Fatigable Weakness Research Articles

MuSK Antibody Positive Myasthenia Gravis Mimicking as Myositis

ABSTRACT Most common neuromuscular junction disorder is Myasthenia gravis (MG) which has variable clinical presentations. Diplopia and drooping of eyelids are the peculiarity of myasthenia gravis. Commonly disease manifests as a fluctuating weakness of skeletal muscles. Although respiratory symptoms may be the initial presenting complaint in a few patients, usually it develops during the later part of the disease course. The initial presentation of isolated prominent respiratory distress is a relatively rare presentation of myasthenia gravis unless accompanied by other clinical features. We report a 40-year-old female patient, who visited our hospital with presenting complaints of breathlessness and generalized myalgia and subsequently developed fatigable weakness during hospitalization.

Characterizing Myasthenia Gravis Symptoms, Exacerbations, and Crises From Neurologist's Clinical Notes Using Natural Language Processing.

Background Myasthenia gravis (MG) is a rare, autoantibody neuromuscular disorder characterized by fatigable weakness. Real-world evidence based on administrative and structured datasets regarding MG may miss important details related to the clinical encounter. Examination of free-text clinical progress notes has the potential to illuminate aspects of MG care. Objective The primary objective was to examine and characterize neurologist progress notes in the care of individuals with MG regarding the prevalence of documentation of clinical subtypes, antibody status, symptomatology, and MG deteriorations, including exacerbations and crises.The secondary objectives were to categorize MG deteriorations into practical, objective states as well as examine potential sources of clinical inertia in MG care. Methods We performed a retrospective, cross-sectional analysis of de-identified neurologist clinical notes from 2017 to 2022. A qualitative analysis of physician descriptions of MG deteriorations and a discussion of risks in MG care (risk for adverse effects, risk for clinical decompensation, etc.) was performed. Results Of the 3,085 individuals with MG, clinical subtypes and antibody status identified included gMG (n = 400; 13.0%), ocular MG (n = 253; 8.2%), MG unspecified (2,432; 78.8%), seropositivity for acetylcholine receptor antibody (n = 441; 14.3%), and MuSK antibody (n = 29; 0.9%). The most common gMG manifestations were dysphagia (n = 712; 23.0%), dyspnea (n = 626; 20.3%), and dysarthria (n = 514; 16.7%). In MG crisis patients, documentation of difficulties with MG standard therapies was common (n = 62; 45.2%). The qualitative analysis of MG deterioration types includes symptom fluctuation, symptom worsening with treatment intensification, MG deterioration with rescue therapy, and MG crisis. Qualitative analysis of MG-related risks included the toxicity of new therapies and concern for worsening MG because of changing therapies. Conclusions This study of neurologist progress notes demonstrates the potential for real-world evidence generation in the care of individuals with MG. MG patients suffer fluctuating symptomatology and a spectrum of clinical deteriorations. Adverse effects of MG therapies are common, highlighting the need for effective, less toxic treatments.

Partial loss of desmin expression due to a leaky splice site variant in the human DES gene is associated with neuromuscular transmission defects

Recessive desminopathies are rare and often present as severe early-onset myopathy. Here we report a milder phenotype in three unrelated patients from southern India (2 M, 1F) aged 16, 21, and 22 years, who presented with childhood-onset, gradually progressive, fatigable limb-girdle weakness, ptosis, speech and swallowing difficulties, without cardiac involvement. Serum creatine kinase was elevated, and repetitive nerve stimulation showed decrement in all. Clinical improvement was noted with pyridostigmine and salbutamol in two patients. All three patients had a homozygous substitution in intron 5: DES(NM_001927.4):c.1023+5G>A, predicted to cause a donor splice site defect. Muscle biopsy with ultrastructural analysis suggested myopathy with myofibrillar disarray, and immunohistochemistry showed partial loss of desmin with some residual staining, while western blot analysis showed reduced desmin. RT-PCR of patient muscle RNA revealed two transcripts: a reduced normal desmin transcript and a larger abnormal transcript suggesting leaky splicing at the intron 5 donor site. Sequencing of the PCR products confirmed the inclusion of intron 5 in the longer transcript, predicted to cause a premature stop codon. Thus, we provide evidence for a leaky splice site causing partial loss of desmin associated with a unique phenotypic presentation of a milder form of desmin-related recessive myopathy overlapping with congenital myasthenic syndrome.

Identifying patients at risk for myasthenic crisis with hemogram and inflammation-related laboratory parameters - a pilot study.

Myasthenia gravis (MG) is a rare autoimmune disease characterized by fatigable weakness of the voluntary muscles and can exacerbate to life-threatening myasthenic crisis (MC), requiring intensive care treatment. Routine laboratory parameters are a cost-effective and widely available method for estimating the clinical outcomes of several diseases, but so far, such parameters have not been established to detect disease progression in MG. We conducted a retrospective analysis of selected laboratory parameters related to inflammation and hemogram for MG patients with MC compared to MG patients without MC. To identify potential risk factors for MC, we applied time-varying Cox regression for time to MC and, as a sensitivity analysis, generalized estimating equations logistic regression for the occurrence of MC at the next patient visit. 15 of the 58 examined MG patients suffered at least one MC. There was no notable difference in the occurrence of MC by antibody status or sex. Both regression models showed that higher counts of basophils (per 0.01 unit increase: HR = 1.32, 95% CI = 1.02-1.70), neutrophils (per 1 unit increase: HR = 1.40, 95% CI = 1.14-1.72), potentially leukocytes (per 1 unit increase: HR = 1.15, 95% CI = 0.99-1.34), and platelets (per 100 units increase: HR = 1.54, 95% CI = 0.99-2.38) may indicate increased risk for a myasthenic crisis. This pilot study provides proof of the concept that increased counts of basophils, neutrophils, leukocytes, and platelets may be associated with a higher risk of developing MC in patients with MG.

Late-Onset Myasthenia Gravis in a Patient with Recurrent Breast Cancer: A Case Report

Introduction: Myasthenia gravis (MG) is an autoimmune disorder characterized by fatigable weakness, typically affecting voluntary muscles. Myasthenia gravis as a paraneoplastic syndrome (PNS) of a thymoma is well known, but it is rare to have MG PNS due to extrathymic neoplasms. Case: We present a case on an 80-year-old female who was diagnosed with myasthenia gravis in the presence of recurrent metastatic breast cancer. Discussion: The question remains whether MG is truly a neoplastic syndrome of breast cancer, or if older individuals are more likely to suffer from both breast cancer and late-onset myasthenia gravis (LOMG) at the same time. It was found that those diagnosed with LOMG are more likely to have extrathymic neoplasms. Regardless, the underlying malignancy should be treated, MG treatment should be initiated, and if PNS is suspected immunosuppressants are indicated. Conclusion: This case highlights the complexity of classifying MG in elderly patients with a concomitant neoplasm, but nonetheless, MG as a PNS of breast cancer remains a possibility.

Immune mediated myasthenia gravis in children, current concepts and new treatments: A narrative review article.

Myasthenia gravis (MG) is the most frequent transmission disease in the neuromuscular junction. Juvenile myasthenia gravis (JMG) is an autoimmune antibody-mediated disease of postsynaptic endplate defined as MG presentation in patients before the age of 18 years old. While many clinical features of JMG are identical to the adults, there are some significant differences between them regarding presentation, clinical course, antibody level, and thymus histopathology. In JMG, ocular symptoms are more frequent, the clinical course is comparably benign, and the outcome is better than adult MG. Antibodies attack the muscle endplate proteins in the postsynaptic membrane and interfere with transmission. These antibodies in most patients are against the acetylcholine receptors, but they may also be directed toward muscle-specific kinase, lipoprotein-related protein 4, and agrin. Findings show racial influences and genetic effects on the occurrence of JMG. The essential clinical symptom is fatigable weakness of muscles that can be in the form of isolated ocular type or more disseminated weakness. The diagnosis of JMG is essentially clinical, with fluctuating patterns of weakness and easy fatigability, but a series of diagnostic evaluations can confirm the diagnosis. Precise diagnostic evaluation and distinction from congenital myasthenic syndromes is critical. The treatment plan is conducted according to the clinical course (ocular or generalized), antibody type, and disease severity. The mainstay of treatment includes symptomatic therapy, long-lasting immunosuppressive treatment and treatment of myasthenic crisis. Novel medications are introduced and conducted to the specific pathophysiologic mechanisms of the disease, and they are used primarily in the refractory MG.

Chapter 12 - Myasthenia gravis

Myasthenia gravis (MG) is a rare neuromuscular junction disorder that is characterized by fatigable weakness of muscles. People with MG experience various clinical manifestations based on the muscles involved. MG can be autoimmune, paraneoplastic, congenital, medication-related, or transient in the neonatal period due to the passive placental transfer of antibodies from mothers with MG. Acetylcholine receptor antibodies are seen in the majority of patients with MG. However, other antibodies have been discovered in the last 20 years, including muscle-specific tyrosine kinase (MuSK) and lipoprotein-related peptide 4 (LRP4), and are now available through commercial testing. More recently, a handful of other antibodies have been associated with MG; however, they are not presently available for routine testing. A disease classification system has been developed by the Myasthenia Gravis Foundation of America (MGFA) and is commonly used worldwide. A number of objective and subjective outcome measures have been developed and validated over the years and have been proven useful for both clinical and research purposes, serving as primary and secondary outcome measures in most clinical trials. A growing number of therapies are available for both acute and chronic management of MG, with several new mechanistic approaches under investigation. An international consensus guidance for the management of MG was first published in 2016 and updated in 2020.

Myasthenia gravis: Frequently asked questions

Myasthenia gravis is a disorder of neuromuscular junction transmission, the result of antibodies against the post-synaptic aspect of the neuromuscular junction. Its clinical hallmark is fatigable weakness of skeletal muscles, which tends to vary in location and severity among patients. It is treated with pyridostigmine, immunotherapy, and thymectomy. Treatment is often individualized according to disease severity, antibody status, comorbidities, and other factors. This review uses a question-and-answer format to provide up-to-date, high-yield, clinically relevant information on myasthenia gravis.

GDP-Mannose Pyrophosphorylase B (GMPPB)-Related Disorders.

GDP-mannose pyrophosphorylase B (GMPPB) is a cytoplasmic protein that catalyzes the formation of GDP-mannose. Impaired GMPPB function reduces the amount of GDP-mannose available for the O-mannosylation of α-dystroglycan (α-DG) and ultimately leads to disruptions of the link between α-DG and extracellular proteins, hence dystroglycanopathy. GMPPB-related disorders are inherited in an autosomal recessive manner and caused by mutations in either a homozygous or compound heterozygous state. The clinical spectrum of GMPPB-related disorders spans from severe congenital muscular dystrophy (CMD) with brain and eye abnormalities to mild forms of limb-girdle muscular dystrophy (LGMD) to recurrent rhabdomyolysis without overt muscle weakness. GMPPB mutations can also lead to the defect of neuromuscular transmission and congenital myasthenic syndrome due to altered glycosylation of the acetylcholine receptor subunits and other synaptic proteins. Such impairment of neuromuscular transmission is a unique feature of GMPPB-related disorders among dystroglycanopathies. LGMD is the most common phenotypic presentation, characterized by predominant proximal weakness involving lower more than upper limbs. Facial, ocular, bulbar, and respiratory muscles are largely spared. Some patients demonstrate fluctuating fatigable weakness suggesting neuromuscular junction involvement. Patients with CMD phenotype often also have structural brain defects, intellectual disability, epilepsy, and ophthalmic abnormalities. Creatine kinase levels are typically elevated, ranging from 2 to >50 times the upper limit of normal. Involvement of the neuromuscular junction is demonstrated by the decrement in the compound muscle action potential amplitude on low-frequency (2-3 Hz) repetitive nerve stimulation in proximal muscles but not in facial muscles. Muscle biopsies typically show myopathic changes with variable degrees of reduced α-DG expression. Higher mobility of β-DG on Western blotting represents a specific feature of GMPPB-related disorders, distinguishing it from other α-dystroglycanopathies. Patients with clinical and electrophysiologic features of neuromuscular transmission defect can respond to acetylcholinesterase inhibitors alone or combined with 3,4 diaminopyridine or salbutamol.

Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome: New Developments in Diagnosis and Treatment.

"Myasthenia Gravis is, like it or not, the neurologist's disease!" (Thomas Richards Johns II, MD Seminars in Neurology 1982). The most common disorders in clinical practice involving defective neuromuscular transmission are myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). The hallmark of weakness related to malfunction of the neuromuscular junction (NMJ) is variability in severity of symptoms from minute to minute and hour to hour. Fatigable weakness and fluctuation in symptoms are common in patients whether the etiology is autoimmune, paraneoplastic, genetic, or toxic. Autoimmune MG is the most common disorder of neuromuscular transmission affecting adults with an estimated prevalence of 1 in 10,000. While LEMS is comparatively rare, the unique clinical presentation, the association with cancer, and evolving treatment strategies require the neurologist to be familiar with its presentation, diagnosis, and management. In this paper we provide a summary of the meaningful recent clinical developments in the diagnosis and treatment of both MG and LEMS.

NCMP-21. PEMBROLIZUMAB-ASSOCIATED MYOSITIS, MYASTHENIC CRISIS, AND MYOCARDITIS IN A PATIENT WITH METASTATIC UROTHELIAL CARCINOMA

Abstract Although immune checkpoint inhibitors (ICIs) have improved systemic cancer care, in rare cases, patients develop neuromuscular immune related adverse events (irAEs), which carry high morbidity and mortality. This case study describes an 85-year-old male who developed the triad of myositis, myasthenic crisis, and myocarditis in association with ICI treatment for metastatic urothelial carcinoma (T3N0M1). The patient developed progressive weakness and gait impairment five weeks after initiating treatment with pembrolizumab. Later, he developed reduced ambulation, fatigue, shortness of breath, and orthopnea with concomitant ECG changes. Clinical exam demonstrated dysphagia, ptosis, proximal muscle weakness, fatigable weakness, and areflexia, ultimately resulting in respiratory failure, intubation, and inability to stand. Lab workup revealed elevated creatinine kinase, myoglobin, lactate dehydrogenase, and aldolase, but was notably negative for acetylcholine receptor and muscle specific kinase antibodies. Labs, clinical timeline, and clinical features supported his diagnoses. Interestingly, the cytokine panel demonstrated a high-normal soluble IL-2 receptor alpha which supports autoimmune pathology and elevated IL-10. The patient was treated with pyridostigmine, prednisone, and plasma exchange (PLEX) for 10 exchanges. EMG 10 days into treatment supported evidence of inflammatory myositis. After methylprednisone and PLEX treatment, the patient’s symptoms improved to ambulation with a walker and occasional BiPap support. His metastatic disease remained stable for several weeks while holding pembrolizumab due to toxicity. This case illustrates how early intervention and aggressive treatment for neuromuscular ICI-induced triad can stabilize patients and improve neurologic recovery. Due to the high morbidity and mortality for these irAEs, the authors support increased clinical scrutiny when evaluating these rare conditions and consideration of investigating the acute inflammatory processes. With improved pathophysiologic understanding of these rare conditions, the community can improve outcomes and refine treatments.

Surgical management prospects for myasthenia gravis in Nigeria

Background: Myasthenia gravis (MG) is an acquired autoimmune neuromuscular disease characterized by fatigable and variable weakness of skeletal muscles as a result of autoimmune attack on postsynaptic antigenic targets. There is paucity of data on the outcome of treatment options available in resource-poor settings. Objective: The aim of this study was to determine the treatment outcome of surgical thymectomy for MG with regard to the local experience in Enugu, southeast Nigeria. Materials and Methods: It was a preliminary report of patients with MG seen at the Neurology Clinic of the University of Nigeria Teaching Hospital, Enugu, Nigeria, from February 2016 to October 2019. The treatment outcomes of the patients were analyzed following thymectomy to determine the effectiveness of the surgical management. Data obtained included patients’ age, response to treatment, intensive care unit (ICU) stay, and total hospital stay. Results: The mean age of the patients was 35.7 ± 15.1. The mean duration of stay at the ICU was 3.9 ± 4.6 days, while the mean total hospital stay was 12 ± 9.70 days. All the patients (100%) had symptomatic improvement following thymectomy and 40% had remission. Conclusion: The general outcome of MG patients following thymectomy was favorable. Thymectomy appears to improve the prognosis of MG in the local setting of Enugu, Nigeria.

P.98 Calculating the genetic prevalence of congenital myasthenic syndromes based on data from genomic databases

Congenital myasthenic syndromes (CMS) are a heterogeneous group of rare inherited neuromuscular disorders characterized by fatigable weakness owing to compromised function of the neuromuscular junction. Next-generation sequencing has dramatically increased the number of genetic defects reported as causative of CMS, with over 30 genes implicated. Although all CMS subtypes share common features, their clinical and genetic heterogeneity, as well as referral and ascertainment biases in diagnostic practice, have made phenotype-based prevalence estimations difficult, with publications in the last decade providing estimates ranging from 1.8 cases per million total population to 22.2 cases per million children. This lack of accurate data hampers diagnosis, healthcare provision and therapy development. Most CMS subtypes are recessive, meaning that carriers of single variants that are pathogenic when present in homozygosity or compound heterozygosity can be found in the healthy general population. The new large-scale population databases of genomic data that have come online in recent years thus provide the opportunity to calculate the genetic prevalence or lifetime risk of autosomal recessive CMS based on the allele frequency of individual variants in an unaffected population. Based on reported pathogenic/likely pathogenic variants in databases including ClinVar, LOVD, HGMD and RD-Connect and predicted pathogenic variants from in silico predictions, we established a comprehensive curated list of known and likely pathogenic variants across 31 disease genes. We then queried the Genome Aggregation Database (gnomAD), the UK Biobank WES Cohort and the RD-Connect Genome-Phenome Analysis Platform to establish the allele frequency of disease-causing variants in genes associated with autosomal recessive congenital myasthenic syndromes. Based on this, we provide a population-genetic estimation of the genetic prevalence of CMS and compare it to existing published estimates. This data may be used to assign diagnostic probabilities, provide insights into numbers of patients amenable to clinical research and novel therapies, and aid resource allocation in therapy development and healthcare provision.

I.01Congenital myasthenic syndromes

Neuromuscular junction disorders are a heterogeneous group of acquired (Myasthenia Gravis, MG) and inherited (Congenital Myasthenic Syndromes, CMS) disorders associated with distinctive clinical, electrophysiological, laboratory and ultrastructural abnormalities. The genetic defects in CMS either impair neuromuscular transmission directly or result in secondary impairments, which eventually compromise the safety margin of neuromuscular transmission. More recently, we have identified two genes (<i>DOK7, GFPT1</i>) that cause fatigable weakness of muscles in a limb-girdle distribution, but rarely affecting facial or eye muscles. Next-generation sequencing and deep phenotyping, in combination with international data sharing, reveals new genetic causes of CMS, but also unusual, overlapping clinical phenotypes, which blur the boundaries with primary myopathies and motor neuropathies. Mitochondrial dysfunction has been implicated with both myopathies and neuromuscular transmission defects. TEFM is a nuclear gene that codes for a mitochondrial transcription elongation factor – the protein responsible for prolonging activity of RNA polymerase to ensure distal transcripts of the mitochondrial genome are transcribed. We identified the first human <i>TEFM</i> variants associated with mitochondrial respiratory chain deficiency in seven patients with varying clinical presentations. While symptoms included classical features of a mitochondrial disease, some patients also presented with a treatable neuromuscular transmission defect. We will cover the significant progress made in understanding the molecular pathogenesis of CMS, which is important for both patients and clinicians in terms of reaching a definite diagnosis and selecting the most appropriate treatment.

Genetic and clinical evaluation of congenital myasthenic syndromes with long-term follow-up: experience of a tertiary center in Turkey.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders affecting the safety factor which required for neuromuscular transmission. Here we reported our experience in children with CMS. We retrospectively collected the data of 18 patients with CMS who were examined in our outpatient clinic between January 2021 and January 2022. The diagnosis of CMS was based on the presence of clinical symptoms such as abnormal fatigability and weakness, absence of autoantibodies against acetylcholine receptor and muscle-specific kinase, electromyographic evidence of neuromuscular junction defect, molecular genetic confirmation, and response to treatment. The most common mutations were in the acetylcholine receptor (CHRNE) gene (8/18) and choline acetyltransferase (ChAT) (2/18) gene. Despite targeted gene sequencing and whole exome sequencing (WES) were underwent, we couldn't detect a genetic mutation in three out of patients. The most commonly determined initial finding was eyelid ptosis, followed by fatigable weakness, and respiratory insufficiency. Although the most commonly used drug was pyridostigmine, we have experienced that caution should be exercised as it may worsen some types of CMS. We reported in detail the phenotypic features of very rare gene mutations associated with CMS and our experience in the treatment of this disease. Although CMS are rare genetic disorder, the prognosis can be very promising with appropriate treatment in most CMS subtypes.

Myasthenia Gravis Presenting after Administration of the mRNA-1273 Vaccine.

The mRNA-1273 SARS-CoV-2 vaccine received emergency use authorization in December 2021. We present a case of myasthenia gravis (MG) which became clinically apparent following vaccination against SARS-CoV-2. A 30-year-old man developed acute onset diplopia, 2 days after receiving his first mRNA-1273 vaccination against SARS-CoV-2. He reported blurred vision with horizontally displaced images, which worsened with increased eye strain. Diplopia resolved when one eye was covered. He also had fatigable arm weakness, but denied dysphagia, dysarthria, dysphonia or dyspnoea. On examination, he had left-sided ptosis and esotropia at rest which worsened with sustained upward gaze and prolonged focus. He also had fatigable weakness of neck flexion and extension (4+/5), and generalized, fatigable weakness (4/5). His single-breath count was 38. Cranial nerves, sensory examination and deep tendon reflexes were normal. A 2-min ice-pack test and neostigmine test temporarily improved his diplopia and ptosis. The acetylcholine receptor (AChR) antibody was borderline high and muscle-specific tyrosine kinase (MuSK) antibody was negative. Chest CT and brain MRI with contrast were unremarkable. The patient was diagnosed with MG and oral pyridostigmine and prednisone therapy were initiated.We present a case of newly diagnosed MG after administration of mRNA-1273 vaccination against SARS-CoV-2. Although there has been long-standing discussion regarding the potential for vaccines to exacerbate autoimmune conditions, data remain sparse and consensus has not been reached. Consequently, this case is important to make providers aware of potential side effects of a novel vaccine, and may also help guide the selection of vaccination candidates and monitoring parameters.LEARNING POINTSWe present a case of newly diagnosed myasthenia gravis after administration of the mRNA-1273 SARS-CoV-2 vaccine.mRNA-1273 vaccination against SARS-CoV-2 may exacerbate subclinical cases of myasthenia gravis.Recognition of new vaccine side effects may guide the selection of vulnerable patients.

P.044 GMPPB mutation causes a muscular dystrophy-myasthenic spectrum

Background: Mutations in GDP-Mannose Pyrophosphorylase B (GMPPB) cause a spectrum of disease ranging from muscular dystrophy to congenital myasthenic syndrome (CMS). Recognition of neuromuscular junction dysfunction has important treatment implications. Methods: We describe a person with GMPPB mutation causing an overlapping limb girdle muscular dystrophy - myasthenic syndrome with robust response to acetylcholinesterase inhibitors. We review the literature on the muscular dystrophy - CMS and explore the phenotypic features that aid in recognizing neuromuscular junction dysfunction. Results: A 35-year-old woman presented with a 10-year history of debilitating myalgias, symmetrical limb girdle and neck weakness, and chronic CK elevation. Electromyography showed a non-irritable myopathy. Biopsies were consistent with muscular dystrophy. Whole genome sequencing revealed two heterozygous pathogenic mutations in the GMPPB gene, giving a diagnosis of genetically confirmed limb girdle muscular dystrophy. Subsequently, repetitive nerve stimulation revealed decrement in the trapezius muscle suggestive of an overlap myasthenic syndrome. She was started on pyridostigmine resulting in recovery of full motor power with significant functional improvement. Conclusions: Identification and treatment of neuromuscular junction dysfunction caused by GMPPB mutations can significantly improve motor power and function. Early onset of progressive fatigable proximal weakness, spared ocular and facial muscles, and pyridostigmine responsiveness are important features of GMPPB-related CMS.

Distinct and Recognisable Muscle MRI Pattern in a Series of Adults Harbouring an Identical GMPPB Gene Mutation.

Mutations in the GMPPB gene affect glycosylation of α-dystroglycan, leading to varied clinical phenotypes. We attempted to delineate the muscle MR imaging spectrum of GMPPB-related Congenital Myasthenic syndrome (CMS) in a single-center cohort study. To identify the distinct patterns of muscle involvement in GMPPB gene mutations. We analyzed the muscle MR images of 7 genetically proven cases of GMPPB dystroglycanopathy belonging to three families and studied the potential qualitative imaging pattern to aid in clinico -radiological diagnosis in neuromuscular practice. All individuals underwent muscle MRI (T1, T2, STIR/PD Fat sat. sequences in 1.5 T machine) of the lower limbs. Qualitative assessment and scoring were done for muscle changes using Mercuri staging for fibro-fatty replacement on T1 sequence and Borsato score for myoedema on STIR sequence. All patients were of South Indian origin and presented as slowly progressive childhood to adult-onset fatigable limb-girdle muscle weakness, elevated creatine kinase level, and positive decrement response in proximal muscles. Muscle biopsy revealed features of dystrophy. All patients demonstrated identical homozygous mutation c.1000G > A in the GMPPB gene. MRI demonstrated early and severe involvement of paraspinal muscles, gluteus minimus, and relatively less severe involvement of the short head of the biceps femoris. A distinct proximo-distal gradient of affliction was identified in the glutei, vasti, tibialis anterior and peronei. Also, a postero-anterior gradient was observed in the gracilis muscle. Hitherto unreported, the distinctive MR imaging pattern described here, coupled with relatively slowly progressive symptoms of fatigable limb-girdle weakness, would facilitate an early diagnosis of the milder form of GMPPB- dystroglycanopathy associated with homozygous GMPPB gene mutation.

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.

Status epilepticus heralding thymomatous paraneoplastic multifocal cortical encephalitis in Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disorder involving the neuromuscular junction characterized by fatigable weakness of the striated muscles [1]. It is primarily mediated by autoantibodies against the acetylcholine receptors (AChR) on post-synaptic membrane of the motor end plate and are present in the serum of 85% of MG patients [1]. Recently, antibodies recognizing other skeletal muscle components have been detected which have provide additional diagnostic and prognostic information [2]. Anti-titin antibodies fall under this category and are found in 20–40% of anti-AChR antibody positive patients.