals of Indian Academy of Neurology 2021
PubMed: 34728966
DOI: 10.4103/aian.AIAN_970_20 -
Neuromuscular Disorders : NMD Nov 2021We report on an adult Turkish patient with mild myopathy with a fiber-type disproportion and mitochondrial disorganization caused by genetic variants in the plectin gene...
We report on an adult Turkish patient with mild myopathy with a fiber-type disproportion and mitochondrial disorganization caused by genetic variants in the plectin gene (PLEC). Molecular genetic panel testing revealed two homozygous variants in PLEC (NM_000445.4): c.8306C>G (p.Pro2769Arg) and c.7506 + 5C>G (p. ?) that were classified as variants of unknown significance (class 3) following ACMG guidelines for variant classification in genetic diagnostics. A thorough reassessment of the patient revealed mild skin blistering (epidermolysis bullosa simplex, EBS). This illustrates the importance of deep phenotyping of neuromuscular patients.
Topics: Adult; Epidermolysis Bullosa Simplex; Homozygote; Humans; Male; Mutation; Myotonia Congenita; Pedigree; Phenotype; Plectin
PubMed: 34702657
DOI: 10.1016/j.nmd.2021.09.009 -
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