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1.
J Vet Intern Med ; 37(6): 2310-2314, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37905444

RESUMO

BACKGROUND: KCNJ10 and CAPN1 variants cause "spinocerebellar" ataxia in dogs, but their association with generalized myokymia and neuromyotonia remains unclear. OBJECTIVE: To investigate the association between KCNJ10 and CAPN1 and myokymia or neuromyotonia, with or without concurrent spinocerebellar ataxia. ANIMALS: Thirty-three client-owned dogs with spinocerebellar ataxia, myokymia neuromytonia, or a combination of these signs. METHODS: Genetic analysis of a cohort of dogs clinically diagnosed with spinocerebellar ataxia, myokymia or neuromyotonia. KCNJ10 c.627C>G and CAPN1 c.344G>A variants and the coding sequence of KCNA1, KCNA2, KCNA6, KCNJ10 and HINT1 were sequenced using DNA extracted from blood samples. RESULTS: Twenty-four Jack Russell terriers, 1 Jack Russell terrier cross, 1 Dachshund and 1 mixed breed with spinocerebellar ataxia were biallelic (homozygous) for the KCNJ10 c.627C>G variant. Twenty-one of those dogs had myokymia, neuromyotonia, or both. One Parson Russell terrier with spinocerebellar ataxia alone was biallelic for the CAPN1 c.344G>A variant. Neither variant was found in 1 Jack Russell terrier with ataxia alone, nor in 3 Jack Russell terriers and 1 Yorkshire terrier with myokymia and neuromyotonia alone. No other causal variants were found in the coding sequence of the investigated candidate genes in these latter 5 dogs. CONCLUSION: The KCNJ10 c.627C>G variant, or rarely the CAPN1 c.344G>A variant, was confirmed to be the causal variant of spinocerebellar ataxia. We also report the presence of the KCNJ10 c.627C>G variant in the Dachshund breed. In dogs with myokymia and neuromyotonia alone the reported gene variants were not found. Other genetic or immune-mediated causes should be investigated to explain the clinical signs of these cases.


Assuntos
Doenças do Cão , Síndrome de Isaacs , Mioquimia , Ataxias Espinocerebelares , Humanos , Cães , Animais , Mioquimia/genética , Mioquimia/veterinária , Síndrome de Isaacs/genética , Síndrome de Isaacs/veterinária , Ataxias Espinocerebelares/veterinária , Ataxia/veterinária , Cruzamento , Proteínas do Tecido Nervoso , Canal de Potássio Kv1.6 , Doenças do Cão/genética
2.
Int J Mol Sci ; 23(20)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36293223

RESUMO

Congenital pseudomyotonia in cattle (PMT) is a rare skeletal muscle disorder, clinically characterized by stiffness and by delayed muscle relaxation after exercise. Muscle relaxation impairment is due to defective content of the Sarco(endo)plasmic Reticulum Ca2+ ATPase isoform 1 (SERCA1) protein, caused by missense mutations in the ATP2A1 gene. PMT represents the only mammalian model of human Brody myopathy. In the Romagnola breed, two missense variants occurring in the same allele were described, leading to Gly211Val and Gly286Val (G211V/G286V) substitutions. In this study, we analyzed the consequences of G211V and G286V mutations. Results support that the reduced amount of SERCA1 is a consequence of the G211V mutation, the G286V mutation almost being benign and the ubiquitin-proteasome system (UPS) being involved. After blocking the proteasome using a proteasome inhibitor, we found that the G211V mutant accumulates in cells at levels comparable to those of WT SERCA1. Our conclusion is that G211/286V mutations presumably originate in a folding-defective SERCA1 protein, recognized and diverted to degradation by UPS, although still catalytically functional, and that the main role is played by G211V mutation. Rescue of mutated SERCA1 to the sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca2+ concentration and prevent the appearance of pathological signs, paving the way for a possible therapeutic approach against Brody disease.


Assuntos
Síndrome de Isaacs , Bovinos , Humanos , Animais , Síndrome de Isaacs/genética , Síndrome de Isaacs/veterinária , Síndrome de Isaacs/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Complexo de Endopeptidases do Proteassoma/genética , Inibidores de Proteassoma , Estresse do Retículo Endoplasmático , Retículo Sarcoplasmático/genética , Mutação , Ubiquitina/genética , Músculo Esquelético/patologia , Mamíferos
3.
Animal ; 16(7): 100569, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35717834

RESUMO

In the last two decades, the molecular cause of six monogenic autosomal recessive disorders has been identified in native Italian beef cattle: two different ATP2A1 variants for the pseudomyotonia congenita, the first in Chianina and Romagnola (PMT1) and the second in Romagnola (PMT2); a KDM2B variant for the paunch calf syndrome (PCS) in Marchigiana and Romagnola; a NID1 variant for the congenital cataract (CC) in Romagnola; a LAMB1 variant for the hemifacial microsomia (HFM) in Romagnola; an ABCA12 variant for the ichthyosis fetalis (IF) in Chianina and a FA2H variant for the ichthyosis congenita (IC) in Chianina. The aim of this study was to evaluate the potential impact of these disorders in the affected Italian populations. For this purpose, 3331 Chianina, 2812 Marchigiana and 1680 Romagnola bulls born in the last 40 years were considered. The allelic frequency (AF) of the variant for PMT1 was 1.0% in Romagnola, 4.6% in Marchigiana and 5.9% in Chianina. The AF of the variant for PMT2 was 3.3% in Romagnola and 0% in the other two breeds. The AF of the variant for PCS was 11.7% in Romagnola, 2.0% in Marchigiana and 0% in Chianina. The AF of the variants for CC, HFM, IF and IC resulted below 3%, being the variants detected only in the breed populations in which they were previously reported. Considering a selected male population in the single breed, Chianina showed carrier prevalence of 11.9% for PMT1, 7.7% for IC and 6.4% for IF. Romagnola showed carrier prevalence of 23.4% for PCS, 6.7% for PMT2, 4.1% for HFM, 3.2% for CC and 2.0% for PMT1. Marchigiana showed carrier prevalence of 9.1% for PMT1 and 4.0% for PCS. With respect to the Romagnola cattle, the concerning presence of a total of five defect alleles in the population hampers a general approach based on the prevention of carriers from artificial insemination. However, identification of carriers may allow conscious mating to prevent the risk of homozygous descendants as well as the spread of heterozygous offspring. Therefore, systematic genotyping for all seven known harmful alleles is recommended to prevent risk mating between carriers, in particular to avoid the occurrence of affected offspring.


Assuntos
Doenças dos Bovinos , Síndrome de Isaacs , Animais , Bovinos/genética , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/genética , Frequência do Gene , Heterozigoto , Síndrome de Isaacs/congênito , Síndrome de Isaacs/veterinária , Masculino , Prevalência
4.
J Vet Intern Med ; 34(1): 253-257, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31729100

RESUMO

BACKGROUND: Paramyotonia congenita and Brody disease are well-described conditions in humans, characterized by exercise-induced myotonic-like muscle stiffness. A syndrome similar to Brody disease has been reported in cattle. Reports of a similar syndrome in dogs are scarce. OBJECTIVES: To define and describe the clinical, diagnostic, and genetic features and disease course of paradoxical pseudomyotonia in Spaniel dogs. ANIMALS: Seven client-owned dogs (4 English Springer Spaniels and 3 English Cocker Spaniels) with clinically confirmed episodes of exercise-induced generalized myotonic-like muscle stiffness. METHODS: Sequential case study. RESULTS: All dogs were <24 months of age at onset. The episodes of myotonic-like generalized muscle stiffness always occurred with exercise, and spontaneously resolved with rest in <45 seconds in all but 1 dog. Extreme outside temperatures seemed to considerably worsen episode frequency and severity in most dogs. Complete blood count, serum biochemistry including electrolytes, urinalysis, brain magnetic resonance imaging, cerebrospinal fluid analysis, electromyography, motor nerve conduction velocity, ECG, and echocardiography were unremarkable. Muscle biopsy samples showed moderate but nonspecific muscle atrophy. The episodes seemed to remain stable or decrease in severity and frequency in 6/7 dogs, and often could be decreased or prevented by avoiding the episode triggers. The underlying genetic cause is not identified yet, because no disease-causing variants could be found in the coding sequence or splice sites of the 2 major candidate genes, SCN4A and ATP2A1. CONCLUSIONS AND CLINICAL IMPORTANCE: Paradoxical pseudomyotonia is a disease affecting Spaniels. It is of variable severity but benign in most cases.


Assuntos
Doenças do Cão/diagnóstico , Síndrome de Isaacs/veterinária , Animais , Doenças do Cão/patologia , Cães , Síndrome de Isaacs/patologia , Condicionamento Físico Animal
5.
J Vet Intern Med ; 33(1): 287-291, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30511761

RESUMO

This article describes the clinical and electromyographic findings of neuromyotonia in a 19-month-old male crossbred Quarter Horse that presented with stiffness and muscle asymmetry in the hind limbs as well as sacrococcygeal, paravertebral, and gluteal myokymia. An electromyographic study showed spontaneous continuous muscle fiber activity with high-frequency discharges, fibrillations, positive sharp waves, fasciculation potentials, and complex repetitive discharges. Histological examination of the gluteal muscle showed a mixed neurogenic and myopathic pattern. The findings are consistent with neuromyotonia.


Assuntos
Doenças dos Cavalos/diagnóstico , Síndrome de Isaacs/veterinária , Animais , Eletromiografia/veterinária , Doenças dos Cavalos/patologia , Doenças dos Cavalos/fisiopatologia , Cavalos , Síndrome de Isaacs/diagnóstico , Síndrome de Isaacs/patologia , Síndrome de Isaacs/fisiopatologia , Glicoproteínas de Membrana , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Receptores de Interleucina-1
6.
Ann Anat ; 207: 21-6, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27210062

RESUMO

Cattle congenital pseudomyotonia (PMT), recognized as naturally occurring animal model of human Brody disease, is an inherited recessive autosomal muscular disorder due to missense mutations in ATP2A1 gene, encoding sarco(endo)plasmic reticulum Ca(2+)-ATPase protein, isoform 1 (SERCA1). PMT has been described in the Chianina and Romagnola italian cattle breeds and as a single case in Dutch improved Red and White cross-breed. The genetic defect turned out to be heterogeneous in different cattle breeds, even though clinical symptoms were homogeneous. Skeletal muscles of affected animals are characterized by a selective deficiency of SERCA1 in sarcoplasmic reticulum (SR) membranes. Recently, we provided evidence that in Chianina breed, the ubiquitin proteasome system is responsible for SERCA1 mutant premature disposal, even when the mutation does not affect the catalytic properties of the pump. Results presented here show that all SERCA1 mutants described until now, although expressed at low level, are correctly targeted to SR membranes. Ultrastructural studies confirm that in pathological muscle fibres, structure, as well as triads, is well preserved. All together these results suggest that a possible therapeutical approach based on the rescue of the defective protein at SR membranes could be hypothesized. Only fully functionally active missense mutants, whem located at the SR membrane could restore the efficient control of Ca(2+) homeostasis and prevent the appearance of the pathological signs. Moreover, these data demonstrate the increasing importance of domestic animals as genetic models of human pathologies.


Assuntos
Doenças dos Bovinos/patologia , Modelos Animais de Doenças , Síndrome de Isaacs/veterinária , Fibras Musculares Esqueléticas/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Retículo Sarcoplasmático/patologia , Animais , Bovinos , Doenças dos Bovinos/genética , Humanos , Síndrome de Isaacs/genética , Síndrome de Isaacs/patologia , Mutação/genética , Retículo Sarcoplasmático/genética
7.
J Am Vet Med Assoc ; 248(5): 532-7, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26885596

RESUMO

CASE DESCRIPTION A 5-year-old castrated male Maltese was evaluated for intermittent clinical signs of muscle cramping and abnormal movements of the skin of the right pelvic limb at the site where an infiltrative lipoma had twice been resected. After the second surgery, the surgical field was treated with radiation therapy (RT). The clinical signs developed approximately 14 months after completion of RT. CLINICAL FINDINGS When clinical signs were present, the right biceps femoris and semitendinosus muscles in the area that received RT were firm and had frequently visible contractions, and the skin overlying those muscles had episodic vermiform movements. Electromyography of those muscles revealed abnormal spontaneous activity with characteristics consistent with myokymic discharges and neuromyotonia. Magnetic resonance imaging of the affected leg revealed no evidence of tumor regrowth. The myokymia and neuromyotonia were considered secondary to RT. TREATMENT AND OUTCOME 4 U of Clostridium botulinum toxin type A (BoNT-A) neurotoxin complex was injected into the affected muscles at each of 6 sites twice during a 24-hour period (ie, 48 U of BoNT-A were administered). The clinical signs were completely resolved 10 days after BoNT-A treatment and were controlled by repeated BoNT-A treatment every 3 to 4 months for > 1 year. CLINICAL RELEVANCE To our knowledge, this is the first report of myokymia and neuromyotonia secondary to RT in a dog. For the dog of this report, injection of BoNT-A into the affected muscles was safe, effective, and easy to perform.


Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Doenças do Cão/tratamento farmacológico , Síndrome de Isaacs/veterinária , Mioquimia/veterinária , Fármacos Neuromusculares/uso terapêutico , Lesões por Radiação/veterinária , Animais , Toxinas Botulínicas Tipo A/administração & dosagem , Doenças do Cão/etiologia , Cães , Eletromiografia/veterinária , Injeções Intralesionais/veterinária , Injeções Intramusculares/veterinária , Síndrome de Isaacs/tratamento farmacológico , Síndrome de Isaacs/etiologia , Masculino , Mioquimia/tratamento farmacológico , Mioquimia/etiologia , Fármacos Neuromusculares/administração & dosagem , Lesões por Radiação/tratamento farmacológico
8.
Neuromuscul Disord ; 25(11): 888-97, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26482047

RESUMO

Missense mutations in ATP2A1 gene, encoding SERCA1 protein, cause a muscle disorder designed as congenital pseudomyotonia (PMT) in Chianina and Romagnola cattle or congenital muscular dystonia1 (CMD1) in Belgian Blue cattle. Although PMT is not life-threatening, CMD1 affected calves usually die within a few weeks of age as a result of respiratory complication. We have recently described a muscular disorder in a double muscle Dutch Improved Red and White cross-breed calf. Mutation analysis revealed an ATP2A1 mutation identical to that described in CMD1, even though clinical phenotype was quite similar to that of PMT. Here, we provide evidence for a deficiency of mutated SERCA1 in PMT affected muscles of Dutch Improved Red and White calf, but not of its mRNA. The reduced expression of SERCA1 is selective and not compensated by the SERCA2 isoform. By contrast, pathological muscles are characterized by a broad distribution of mitochondrial markers in all fiber types, not related to intrinsic features of double muscle phenotype and by an increased expression of sarcolemmal calcium extrusion pump. Calcium removal mechanisms, operating in muscle fibers as compensatory response aimed at lowering excessive cytoplasmic calcium concentration caused by SERCA1 deficiency, could explain the difference in severity of clinical signs.


Assuntos
Síndrome de Isaacs/veterinária , Fibras Musculares de Contração Rápida/fisiologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/deficiência , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Adaptação Fisiológica/fisiologia , Animais , Bovinos , Células HEK293 , Humanos , Síndrome de Isaacs/patologia , Síndrome de Isaacs/fisiopatologia , Isoenzimas/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fibras Musculares de Contração Rápida/patologia , Mutação de Sentido Incorreto , RNA Mensageiro/metabolismo
9.
J Biol Chem ; 289(48): 33073-82, 2014 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-25288803

RESUMO

A missense mutation in ATP2A1 gene, encoding sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) protein, causes Chianina cattle congenital pseudomyotonia, an exercise-induced impairment of muscle relaxation. Skeletal muscles of affected cattle are characterized by a selective reduction of SERCA1 in sarcoplasmic reticulum membranes. In this study, we provide evidence that the ubiquitin proteasome system is involved in the reduced density of mutated SERCA1. The treatment with MG132, an inhibitor of ubiquitin proteasome system, rescues the expression level and membrane localization of the SERCA1 mutant in a heterologous cellular model. Cells co-transfected with the Ca(2+)-sensitive probe aequorin show that the rescued SERCA1 mutant exhibits the same ability of wild type to maintain Ca(2+) homeostasis within cells. These data have been confirmed by those obtained ex vivo on adult skeletal muscle fibers from a biopsy from a pseudomyotonia-affected subject. Our data show that the mutation generates a protein most likely corrupted in proper folding but not in catalytic activity. Rescue of mutated SERCA1 to sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca(2+) concentration and prevent the appearance of pathological signs of cattle pseudomyotonia.


Assuntos
Doenças dos Bovinos/enzimologia , Síndrome de Isaacs/enzimologia , Síndrome de Isaacs/veterinária , Proteínas Musculares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/enzimologia , Ubiquitina/metabolismo , Animais , Cálcio/metabolismo , Bovinos , Doenças dos Bovinos/genética , Doenças dos Bovinos/patologia , Cricetinae , Células HEK293 , Humanos , Síndrome de Isaacs/genética , Síndrome de Isaacs/patologia , Leupeptinas/farmacologia , Proteínas Musculares/genética , Mutação , Complexo de Endopeptidases do Proteassoma/genética , Inibidores de Proteassoma/farmacologia , Dobramento de Proteína/efeitos dos fármacos , Retículo Sarcoplasmático/genética , Retículo Sarcoplasmático/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Ubiquitina/genética
10.
Vet J ; 197(2): 153-62, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23583699

RESUMO

Involuntary muscle hyperactivity can result from muscle or peripheral nerve hyperexcitability or central nervous system dysfunction. In humans, diseases causing hyperexcitability of peripheral nerves are grouped together under the term 'peripheral nerve hyperexcitability' (PNH). Hyperexcitability of the peripheral motor nerve can result into five different phenotypic main variants, i.e. fasciculations, myokymia, neuromyotonia, cramps and tetany, each with their own clinical and electromyographic characteristics. This review focuses on the most commonly described expressions of PNH in veterinary medicine, i.e. myokymia and neuromyotonia, in particular in young Jack Russell terriers. Data from 58 veterinary cases with generalized myokymia and neuromyotonia were analyzed, including unpublished treatment and follow-up data on eight Jack Russell terriers from a previous study and seven additional Jack Russell terriers. A dysfunction of the potassium channel or its associated proteins has been found in many human syndromes characterized by PNH, in particular in generalized myokymia and neuromyotonia, and is suspected to occur in veterinary medicine. Potential pathomechanisms of potassium channel dysfunction leading to signs of PNH are broad and include genetic mutations, antibody-mediated attack or ion channel maldistribution due to axonal degeneration or demyelination. A more accurate classification of the different PNH syndromes will facilitate a more rapid diagnosis and guide further research into natural occurring PNH in animals.


Assuntos
Síndrome de Isaacs/veterinária , Mioquimia/veterinária , Doenças do Sistema Nervoso Periférico/patologia , Animais , Humanos , Cãibra Muscular/patologia , Tetania/patologia
11.
BMC Vet Res ; 8: 186, 2012 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-23046865

RESUMO

BACKGROUND: Bovine congenital pseudomyotonia (PMT) is an impairment of muscle relaxation induced by exercise preventing animals from performing rapid movements. Forms of recessively inherited PMT have been described in different cattle breeds caused by two independent mutations in ATP2A1 encoding a skeletal-muscle Ca2+-ATPase (SERCA1). We observed symptoms of congenital PMT in four related Romagnola beef cattle from Italy and evaluated SERCA1 activity and scanned ATP2A1 for possible causative mutations. RESULTS: We obtained four PMT affected Romagnola cattle and noted striking clinical similarities to the previously described PMT cases in other cattle breeds. The affected animals had a reduced SERCA1 activity in the sarcoplasmic reticulum. A single affected animal was homozygous for a novel complex variant in ATP2A1 exon 8 (c.[632 G>T; 857 G>T]). Three out of four cases were compound heterozygous for the newly identified exon 8 variant and the exon 6 variant c.491 G>A(p. Arg146Gly), which has previously been shown to cause PMT in Chianina cattle. Pedigree analysis showed that the exon 8 double mutation event dates back to at least 1978. Both nucleotide substitutions are predicted to alter the SERCA1 amino acid sequence (p.[(Gly211Val; Gly284Val)]), affect highly conserved residues, in particular the actuator domain of SERCA1. CONCLUSION: Clinical, biochemical and DNA analyses confirmed the initial hypothesis. We provide functional and genetic evidence that one novel and one previously described ATP2A1 mutation lead to a reduced SERCA1 activity in skeletal muscles and pseudomyotonia in affected Romagnola cattle. Selection against these mutations can now be used to eliminate the mutant alleles from the Romagnola breed.


Assuntos
Doenças dos Bovinos/genética , Síndrome de Isaacs/veterinária , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Animais , Bovinos , Doenças dos Bovinos/enzimologia , DNA/química , DNA/genética , Feminino , Genótipo , Histocitoquímica/veterinária , Síndrome de Isaacs/enzimologia , Síndrome de Isaacs/genética , Masculino , Músculo Esquelético/enzimologia , Mutação , Linhagem , Análise de Sequência de DNA
12.
Neuromuscul Disord ; 22(6): 558-65, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22342001

RESUMO

KCNA1, KCNA2, KCNA6 and KCNQ2 are associated with peripheral nerve hyperexcitability in humans. In order to determine if these genes are also involved in Jack Russell Terriers with a similar syndrome characterized by myokymia and neuromyotonia, their predicted canine orthologs were first validated experimentally. They were found either incompletely or even incorrectly annotated, mainly due to gaps in the canine genomic sequence and insufficient transcript data. Canine KCNQ2 was found to contain 20 coding exons, of which three are not described in humans. It encodes for at least 14 different transcript variants in the frontal cortex of a single dog, of which only four are also described in humans. Mutation detection in Jack Russell Terriers diagnosed with peripheral nerve hyperexcitability revealed no pathogenetic relevant structural mutations. However, the four missense sequence variations and the 14 transcript variants of KCNQ2 will contribute to the study of the functional diversity of voltage-gated potassium channels.


Assuntos
Doenças do Cão/genética , Canal de Potássio KCNQ2/genética , Canal de Potássio Kv1.1/genética , Canal de Potássio Kv1.2/genética , Canal de Potássio Kv1.6/genética , Doenças do Sistema Nervoso Periférico/veterinária , Animais , Cães , Estudos de Associação Genética , Síndrome de Isaacs/genética , Síndrome de Isaacs/veterinária , Mutação , Mioquimia/genética , Mioquimia/veterinária , Doenças do Sistema Nervoso Periférico/genética
13.
J Small Anim Pract ; 52(10): 547-50, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21967102

RESUMO

A 10-month-old dachshund was presented with a recent history of episodic muscle rippling and generalised stiffness. An uncoordinated gait was present since eight weeks of age. On presentation the dog showed cerebellar-like ataxia and poor menace responses. Myokymic contractions were visible in the appendicular and truncal muscles and neuromyotonic discharges were detected by electromyography. Central components of the brain auditory evoked potentials were absent and the onset latencies of the tibial sensory-evoked potentials recorded at the lumbar intervertebral level were delayed. Response to slow-release phenytoin was temporary. The clinical picture together with the electrophysiological findings in this dachshund are identical to the findings in Jack Russell terriers with hereditary ataxia and neuromyotonia. This is the first description of neuromyotonia associated with clinical and electrophysiological signs of spinocerebellar ataxia in a breed other than the Jack Russell terrier. This case also strengthens the theory that spinocerebellar ataxia and neuromyotonia are related. An ion channel dysfunction is presumed to link both disorders.


Assuntos
Doenças do Cão/diagnóstico , Síndrome de Isaacs/veterinária , Ataxias Espinocerebelares/veterinária , Animais , Cães , Fenômenos Eletrofisiológicos , Eutanásia Animal , Síndrome de Isaacs/diagnóstico , Masculino , Ataxias Espinocerebelares/diagnóstico
14.
Vet J ; 189(3): 284-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20724183

RESUMO

The clinical and clinicopathological characteristics, treatment and outcome of vermicular muscle contractions (myokymia) and generalized muscle stiffness (neuromyotonia) in 37 Jack Russell terriers were evaluated retrospectively. Thirty dogs were affected by both disorders, whereas seven were presented with myokymia and never developed neuromyotonia. Clinical signs started at the mean age of 8 months. Except for signs of myokymia and neuromyotonia, clinical and neurological examination was normal in all dogs. Thirty dogs demonstrated typical signs of hereditary ataxia. Changes in serum chemistry included increased creatine kinase, aspartate aminotransferase and alanine aminotransferase concentrations. Electromyographic abnormalities, especially in muscles showing macroscopically visible myokymia, consisted of semirhythmic bursts of doublet, triplet, or multiplet discharges of a single motor unit. The amplitudes varied between 80 µV and 1 mV and occurred with an interburst frequency between 10 and 40 Hz and an intraburst frequency between 150 and 280 Hz. Most dogs were treated with a sodium channel blocker with variable results. Seven dogs died (most likely because of hyperthermia) or were euthanased during a neuromyotonic attack; 15 dogs were euthanased due to worsening of clinical signs, or lack of or no long-lasting effect of medication, and three were euthanased for unknown or unrelated reasons. Nine dogs were lost to follow-up and three were still alive 5-10.5 years after the start of clinical signs. In conclusion, young Jack Russell terriers with myokymia and neuromyotonia should undergo a complete blood and electrophysiological examination. Long-term prognosis is not favourable.


Assuntos
Doenças do Cão/tratamento farmacológico , Doenças do Cão/patologia , Síndrome de Isaacs/veterinária , Mioquimia/veterinária , Animais , Bélgica , Análise Química do Sangue/veterinária , Cães , Eletromiografia/veterinária , Feminino , Seguimentos , Síndrome de Isaacs/tratamento farmacológico , Síndrome de Isaacs/patologia , Masculino , Mioquimia/tratamento farmacológico , Mioquimia/patologia , Estudos Retrospectivos , Resultado do Tratamento
15.
Neuromuscul Disord ; 20(7): 467-70, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20547455

RESUMO

A Dutch Improved Red and White cross-breed heifer calf was evaluated for a muscular disorder resulting in exercise induced muscle stiffness. Clinical findings included generalized exercise-induced muscle spasms with normal response to muscle percussion. Electromyography showed no myotonic discharges, thus ruling out myotonia. Whereas histological examination of muscle tissue was unremarkable, Ca(2+)-ATPase activity of sarcoplasmatic reticulum membranes (SERCA1) was markedly decreased compared to control animals. Mutation analysis revealed the presence of a missense mutation in the ATP2A1 gene encoding the SERCA1 protein (p.Arg559Cys). The present case presents similarities to human Brody's disease, but also to pseudomyotonia and congenital muscular dystonia previously described in different cattle breeds.


Assuntos
Síndrome de Isaacs , Mutação/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Animais , Bovinos , Análise Mutacional de DNA , Síndrome de Isaacs/genética , Síndrome de Isaacs/patologia , Síndrome de Isaacs/veterinária , Fibras Musculares de Contração Rápida/patologia , Retículo Sarcoplasmático/genética , Retículo Sarcoplasmático/metabolismo
16.
J Vet Intern Med ; 24(4): 882-9, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20492485

RESUMO

BACKGROUND: Generalized myokymia and neuromyotonia (M/NM) in Jack Russell Terriers (JRTs) is related to peripheral nerve hyperexcitability syndrome in humans, a symptom complex resulting from diverse etiologies. OBJECTIVE: Clinical and electrodiagnostic evaluation is used to narrow the list of possible etiological diagnoses in JRTs with M/NM. ANIMALS: Nine healthy JRTs and 8 affected JRTs. METHODS: A prospective study was conducted comparing clinical and electrophysiological characteristics in 8 JRTs affected by M/NM with 9 healthy JRT controls. RESULTS: All affected dogs except 1 had clinical signs typical of hereditary ataxia (HA). In 6 dogs, neuromyotonic discharges were recorded during electromyogram. Motor nerve conduction studies showed an axonal neuropathy in only 1 affected dog. Compared with controls, brainstem auditory-evoked potentials (BAEP) showed prolonged latencies (P<.05) accompanied by the disappearance of wave components in 3 dogs. Onset latencies of tibial sensory-evoked potentials (SEP) recorded at the lumbar intervertebral level were delayed in the affected group (P<.001). The BAEP and SEP results of the only neuromyotonic dog without ataxia were normal. CONCLUSIONS AND CLINICAL IMPORTANCE: The BAEP and spinal SEP abnormalities observed in JRTs with M/NM were associated with the presence of HA. Therefore, these electrophysiological findings presumably arise from the neurodegenerative changes characterizing HA and do not directly elucidate the pathogenesis of M/NM. An underlying neuronal ion channel dysfunction is thought to be the cause of M/NM in JRTs.


Assuntos
Doenças do Cão/fisiopatologia , Síndrome de Isaacs/veterinária , Mioquimia/veterinária , Animais , Cães , Fenômenos Eletrofisiológicos , Feminino , Síndrome de Isaacs/fisiopatologia , Masculino , Mioquimia/fisiopatologia , Condução Nervosa/fisiologia
17.
Am J Pathol ; 174(2): 565-73, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19116366

RESUMO

Recently, a muscular disorder defined as "congenital pseudomyotonia" was described in Chianina cattle, one of the most important Italian cattle breeds for quality meat and leather. The clinical phenotype of this disease is characterized by an exercise-induced muscle contracture that prevents animals from performing muscular activities. On the basis of clinical symptoms, Chianina pseudomyotonia appeared related to human Brody's disease, a rare inherited disorder of skeletal muscle function that results from a sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1) deficiency caused by a defect in the ATP2A1 gene that encodes SERCA1. SERCA1 is involved in transporting calcium from the cytosol to the lumen of the sarcoplasmic reticulum. Recently, we identified the genetic defect underlying Chianina cattle pseudomyotonia. A missense mutation in exon 6 of the ATP2A1 gene, leading to an R164H substitution in the SERCA1 protein, was found. In this study, we provide biochemical evidence for a selective deficiency in SERCA1 protein levels in sarcoplasmic reticulum membranes from affected muscles, although mRNA levels are unaffected. The reduction of SERCA1 levels accounts for the reduced Ca(2+)-ATPase activity without any significant change in Ca(2+)-dependency. The loss of SERCA1 is not compensated for by the expression of the SERCA2 isoform. We believe that Chianina cattle pseudomyotonia might, therefore, be the true counterpart of human Brody's disease, and that bovine species might be used as a suitable animal model.


Assuntos
Síndrome de Isaacs/metabolismo , Síndrome de Isaacs/veterinária , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/deficiência , Animais , Western Blotting , Bovinos , Feminino , Imuno-Histoquímica , Síndrome de Isaacs/congênito , Masculino , Microscopia Confocal , Microscopia de Fluorescência , Músculo Esquelético/enzimologia , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Retículo Sarcoplasmático/enzimologia
18.
Genomics ; 92(6): 474-7, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18786632

RESUMO

Congenital pseudomyotonia in Chianina cattle is a muscle function disorder very similar to that of Brody disease in humans. Mutations in the human ATP2A1 gene, encoding SERCA1, cause Brody myopathy. The analysis of the collected Chianina pedigree data suggested monogenic autosomal recessive inheritance and revealed that all 17 affected individuals traced back to a single founder. A deficiency of SERCA1 function in skeletal muscle of pseudomyotonia affected Chianina cattle was observed as SERCA1 activity in affected animals was decreased by about 70%. Linkage analysis showed that the mutation was located in the ATP2A1 gene region on BTA25 and subsequent mutation analysis of the ATP2A1 exons revealed a perfectly associated missense mutation in exon 6 (c.491G>A) leading to a p.Arg164His substitution. Arg164 represents a functionally important and strongly conserved residue of SERCA1. This study provides a suitable large animal model for human Brody disease.


Assuntos
Bovinos/genética , Modelos Animais de Doenças , Síndrome de Isaacs/veterinária , Mutação de Sentido Incorreto , Miotonia Congênita/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Sequência de Aminoácidos , Animais , Arginina/genética , Análise Mutacional de DNA , Feminino , Humanos , Síndrome de Isaacs/congênito , Síndrome de Isaacs/genética , Masculino , Dados de Sequência Molecular , Linhagem , Condicionamento Físico Animal
20.
J Am Vet Med Assoc ; 227(10): 1608-12, 1591, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16313038

RESUMO

A 6-year-old spayed female domestic shorthair cat was examined because of a 2-week history of rhythmic muscle movements. Physical examination revealed thoracic limb rigidity, contracture of the carpi, generalized muscle atrophy, and rhythmic rippling of the muscles of all 4 limbs. Results of a CBC and serum biochemistry profile were unremarkable other than high creatine kinase activity. Electromyography revealed unique high-frequency discharges, including rhythmic bursts of single motor unit potentials appearing as doublets (myokymia) and more prolonged bursts of nonrhythmic motor unit potentials with characteristic waning amplitudes (neuromyotonia). Histologic examination of muscle biopsy specimens revealed noninflammatory necrotizing myopathy with regeneration. The cat did not respond to treatment with carbamazepine or prednisone but improved rapidly after treatment with phenytoin was initiated. Six months after initial examination, electromyography revealed a substantial decrease in the amount of spontaneous activity in previously affected muscles. However, the myokymic and neuromyotonic discharges were still present, albeit with a substantial decrease in frequency.


Assuntos
Doenças do Gato/patologia , Síndrome de Isaacs/veterinária , Mioquimia/veterinária , Fenitoína/uso terapêutico , Animais , Doenças do Gato/tratamento farmacológico , Gatos , Eletromiografia/veterinária , Feminino , Síndrome de Isaacs/tratamento farmacológico , Síndrome de Isaacs/patologia , Mioquimia/tratamento farmacológico , Mioquimia/patologia , Resultado do Tratamento
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