Hereditary myotonia in cats associated with a new homozygous missense variant p.Ala331Pro in the muscle chloride channel ClC-1.

Three-related cats were evaluated for a history of short-strided gait and temporary recumbency after startle. Neurological examination, electromyography (EMG), muscle biopsies, and a chloride voltage-gated channel 1 (CLCN1) molecular study were performed. Clinically, all 3 cats presented myotonia with warm-up phenomenon and myotonic discharges during EMG examination. Muscle biopsies showed normal muscle architecture and variation in the diameter of myofiber size with the presence of numerous hypertrophic fibers. The molecular study revealed a missense variant (c.991G>C, p.Ala331Pro) in exon 9 of the CLCN1 gene, responsible for the first chloride channel extracellular loop. This mutation was screened in 104 control phenotypically normal unrelated cats, and all were wildtype. The alanine at this position is conserved in ClC-1 (chloride channel protein 1) in different species, and 2 mutations at this amino acid position are associated with human myotonia. This is the third CLCN1 mutation described in the literature associated with hereditary myotonia in cats and the first in domestic animals located in an extracellular muscle ClC-1 loop.

Trismus due to myotonia associated with hyperadrenocorticism in a dog.

We present the report of trismus due to hyperadrenocorticism-associated myotonia diagnosed by electromyography in a dog. An intact female Miniature Dachshund, 13 years and 9 months old, presented with stiff gait and trismus as well as polyuria and polydipsia. Abdominal ultrasonography showed enlarged adrenal glands. An adrenocorticotropic hormone stimulation test revealed an exaggerated response. Based on these findings, this case was diagnosed with hyperadrenocorticism. Electromyography revealed myotonic discharge in the temporalis muscle and limbs. Therefore, trismus was considered to be caused by hyperadrenocorticism-associated myotonia, and the case was treated with oral trilostane (1.3 mg/kg, once daily). During the 4-month follow-up period, despite the partial improvement in stiff gait, trismus did not recover. Long-term data on more cases are warranted to assess the prognosis and clinical characteristics of trismus due to hyperadrenocorticism-associated myotonia.

A complex CLCN1 variant associated with hereditary myotonia in a mixed-breed dog.

Hereditary myotonia (HM) is characterized by delayed muscle relaxation after contraction as a result of a mutation in the CLCN1 gene. We describe here a complex CLCN1 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 CLCN1. After sequencing the CLCN1 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 CLCN1 variant; its parents were heterozygous, and its male littermate was homozygous wild-type. Knowledge of the CLCN1 mutations responsible for the development of hereditary myotonia allows greater clarification of this condition.

Classification of Involuntary Movements in Dogs: Myoclonus and Myotonia.

Myoclonus is a sudden brief, involuntary muscle jerk. Of all the movement disorders, myoclonus is the most difficult to encapsulate into any simple framework. On the one hand, a classification system is required that is clinically useful to aid in guiding diagnosis and treatment. On the other hand, there is need for a system that organizes current knowledge regarding biological mechanisms to guide scientific research. These 2 needs are distinct, making it challenging to develop a robust classification system suitable for all purposes. We attempt to classify myoclonus as "epileptic" and "nonepileptic" based on its association with epileptic seizures. Myotonia in people may be divided into 2 clinically and molecularly defined forms: (1) nondystrophic myotonias and (2) myotonic dystrophies. The former are a group of skeletal muscle channelopathies characterized by delayed skeletal muscle relaxation. Many distinct clinical phenotypes are recognized in people, the majority relating to mutations in skeletal muscle voltage-gated chloride (CLCN1) and sodium channel (SCN4A) genes. In dogs, myotonia is associated with mutations in CLCN1. The myotonic dystrophies are considered a multisystem clinical syndrome in people encompassing 2 clinically and molecularly defined forms designated myotonic dystrophy types 1 and 2. No mutation has been linked to veterinary muscular dystrophies. We detail veterinary examples of myotonia and attempt classification according to guidelines used in humans. This more precise categorization of myoclonus and myotonia aims to promote the search for molecular markers contributing to the phenotypic spectrum of disease. Our work aimed to assist recognition for these 2 enigmatic conditions.

Doenças hereditárias e defeitos congênitos diagnosticados em búfalos (Bubalus bubalis) no Brasil / Hereditary diseases and congenital defects diagnosed in water buffalo (Bubalus bubalis) in Brazil

A review on hereditary diseases and/or congenital defects diagnosed in water buffaloes in Brazil is performed. The epidemiological, clinical and pathological aspects of each disease or group of diseases are briefly described. Hereditary diseases include acantholytic mechanobullous dermatosis, arthrogryposis, myotonia, hydranencephaly, chondrodysplasia, and albinism. Congenital defects of unknown cause include megaesophagus, heart defects (patent ductus arteriosus), dermatosparaxia, and different defects of the reproductive system. The breeds most affected by genetic diseases are those from Asian Continent (Murrah and Jafarabadi), probably as a result of inbreeding in Brazilian herds due the prohibition of importation of breeding buffalo from that continent. The diagnosis of two hereditary diseases, arthrogryposis and myotonia, in Rio Grande do Sul (southern Brazil) and Pará (nothern Brazil) suggests that the undesirable genes are widespread in the buffalo population. The identification of these genes by molecular techniques associated with the buffalo breeding with correct sanitary, zootechnical, and reproductive control practices can decrease the negative effects of genetic diseases in the Brazilian buffalo herd.

É realizada uma revisão sobre as doenças hereditárias e/ou defeitos congênitos diagnosticados em búfalos no Brasil. São descritos brevemente os aspectos epidemiológicos, clínicos e patológicos de enfermidades hereditárias ou provavelmente hereditárias já observadas no Brasil, como dermatose mecanobolhosa, artrogripose, miotomia, hidranencefalia, condrodisplasia e albinismo; e dos defeitos congênitos que não tem uma causa ainda comprovada como megaesôfago, defeitos cardíacos (persistência do ducto arterioso), dermatosparaxia, defeitos no sistema reprodutivo e outros defeitos. Observou-se que as raças mais afetadas por enfermidades de natureza genética são as que têm origem no Continente Asiático (Murrah e Jafarabadi), provavelmente em consequência da consanguinidade existente nos rebanhos devido a proibição da importação de reprodutores, sêmen e embriões daquele continente. O diagnóstico de duas dessas doenças, artrogripose e miotomia hereditária no Rio Grande do Sul e no Pará, demonstra que os genes indesejáveis estão disseminados na população de búfalos no país e que a identificação desses genes por meio de técnicas moleculares associada à criação desta espécie com maior controle sanitário, reprodutivo e zootécnico pode minimizar os prejuízos decorrentes dessas enfermidades à bubalinocultura.

Confirmed 2,4-dichlorophenoxyacetic acid toxicosis in a dog.

A 2-year-old, intact male Weimaraner was evaluated for episodic extensor rigidity and a stiff gait of 24 hours' duration. Percussion of the proximal appendicular muscles with a reflex hammer resulted in formation of dimples consistent with myotonia. Electromyography identified myotonic potentials. Residues of 2,4-dichlorophenoxyacetic acid (2,4-D) were detected in both serum and urine. The dog was treated with intravenous fluid therapy for 36 hours, and clinical signs improved dramatically. Toxicosis with 2,4-D should be considered a differential for acquired myotonia in dogs with or without systemic signs. Exposed dogs with only clinical signs of myotonia can have good clinical outcomes. A confirmed clinical case of 2,4-D toxicosis in the dog has not previously been reported.

A novel mutation of the CLCN1 gene associated with myotonia hereditaria in an Australian cattle dog.

BACKGROUND: Heritable myotonia is a genetic muscle disorder characterized by slow relaxation of skeletal muscles. The main clinical signs are skeletal muscle stiffness, especially after vigorous contraction, and muscle hypertrophy. Muscle stiffness may be enhanced by inactivity, and often is relieved by exercise. Myotonia can be inherited in an autosomal dominant or recessive manner (Thomsen- or Becker-type myotonia, respectively). In mice, goats, Miniature Schnauzer dogs, and most affected humans, the disorder is caused by mutations in CLCN1, which encodes the skeletal muscle voltage-gated chloride channel, Cl1C-1. HYPOTHESIS: We hypothesized that an Australian Cattle Dog with generalized muscle stiffness and hypertrophy examined at the Ontario Veterinary College would have a mutation in the CLCN1 gene. ANIMALS: A pure-bred Australian Cattle Dog from Ontario, Canada, was used. METHODS: Based on clinical signs and electromyographic test results, a diagnosis of myotonia hereditaria was made, and a muscle biopsy was collected for genetic analysis. RESULTS: Sequence data obtained from the affected dog confirmed that it was homozygous for a single base insertion in the CLCN1 coding sequence. This mutation would result in a truncated ClC-1 protein being expressed, which, based on molecular evidence from other studies, would result in functionally compromised chloride conduction in the skeletal muscles of the animal. CONCLUSIONS AND CLINICAL IMPORTANCE: To the authors' knowledge, this report describes the Ist case of myotonia in an Australian Cattle Dog and represents the 1st non-Schnauzer canine myotonia to be genetically characterized. In addition, we developed a polymerase chain reaction-based genetic screen to detect heterozygotes with this mutation in the at-large Australian Cattle Dog population.

Myotonia and disorders of altered muscle cell membrane excitability.

Altered excitability of the skeletal muscle membrane (sarcolemma) can result in clinical signs of muscle dysfunction. Hyperexcitability of the sarcolemma results in myotonia, and hypoexcitability results in paresis or paralysis. Our understanding of the physiologic and molecular bases of disorders of sarcolemmal excitability is rapidly increasing as techniques for evaluation are improved. This article reviews muscle excitability disorders in dogs and cats and their pathogenesis.

Equine muscular dystrophy with myotonia.

OBJECTIVES: To describe a case of equine muscular dystrophy with myotonia. METHODS: A 5-year-old horse presented with hypertrophy and delayed relaxation of the muscles of the hindlimbs from age 2 months. Testicular atrophy developed from 2 years of age. Action and percussion myotonia was associated with weakness in these muscles, and EMG showed diffuse myotonic discharges and myopathic features. Biopsy of the gluteal muscle showed adipose and connective tissue infiltration, marked variation in muscle fibre size, and moth-eaten, ring and whorled fibres. RESULTS: Injection of apamin, a peptide blocker of calcium-activated potassium channels, which inhibits myotonia in human myotonic dystrophy, was ineffective in blocking myotonic discharges. Discharges promptly abated with 2% lidocaine injection. CONCLUSIONS: Myotonia in this horse is associated with dystrophic changes similar to human myotonic dystrophy, though there are some pharmacological differences.

Myotonia associated with hyperadrenocorticism in two dogs.

Two dogs developed a disabling gait abnormality characterised by stiffness. The abnormality was consistent with a diagnosis of myotonia secondary to hyperadrenocorticism. The first dog had iatrogenic hyperadrenocorticism, and its signs improved substantially after corticosteroid administration was gradually withdrawn. The second had pituitary-dependent hyperadrenocorticism, but myotonic signs progressed despite effective mitotane therapy. Procainamide administration reduced the myotonic stiffness in the second case.

Suspected herbicide toxicosis in a dog.

An 8-year-old 38-kg spayed female Golden Retriever was admitted for vomiting, signs of abdominal pain on palpation, ataxia, anorexia, and generalized weakness of 2 days' duration. Ten hours prior to onset of clinical signs, the dog was found standing in and drinking from large pools of an accidentally spilled herbicide that contained an octanoic acid ester of bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) and an isooctyl ester of (2-methyl-4-chloro) phenoxyacetic acid (MCPA). Appendicular muscles were firm on palpation and persistent muscle contraction (myotonia > 1 minute duration) was found on muscle percussion, using a reflex hammer. Electrical activity indicative of myotonia was identified on electromyographic evaluation. With supportive treatment, the dog eventually recovered from suspected MCPA toxicosis. Although rare, MCPA toxicosis should be considered as a cause of acquired myotonia in dogs.

Myotonia in a cocker spaniel.

A 16-week-old, male cocker spaniel suffering from pelvic-limb "bunny hopping" as well as rigidity, spasticity, and ataxia in all limbs was evaluated. The clinical features, electrophysiological abnormalities, and muscle histopathological and histochemical evaluations led to a diagnosis of congenital myotonia. Myotonia is a disorder of skeletal muscle characterized by delayed relaxation of the muscle fiber in response to voluntary, mechanical, or electrical stimulation. The pathophysiology of congenital myotonia remains controversial; currently proposed pathomechanisms are discussed. To the authors' knowledge, this is the first case of congenital myotonia reported in a cocker spaniel.

Inherited muscular disorder in mutant Japanese quail (Coturnix coturnix japonica): relationship between the development of muscle lesions and age.

The progression of the pathological changes that occur in the skeletal muscle was examined in 19 Japanese quail of the LWC strain, affected with an autosomal dominant inherited muscular disorder producing electrical myotonia. The muscle samples were obtained every 10 days from 20 to 70 days of age. Muscle samples from 18 age-matched commercial quail were used as normal controls. Characteristic histological lesions found in the skeletal muscles included sarcoplasmic masses, ringed fibres, internal migration of nuclei and fibre size variation. These lesions, which mainly occurred in the proximal muscles, appeared first in the pectoral region and later in the muscles of the thoracic and pelvic limbs. The most predominant lesion observed at all ages consisted of sarcoplasmic masses. The presence of histological changes did not affect muscle fibre typing by two staining methods, for myosin ATPase at pH 4.5, and by NADH-TR stain. The histological changes were observed in type 2A and less commonly in 2B fibres, but not in type 1. The pectoralis thoracicus muscle, in which lesions were particularly common, showed abnormally large type 2B muscle fibres at 20 days of age. These fibres began to decrease in size at 30 days of age, and at 70 days had become strikingly atrophic, their diameter being only about half that observed at 20 days. The atrophic type 2B muscle fibres were eventually replaced by lipocytes. Chronological staging of the histopathological changes in muscle was impossible since no inter-relationship was observed between the age of the quail, the severity of clinical signs and the extent of muscle lesions. This variability in the severity and age of onset may have been due to the variable expression or incomplete penetrance of the defective gene. Because the disorder is hereditary and progressive in nature, it can be classified as a type of progressive muscular dystrophy.

Voltage-gated ion channelopathies: inherited disorders caused by abnormal sodium, chloride, and calcium regulation in skeletal muscle.

The pathological genetic defects in the inherited myotonias and periodic paralyses were recently elucidated using molecular genetic studies. These disorders are usually transmitted as a dominant trait from an affected parent to a child. The many clinical symptoms include cold-induced uncontrollable contraction of muscle, potassium-induced contraction and paralysis, myotonia with dramatic muscular hypertrophy, muscle stiffness, and insulin-induced paralysis (in males). Horses afflicted with the disorder can suddenly collapse, despite an impressive physique. In the past three years, these clinically defined disorders have been shown to share a common etiology: subtle defects of ion channels in the muscle-fiber membrane. Although the specific ion channel involved varies depending on the disease, most patients have single amino acid changes in the channel proteins, with both normal and mutant channels present in each muscle fiber. For each patient, we can now establish a precise molecular diagnosis in the face of overlapping clinical symptoms and begin specific pharmacological treatment based on the primary problem. These studies have also provided insight into basic muscle biology and emphasize the careful regulation of ions in muscle excitation.

Effect of phenytoin on the clinical signs and in vitro muscle twitch characteristics in horses with chronic intermittent rhabdomyolysis and myotonia.

In vitro twitch characteristics of the semimembranosus muscle were evaluated in 9 clinically normal horses, in 15 horses with chronic intermittent rhabdomyolysis (CIR) and in 2 horses with myotonia. Effects of phenytoin on in vitro muscle twitch and clinical signs of CIR and myotonia were evaluated in these same horses. Times to 90% relaxation were prolonged in the horses with CIR (mean +/- SEM, 186 +/- 5.9 ms) and in 2 horses with myotonia (197 and 177 ms) compared with those in clinically normal horses (mean +/- SEM, 146 +/- 2.1 ms). Horses with CIR also had significantly (P less than 0.05) longer times to 50% relaxation, compared with clinically normal horses. In the group of horses with CIR, Standardbreds had significantly (P less than 0.05) longer times to 90% and 50% relaxation, compared with Thoroughbreds. Times to 100% peak tension did not differ among the groups. Administration of phenytoin directly into a muscle preparation bath solution had no effect on muscle twitch properties. After the initial muscle biopsy, phenytoin was administered orally for 7 to 10 days to 4 horses with CIR, 2 myotonic horses, and 2 clinically normal horses before repeat biopsy from the same site in the contralateral semimembranosus muscle. Times to 90% relaxation decreased from 197 and 177 ms to 144 and 126 ms, respectively, in the 2 myotonic horses, from a mean of 192 (+/- 9) ms to 170 (+/- 9) ms in the 4 horses with CIR and remained unchanged (154 and 140 ms before vs 155 and 139 ms after treatment) in the 2 clinically normal horses.(ABSTRACT TRUNCATED AT 250 WORDS)

Progressive myotonia in foals resembling human dystrophia myotonica.

A severe and progressive neuromuscular disorder accompanied by clinical, electrophysiological, and pathological features resembling human dystrophia myotonica was observed in three foals. This disorder was apparent as early as 1 month of age and involved progressive skeletal muscle dysfunction, initially characterized by proximal muscle hypertrophy and hypertonicity with subsequent muscle stiffness, weakness, and atrophy. Multisystem involvement was manifested in one case by testicular hypoplasia, early cataract formation, and borderline glucose intolerance. Prolonged dimpling of these large rear-limb muscles was elicited by percussion. Myotonic discharges were identified by electromyography. Percussion dimpling and the typical myotonic discharges persisted after neuromuscular blockade. Distinctive histologic muscle changes included ring fibers, sarcoplasmic mass formation, variation in fiber diameter size, and internally positioned nuclei.