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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 -
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 -
Brain : a Journal of Neurology Feb 2020Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the...
Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.
Topics: Adolescent; Adult; Calcium-Transporting ATPases; Child; Female; Humans; Male; Muscle, Skeletal; Muscular Diseases; Mutation; Myotonia Congenita; Phenotype; Sarcoplasmic Reticulum; Young Adult
PubMed: 32040565
DOI: 10.1093/brain/awz410 -
PloS One 2020Myotonia congenita and hypokalemic periodic paralysis type 2 are both rare genetic channelopathies caused by mutations in the CLCN1 gene encoding voltage-gated chloride...
Myotonia congenita and hypokalemic periodic paralysis type 2 are both rare genetic channelopathies caused by mutations in the CLCN1 gene encoding voltage-gated chloride channel CLC-1 and the SCN4A gene encoding voltage-gated sodium channel Nav1.4. The patients with concomitant mutations in both genes manifested different unique symptoms from mutations in these genes separately. Here, we describe a patient with myotonia and periodic paralysis in a consanguineous marriage pedigree. By using whole-exome sequencing, a novel F306S variant in the CLCN1 gene and a known R222W mutation in the SCN4A gene were identified in the pedigree. Patch clamp analysis revealed that the F306S mutant reduced the opening probability of CLC-1 and chloride conductance. Our study expanded the CLCN1 mutation database. We emphasized the value of whole-exome sequencing for differential diagnosis in atypical myotonic patients.
Topics: Adolescent; Adult; Aged; Amino Acid Sequence; China; Chloride Channels; Consanguinity; Conserved Sequence; Diagnosis, Differential; Female; HEK293 Cells; Humans; Hypokalemic Periodic Paralysis; Male; Middle Aged; Models, Molecular; Mutant Proteins; Mutation; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Pedigree; Recombinant Proteins; Exome Sequencing; Young Adult
PubMed: 32407401
DOI: 10.1371/journal.pone.0233017 -
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 -
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 Biomedical Science Jan 2021Congenital myopathy (CM) is a group of clinically and genetically heterogeneous muscle disorders, characterized by muscle weakness and hypotonia from birth. Currently,...
BACKGROUND
Congenital myopathy (CM) is a group of clinically and genetically heterogeneous muscle disorders, characterized by muscle weakness and hypotonia from birth. Currently, no definite treatment exists for CM. A de novo mutation in Tropomyosin 3-TPM3(E151G) was identified from a boy diagnosed with CM, previously TPM3(E151A) was reported to cause CM. However, the role of TPM3(E151G) in CM is unknown.
METHODS
Histopathological, swimming behavior, and muscle endurance were monitored in TPM3 wild-type and mutant transgenic fish, modelling CM. Gene expression profiling of muscle of the transgenic fish were studied through RNAseq, and mitochondria respiration was investigated.
RESULTS
While TPM3(WT) and TPM3(E151A) fish show normal appearance, amazingly a few TPM3(E151G) fish display either no tail, a crooked body in both F0 and F1 adults. Using histochemical staining for the muscle biopsy, we found TPM3(E151G) displays congenital fiber type disproportion and TPM3(E151A) resembles nemaline myopathy. TPM3(E151G) transgenic fish dramatically swimming slower than those in TPM3(WT) and TPM3(E151A) fish measured by DanioVision and T-maze, and exhibit weaker muscle endurance by swimming tunnel instrument. Interestingly, L-carnitine treatment on TPM3(E151G) transgenic larvae significantly improves the muscle endurance by restoring the basal respiration and ATP levels in mitochondria. With RNAseq transcriptomic analysis of the expression profiling from the muscle specimens, it surprisingly discloses large downregulation of genes involved in pathways of sodium, potassium, and calcium channels, which can be rescued by L-carnitine treatment, fatty acid metabolism was differentially dysregulated in TPM3(E151G) fish and rescued by L-carnitine treatment.
CONCLUSIONS
These results demonstrate that TPM3(E151G) and TPM3(E151A) exhibit different pathogenicity, also have distinct gene regulatory profiles but the ion channels were downregulated in both mutants, and provides a potential mechanism of action of TPM3 pathophysiology. Our results shed a new light in the future development of potential treatment for TPM3-related CM.
Topics: Animals; Animals, Genetically Modified; Carnitine; Muscle, Skeletal; Myotonia Congenita; Tropomyosin; Zebrafish
PubMed: 33435938
DOI: 10.1186/s12929-020-00707-1 -
JA Clinical Reports Nov 2019Sodium-channel myotonia (SCM) is a nondystrophic myotonia, characterized by pure myotonia without muscle weakness or paramyotonia. The prevalence of skeletal muscle...
BACKGROUND
Sodium-channel myotonia (SCM) is a nondystrophic myotonia, characterized by pure myotonia without muscle weakness or paramyotonia. The prevalence of skeletal muscle channelopathies is approximately 1 in 100,000, and the prevalence of SCM is much lower. To our knowledge, this is the first report on anesthetic management of a patient with SCM.
CASE PRESENTATION
A 23-year-old woman with congenital nasal dysplasia and SCM was scheduled to undergo rhinoplasty with autologous costal cartilage. Total intravenous anesthesia without muscle relaxants was administered followed by continuous intercostal nerve block. Although transient elevation of potassium level in the blood was observed during surgery, the patient did not show exacerbation of myotonic or paralytic symptoms in the postoperative period.
CONCLUSION
Total intravenous anesthesia and peripheral nerve block can be administered safely to a patient with SCM. However, careful monitoring of the symptoms and electrolytes is recommended.
PubMed: 32026975
DOI: 10.1186/s40981-019-0300-8 -
BMC Neurology Apr 2023Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy...
BACKGROUND
Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen's congenital myotonia.
CASE PRESENTATION
We describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan's anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described.
CONCLUSIONS
Although uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.
Topics: Humans; Acyltransferases; Chloride Channels; Lipase; Muscular Diseases; Mutation; Myotonia; Myotonia Congenita
PubMed: 37106355
DOI: 10.1186/s12883-023-03195-6 -
Annals of Medicine and Surgery (2012) Feb 2024Sodium channel myotonia (SCM) belongs to the group of sodium channelopathies with mutations involving gene. The main feature of sodium channel myotonia is pure myotonia...
INTRODUCTION AND IMPORTANCE
Sodium channel myotonia (SCM) belongs to the group of sodium channelopathies with mutations involving gene. The main feature of sodium channel myotonia is pure myotonia without episodes of weakness or paralysis. One of the sodium channel myotonia has been classified as acetazolamide-responsive myotonia because of the effectiveness of acetazolamide as an antimyotonic drug.
CASE PRESENTATION
The child presented with generalized muscle hypertrophy and stiffness involving arms, thighs, calves, chest, and back muscles with unusually prominent trapezius muscle. The parents described the warm-up phenomenon as an improvement in stiffness as the day passes and with repetitive action. Percussion myotonia was illustrated in the thenar eminence and trapezius muscle. Characteristic 'dive-bomber' sound was present in electromyography, and whole-exome sequencing revealed a novel Ile239Thr mutation in the gene. Acetazolamide was prescribed for the condition, and regular follow-up shows an excellent clinical response.
CLINICAL DISCUSSION
This case presents a pure myotonic phenotype without episodes of weakness or paralysis. Generalized myotonia with muscle hypertrophy and demonstrating warm-up phenomenon resembles myotonia congenita (a chloride channelopathy). However, genetic analysis revealed a novel Ile239Thr mutation involving gene indicating this case to be a sodium channelopathy.
CONCLUSION
This case limelight sodium channel myotonia with a novel Ile239Thr mutation in gene that phenotypically resembles myotonia congenita but genetically belongs to sodium channelopathy highlighting the poor correlation between genotypes and phenotypes in non-dystrophic myotonia. Acetazolamide can be a safe and cost-effective antimyotonic drug in sodium channel myotonia.
PubMed: 38333241
DOI: 10.1097/MS9.0000000000001673