Repetitive Compound Muscle Action Potential Research Articles

A novel mutation of the COLQ gene causes congenital myasthenic syndromes: A case report

Congenital myasthenic syndromes (CMS) are a group of heterogeneous disorders of the neuromuscular junctions, characterised by fluctuating and fatigable weakness with an early onset. Endplate acetylcholinesterase deficiency (EAD) due to mutations in COLQ is a subtype of CMS whose key clue for diagnosis is repetitive compound muscle action potential (R-CMAP) under nerve conduction studies. In light of the significant overlap of clinical symptoms, misdiagnosis is common for CMS, causing delayed or incorrect treatments. Here, we report a case of CMS due to a novel mutation in COLQ with a typical R-CMAP and discuss the significance of R-CMAP for diagnosis.

Cholinergic hyperactivity in patients with myasthenia gravis with MuSK antibodies: A neurophysiological study

ObjectivePatients with myasthenia gravis associated with muscle-specific tyrosine kinase antibodies (MuSK-MG) often manifest signs of cholinergic hyperactivity with standard doses of acetylcholinesterase inhibitors (AChE-Is). Aim of the study was to investigate whether repetitive compound muscle action potential (R-CMAP), the neurophysiological correlate of cholinergic hyperactivity, was present in MuSK-MG irrespective of AChE-I treatment. MethodsPatients with confirmed diagnosis of MuSK-MG were consecutively enrolled during follow-up visits, from January 2019 to April 2020. All these subjects underwent the same neurophysiological protocol, including motor nerve conduction studies and repetitive nerve stimulation. In patients taking pyridostigmine, neurophysiological testing was performed at least 12 hours after the last dose. For comparison, the presence of R-CMAP was investigated in 20 consecutive acetylcholine receptor antibody positive myasthenia gravis (AChR-MG) patients. ResultsWe enrolled 25 MuSK-MG patients (20 females), aged 16–79 years at the study time, with disease duration ranging 0.6–48.8 years (median: 17.7 years). R-CMAP was detected in 12/25 (48%) MuSK-MG cases and in none of the AChR-MG controls (p = 0.0003). In the MuSK-MG population, a history of muscle cramps and fasciculations, during low-dose pyridostigmine therapy, was significantly more frequent in R-CMAP positive than in R-CMAP negative patients (100% vs 31%, p = 0.001). At the time of the study, the proportion of patients still symptomatic for MG was higher among R-CMAP positive cases (92% vs 23%, p = 0.0005). ConclusionsCholinergic hyperactivity is a relatively common finding in MuSK-MG patients, independent of AChE-I treatment, and may constitute an intrinsic feature of the disease. SignificanceR-CMAP detection can represent a useful diagnostic clue for MuSK-MG and predicts poor tolerance to AChE-Is.

Prospective Hospital-Based Clinical and Electrophysiological Evaluation of Acute Organophosphate Poisoning.

Introduction:Acute organophosphate (OP) poisoning is one of the most common poisoning causing significant morbidity and mortality in developing countries. Acute cholinergic manifestations predominate with many patients requiring intensive care management and ventilator support. Nerve conduction studies including repetitive nerve stimulation can evaluate the altered neuromuscular transmission and peripheral nerve function by OPs.Objective:To evaluate the electrophysiological abnormalities in patients with acute OP poisoning and correlate with clinical status.Materials and Methods:Patients with acute OP poisoning admitted from August 2016 to August 2017 were prospectively studied. Nerve conduction studies including phrenic nerve conduction were performed within 24 h of admission. Repetitive nerve stimulation was performed at 3 and 30 Hz. Nerve conduction findings were compared with data from age-matched healthy controls.Results:Thirty patients were included (18 men and 12 women) in the study. Their age ranged from 16 to 47 years (30 ± 9.2). The first assessment revealed a mild reduction of compound muscle action potential (CMAP) amplitude and reduced F-wave persistence. Eleven patients had repetitive CMAPs suggesting cholinergic excess. Seven among the 11 patients requiring mechanical ventilation had decrement–increment response with 30 Hz stimulation and reduced diaphragmatic CMAP amplitude (P = 0.02).Conclusion:The presence of repetitive CMAPs, decrement–increment response to tetanic stimulation and reduced diaphragmatic CMAP amplitude in OP poisoning patients correlate with neuromuscular paralysis and need for mechanical ventilation.

Repetitive compound muscle action potential: a characteristic diagnostic clue

A 27-year-old woman complained of gradually deteriorating symmetrical weakness of finger extension over 18 months since the start of her first pregnancy. She had no other neurological symptoms but did...

Electromyography: Beyond positive diagnosis of myastenic syndrome

Objectives Electromyography (EMG) plays a major role to confirm the presence of neuromuscular transmission disorders. Furthermore, it helps to recognize the presynaptic or postsynaptic nature of the disorder. Indeed, specialized neurophysiological tests and characteristic electrophysiological findings are widely useful for etiological diagnosis [1] , [2] . Results Here we report two cases, a 36 years-old woman and 37 years-old men who presented to our department for facial muscle weakness. The female presented for drooping of both eyelids with diplopia, which appears while reading. Neurological examination showed bilateral asymmetric ptosis and complete ophtalmoplegia. Pupillary light reflex was normal as well as the rest of the neurological examination. The neostigmine test was positive. Repetitive nerve stimulation (RNS) testat 3 Hz stimulation, showed a significant decremental response in both area and amplitude with repetitive compound muscle action potentials (R-CMAP). Muscle biopsy eliminated centro-nuclear myopathy. We then considered the diagnosis of postsynaptic congenital myasthenic syndrome. The man presented with a ten days history of facial muscle weakness, dysphonia and swallowing disorders without diurnal fluctuation. Neurological examination noted symmetric proximal limb weakness. Clinical picture was concordant with acute inflammatory demyelinating polyradiculoneuropathy. Lumbar puncture did not evidence albumino-cytologic dissociation. Electrodiagnostic studies demonstrated a reduction in the initial CMAP amplitude, a decremental response to slow stimulation rates (3 Hz), followed by incremental response after a tetanic stimulation consistant with Lambert Eaton Syndrome. Conclusion In general, full anamnestic data and careful clinical examination are sufficient to make the diagnosis of myastenic syndrome. Nevertheless, the lack of diurnal fluctuation and a clear pattern of muscle distribution can sometimes lead to misdiagnosing this disorder [2] , [3] . Moreover, myastenic syndrome with predominant facial muscle involvement share overlapping symptoms with other muscle disease like mitochondrial and centro-nuclear myopathy. These findings delineate the contribution of EMG to differential and etiologic diagnosis [1] .

Congenital myasthenic syndromes in Turkey: Clinical clues and prognosis with long term follow-up

Congenital myasthenic syndromes (CMS) are a group of hereditary disorders affecting the neuromuscular junction. Here, we present clinical, electrophysiological and genetic findings of 69 patients from 51 unrelated kinships from Turkey. Genetic tests of 60 patients were performed at Mayo Clinic. Median follow-up time was 9.8 years (range 1–22 years). The most common CMS was primary acetylcholine receptor (AChR) deficiency (31/51) and the most common mutations in AChR were c.1219 + 2T > G (12/51) and c.1327delG (6/51) in CHRNE. Four of our 5 kinships with AChE deficiency carried p.W148X that truncates the collagen domain of COLQ, and was previously reported only in patients from Turkey. These were followed by GFPT1 deficiency (4/51), DOK7 deficiency (3/51), slow channel CMS (3/51), fast channel CMS (3/51), choline acetyltransferase deficiency (1/51) and a CMS associated with desmin deficiency (1/51). Distribution of muscle weakness was sometimes useful in giving a clue to the CMS subtype. Presence of repetitive compound muscle action potentials pointed to AChE deficiency or slow channel CMS. Our experience confirms that one needs to be cautious using pyridostigmine, since it can worsen some types of CMS. Ephedrine/salbutamol were very effective in AChE and DOK7 deficiencies and were useful as adjuncts in other types of CMS. Long follow-up gave us a chance to assess progression of the disease, and to witness 12 mainly uneventful pregnancies in 8 patients. In this study, we describe some new phenotypes and detail the clinical features of the well-known CMS.

A Missense Mutation in Epsilon-subunit of Acetylcholine Receptor Causing Autosomal Dominant Slow-channel Congenital Myasthenic Syndrome in a Chinese Family.

Background:Congenital myasthenic syndromes are a group of rare disorders that are clinically and genetically heterogeneous and caused by mutations in the genes encoding proteins of the neuromuscular junction. Here, we described a Chinese family that presented with phenotypes of classic slow-channel congenital myasthenic syndrome (SCCMS).Methods:Clinical characteristics and electrophysiological features of three patients from a Chinese family were examined, and next-generation sequencing followed by direct sequencing was carried out.Results:The patients revealed variability in clinical and electrophysiological features. However, weakness, scoliosis, and repetitive-compound muscle action potential were found in all affected members in the family. A heterozygous C>T missense mutation at nucleotide 865 in acetylcholine receptor epsilon-subunit (CHRNE) gene that causes a leucine-to-phenylalanine substitution at position 289 (L289F) was found.Conclusions:We reported a SCCMS family of Chinese origin. In the family, classical clinical phenotype with phenotypic variability among different members was found. Genetic testing could help diagnose this rare disease.

Clinical Significance of Repetitive Compound Muscle Action Potentials in Patients with Myasthenia Gravis: A Predictor for Cholinergic Side Effects of Acetylcholinesterase Inhibitors.

Background and PurposeAcetylcholinesterase inhibitors (AChEIs) are widely used to treat myasthenia gravis (MG). Although AChEIs are usually tolerated well, some MG patients suffer from side effects. Furthermore, a small proportion of MG patients show cholinergic hypersensitivity and cannot tolerate AChEIs. Because repetitive compound muscle action potentials (R-CMAPs) are an electrophysiologic feature of cholinergic neuromuscular hyperactivity, we investigated the clinical characteristics of MG patients with R-CMAPs to identify their clinical usefulness in therapeutic decision-making.MethodsWe retrospectively reviewed the clinical records and electrodiagnostic findings of MG patients who underwent electrodiagnostic studies and diagnostic neostigmine testing (NT).ResultsAmong 71 MG patients, 9 could not tolerate oral pyridostigmine bromide (PB) and 17 experienced side effects of PB. R-CMAPs developed in 24 patients after NT. The highest daily dose of PB was lower in the patients with R-CMAPs (240 mg/day vs. 480 mg/day, p<0.001). The frequencies of PB intolerance and side effects were higher in the patients with R-CMAPs than in those without R-CMAPs [37.5% vs. 0% (p<0.001) and 45.8% vs. 12.8% (p=0.002), respectively]. The MG Foundation of America postintervention status did not differ significantly between MG patients with and without R-CMAPs, and the response to immunotherapy was also good in both groups.ConclusionsSide effects of and intolerance to AChEIs are more common in MG patients with R-CMAPs than in those without R-CMAPs. AChEIs should be used carefully in MG patients with R-CMAPs. The presence of R-CMAPs after NT may be a good indicator of the risks of PB side effects and intolerance.

Clinical and Electrophysiologic Responses to Acetylcholinesterase Inhibitors in MuSK-Antibody-Positive Myasthenia Gravis: Evidence for Cholinergic Neuromuscular Hyperactivity.

Background and PurposePatients with muscle-specific tyrosine kinase (MuSK) antibody (MuSK-Ab)-positive myasthenia gravis (MG) show distinct responses to acetylcholinesterase inhibitors (AChEIs). Although clinical responses to AChEIs in MuSK-Ab MG are reasonably well known, little is known about the electrophysiologic responses to AChEIs. We therefore investigated the clinical and electrophysiologic responses to AChEIs in MuSK-Ab-positive MG patients.MethodsWe retrospectively reviewed the medical records and electrodiagnostic findings of 17 MG patients (10 MuSK-Ab-positive and 7 MuSK-Ab-negative patients) who underwent electrodiagnostic testing before and after a neostigmine test (NT).ResultsThe frequency of intolerance to pyridostigmine bromide (PB) was higher in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (50% vs. 0%, respectively; p=0.044), while the maximum tolerable dose of PB was lower in the former (90 mg/day vs. 480 mg/day, p=0.023). The frequency of positive NT results was significantly lower in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (40% vs. 100%, p=0.035), while the nicotinic side effects of neostigmine were more frequent in the former (80% vs. 14.3%, p=0.015). Repetitive compound muscle action potentials (R-CMAPs) developed more frequently after NT in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (90% vs. 14.3%, p=0.004). The frequency of a high-frequency-stimulation-induced decrement-increment pattern (DIP) was higher in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (100% vs. 17.7%, p=0.003).ConclusionsThese results suggest that MuSK-Ab-positive MG patients exhibit unique and hyperactive responses to AChEIs. Furthermore, R-CMAP and DIP development on a standard AChEI dose may be a distinct neurophysiologic feature indicative of MuSK-Ab-positive MG.

Neuromuscular Junction Acetylcholinesterase Deficiency Responsive to Albuterol

Congenital myasthenic syndrome caused by endplate acetylcholinesterase deficiency constitutes a rare autosomal recessive disease. We describe a child with early-onset ptosis, complete ophthalmoplegia, facial and proximal muscle weakness, easy fatigability, a decremental electromyographic response, and a repetitive compound muscle action potential not improved by anti-acetylcholinesterase medication. Mutation analysis of the collagenic tail of endplate acetylcholinesterase (COLQ) that encodes the collagenic structural subunit of acetylcholinesterase revealed two canonic splice-site mutations: a previously identified IVS15+ 1G>A mutation and a novel IVS2- 1G>A mutation. Treatment with albuterol resulted in progressive improvement of muscle strength, exercise tolerance, and ophthalmoplegia. Further studies are needed of the efficacy of albuterol in different types of congenital myasthenic syndrome and the physiologic basis of its beneficial effects.

Acquired neuromyotonia as a paraneoplastic manifestation of ovarian cancer

Neuromyotonia, or Isaacs syndrome, is a neuromuscular disorder characterized by peripheral nerve hyperexcitability.1,–,3 It may be hereditary or acquired. Clinical features include muscle twitching, cramps, stiffness, delayed muscle relaxation, and transient paresthesias. Electrophysiologic studies show motor nerve hyperexcitability, including myokymic or neuromyotonic discharges, fasciculations, and repetitive compound muscle action potential (CMAP) afterdischarges. An associated axonal polyneuropathy is present in a few cases. About 40% of patients with acquired neuromyotonia demonstrate antibodies to the voltage-gated potassium channel (VGKC). Symptoms may respond to anticonvulsants or immunosuppression. Acquired neuromyotonia is a recognized paraneoplastic syndrome commonly associated with chest tumors (thymoma, lung cancer, Hodgkin lymphoma), with rare reports of plasmacytoma and renal cell and bladder carcinoma.1,2 We report a patient presenting with acquired neuromyotonia attributed to ovarian cancer, whose diagnosis was delayed due to the atypical location of her cancer. ### Case reports. A 59-year-old woman with a history of migraine headaches and systemic lupus erythematosus (SLE), quiescent since 1980, presented with 1 year of intermittent twitching of her face, fingers, and toes, and multiple episodes of loss of muscle tone while standing or walking, in the setting of a clear sensorium; strength and tone returned …

Neuromuscular pathology in mice lacking alpha-synuclein

This work was undertaken in order to study the possible role of alpha-synuclein in the function of the neuro-muscular junction in skeletal muscles. Repeated stimulation of skeletal muscle motor neurons revealed signs of neuromuscular pathology in alpha-synuclein null mutated (C57Bl/6JOlaHsd) and knockout (B6;129X1-Sncatm1Rosl/J) mice. This stimulation produced repetitive compound muscle action potentials in both lines of alpha-synuclein deficient mice. Muscle strength and muscle coordination during ambulation were unaffected, though motor learning was slower in alpha-synuclein deficient mice in the Rotarod test. We conclude that alpha-synuclein may play a role in acetylcholine compartmentalization at the neuromuscular junction, and in the fine control of activity of skeletal muscles.

An electrophysiological study of the intermediate syndrome of organophosphate poisoning

Acute organophosphate (OP) poisoning is commonly seen in emergency medicine. Neurologists must be alert to detect neuromuscular transmission failure and other neurological complications that follow OP poisoning. We report a 37-year-old male with acute OP poisoning to emphasize the electrophysiological abnormalities during the intermediate syndrome (IMS). Motor nerve conduction studies revealed that a single nerve stimulation evoked a repetitive compound muscle action potential, whereas repetitive nerve stimulation resulted in a combination of a decrement-increment pattern and a repetitive fade response. Thus, electrophysiological studies can be used to monitor patients with IMS, and these test results correlate well with clinical findings in acute OP poisoning.

Repetitive compound muscle action potentials in electrophysiological diagnosis of congenital myasthenic syndromes: A case report and review of literature

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of disorders, characterized by dysfunction of neuromuscular junction (NMJ) transmission. These syndromes are genetically inherited and are present since birth. Some have characteristic clinical or electrodiagnostic features but in many cases determination of the specific form requires genetic studies or specialized morphological and electrophysiological studies on muscle tissue. We report a case of a 4-year-old boy with progressive ptosis and limitation of ocular movements who was diagnosed as slow-channel CMS based on the characteristic electrodiagnostic features. Repetitive compound muscle action potentials (R-CMAPs) were recorded after single nerve stimulus, with decremental response after repetitive trains performed at 3 Hz. CMSs are at times clinically difficult to distinguish from acquired myasthenia. The characteristic clinical and electrodiagnostic features help in the diagnosis and enable rational therapy. In this article we discuss the characteristics of synaptic R-CMAPs.

Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COLQ) cause synaptic basal-lamina associated CMS with end-plate AChE deficiency. Here we present the clinical and molecular genetic findings of 22 COLQ-mutant CMS patients, carrying a total of 20 different COLQ mutations, 11 of them had not previously been reported. Typically, patients with esterase deficiency suffer from a severe, progressive weakness with onset at birth or in early infancy. In addition, patients with a late onset showing a mild course of disease are described. AChE inhibitor therapy, beneficial for other forms of CMS, is of no effect in cases of esterase deficiency. The large cohort of COLQ patients studied here enabled us to define additional clinical presentations associated with COLQ mutations that differ from the 'classical' phenotypes: several patients with disease onset at birth or in early infancy presented an unexpected, mild disease course without significant progression of weakness. Moreover, many patients had clinical features reminiscent of limb-girdle CMS with mutations in the recently discovered DOK7 gene, including sparing of eye movements and a predominantly proximal muscle weakness. There was no long-term objective benefit from esterase inhibitors treatment in COLQ patients. Surprisingly, a short-term beneficial effect was observed in four patients and a Tensilon test was positive in two. Treatment with ephedrine was efficient in all five cases where it was administered. The variability of phenotypes caused by COLQ mutations, the divergence from the previously published classical clinical features and an initial positive response to esterase inhibitors in some patients may obscure AChE deficiency as the molecular cause of the disease and delay the start of appropriate therapy. Moreover, overlap with other CMS subtypes and potentially absence of a repetitive compound muscle action potential should be considered in the diagnosis of COLQ-mutated patients.

Estudo neurofisiológico na síndrome miastênica congênita do canal lento: relato de caso

The slow-channel syndrome is one of the congenital myasthenic syndromes attributed to inherited kinetic disorders of the ion channel of the acetylcholine receptor of the neuromuscular junction. This is a case report of 25-years-old man with progressive ptosis and limitation of ocular movements since infancy, presented a 6-years history of worse of the external ophthalmoparesis and muscular weakness in the shoulders and hands. The motor nerve conduction studies after a supramaximal single stimulus disclosed a double compound muscle action potential (CMAP) that disappeared after a voluntary contraction of 30 seconds. Repetitive stimulation of facial and spinal accessory nerves showed a CMAP decrement greater than 10% with disappeared of the second potential. The patient received fluoxetine with mild improvement of muscular weakness, but persisted with: ptosis, limitation of ocular movements and repetitive CMAP in the motor nerve conduction study. The characteristic of disease are discussed.

Novel β subunit mutation causes a slow-channel syndrome by enhancing activation and decreasing the rate of agonist dissociation

We traced the cause of a slow-channel syndrome (SCS) in a patient with progressive muscle weakness, repetitive compound muscle action potential and prolonged low amplitude synaptic currents to a V → F substitution in the M1 domain of the β subunit (βV229F) of the muscle acetylcholine receptor (AChR). In vitro expression studies in Xenopus oocytes indicated that the novel mutation βV229F expressed normal amounts of AChRs and decreased the ACh EC 50 by 10-fold compared to wild type. Kinetic analysis indicated that the mutation displayed prolonged mean open duration and repeated openings during activation. Prolonged openings caused by the βV229F mutation were due to a reduction in the channel closing rate and an increase in the effective channel opening rate. Repeated openings of the channel during activation were caused by a significant reduction in the agonist dissociation constant. In addition, the βV229F mutation produced an increase in calcium permeability. The kinetic and permeation studies presented in this work are sufficient to explain the consequences of the βV229F mutation on the miniature endplate currents and thus are direct evidence that the βV229F mutation is responsible for compromising the safety margin of neuromuscular transmission in the patient.

Repetitive CMAPs: Mechanisms of neural and synaptic genesis

Repetitive compound muscle action potentials (R-CMAPs) occur when a single nerve shock excites muscle fibers repeatedly. “Double discharges” are due to intramuscular nerve reexcitation. “Synaptic” R-CMAPs, due to excess acetylcholine in the neuromuscular synapse, can occur in congenital myasthenia, the slow-channel syndrome, and acetylcholinesterase inhibition. Secondary nerve excitation can reexcite muscle fibers. Synaptic R-CMAPs in a patient consisted of two discharges. The second diminished during repetitive stimulation and began 3.5–4.0 ms after the first, which is slightly longer than the synapse-muscle refractory period. Neural R-CMAPs, due to ectopic nerve activity, occur in neuromyotonia (NMT). R-CMAPs in a patient consisted of about 20 discharges at 200–300 Hz. Studies in healthy subjects showed that such trains represent added single CMAPs. Impulse frequency in the patient lies close to the threshold of refractoriness. Refractoriness of the synapse-muscle cell assembly determines the characteristics of R-CMAPs regardless of the primary cause. © 1996 John Wiley & Sons, Inc.

Repetitive CMAPs: Mechanisms of neural and synaptic genesis

Repetitive compound muscle action potentials (R-CMAPs) occur when a single nerve shock excites muscle fibers repeatedly. "Double discharges" are due to intramuscular nerve reexcitation. "Synaptic" R-CMAPs, due to excess acetylcholine in the neuromuscular synapse, can occur in congenital myasthenia, the slow-channel syndrome, and acetylcholinesterase inhibition. Secondary nerve excitation can reexcite muscle fibers. Synaptic R-CMAPs in a patient consisted of two discharges. The second diminished during repetitive stimulation and began 3.5-4.0 ms after the first, which is slightly longer than the synapse-muscle refractory period. Neural R-CMAPs, due to ectopic nerve activity, occur in neuromyotonia (NMT). R-CMAPs in a patient consisted of about 20 discharges at 200-300 Hz. Studies in healthy subjects showed that such trains represent added single CMAPs. Impulse frequency in the patient lied close to the threshold of refractoriness. Refractoriness of the synapse-muscle cell assembly determines the characteristics of R-CMAPs regardless of the primary cause.

A transgenic mouse model of the slow-channel syndrome

To investigate the effect of acetylcholine receptor (AChR) mutations on neuromuscular transmission and to develop a model for the human neuromuscular disease, the slow-channel syndrome, we generated transgenic mice with abnormal AChRs using a delta subunit with a mutation in the ion channel domain. In three transgenic lines, nerve-evoked end-plate currents and spontaneous miniature end-plate currents (MEPCs) had prolonged decay phases and MEPC amplitudes were reduced by 33%. Single nerve stimuli elicited repetitive compound muscle action potentials in vivo. Transgenic mice were abnormally sensitive to the neuromuscular blocker, curare. These observations demonstrate that we can predictably alter AChR function, synaptic responses, and muscle fiber excitation in vivo by overexpressing subunits containing well-defined mutations. Furthermore these data support the hypothesis that the electrophysiological findings in the neuromuscular disorder, the slow-channel syndrome, are due to mutant AChRs.