Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders.

Autoimmune neuromuscular junction disorders are rare. However, myasthenia gravis is being increasingly recognised in people older than 50 years. In the past 5-10 years, epidemiological studies worldwide suggest an incidence of acetylcholine receptor antibody-positive myasthenia gravis of up to 29 cases per 1 million people per year. Muscle-specific tyrosine kinase antibody-positive myasthenia gravis and Lambert-Eaton myasthenic syndrome are about 20 times less common. Several diagnostic methods are available for autoimmune neuromuscular junction disorders, including serological antibody, electrophysiological, imaging, and pharmacological tests. The course of disease can be followed up with internationally accepted clinical scores or patient-reported outcome measures. For prognostic purposes, determining whether the disease is paraneoplastic is of great importance, as myasthenia gravis can be associated with thymoma and Lambert-Eaton myasthenic syndrome with small-cell lung cancer. However, despite well defined diagnostic parameters to classify patients into subgroups, objective biomarkers for use in the clinic or in clinical trials to predict the course of myasthenia gravis and Lambert-Eaton myasthenic syndrome are needed.

Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures.

The heterozygous deletion of 15q13.3 is a recurrently observed microdeletion syndrome associated with a relatively mild phenotype including learning disability and language impairment. In contrast, the homozygous deletion of 15q13.3 is extremely rare and is associated with a much severer phenotype that includes epileptic encephalopathy, profound intellectual disability, and hypotonia. Which of the genes within the deleted interval is responsible for the more severe features when biallelically deleted is currently unknown. Here, we report a patient with profound hypotonia, severe intellectual disability, and seizures who had biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del, p.(Glu375Aspfs*11). Unexpectedly, both aberrations occurred de novo. Our experiment using Caenorhabditis elegans showed that worms carrying a corresponding homozygous variant in the homolog OTUB-2 exhibited weakened muscle contraction suggestive of aberrant neuromuscular transmission. We concluded that the biallelic complete loss of OTUD7A in humans represents a presumably new autosomal recessive disorder characterized by profound hypotonia, severe intellectual disability, and seizures.

Respuesta clínica y neurofisiológica a la efedrina en un paciente con síndrome miasténico congénito de canal lento / Clinical and neurophysiological response to ephedrine in a patient affected with slow-channel congenital myasthenic syndrome

INTRODUCCIÓN: El síndrome miasténico congénito de canal lento, o síndrome de canales lentos, es un trastorno neuromuscular progresivo hereditario, autosómico dominante, causado por una activación anormal de los receptores de la acetilcolina en la unión neuromuscular. La alteración histopatológica característica es la degeneración selectiva de la placa terminal y la membrana postsináptica debido a la sobrecarga de calcio. La piridostigmina debe evitarse en este síndrome, y la quinidina o la fluoxetina son las terapias recomendadas actualmente. CASO CLÍNICO: Niña de 11 años con un fenotipo de cinturas de síndrome miasténico congénito de canal lento que presenta debilidad y fatiga lentamente progresivas desde los 8 años. Tras un empeoramiento clínico con piridostigmina, iniciado empíricamente antes de que los resultados de la secuenciación del exoma estuvieran disponibles, se observó una respuesta espectacular y sostenida con efedrina en monoterapia. La secuenciación del exoma reveló una mutación heterocigota de novo en el gen CHRNB1: c.865G>A; p.Val289Met (NM_000747.2). El estudio electromiográfico con estimulación repetitiva en el nervio peroneo mostró una disminución anormal en la amplitud (23,9%) y también la génesis de un segundo potencial de acción muscular compuesto más pequeño después del pico de la onda M principal en los nervios motores mediano, cubital y peroneo. CONCLUSIÓN: Aunque se han documentado respuestas favorables a agonistas adrenérgicos en asociación con la fluoxetina, ésta representa la primera aportación que documenta una respuesta clínica relevante con efedrina en monoterapia en un paciente con síndrome miasténico congénito de canal lento. Los agonistas adrenérgicos pueden considerarse una opción terapéutica en pacientes con este síndrome

INTRODUCTION: Slow-channel congenital myasthenic syndrome is an autosomal dominant inherited progressive neuromuscular disorder caused by abnormal gating of mutant acetylcholine receptors in the neuromuscular junction. Its pathological hallmark is selective degeneration of the endplate and postsynaptic membrane due to calcium overload. Pyridostigmine should be avoided in this syndrome, being quinidine or fluoxetine the current recommended therapies. CASE REPORT: An 11-year-old girl with a limb-girdle phenotype of slow-channel congenital myasthenic syndrome presenting with a slowly progressive fatigable weakness at the age of 8 years. After a clinical worsening with pyridostigmine, empirically started before the exome sequencing results were available, a dramatic and sustained response to ephedrine monotherapy was observed. Whole exome sequencing revealed a de novo heterozygous mutation in CHRNB1 gene: c.865G>A; p.Val289Met (NM_000747.2). An abnormal decrement in amplitude (23.9%) from the first to fifth intravollley waveform was revealed after repetitive peroneal nerve stimulation at low frequencies. In addition, a second smaller compound muscle action potential after the peak of the main M-wave in median, ulnar and peroneal motor nerves was observed. CONCLUSION: Favorable responses to adrenergic agonists added to fluoxetine had been reported. However, to the best of our knowledge this is the first report on effective monotherapy with ephedrine in a slow-channel congenital myasthenic syndrome patient. Adrenergic agonists may be considered as a therapeutic option in patients with this syndrome

[Electrophysiological evidence of impaired neuromuscular junction in a case of phosphoglucomutase 1 deficiency manifesting fluctuating muscle weakness].

A 27 year-old Canadian man suffered from fluctuating muscle weakness in the past several years. The patient had a past history of intestinal bleeding, bifid uvula and hypothyroidism in his childhood. Repetitive nerve stimulation tests showed a decrement pattern in the left deltoid muscle. The single fiber electromyography of the left extensor digitorum muscle showed an increment of jitter. Both findings were improved by the edrophonium test. He was diagnosed as having phosphoglucomutase 1 (PGM1) deficiency, as the compound heterozygote mutation of the PGM1 gene was recognized in the whole-exome sequencing and the enzyme activity of PGM1 was defective in the biopsied muscle. Treatment with the galactose lead to improvement of the fluctuating muscle weakness and decremental pattern in the repetitive stimulation test. PGM1 deficiency should be listed in the differential diagnosis of the neuromuscular junction disorder, when the patient is seronegative for antibodies related with myasthenia gravis and shows symptoms or signs consistent with PGM1 deficiency.

Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission.

Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins.

Miller Fisher syndrome with presynaptic neuromuscular transmission disorder.

Miller Fisher syndrome is defined by a triad of symptoms, namely areflexia, ataxia, and ophthalmoparesis. The ophthalmoparesis is mostly severe, undulating weakness of eye movements with ptosis and increased fatigability resembling a neuromuscular transmission disorder. We present a 52-year-old man with severe Miller Fisher syndrome with a high level of anti-GQ1b antibodies and a presynaptic type of neuromuscular transmission disorder. The diagnosis was confirmed by stimulated single-fiber electromyography with the use of a concentric needle electrode and various stimulation rates.

Patients with neuromuscular disorder.

This article describes the preoperative preparation of patients with neuromuscular disorders. These entities are a relatively rare and diverse group of diseases that can affect various organ systems in addition to the central nervous system. The anesthetic implications for the various comorbidities are varied and can be profound. These patients should be optimized before surgery, with the involvement of a multidisciplinary team of specialists.

Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice.

Myasthenia gravis is a paralytic disorder with autoantibodies against acetylcholine receptors at the neuromuscular junction. A proportion of patients instead has antibodies against muscle-specific kinase, a protein essential for acetylcholine receptor clustering. These are generally of the immunoglobulin-G4 subclass and correlate with disease severity, suggesting specific myasthenogenic activity. However, immunoglobulin-G4 subclass antibodies are generally considered to be 'benign' and direct proof for their pathogenicity in muscle-specific kinase myasthenia gravis (or other immunoglobulin-G4-associated disorders) is lacking. Furthermore, the exact electrophysiological synaptic defects caused at neuromuscular junctions by human anti-muscle-specific kinase autoantibodies are hitherto unknown. We show that purified immunoglobulin-G4, but not immunoglobulin-G1-3, from patients with muscle-specific kinase myasthenia gravis binds to mouse neuromuscular junctions in vitro, and that injection into immunodeficient mice causes paralysis. Injected immunoglobulin-G4 caused reduced density and fragmented area of neuromuscular junction acetylcholine receptors. Detailed electrophysiological synaptic analyses revealed severe reduction of postsynaptic acetylcholine sensitivity, and exaggerated depression of presynaptic acetylcholine release during high-rate activity, together causing the (fatigable) muscle weakness. Intriguingly, compensatory transmitter release upregulation, which is the normal homeostatic response in acetylcholine receptor myasthenia gravis, was absent. This conveys extra vulnerability to neurotransmission at muscle-specific kinase myasthenia gravis neuromuscular junctions. Thus, we demonstrate that patient anti-muscle-specific kinase immunoglobulin-G4 is myasthenogenic, independent of additional immune system components, and have elucidated the underlying electrophysiological neuromuscular junction abnormalities.

Evidence of neuroaxonal degeneration in myofascial pain syndrome: a study of neuromuscular jitter by axonal microstimulation.

The mechanism of myofascial pain syndrome (MPS) is unclear. Previous reports pointed out that pathogenesis of either referred pain or local twitch response in trigger point of MPS is related to the nerve degeneration and disintegration of motor and sensory nerves in spinal cord. The purpose of the present study is to investigate the evidence of neuromuscular transmission disorders in trigger point muscles of patients with MPS by using stimulated single-fiber electromyography (SFEMG) examination. Twenty-three patients with neck MPS and 16 age-matched controls attended for the present study. The jitter or mean consecutive difference (MCD) was calculated as the mean of the absolute differences for 30 consecutive interpotential intervals between stimuli and single-fiber potentials in trapezius and levator scapulae muscles. The relationship between the MCD values and the disease duration was measured. The results showed significantly increased MCDs in trapezius and levator scapulae muscles in MPS patients. MCD values measured in the trigger point muscles were found to be positively correlated with the disease duration. The present study with axonal microstimulation and SFEMG demonstrates a prominent evidence of neuroaxonal degeneration and neuromuscular transmission disorders in the trigger point muscles of MPS patients. The mechanism of MPS is possibly implicated with the degeneration of motor neurons.

Neuromuscular junction in health and disease.

A number of illnesses and other factors can affect the function of the neuromuscular junction (NMJ). These may have an affect at pre- or post-junctional sites. This review outlines the anatomy and the physiology of the NMJ. It also describes the mechanisms and physiological basis of many of the disorders of the NMJ. Finally, the importance of these disorders in anaesthetic practice is discussed.

The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade.

RATIONALE: Partial neuromuscular transmission failure by acetylcholine receptor blockade (neuromuscular blockade) or antibody-mediated functional loss (myasthenia gravis), even with a magnitude of muscle weakness that does not evoke respiratory symptoms, can evoke dysphagia and decreased inspiratory airflow, and increases the risk of susceptible patients to develop severe pulmonary complications. OBJECTIVES: To assess whether impaired neuromuscular transmission predisposes individuals to inspiratory upper airway collapse, we assessed supraglottic airway diameter and volume by respiratory-gated magnetic resonance imaging, upper airway dilator muscle function (genioglossus force and EMG), and changes in lung volume, respiratory timing, and peripheral muscle function before, during, and after partial neuromuscular blockade in healthy, awake volunteers. MEASUREMENTS AND MAIN RESULTS: Partial neuromuscular blockade (train-of-four [TOF] ratio: 0.5 and 0.8) was associated with the following: (1) a decrease of inspiratory retropalatal and retroglossal upper airway volume to 66 +/- 22 and 82 +/- 12% of baseline, which was significantly more intense in the retropalatal area; (2) an attenuation of the normal increase in anteroposterior upper airway diameter during forced inspiration to 74 +/- 18% of baseline; (3) a decrease in genioglossus activity during maximum voluntary tongue protrusion to 39 +/- 19% (TOF, 0.5) and 73 +/- 29% (TOF, 0.8) of baseline; and (4) no effects on upper airway size during expiration, lung volume, and respiratory timing. CONCLUSIONS: Thus, impaired neuromuscular transmission, even to a degree insufficient to evoke respiratory symptoms, markedly impairs upper airway dimensions and function. This may be explained by an impairment of the balance between upper airway dilating forces and negative intraluminal pressure generated during inspiration by respiratory "pump" muscles.

Irritable bowel syndrome: update on colonic neuromuscular dysfunction and treatment.

Recent discoveries regarding the relatively autonomous workings of the enteric nervous system have expanded our understanding of the pathophysiology of irritable bowel syndrome (IBS). However, the heterogeneity of the pathogenesis of IBS continues to create unique challenges for clinicians who care for these patients. Advances in our understanding of the structure and functions of the brain-gut axis and its interplay with other potentially important factors, such as genetic predisposition, inflammation, and psychological unrest, have led to new developments in the field of targeted pharmacotherapy for IBS sufferers. Therapies designed specifically to modulate gut motility, secretion, and/or sensation have been created and introduced into the marketplace in recent years, and additional designer formulations are in various stages of development. Concurrently, new discoveries of potentially beneficial effects of agents approved for other, often non-gastroenterologic, conditions continue to be reported. This article reviews the accumulating body of evidence supporting the importance of neuromuscular dysfunction as a central cause of IBS symptoms and provides a rationale for the discussion of current and future drug development.

Anesthesia for sickle cell disease and congenital myopathy in combination.

We report on the perioperative management of anesthesia and analgesia in a child with sickle cell disease and a congenital myopathy, presenting for corrective orthopedic surgery. The case illustrates two valuable points of interest: the many benefits of regional anesthesia in complex medical cases and the successful use of tourniquets in children with sickle cell disease.

A single-fibre EMG study of neuromuscular transmission in migraine patients.

It is known that mutations of CACNA1A, which encodes a neuronal P/Q Ca(2+) channel, are present in patients with familial hemiplegic migraine, and possibly in other types of migraine as well. This calcium channel is also involved in neuromuscular transmission. To assess if the single-fibre EMG (SFEMG) method can demonstrate a neuromuscular transmission deficit in migraine, a group of 26 patients with different types of migraine and 20 healthy control subjects were studied. The migraine patients were divided into three groups: 8 patients with migraine without aura (MoA), 12 with migraine with aura excluding visual aura (MA) and 6 with visual aura (VA). A SFEMG of the voluntarily activated extensor digitorum communis muscle was performed. The SFEMG results were normal in the healthy controls and the MoA group (migraine without aura). Slight neuromuscular transmission disturbances were present in 6/12 (50%) of patients with MA and in 1/6 (17%) of patients with VA. We suggest that abnormal neuromuscular transmission detectable by SFEMG may reflect a genetically determined dysfunction of the P/Q Ca(2+) channels in a subgroup of migraineurs with aura.

Neuro-ophthalmic emergencies for the neurologist.

A variety of acute neurologic disorders present with visual signs and symptoms. In this review the authors focus on those disorders in which the clinical outcome is dependent on timely and accurate diagnosis. The first section deals with acute visual loss, specifically optic neuritis, ischemic optic neuropathy (ION), retinal artery occlusion, and homonymous hemianopia. The authors include a discussion of those clinical features that are helpful in distinguishing between inflammatory and ischemic optic nerve disease and between arteritic and nonarteritic ION. The second section concerns disc edema with an emphasis on the prevention of visual loss in patients with increased intracranial pressure. The third section deals with abnormal ocular motility, and includes orbital inflammatory disease, carotid-cavernous fistulas, painful ophthalmoplegia, conjugate gaze palsies, and neuromuscular junction disorders. The final section concerns pupillary abnormalities, with a particular emphasis on the dilated pupil and on carotid artery dissection. Throughout there are specific guidelines for the management of these disorders, and areas are highlighted in which there is ongoing controversy.

Binocular diplopia. A practical approach.

BACKGROUND: Diplopia is a common complaint in both inpatient and outpatient neurologic practice. Its causes are many, and special historical and examination features are important to localization and accurate diagnosis. REVIEW SUMMARY: This review is divided into 2 sections: the first related to diagnosis and the second to treatment of binocular diplopia. In the diagnostic section, emphasis is placed on identification of historical and examination features that can help to differentiate diplopia caused by dysfunction of cranial nerves versus neuromuscular junction, or orbital extraocular muscle. Techniques available to the neurologist for examining ocular motility and ocular misalignment and focused laboratory testing to evaluate diplopia are discussed in detail. The final section covers the various treatments for binocular diplopia, with recommendations regarding the utility of each treatment for different types of diplopia. CONCLUSIONS: A logical step-by-step approach applied to each patient with diplopia will help prevent misdiagnosis and improve patient care.

Clinical classification of patellofemoral pain syndrome: guidelines for non-operative treatment.

The patellofemoral pain syndrome (PFPS) remains a challenging musculoskeletal entity encountered by clinicians. Reviewing the literature, conflicting data seem to exist regarding the effect of non-operative treatment in PFPS patients. A possible explanation may be lack of a clear classification system of patients with PFPS. It is our opinion that the term PFPS still is a 'wastebasket', which probably comprises several different entities. Therefore, it seems important to subdivide this broad group of patients into different categories with a specific rehabilitation approach. In this study, we introduce a classification system, which reflects a consensus reached by the European Rehabilitation Panel. This classification system should help the clinicians to identify the cause(s) of patellofemoral pain, and consequently help to select the most appropriate non-operative treatment. The authors are aware that no rehabilitation protocol will work for all PFPS patients, since the underlying mosaic of pathophysiology and tissue-healing responses are unique. Therefore, the aim of this study with a classification system was to guide the clinician through clinical examination in order to develop a non-operative treatment protocol, specific for each individual with PFPS.

[Epilepsy and myasthenia: a case report]. / L'association myasthénie et épilepsie: à propos d'une observation.

Epilepsy is 5 to 7 times more frequent among patients with myasthenia than in the general population. Myasthenia gravis is often associated with other affectsion, most of immunological origin. However, hypotheses explaining the association are still uncertain. We report a case of association in a woman who had epilepsy since the age of 9 years and developed myasthenia at the age of 23 years after having discontinued here anti-epileptic treatment for two years.