Muscle-specific Tyrosine Kinase Research Articles

Treatment of Myasthenia Gravis in the Aged.

Myasthenia gravis is diagnosed at a progressively later age and the incidence continuously increases in the aged with a clear male predominance. People above the age of 65 constitute more than 50% of the newly diagnosed. Commonly, patients present with focal (ocular or bulbar) weakness. A high index of suspicion is needed to achieve early diagnosis and improve prognosis. Management options include acetylcholinesterase inhibitors, steroids, and immunosuppressants. Of the immunosuppressants, azathioprine is one of the most widely used due to its demonstrated effect and favorable side-effect profile. Others include cyclosporine, tacrolimus, mycophenolate mofetil, and cyclophosphamide. The use of mycophenolate mofetil is still controversial. Monoclonal antibodies, like rituximab, eculizumab, and belimumab, are relatively new therapeutic options in autoimmune diseases. Rituximab is of special interest in muscle-specific tyrosine kinase antibody-positive patients. A novel skeletal muscle activator and stem cell transplantation are being studied. There is no place for standard thymectomy in the older age groups except for thymomas and with computer-assisted endoscopy. Generally, the disease responds well to treatment at this age but comorbidities make medication choice more complex. Successful treatment is associated with improved survival, and quality of life can be remarkably improved during the whole survival period. As the median age of onset is 65 years and has been increasing steadily, it appears necessary to review the subject of treatment of myasthenia gravis in the aged.

Flow Cytofluorimetric Analysis of Anti-LRP4 (LDL Receptor-Related Protein 4) Autoantibodies in Italian Patients with Myasthenia Gravis

BackgroundMyasthenia gravis (MG) is an autoimmune disease in which 90% of patients have autoantibodies against the muscle nicotinic acetylcholine receptor (AChR), while autoantibodies to muscle-specific tyrosine kinase (MuSK) have been detected in half (5%) of the remaining 10%. Recently, the low-density lipoprotein receptor-related protein 4 (LRP4), identified as the agrin receptor, has been recognized as a third autoimmune target in a significant portion of the double sero-negative (dSN) myasthenic individuals, with variable frequency depending on different methods and origin countries of the tested population. There is also convincing experimental evidence that anti-LRP4 autoantibodies may cause MG.MethodsThe aim of this study was to test the presence and diagnostic significance of anti-LRP4 autoantibodies in an Italian population of 101 myasthenic patients (55 dSN, 23 AChR positive and 23 MuSK positive), 45 healthy blood donors and 40 patients with other neurological diseases as controls. All sera were analyzed by a cell-based antigen assay employing LRP4-transfected HEK293T cells, along with a flow cytofluorimetric detection system.ResultsWe found a 14.5% (8/55) frequency of positivity in the dSN-MG group and a 13% frequency of co-occurrence (3/23) in both AChR and MuSK positive patients; moreover, we report a younger female prevalence with a mild form of disease in LRP4-positive dSN-MG individuals.ConclusionOur data confirm LRP4 as a new autoimmune target, supporting the value of including anti-LRP4 antibodies in further studies on Myasthenia gravis.

Polyclonal neural cell adhesion molecule antibody prolongs the effective duration time of botulinum toxin in decreasing muscle strength.

This study aimed to investigate if the effective duration time of botulinum toxin A (Btx-A) could be prolonged by polyclonal neural cell adhesion molecule antibody (P-NCAM-Ab). 175 male SD rats were randomly divided into three major groups: control group (n=25), Btx-A group (n=25), and P-NCAM-Ab groups. P-NCAM-Ab groups were composed of five sub-groups, with 25 rats each in the dose-response study. Muscle strength of rat lower limbs was determined using a survey system. The expressions of muscle-specific receptor tyrosine kinase (MuSK) and neural cell adhesion molecule (NCAM) were determined by real-time polymerase chain reactions (RT-PCR) and western blotting (WB). The muscle strength was significantly decreased by Btx-A in Btx-A/P-NCAM-Ab groups compared with normal control group. Besides, the muscle strength of P-NCAM-Ab group was significantly decreased compared with the Btx-A group. The recovery time of muscle strength in P-NCAM-Ab group was significantly longer compared with Btx-A group. RT-PCR and WB assay showed that PNCAM-Ab delayed the increase of MuSK and NCAM after Btx-A injection. P-NCAM-Ab prolongs the effective duration time of Btx-A in decreasing muscle strength, which could provide a novel enhancement in clinical application.

SPECIAL ASPECTS OF CHILDHOOD MYASTHENIA WITH MUSCLE-SPECIFIC TYROSINE KINASE ANTIBODIES

The article presents a case report of autoimmune myasthenia gravis with antibodies to muscle specific tyrosine kinase (MuSK) in a girl of 5 and half years old. Till the age of 10 years she has had only isolated ocular syndrome: symmetrical ptosis, diplopy and progressive oculomotor disturbances. Taking into account the detection of mutation in the mitochondrial genome of the gene 16S r RNA (Homoplasmia) in the girl, in her mother and brother, mitochondrial genetically confirmed myopathy was initially diagnosed to the patient. The generalization of myasthenia occurred at the age of 10–11 years, bulbar paralysis, weakness of facial and respiratory muscles and muscles of neck and limbs joined to the eye syndrome. Serum examination did not reveal antibodies to the acetylcholine receptors (AChRs), but found out significant increase of the MuSK antibodies level. The special aspects of the case are the absence of neuromuscular transmission defects in clinically affected muscles, intolerance of anticholinesterase drugs, and insensibility to traditional pathogenetic drugs: glucocorticoids (GCS) and azathioprine. At the same time benefit from immunoglobulin G was revealed. Combined therapy with azathioprine and Sandimmune managed to reach medical remission, including fully regression of oculomotor disturbances. Thymectomy was taken after several unsuccessful attempts to reduce the doses of immunosuppressive drugs. Thoracoscopic thymectomy at the age of 12 years caused a long-term remission and exempted the patient from a pharmacological dependence.

Mouse models of myasthenia gravis.

Myasthenia gravis is a muscle weakness disease characterized by autoantibodies that target components of the neuromuscular junction, impairing synaptic transmission. The most common form of myasthenia gravis involves antibodies that bind the nicotinic acetylcholine receptors in the postsynaptic membrane. Many of the remaining cases are due to antibodies against muscle specific tyrosine kinase (MuSK). Recently, autoantibodies against LRP4 (another component of the MuSK signaling complex in the postsynaptic membrane) were identified as the likely cause of myasthenia gravis in some patients. Fatiguing weakness is the common symptom in all forms of myasthenia gravis, but muscles of the body are differentially affected, for reasons that are not fully understood. Much of what we have learnt about the immunological and neurobiological aspects of the pathogenesis derives from mouse models. The most widely used mouse models involve either passive transfer of autoantibodies, or active immunization of the mouse with acetylcholine receptors or MuSK protein. These models can provide a robust replication of many of the features of the human disease. Depending upon the protocol, acute fatiguing weakness develops 2 - 14 days after the start of autoantibody injections (passive transfer) or might require repeated immunizations over several weeks (active models). Here we review mouse models of myasthenia gravis, including what they have contributed to current understanding of the pathogenic mechanisms and their current application to the testing of therapeutics.

Characterization of B cells in muscle-specific kinase antibody myasthenia gravis.

Objective:To characterize B-cell subsets in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG).Methods:In accordance with Human Immunology Project Consortium guidelines, we performed polychromatic flow cytometry and ELISA assays in peripheral blood samples from 18 patients with MuSK MG and 9 healthy controls. To complement a B-cell phenotype assay that evaluated maturational subsets, we measured B10 cell percentages, plasma B cell–activating factor (BAFF) levels, and MuSK antibody titers. Immunologic variables were compared with healthy controls and clinical outcome measures.Results:As expected, patients treated with rituximab had high percentages of transitional B cells and plasmablasts and thus were excluded from subsequent analysis. The remaining patients with MuSK MG and controls had similar percentages of total B cells and naïve, memory, isotype-switched, plasmablast, and transitional B-cell subsets. However, patients with MuSK MG had higher BAFF levels and lower percentages of B10 cells. In addition, we observed an increase in MuSK antibody levels with more severe disease.Conclusions:We found prominent B-cell pathology in the distinct form of MG with MuSK autoantibodies. Increased BAFF levels have been described in other autoimmune diseases, including acetylcholine receptor antibody–positive MG. This finding suggests a role for BAFF in the survival of B cells in MuSK MG, which has important therapeutic implications. B10 cells, a recently described rare regulatory B-cell subset that potently blocks Th1 and Th17 responses, were reduced, which suggests a potential mechanism for the breakdown in immune tolerance in patients with MuSK MG.

Anti-musk Myasthenic Crisis in the Puerperium: The Management Dilemma

Myasthenia gravis (MG) is a chronic neuromuscular junction (NMJ) dysfunction with a wide spectrum of neurological manifestations. MG is as a result of autoantibodies directed against NMJ at the postsynaptic level involving nicotinic or other postsynaptic antigens. The newly identified subtype of MG with antibodies against the muscle-specific receptor tyrosine kinase (Anti-MuSK) shows an unpredictable response to current MG treatment. The initial presentation of this disease entity often poses a diagnostic challenge and a treatment dilemma to the clinician. We present a case of life threatening Anti-MuSK-positive myasthenic crisis occurring during puerperium which required a temporary surgical airway and percutaneous endoscopic gastrostomy tube for feeding. She had dysphonia for 7 years but was not diagnosed. The complications and management dilemma of this case report are highlighted. Case Study Thompson et al.; BJMMR, 10(7): 1-5, 2015; Article no.BJMMR.20381 2

The Myotonic Plot Thickens: Electrical Myotonia in Antimuscle-Specific Kinase Myasthenia Gravis.

Electrical myotonia is known to occur in a number of inherited and acquired disorders including myotonic dystrophies, channelopathies, and metabolic, toxic, and inflammatory myopathies. Yet, electrical myotonia in myasthenia gravis associated with antibodies against muscle-specific tyrosine kinase (MuSK) has not been previously reported. We describe two such patients, both of whom had a typical presentation of proximal muscle weakness with respiratory failure in the context of a significant electrodecrement in repetitive nerve stimulation. In both cases, concentric needle examination revealed electrical myotonia combined with myopathic motor unit morphology and early recruitment. These findings suggest that MuSK myasthenia should be included within the differential diagnosis of disorders with electrical myotonia.

Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis

Muscle-specific tyrosine kinase (MuSK) autoantibodies are the hallmark of a form of myasthenia gravis (MG) that can challenge the neurologist and the experimentalist. The clinical disease can be difficult to treat effectively. MuSK autoantibodies affect the neuromuscular junction in several ways. When added to muscle cells in culture, MuSK antibodies disperse acetylcholine receptor clusters. Experimental animals actively immunized with MuSK develop MuSK autoantibodies and muscle weakness. Weakness is associated with reduced postsynaptic acetylcholine receptor numbers, reduced amplitudes of miniature endplate potentials and endplate potentials, and failure of neuromuscular transmission. Similar impairments have been found in mice injected with IgG from MG patients positive for MuSK autoantibody (MuSK-MG). The active and passive models have begun to reveal the mechanisms by which MuSK antibodies disrupt synaptic function at the neuromuscular junction, and should be valuable in developing therapies for MuSK-MG. However, translation into new and improved treatments for patients requires procedures that are not too cumbersome but suitable for examining different aspects of MuSK function and the effects of potential therapies. Study design, conduct and analysis should be carefully considered and transparently reported. Here we review what has been learnt from animal and culture models of MuSK-MG, and offer guidelines for experimental design and conduct of studies, including sample size determination, randomization, outcome parameters and precautions for objective data analysis. These principles may also be relevant to the increasing number of other antibody-mediated diseases that are now recognized.

Collagen Q – A potential target for autoantibodies in myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disorder caused by autoantibodies targeting proteins expressed at the neuromuscular junction (NMJ). In most cases the targets are acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK), or occasionally low-density lipoprotein receptor-related protein 4 (LRP4), but there is still a group of patients, often called seronegative MG (SNMG), with unknown antibody targets. One potential target is collagen Q (COLQ), which is restricted to the NMJ and is crucial for anchoring the NMJ-specific form of acetylcholinesterase (AChE). 415 serum samples with a clinical diagnosis of MG and 43 control samples were screened for the presence of COLQ autoantibodies using a cell-based assay (CBA) with HEK293 cells overexpressing COLQ at the cell surface. COLQ antibodies were detected in 12/415 MG sera and in one/43 control samples. Five of the COLQ-Ab+individuals were also positive for AChR-Abs and 2 for MuSK-Abs. Although the COLQ antibodies were only present at low frequency, and did not differ significantly from the small control cohort, further studies could address whether they modify the clinical presentation or the benefits of anti-cholinesterase therapy.

Altered active zones, vesicle pools, nerve terminal conductivity, and morphology during experimental MuSK myasthenia gravis.

Recent studies demonstrate reduced motor-nerve function during autoimmune muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). To further understand the basis of motor-nerve dysfunction during MuSK-MG, we immunized female C57/B6 mice with purified rat MuSK ectodomain. Nerve-muscle preparations were dissected and neuromuscular junctions (NMJs) studied electrophysiologically, morphologically, and biochemically. While all mice produced antibodies to MuSK, only 40% developed respiratory muscle weakness. In vitro study of respiratory nerve-muscle preparations isolated from these affected mice revealed that 78% of NMJs produced endplate currents (EPCs) with significantly reduced quantal content, although potentiation and depression at 50 Hz remained qualitatively normal. EPC and mEPC amplitude variability indicated significantly reduced number of vesicle-release sites (active zones) and reduced probability of vesicle release. The readily releasable vesicle pool size and the frequency of large amplitude mEPCs also declined. The remaining NMJs had intermittent (4%) or complete (18%) failure of neurotransmitter release in response to 50 Hz nerve stimulation, presumably due to blocked action potential entry into the nerve terminal, which may arise from nerve terminal swelling and thinning. Since MuSK-MG-affected muscles do not express the AChR γ subunit, the observed prolongation of EPC decay time was not due to inactivity-induced expression of embryonic acetylcholine receptor, but rather to reduced catalytic activity of acetylcholinesterase. Muscle protein levels of MuSK did not change. These findings provide novel insight into the pathophysiology of autoimmune MuSK-MG.

Myasthenia gravis and risks for comorbidity

Myasthenia gravis (MG) is an autoimmune disorder leading to skeletal muscle weakness and fatigability. MG subgroups are defined according to pathogenetic autoantibody (against acetylcholine receptor, muscle-specific tyrosine kinase or lipoprotein receptor-related protein 4), thymus pathology and clinical manifestations. MG patients have an increased risk for concordant autoimmune disease, in particular with early onset MG. Most common comorbidities are thyroid disease, systemic lupus erythematosus and rheumatoid arthritis. Cardiomyositis and subclinical heart dysfunction have been described in patients with thymoma MG and late onset MG but represent no major threat. A thymic lymphoepithelioma implies an increased risk for another cancer. Autoimmune MG represents no distinct cancer risk factor, although lymphomas and a few other cancer types have been reported with slightly increased frequency. Severe MG-related muscle weakness means a risk for respiratory failure and respiratory tract infection. Drug MG treatment can lead to side-effects. Thymectomy is regarded as a safe procedure both short and long term. Non-MG-related comorbidity represents a diagnostic and therapeutic challenge, especially in elderly patients. Diagnostic accuracy and optimal follow-up is necessary to identify and treat all types of coexisting disease in MG.

HnRNP C, YB-1 and hnRNP L coordinately enhance skipping of human MUSK exon 10 to generate a Wnt-insensitive MuSK isoform.

Muscle specific receptor tyrosine kinase (MuSK) is an essential postsynaptic transmembrane molecule that mediates clustering of acetylcholine receptors (AChR). MUSK exon 10 is alternatively skipped in human, but not in mouse. Skipping of this exon disrupts a cysteine-rich region (Fz-CRD), which is essential for Wnt-mediated AChR clustering. To investigate the underlying mechanisms of alternative splicing, we exploited block-scanning mutagenesis with human minigene and identified a 20-nucleotide block that contained exonic splicing silencers. Using RNA-affinity purification, mass spectrometry, and Western blotting, we identified that hnRNP C, YB-1 and hnRNP L are bound to MUSK exon 10. siRNA-mediated knockdown and cDNA overexpression confirmed the additive, as well as the independent, splicing suppressing effects of hnRNP C, YB-1 and hnRNP L. Antibody-mediated in vitro protein depletion and scanning mutagenesis additionally revealed that binding of hnRNP C to RNA subsequently promotes binding of YB-1 and hnRNP L to the immediate downstream sites and enhances exon skipping. Simultaneous tethering of two splicing trans-factors to the target confirmed the cooperative effect of YB-1 and hnRNP L on hnRNP C-mediated exon skipping. Search for a similar motif in the human genome revealed nine alternative exons that were individually or coordinately regulated by hnRNP C and YB-1.

Clinical and scientific aspects of muscle-specific tyrosine kinase-related myasthenia gravis.

Antibodies to muscle-specific tyrosine kinase (MuSK) characterize up to 5% of myasthenia gravis patients. This review focuses on the differences to clinical antiacetylcholine receptor-myasthenia gravis, and on the physiology and animal studies that elucidate the role of MuSK and help explain the clinical disease. MuSK forms the core of a protein complex in the postsynaptic membrane at the neuromuscular junction. During development, MuSK tyrosine kinase signaling is vital for the formation and stabilization of the postsynaptic endplate; it is now clear that long-term homeostasis of mature neuromuscular junctions requires MuSK function. Patient MuSK-antibodies are largely of the IgG4 type and in cell culture block the assembly and activation of MuSK kinase. Active immunization and passive transfer mouse models show reduced postsynaptic acetylcholine receptors and disturbed synaptic alignment, diminished synaptic potentials and impaired muscle activation.MuSK myasthenia gravis patients display particular bulbar and respiratory muscle involvement, with a high rate of myasthenic crises. Plasma exchange and immunosuppression with corticosteroids and rituximab appear to be most effective in treating MuSK myasthenia gravis. In contrast, the cholinesterase inhibitors, such as pyridostigmine, appear less suitable for this form of myasthenia gravis. MuSK myasthenia gravis has distinct clinical and pathophysiological features.

Investigation of the impact of intravenous injection of mesenchymal stem cells from mouse bone marrow on muscle weakness and immunological parameters in experimental autoimmune myasthenia gravis model

Myasthenia gravis (MG) is a T cell dependent and antibody mediated autoimmune disease. Around 85% of the patients show AChR antibodies, 5% have muscle specific tyrosine kinase (MuSK) antibodies, whereas the remaining patients are seronegative. Although experimental autoimmune myasthenia gravis (EAMG) model has provided important information on MG pathogenesis, treatment strategies are still somewhat limited. In recent years, mesenchymal stem cells from human umbilical cord or blood marrow have been successfully tried in AChR related EAMG model, reducing muscle weakness and AChR reactive lymphocytes.

Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome

This article reviews the clinical presentations, diagnostic findings, and treatment options for autoimmune myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome. Immunologic research is unraveling the immunopathology of MG and identifying targets for novel immune-based therapy of this condition. MG patients with antibodies to muscle-specific tyrosine kinase (MuSK) frequently present with symptoms and clinical findings that suggest nerve or muscle disease. Early diagnosis and treatment have a marked effect on outcome in these diseases. In most cases, the diagnosis of MG or Lambert-Eaton myasthenic syndrome can be made from the history, supplemented with directed questions, and a physical examination designed to demonstrate variable weakness in affected muscle groups. Appropriate confirmatory tests almost always establish the diagnosis. Although several novel treatment modalities for MG are under investigation, currently available therapies produce substantial improvement in function and quality of life in most patients with this condition. Knowledge about the dosing, adverse effects, and costs of immunomodulatory therapies is essential for the effective management of patients with MG and Lambert-Eaton myasthenic syndrome.

Poster 115 “Dropped Head,” A Rare Manifestation in Muscle-Specific Tyrosine Kinase Antibody-Positive Myasthenia Gravis (MuSK-MG): A Case Report

PM&RVolume 6, Issue 9S p. S223-S224 Friday Poster Presentations - Poster Hall Poster 115 “Dropped Head,” A Rare Manifestation in Muscle-Specific Tyrosine Kinase Antibody-Positive Myasthenia Gravis (MuSK-MG): A Case Report Raj Raval MD, Raj Raval MD SUNY Downstate Medical Center, Brooklyn, NY, United StatesSearch for more papers by this authorMatthew G. Hadilaksono DO, Matthew G. Hadilaksono DO SUNY Downstate Medical Center, Brooklyn, NY, United StatesSearch for more papers by this authorManisha Bawa MD, Manisha Bawa MD SUNY Downstate Medical Center, Brooklyn, NY, United StatesSearch for more papers by this authorSeung J. Park MD, Seung J. Park MD SUNY Downstate Medical Center, Brooklyn, NY, United StatesSearch for more papers by this authorSanjeev Agarwal MD, Sanjeev Agarwal MD SUNY Downstate Medical Center, Brooklyn, NY, United StatesSearch for more papers by this author Raj Raval MD, Raj Raval MD SUNY Downstate Medical Center, Brooklyn, NY, United StatesSearch for more papers by this authorMatthew G. Hadilaksono DO, Matthew G. Hadilaksono DO SUNY Downstate Medical Center, Brooklyn, NY, United StatesSearch for more papers by this authorManisha Bawa MD, Manisha Bawa MD SUNY Downstate Medical Center, Brooklyn, NY, United StatesSearch for more papers by this authorSeung J. Park MD, Seung J. Park MD SUNY Downstate Medical Center, Brooklyn, NY, United StatesSearch for more papers by this authorSanjeev Agarwal MD, Sanjeev Agarwal MD SUNY Downstate Medical Center, Brooklyn, NY, United StatesSearch for more papers by this author First published: 29 September 2014 https://doi.org/10.1016/j.pmrj.2014.08.509Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume6, Issue9SSeptember 2014Pages S223-S224 RelatedInformation

The presence of dysautonomia in different subgroups of myasthenia gravis patients.

To analyze the presence of autonomic dysfunction in different subgroups of myasthenia gravis (MG) patients. Standard cardiovascular reflex tests according to Ewing, spectral and time domain analysis of heart rate variability (HRV) at rest were assessed in 27 patients with thymoma-associated acetylcholine receptor (AChR)-positive MG, 25 AChR-positive MG patients without thymoma and 23 patients with muscle-specific tyrosine kinase (MuSK) MG. All patients were compared to the healthy controls, matched for sex and age. In the group of AChR-positive MG patients with thymoma, hand grip (p < 0.05), orthostasis (p < 0.05), breathing test (p < 0.05) and Valsalva maneuver (p < 0.01) were more often pathological than in the controls. Analysis of the spectral domain of HRV showed increased low-frequency (p < 0.05) and decreased high-frequency component (p < 0.05). Time domain parameters of HRV and baroreflex sensitivity (BRS) at rest were significantly reduced (p < 0.01). In the patients with AChR MG without thymoma, Valsalva maneuver test was more often pathological (p < 0.05) and higher rate of supraventricular extrasystoles (p < 0.01) was registered than in the healthy controls. In the patients with MuSK-positive MG, hand grip and Valsalva maneuver tests were more often pathological than in the controls (p < 0.05). Low-frequency component of the spectral domain of HRV (p < 0.05) and the frequency of cardiac arrhythmia were increased. BRS at rest was significantly lower in patients compared to the controls (p < 0.01). We determined the presence of autonomic failure in all subgroups of MG patients. Since autonomic dysfunction can lead to cardiac arrhythmias and even sudden death, it is of major importance to be aware of this association and to properly diagnose and treat these patients.

High frequency of DQB1*05 and absolute absence of DRB1*13 in muscle-specific tyrosine kinase positive myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease but certain genetic factors predispose its development. Since susceptibility to different forms of MG is linked to a number of allelic variants, the aim of this study was to explore the human leukocyte antigen (HLA) profile of our patients with muscle-specific tyrosine kinase (MuSK) MG. Human leukocyte antigen (HLA) typing was performed in our cohort of 31 MuSK MG patients available for the study. The allele groups of DRB1* and DQB1* loci were typed with sequence-specific oligonucleotide probes and high resolution typing for DQB1* was performed using sequence-specific primers. HLA frequencies were compared with unrelated healthy bone marrow donors. Significant association of MuSK MG with alleles DRB1*14 [odds ratio (OR) 3.8], DRB1*16 (OR 3.3) (P < 0.01) and DQB1*05 (OR 2.2) (P < 0.05) was found. In our patients the most frequent DQB1* allele was DQB1*05:02. An absolute absence of DRB1*13 in our cohort of MuSK MG patients was also found, whilst this allele was present in 25% (495/1992) of control subjects (OR 0) (P < 0.01). The HLA DRB1*16-DQB1*05 (OR 2.9) haplotype was found to be associated with MuSK MG (P < 0.05). The strong association of MuSK MG with DQB1*05 alleles observed in patient series from other countries was confirmed. The novel finding in our cohort of MuSK MG patients was the absolute absence of DRB1*13 allele, which might have a protective role in the development of MuSK MG, at least in our population.

Electrophysiological profile of the patients with MuSK positive myasthenia gravis

Objectives:To determine the electrophysiological profile of our cohort of patients with muscle-specific tyrosine kinase (MuSK) positive myasthenia gravis (MG).Methods:Repetitive nerve stimulation test (RNS) and jitter analysis using concentric needle electrode were performed in 31 MuSK and in 28 acetylcholine receptor (AChR) positive MG patients.Results:Pathological RNS was verified in 16 (51·6%) MuSK and 26 (92·9%) AChR MG patients (P < 0·01). Pathological jitter analysis was registered in 28 (90·3%) MuSK and 26 (92·9%) AChR MG patients (P > 0·05). Increased jitter was present in extensor digitorum communis (EDC) in 23 (74·2%) MuSK and in 25 (89·3%) AChR MG patients (P > 0·05) as well as in orbicularis oculi (OO) muscle in 24 (85·7%) MuSK and 22 (81·5%) AChR MG patients (P > 0·05). Lower mean value of mean consecutive difference (MCD) and fewer potential pairs with increased jitter were registered in MuSK MG compared to AChR MG patients only in EDC muscle (P < 0·05). In MuSK MG patients, increased jitter was observed to be more frequent in patients with longer disease duration (P < 0·05) and also in those patients exhibiting more severe disease forms (P < 0·01) only in EDC muscle.Discussion:Repetitive nerve stimulation test has low sensitivity in MuSK MG patients, while jitter analysis shows high sensitivity, especially in facial muscles. The EDC muscle in MuSK MG patients usually shows increased jitter in more severe disease forms and later in the course of the disease.