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Background: Autosomal recessive inherited pathogenetic variants in the histidine triad nucleotide-binding protein 1 ( HINT1 ) gene are responsible for an axonal Charcot-Marie-Tooth neuropathy associated with neuromyotonia, a phenomenon resulting from peripheral nerve hyperexcitability that causes a spontaneous muscle activity such as persistent muscle contraction, impaired relaxation and myokymias., Methods: Herein, we describe two brothers in whom biallelic HINT1 variants were identified following a multidisciplinary approach., Results: The younger brother came to our attention for clinical evaluation of moderate intellectual disability, language developmental delay, and some behavioral issues. His elder brother presented mild intellectual disability, hyperactivity, tiptoe walking, and gait ataxia. At first evaluation, motor impairment with frequent falls, pes cavus, and distal hyposthenia with reduced osteotendinous reflexes were found in both. Grip myotonic phenomenon was also noted. Blood tests revealed mildly elevated creatine kinase, and neurophysiology investigations revealed predominantly axonal polyneuropathy. Muscle MRI highlighted fibro-adipose infiltration, prevalent in the lower limbs. Gene panel testing detected a heterozygous HINT1 variant (c.355C>T/p.(Arg119Trp)) on the paternal allele. A further in-depth analysis using Integrative Genomics Viewer and Optical Genome Mapping led us to identify an additional variant in HINT1 represented by a complex rearrangement located in the region 5'UTR-exon 1-intron 1, not previously described., Conclusions: This complex rearrangement could have been overlooked if the clinical picture had not been evaluated as a whole (from a clinical, neurophysiological, and neuroimaging point of view). Neuropsychiatric manifestations (intellectual disability, hyperactivity, etc.) are part of the picture of HINT1 -related neuromyotonia.

Inherited peripheral neuropathy (IPN) is a heterogeneous group of disorders due to pathogenic variation in more than 100 genes. In 2012, the first cases of IPN associated with HINT1 pathogenic variations were described in 33 families sharing the same phenotype characterized by an axonal neuropathy with neuromyotonia and autosomal recessive inheritance (NMAN: OMIM #137200). Histidine Triad Nucleotide Binding Protein 1 regulates transcription, cell-cycle control, and is possibly involved in neuropsychiatric pathophysiology. Herein, we report seven French patients with NMAN identified by Next Generation Sequencing. We conducted a literature review and compared phenotypic and genotypic features with our cohort. We identified a new HINT1 pathogenic variation involved in NMAN: c.310G>C p.(Gly104Arg). This cohort is comparable with literature data regarding age of onset (7,4yo), neuronal involvement (sensorimotor 3/7 and motor pure 4/7), and skeletal abnormalities (scoliosis 3/7, feet anomalies 6/7). We expand the phenotypic spectrum of HINT1-related neuropathy by describing neurodevelopmental or psychiatric features in six out of seven individuals such as generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), mood disorder and attention deficit hyperactivity disorder (ADHD). However, only 3/128 previously described patients had neuropsychiatric symptomatology or neurodevelopmental disorder. These features could be part of HINT1-related disease, and we should further study the clinical phenotype of the patients., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

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 Ca 2+ 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 Ca 2+ concentration and prevent the appearance of pathological signs, paving the way for a possible therapeutic approach against Brody disease.

Purpose: To report five cases of ocular neuromyotonia in children and adolescents following radiation therapy for a variety of pediatric brain tumors. Notably, three cases occurred in children younger than 11 years., Methods: Case series of five patients with ocular neuromyotonia following proton beam therapy or conventional radiation., Results: Five cases of ocular neuromyotonia were identified following radiation treatment of various pediatric brain tumors. Onset ranged from 5 to 142 months after radiation treatment. The abducens nerve/lateral rectus muscle was affected in three patients, and the trochlear nerve/superior oblique muscle was affected in two patients. Ages at symptom presentation were 4 years (intermittent head tilt), 9 years (intermittent blurry vision and head tilt), 10 years (intermittent blurry vision progressing to intermittent diplopia), 15 years (intermittent diplopia), and 17 years (intermittent diplopia). One patient improved with gabapentin. Two patients experienced spontaneous resolution. One patient died due to meta-static disease, and one patient has planned follow-up., Conclusions: Ocular neuromyotonia occurs most commonly following radiation to the brain and skull base. Clinicians need to be aware that ocular neuromyotonia presents differently in children (who may not report diplopia) than in adults or adolescents (who typically report diplopia). Two children in this series never reported diplopia, only intermittent head tilt and blurry vision. Ocular neuromyotonia requires a high index of suspicion to diagnose, especially in children. Membrane stabilizers can be used effectively, but observation may be a valid option in children because spontaneous resolution was seen. [ J Pediatr Ophthalmol Strabismus . 2022;59(5):338-343.] .

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., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) is a rare form of hereditary neuropathy. Mutations in HINT1 gene have been identified to be the cause of this disorder. We report two unrelated patients who presented gait impairment, progressive distal muscle weakness and atrophy, neuromyotonia and foot deformities. Electrophysiological studies showed axonal motor neuropathy and neuromyotonic discharges. Using Next-generation sequencing, we identified two homozygous mutations, NM&#95;005340.6: c.112T > C; p.(Cys38Arg) and NM&#95;005340.6: c.289G > A; p.(Val97Met) in HINT1 gene. Based on the clinical presentation and molecular genetic analyses, ARAN-NM was diagnosed in both patients and NM&#95;005340.6: c.112T > C; p.(Cys38Arg) and NM&#95;005340.6: c.289G > A; p.(Val97Met) in HINT1 gene were believe to be causative for the disorder., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

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., (© 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Recessive mutations in the gene encoding the histidine triad nucleotide binding protein 1 (HINT1) were recently shown to cause a motor-predominant Charcot-Marie-Tooth neuropathy. About 80% of the patients exhibit neuromyotonia, a striking clinical and electrophysiological hallmark that can help to distinguish this disease and to guide diagnostic screening. HINT1 neuropathy has worldwide distribution and is particularly prevalent in populations inhabiting central and south-eastern Europe. With 12 different mutations identified in more than 60 families, it ranks among the most common subtypes of axonal Charcot-Marie-Tooth neuropathy. This article provides an overview of the present knowledge on HINT1 neuropathy with the aim to increase awareness and spur interest among clinicians and researchers in the field. We propose diagnostic guidelines to recognize and differentiate this entity and suggest treatment strategies to manage common symptoms. As a recent player in the field of hereditary neuropathies, the role of HINT1 in peripheral nerves is unknown and the underlying disease mechanisms are unexplored. We provide a comprehensive overview of the structural and functional characteristics of the HINT1 protein that may guide further studies into the molecular aetiology and treatment strategies of this peculiar Charcot-Marie-Tooth subtype., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Paraneoplastic neurological syndromes and autoimmune encephalitides are immune neurological disorders occurring or not in association with a cancer. They are thought to be due to an autoimmune reaction against neuronal antigens ectopically expressed by the underlying tumour or by cross-reaction with an unknown infectious agent. In some instances, paraneoplastic neurological syndromes and autoimmune encephalitides are related to an antibody-induced dysfunction of ion channels, a situation that can be labelled as autoimmune channelopathies. Such functional alterations of ion channels are caused by the specific fixation of an autoantibody upon its target, implying that autoimmune channelopathies are usually highly responsive to immuno-modulatory treatments. Over the recent years, numerous autoantibodies corresponding to various neurological syndromes have been discovered and their mechanisms of action partially deciphered. Autoantibodies in neurological autoimmune channelopathies may target either directly ion channels or proteins associated to ion channels and induce channel dysfunction by various mechanisms generally leading to the reduction of synaptic expression of the considered channel. The discovery of those mechanisms of action has provided insights on the regulation of the synaptic expression of the altered channels as well as the putative roles of some of their functional subdomains. Interestingly, patients' autoantibodies themselves can be used as specific tools in order to study the functions of ion channels. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: To provide an overview of paraneoplastic nerve hyperexcitability syndromes., Methods: An extensive review of the literature on nerve hyperexcitability was performed. Particular attention was paid to Isaacs' syndrome and Morvan's syndrome, as well as their relationship to neoplasia., Results: An overview of the history, clinical manifestations (including neurophysiologic findings), pathophysiology, and management is presented. Clinical differences between the exclusively peripheral nervous system involving Isaacs' syndrome and Morvan's syndrome, which also involves the central nervous system (CNS) are detailed. The role of immune-mediated dysfunction of specific components of the voltage-gated potassium channel (VGKC) complex in the pathophysiology of these syndromes is explained. Finally, the limited data on management of these syndromes, including the use of antiepileptic and immunomodulatory therapies are discussed., Conclusion: Nerve hyperexcitability syndrome represents a spectrum of neuroimmunologic diseases, which are often paraneoplastic in etiology.

A 44-year-old man with a bilateral hand tremor suffered from a decline in concentration and abnormal vision for several months. He also complained of easily falling down because of muscle stiffness and cramps in his lower limbs. On admission, he demonstrated lower limb stiffness, muscle cramps, diplopia, hyperhidrosis, left upper limb ataxia and dysesthesia in all limbs. Laboratory examination showed a marked elevation in his serum creatine kinase level (26,890 U/l), and needle electromyography demonstrated myokymic discharges in the muscles of his lower extremities. Isaacs' syndrome was diagnosed based on a positive voltage-gated potassium channel antibody titer of 1,007 pM. Administration of an anticonvulsant (phenytoin, 200 mg/day) did not resolve his symptoms; however, high-dose intravenous methylprednisolone therapy (1 g/day for 3 days) resulted in marked clinical improvement. This case suggests that high-dose intravenous methylprednisolone therapy for Isaacs' syndrome might be as effective as other immunosuppressive therapies such as plasma exchange or intravenous immunoglobulin.

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., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Ocular neuromyotonia (ONM) is a rare disorder of ocular mal-alignment in which painless, transient spontaneous or gaze-induced abnormal deviation of the eye manifests as episodic diplopia. With only a few cases reported in the literature, ONM mostly follows months to years after cranial irradiation for sellar or suprasellar lesions. Here we present two patients with this rare ocular condition, secondary to brainstem demyelination, the association of which is hitherto unreported in the literature. Both patients were 15-year-old girls who presented to us with episodic forced-eye deviation with diplopia. Examination during these attacks revealed ONM involving the superior rectus and medial rectus in the first and second patient, respectively. There was clinical evidence of intrinsic brainstem involvement with downbeat nystagmus and skew deviation in one patient without any other cerebellar or long tract signs. MRI showed evidence of demyelination involving the brainstem in both, with CSF showing positive immunological markers and with positive aquaporin-4 antibody in one patient. Both patients responded remarkably to immunomodulatory therapy and are asymptomatic at follow-up. That ONM can occur with brainstem demyelination has not been reported in the literature. This association may help in explaining the pathophysiology of ONM as secondary to segmental demyelination., (© The Author(s) 2014.)

Mutations in HINT1, the gene encoding histidine triad nucleotide-binding protein 1 (HINT1), cause a recessively inherited peripheral neuropathy that primarily involves motor dysfunction and is usually associated with neuromyotonia (i.e. prolonged muscle contraction resulting from hyperexcitability of peripheral nerves). Because these mutations are hypothesized to cause loss of function, we analyzed Hint1 knockout mice for their relevance as a disease model. Mice lacking Hint1 appeared normal and yielded normal behavioral test results or motor performance, although they moved more slowly and for a smaller fraction of time in an open-field arena than wild-type mice. Muscles, neuromuscular junctions, and nodes of Ranvier were anatomically normal and did not show evidence of degeneration or regeneration. Axon numbers and myelination in peripheral nerves were normal at ages 4 and 13 months. Axons were slightly smaller than those in wild-type mice at age 4 months, but this did not cause a decrease in conduction velocity, and no differences in axon diameters were detected at 13 months. With electromyography, we were unable to detect neuromyotonia even after using supraphysiologic stimuli and stressors such as reduced temperature or 3,4-diaminopyridine to block potassium channels. Therefore, we conclude that Hint1 knockout mice may be useful for studying the biochemical activities of HINT1, but these mice do not provide a disease model or a means for investigating the basis of HINT1-associated neuropathy and neuromyotonia.

Ocular neuromyotonia is an unusual condition in which sustained, undesired contraction of one or more extraocular muscles occurs after normal muscle activation. Although most commonly reported after paraseller cranial irradiation for tumor, chronic nonaneurysmal vascular compression of the third nerve can produce partial ocular motor nerve paresis and ocular neuromyotonia. A 75-year-old woman presented with intermittent left-gaze-evoked binocular diplopia. She had an incomplete right third nerve palsy but became symptomatically diplopic and esotropic upon sustained left gaze. High-resolution brain magnetic resonance imaging showed displacement of the right posterior communicating artery and contact with the right third nerve. Gaze-evoked diplopia resolved with carbamazepine, but a partial third nerve paresis remained.

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., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A 25-year-old woman complained of numbness of the extremities, following muscle rigidity and tenderness. The presence of anti-voltage-gated potassium channel antibody led to the diagnosis of Isaacs' syndrome. Twenty-seven months after the first symptom, she developed a pricking pain sensation in the lateral left foot, and then gradually developed a purple skin lesion resembling frostbite. The lesion completely disappeared 2 days later. An incidental episode occurred at the same site 8 months later. Frostbite-like skin lesions may be a rare autonomic manifestation in Isaacs' syndrome.

We present a rare case of focal neuromyotonia in a 73-year-old woman with a follow up of 5 years. The clinical picture showed a fixed contraction of the 3rd and 4th finger of the left hand. Similar to other published cases, our patient suffered from COPD and was treated with beta-2-sympathomimetics. This clinical picture shows a rare but rather salient differential diagnosis of Dupuytren's contracture. EMG of the affected muscles may yield a diagnosis and prevent the patient from a long and ineffective treatment "odyssey".

Acquired neuromyotonia encompasses a group of inflammatory disorders characterized by symptoms reflecting peripheral nerve hyperexcitability, which may be clinically confused in the early stages with amyotrophic lateral sclerosis. Despite a clear peripheral nerve focus, it remains unclear whether the ectopic activity in acquired neuromyotonia receives a central contribution. To clarify whether cortical hyperexcitability contributes to development of clinical features of acquired neuromyotonia, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical hyperexcitability in acquired neuromyotonia, and whether this technique could differentiate acquired neuromyotonia from amyotrophic lateral sclerosis. Cortical excitability studies were undertaken in 18 patients with acquired neuromyotonia and 104 patients with amyotrophic lateral sclerosis, with results compared to 62 normal controls. Short-interval intracortical inhibition in patients with acquired neuromyotonia was significantly different when compared to patients with amyotrophic lateral sclerosis (averaged short interval intracortical inhibition acquired neuromyotonia 11.3 +/- 1.9%; amyotrophic lateral sclerosis 2.6 +/- 0.9%, P < 0.001). In addition, the motor evoked potential amplitudes (acquired neuromyotonia 21.0 +/- 3.1%; amyotrophic lateral sclerosis 38.1 +/- 2.2%, P < 0.0001), intracortical facilitation (acquired neuromyotonia -0.9 +/- 1.3%; amyotrophic lateral sclerosis -2.3 +/- 0.6%, P < 0.0001), resting motor thresholds (acquired neuromyotonia 62.2 +/- 1.6%; amyotrophic lateral sclerosis 57.2 +/- 0.9%, P < 0.05) and cortical silent period durations (acquired neuromyotonia 212.8 +/- 6.9 ms; amyotrophic lateral sclerosis 181.1 +/- 4.3 ms, P < 0.0001) were significantly different between patients with acquired neuromyotonia and amyotrophic lateral sclerosis. Threshold tracking transcranial magnetic stimulation established corticomotoneuronal integrity in acquired neuromyotonia, arguing against a contribution of central processes to the development of nerve hyperexcitability in acquired neuromyotonia.

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., (2010 Elsevier B.V. All rights reserved.)

Neuromyotonia is a disorder of hyperexcitability of the peripheral nerve. It has electromyographic features of spontaneous, continuous, irregularly occurring doublets, or multiplets of motor unit potential discharges. Neuromyotonia is characterized by both myokymic and neuromyotonic discharges. To our knowledge, this is the first report in the literature to assess the sensitivity of skeletal muscle to a nondepolarizing muscle relaxant drug, rocuronium, in a woman with acquired neuromyotonia. She had a past medical history notable for prolonged postoperative paralysis following anesthesia. The patient showed increased sensitivity to the neuromuscular effects of rocuronium. This increase in sensitivity may be explained by downregulation of acetylcholine receptors in response to chronic high agonist (acetylcholine) concentrations. If patients with neuromyotonia receive anesthesia, we recommend that smaller doses of a nondepolarizing muscle relaxant be administered, accompanied by monitoring of neuromuscular function, so as to provide optimal muscle relaxation while avoiding overdose and prolonged postoperative recovery.

Ocular neuromyotonia refers to paroxysmal involuntary contraction of one or more ocular muscles resulting in paroxysmal diplopia and strabismus. A 73-year-old woman reported spells of horizontal diplopia that usually developed after leftward gaze and mostly lasted less than one minute. Between the episodes, the extraocular movements were normal without aberrant regeneration. The diplopic paroxysms could be triggered by leftward gaze for several seconds. During the episode, the left eye was exotropic with mild adduction limitation. Brain imaging revealed an aneurysm in the left internal carotid artery. The episodes resolved with carbamazepine. Aneurysm of the internal carotid artery is a rare cause of abducens neuromyotonia. A compressive lesion may give rise to ocular neuromyotonia even in the absence of prior irradiation.

Objectives: We are presenting 20 cases of the intriguing clinico-electromyographic entity, now considered a potassium channel disorder, Neuromyotonia. Our experience with the clinical manifestations, underlying abnormalities and response to various therapies is documented., Materials and Methods: Patients with diffuse pain or undulating muscle movements, with or without stiffness were sent for electromyographic and further studies. Patients with "neuromyotonic discharges" were included after exclusion of hypocalcaemia., Results: Our cases included 19 males and one female of age group 15 to 52 years, the majority being between 30 to 45 years. Undulating movements were seen in 19, of which two had focal twitching. Muscle stiffness was a complaint in five; pain was the chief presenting complaint of 19, which started in the calf in all. Irritability, insomnia and a peculiar worried pinched face were present in 12 patients. CSF was abnormal with mildly raised protein in eight. Curiously, 11 of these patients had taken ayurvedic treatment for various complaints in the preceding one month. Bell's palsy was associated in four, peripheral neuropathy in two and residual poliomyelitis in two. Electromyographic evidence of spontaneous activity in the form of "neuromyotonic discharges" was seen in all. Antibodies to voltage gated potassium channels was tested in one patient and was positive (titer was 1028 pM). Membrane stabilizers (e.g, phenytoin sodium) in our experience did not provide adequate rapid relief; we tried high-dose intravenous Methylprednisolone in 19 with significant amelioration of complaints. One patient was offered intravenous immunoglobulin, to which he responded., Conclusions: Neuromyotonia is a heterogeneous condition and can present in varied ways including diffuse nonspecific pain. This uncommon condition is potentially treatable and can be picked up with high index of suspicion.

Neuromyotonia is a rare condition of spontaneous and continuous muscle fibre activity of peripheral nerve origin. It represents the more severe phenotype of peripheral nerve hyperexcitability, and when acquired is often associated with antibodies to voltage-gated potassium channels. There are no specific published electromyographic or clinical diagnostic criteria for this disorder. This review highlights the classical clinical, electrophysiological and immunological features of this disorder from what is currently known in the literature to date, and also from the author's own patients' studies. Neuromyotonia is best classified as a moderately severe disorder of peripheral nerve hyperexcitability, with electromyographic features of spontaneous, continuous, irregularly occurring doublet, or multiplet single motor unit (or partial motor unit) discharges, firing at a high intraburst frequency (30-300Hz). Invariably, patients develop persistent muscle contraction, often worse following exercise. About 40% of patients with acquired neuromyotonia will have detectable voltage-gated potassium-channel antibodies. Clinical, electrophysiological and immunological measurements are important in defining the phenotype of neuromyotonia, and other, milder forms of peripheral nerve hyperexcitability.

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.

We report an unusual family in which the same point mutation in the voltage-gated potassium channel gene KCNA1 resulted in markedly different clinical phenotypes. The propositus presented in infancy with marked muscle stiffness, motor developmental delay, short stature, skeletal deformities, muscle hypertrophy and muscle rippling on percussion. He did not experience episodic ataxia. His mother presented some years later with typical features of Episodic Ataxia type 1 (EA1), with episodes of ataxia lasting a few minutes provoked by exercise. On examination she had myokymia, joint contractures and mild skeletal deformities. A heterozygous point mutation in the voltage-gated K(+) channel (KCNA1) gene (ACG-AGG, Thr226Arg) was found in both. We conclude that mutations in the potassium channel gene (KCNA1) can cause severe neuromyotonia resulting in marked skeletal deformities even if episodic ataxia is not prominent.

A young woman presented with facial myokymia in association with dermatomyositis. There was no evidence of peripheral neuropathy. Needle electromyography showed prominent myokymic discharges and brief neuromyotonic discharges in addition to many small-amplitude, short-duration motor unit potentials. Myokymia and dermatomyositis both responded to immunosuppressive treatment. The presence of antibodies to voltage-gated potassium channels and the association with dermatomyositis indicated an autoimmune cause for myokymia, which may have been due to reversible peripheral nerve hyperexcitability.

Ocular neuromyotonia is a rare clinical entity, which is characterized by spontaneous spasm of ocular muscles resulting in paroxysmal diplopia and strabismus. Inappropriate discharges from ocular motor neurons or axons with unstable cell membranes may cause the sustained contraction of their respective ocular muscles. In most cases, ocular neuromyotonia resulted from radiation therapy to the parasellar and sellar regions or compressive lesions on ocular motor nerves. Among 30 patients reported in the literatür only six patients were accepted as idiopathic. Here, we reported a patient with third nerve myotonia representing with spells of diplopia. No lesion was found and she was accepted as idiopathic ocular neuromyotonia.

Ocular neuromyotonia in the muscles innervated by the right oculomotor nerve was diagnosed in a patient without a history of radiation therapy. Electromyography of the levator palpebrae showed continuous motor unit activity. Brain MRI disclosed a close contact between the right third cranial nerve and a basilar artery dolichoectasia. The patient partly benefited from carbamazepine therapy. This unique finding suggests that neurovascular compression syndrome could be an hitherto unrecognised cause of ocular neuromyotonia.