Congenital Myasthenia Gravis Research Articles

Type and Frequency of Misdiagnosis and Time Lag to Diagnosis in Patients with Chronic Progressive External Ophthalmoplegia.

Since ptosis is an early feature of chronic progressive external ophthalmoplegia (CPEO), patients are commonly misdiagnosed with other causes of ptosis. This study aims to report the type and frequency of misdiagnosis and time lag to diagnosis and the palpebral fissure transfer (PFT) procedure in patients with CPEO. This is a retrospective analysis of consecutive patients with CPEO who underwent PFT between 2006 and 2017. The data on previous diagnoses and treatments, age at definitive diagnosis of CPEO, and clinical manifestations were recorded. While the diagnosis of CPEO was based on clinical examination, 75% (24/32) of patients had undergone a confirmatory muscle biopsy and genetic tests. There were 32 patients (19 females) with a mean age of 24.8 years (range, 13-36) at the final diagnosis and 34.1 years (range, 15-56) at the time of PFT. Also, 78% (25/32) of patients had been initially misdiagnosed with congenital ptosis (60%; 15/25) and ocular myasthenia gravis (OMG) (40%; 10/25). The majority of patients (20/32) had one to three previous eyelid surgical procedures, of which 90% (18/20) were performed before the definitive diagnosis of CPEO. The mean time lag from the first surgical procedure to CPEO diagnosis and PFT was 6.2 and 14.7 years, respectively. In a referral center, 78% of the patients with CPEO were initially misdiagnosed with congenital ptosis and OMG, and 56% of them underwent ptosis repair before the diagnosis. While the onset of the disease was in the first or second decades of life, diagnosis was delayed up to a mean age of 25 years. Reviewing early family photos and paying attention to other signs of CPEO could prevent misdiagnosis.

Clinical Characteristics Associated With Secondary Generalization in Patients With Ocular Myasthenia Gravis: A Systematic Review and Meta-analysis.

Ocular myasthenia gravis (OMG) is an autoimmune disorder resulting in ocular symptoms such as diplopia and ptosis. The proportion of patients who convert to secondary generalized myasthenia gravis (SGMG) reported in the literature has been varied. The aim of this systematic review was to determine the clinical characteristics of patients with OMG and the proportion of SGMG conversion. We conducted an electronic database search for randomized controlled trials, prospective nonrandomized studies, observational studies, and retrospective studies in EMBASE, CENTRAL, MEDLINE, and Web of Science. We included studies with patients with OMG who initially presented with ocular symptoms and signs only and were seen in clinical practice, reporting on the characteristics and outcomes of SGMG. We excluded studies with pediatric and congenital myasthenia gravis populations. Eligible studies included articles written in any language and containing data on patients with OMG. The main outcome measured was the proportion of patients with OMG who converted to SGMG and risk factors associated with secondary generalization of OMG. Two independent reviewers screened titles and abstracts and extracted data from full texts, reporting findings according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The methodology was evaluated using the Joanna Briggs Institute critical appraisal forms. PROSPERO registration number: CRD2021285257. Thirty-one studies were included in the quantitative and qualitative analysis. The proportion of generalization ranged from 11% to 84%. The pooled proportion was 39% (95% CI 32%-47%, I 2 = 95.86%, p < 0.001 unweighted, low certainty). The pooled risk ratio of female sex for conversion to SGMG was 1.06 (95% CI 0.96-1.17, I 2 = 0% p = 0.614, 21 studies included, very low certainty), and the pooled risk ratio of acetylcholine receptor (AChR) positivity was 1.30 (95% CI 1.05-1.56, I 2 = 0% p = 0.455, 16 studies included, very low certainty). Risk factors such as female sex and anti-AChR positivity have been identified to have possible associations with SGMG, but there are not enough quality observational studies. There is a need for a prospective global database of patients with OMG, including all countries with different populations.

Congenital Myasthenia Gravis in Newborn

Congenital myasthenia gravis are very rare, which is an autosomal recessive disease originating from rare genetic disorders. Symptoms of congenital MG usually start at birth and are lifelong. Our case weakness started from birth, need respiratory support and failure of extubation many times, and absent fetal movements with positive family history his cousin was neonatal myasthenia gravis and died.

Clinical characteristics of ocular myasthenia gravis and outcomes of secondary generalisation: a systematic review protocol

ObjectiveWe aim to systematically assess the clinical characteristics of ocular myasthenia gravis (OMG) and report on the proportion of patients who develop secondary generalised myasthenia gravis (SGMG).IntroductionOMG is an autoimmune...

Brain MR imaging findings in children with congenital muscular dystrophies

Congenital muscular dystrophies (CMDs) are a heterogeneous group of disorders presenting early in life during infancy or soon after birth with muscle weakness and hypotonia, sometime associated to severe brain involvement and histologically presenting with dystrophic lesions. They are classified on the basis of the clinical features, pathologic findings and pattern of inheritance. In fact most of these disorders are inherited and linked to specific genes. Several CDMs classifications have been proposed [1-3]. The main CMD subtypes, classified by pathogenic gene, are laminin alpha‐2 (merosin) deficiency (MDC1A), collagen VI-related CMD (COL6-RD), the dystroglycanopathies -such as Walker‐Warburg syndrome (WWS), Fukuyama CMD (FCMD), and muscle-eye-brain disease (MEB)-, SELENON (SEPN1)‐related CMD, and LMNA‐related CMD (L‐CMD) [4]. The incidence and prevalence of CMDs in various populations is not sufficiently known and may have been underestimated in early published CMD surveys owing to more limited diagnostic means available. Point prevalence in various studies ranges from 0.56 to 2.5 per 100,000 [5-10]. The relative frequency of CMD subtypes also varies in different populations. The most common CMD subtypes are laminin-α2 related CMD and dystroglycanopathies, followed by collagen VI-related CMD. The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA are less frequent [9,11]. CMDs are often autosomal recessive, but some cases have been found to follow autosomal dominant patterns, by direct inheritance, spontaneous mutations, or mosaicism. Clinical genetic testing is available for virtually all genes known to be associated with CMDs. However, many affected individuals remain without a genetic diagnosis, an indicator that novel disease genes have yet to be identified [3]. Differential diagnosis of patients presenting with weakness in early infancy includes: Congenital myopathies like central core, nemaline road, and centronuclear myopathy and those secondary to metabolic disorders; Disorders of the myoneural junction including congenital myasthenia gravis and infant botulism and Neuropathies like spinal muscular atrophy (SMA) and hereditary motor sensory neuropathy (HMSN) [12]. Nowadays the diagnosis is based on clinical presentation, laboratory tests and genetic investigations. Muscular biopsy can be an important diagnostic tool if genetic tests are not available. Brain MRI and muscular MRI are performed if available. We discuss brain MR imaging findings in our patients with CMDs trying to outline common features and differences in order to aid in the diagnosis of these rare disorders before performing genetic tests.

The Neuromuscular Junction: Roles in Aging and Neuromuscular Disease.

The neuromuscular junction (NMJ) is a specialized synapse that bridges the motor neuron and the skeletal muscle fiber and is crucial for conversion of electrical impulses originating in the motor neuron to action potentials in the muscle fiber. The consideration of contributing factors to skeletal muscle injury, muscular dystrophy and sarcopenia cannot be restricted only to processes intrinsic to the muscle, as data show that these conditions incur denervation-like findings, such as fragmented NMJ morphology and corresponding functional changes in neuromuscular transmission. Primary defects in the NMJ also influence functional loss in motor neuron disease, congenital myasthenic syndromes and myasthenia gravis, resulting in skeletal muscle weakness and heightened fatigue. Such findings underscore the role that the NMJ plays in neuromuscular performance. Regardless of cause or effect, functional denervation is now an accepted consequence of sarcopenia and muscle disease. In this short review, we provide an overview of the pathologic etiology, symptoms, and therapeutic strategies related to the NMJ. In particular, we examine the role of the NMJ as a disease modifier and a potential therapeutic target in neuromuscular injury and disease.

Anaesthetic Management of a Patient with Myasthenia Gravis Posted for Tonsillectomy- A Case Report

Myasthenia gravis is a chronic autoimmune disease of neuromuscular junction which causes skeletal muscle weakness and fatigability, characterised by decrement in postsynaptic acetylcholine receptor at neuromuscular junction caused by auto-antibodies destruction. There are three types of myasthenia gravis in children- transient neonatal, congenital and juvenile. Juvenile Myasthenia Gravis (JMG) is an autoimmune disorder that can affect the all skeletal muscles including extraocular muscles, which may lead to fatigability and generalised weakness. This report is about a case of seven-year-old patient weighing 25 kg presented with throat pain since one and half month. Patient was a known case of congenital myasthenia gravis and diagnosis was confirmed by Edrophonium test. He underwent tonsillectomy and was successfully managed under general anaesthesia with no muscle relaxant technique. Tonsillectomy in paediatric patients is not an uncommon surgical procedure. In spite of being a common surgery, it is still challenging to the surgeon as well as the anaesthesiologist as there is a shared airway between the two. Also, in the postoperative period there are chances of post-tonsillectomy bleeding causing airway obstruction, if not diagnosed and treated early could risk the life of the patient. Therefore, this surgery poses an increased risk of mortality and morbidity.

Congenital Myasthenia Gravis: A Case Report

Congenital myasthenia gravis (CMS) is not very uncommon but could be easily missed. Timely identification and management can improve quality of life. Here we present a case of congenital myasthenia gravis, confirmed by genetic studies, detected at 2 years of age.

Neuromuscular Junction Disorders and Floppy Infant Syndrome: A Comprehensive Review.

Floppy infant syndrome, also sometimes referred to as rag-doll syndrome, is characterized by hypotonia that could present as either peripheral hypotonia or central. Depending on the origin of hypotonia, the infant will present with different symptoms that ultimately have the characteristic feature of hypotonia. The clinical examination is crucial in diagnosing floppy infant syndrome in the neonate period, but the most critical factor is investigating and diagnosing the underlying cause of hypotonia. Regardless of whether the underlying cause of hypotonia is peripheral or central in origin, the presentation of floppy infant syndrome focuses on observing for the presence or absence of specific signs such as ‘frog-leg’ posture, significant head lag on traction or pull-to-sit maneuver, or the feeling of ‘slipping through the hands’ when the infant is held under the arms. Infantile botulism, transient neonatal myasthenia gravis, congenital myasthenia gravis, hypermagnesemia, and aminoglycoside toxicity are all neuromuscular junction disorders that are considered to be a differential diagnosis of floppy infant syndrome. These neuromuscular junction disorders ultimately impact the presence of acetylcholine within the neuromuscular junction. While some of these disorders may impact the acetylcholine receptors, others may cause a depletion within the end-plate anticholinesterase enzyme. A deficiency within the anticholinesterase deficiency may cause desensitization to acetylcholine, which could also cause present with floppy infant syndrome as well. Depending on the underlying causative disorder leading to the presence of floppy infant syndrome, the treatment will vary considerably. Treatment of the underlying causative syndrome resulting in the presentation of floppy infant syndrome deals with the symptoms of hypotonia, and as a result, the decreased muscle tone, diminished tendon reflexes, any feeding or respiratory difficulties diminish.

Feline myasthenia gravis: a review

Myasthenia gravis is an immune mediated disorder of neuromuscular transmission. Both an acquired and a congenital form have been reported in cats. Generalised weakness is considered a hallmark of myasthenia gravis, but in cats, due to their sedentary nature, this may not be as evident as in dogs. Feline acquired myasthenia gravis is associated with a significant incidence of cranial mediastinal masses, and a lower percentage of associated megaoesophagus than myasthenia gravis in dogs. The diagnosis of acquired myasthenia gravis remains challenging for the clinician, and there are currently no evidence-based treatment protocols. Reports describing outcomes in acquired feline myasthenia gravis are conflicting, with survival rates ranging from 42–85%. Data concerning the rate of spontaneous remission in feline acquired myasthenia gravis is limited, however the reported incidence appears low (9.2%). Recently, a mutation affecting the COLQ gene has been identified in the Sphynx and Devon Rex breeds, demonstrating a genetic basis to feline congenital myasthenia gravis.

Deficiency of lrp4 in zebrafish and human LRP4 mutation induce aberrant activation of Jagged-Notch signaling in fin and limb development.

Low-density lipoprotein receptor-related protein 4 (LRP4) is a multi-functional protein implicated in bone, kidney and neurological diseases including Cenani-Lenz syndactyly (CLS), sclerosteosis, osteoporosis, congenital myasthenic syndrome and myasthenia gravis. Why different LRP4 mutation alleles cause distinct and even contrasting disease phenotypes remain unclear. Herein, we utilized the zebrafish model to search for pathways affected by a deficiency of LRP4. The lrp4 knockdown in zebrafish embryos exhibits cyst formations at fin structures and the caudal vein plexus, malformed pectoral fins, defective bone formation and compromised kidney morphogenesis; which partially phenocopied the human LRP4 mutations and were reminiscent of phenotypes resulting form a perturbed Notch signaling pathway. We discovered that the Lrp4-deficient zebrafish manifested increased Notch outputs in addition to enhanced Wnt signaling, with the expression of Notch ligand jagged1b being significantly elevated at the fin structures. To examine conservatism of signaling mechanisms, the effect of LRP4 missense mutations and siRNA knockdowns, including a novel missense mutation c.1117C > T (p.R373W) of LRP4, were tested in mammalian kidney and osteoblast cells. The results showed that LRP4 suppressed both Wnt/β-Catenin and Notch signaling pathways, and these activities were perturbed either by LRP4 missense mutations or by a knockdown of LRP4. Our finding underscore that LRP4 is required for limiting Jagged-Notch signaling throughout the fin/limb and kidney development, whose perturbation representing a novel mechanism for LRP4-related diseases. Moreover, our study reveals an evolutionarily conserved relationship between LRP4 and Jagged-Notch signaling, which may shed light on how the Notch signaling is fine-tuned during fin/limb development.

What's in the Literature?

In this edition, we focus on neuromuscular junction disorders and myopathy. The newly published international consensus guidelines for the management of myasthenia gravis are reviewed. In addition, various emerging treatment options for myasthenia, including the use of methotrexate, rituximab, subcutaneous immunoglobulin, and thymectomy, are discussed. Recent studies examining the clinical and genetic features of several forms of congenital myasthenia gravis are also highlighted. The clinical features and treatment of late-onset Pompe disease are reviewed, as are studies in facioscapulohumeral dystrophy, idiopathic inflammatory myopathies, and calpainopathy.

Congenital myasthenic syndromes and myasthenia gravis are challenging diagnoses in neurological practice

Congenital myasthenic syndromes and myasthenia gravis are challenging diagnoses in neurological practice

Neuromuscular Junction Formation, Aging, and Disorders.

Synapses, the fundamental unit in neuronal circuits, are critical for learning and memory, perception, thinking, and reaction. The neuromuscular junction (NMJ) is a synapse formed between motoneurons and skeletal muscle fibers that is covered by Schwann cells (SCs). It is essential for controlling muscle contraction. NMJ formation requires intimate interactions among motoneurons, muscles, and SCs. Deficits in NMJ formation and maintenance cause neuromuscular disorders, including congenital myasthenic syndrome and myasthenia gravis. NMJ decline occurs in aged animals and may appear before clinical presentation of motoneuron disorders such as amyotrophic lateral sclerosis. We review recent findings in NMJ formation, maintenance, neuromuscular disorders, and aging of the NMJ, focusing on communications among motoneurons, muscles and SCs, and underlying mechanisms.

Juvenile Myasthenia Gravis: A Case Report and Review of Literatures

Juvenile myasthenia gravis (JMG) is a rare autoimmune disorder of childhood. Pediatric presentation of MG is more common in Oriental than in Caucasian populations. JMG need to be differentiated from congenital myasthenia gravis which do not have haan autoimmune basis. An 11 years old girl presented with drooping of eye lids which was more marked at the later part of day and was gradually progressive . She had complained of double vision. She had no family history of myasthenia gravis. Ice pack test, repetitive nerve stimulation test, and anti acetylcholine receptor antibody test support the diagnosis. She was treated with pyridostigmine and was started as 30mg four times daily and increased to 60 mg/qds. Subsequently her symptoms improved gradually and she became stable.&#x0D; Bangladesh Journal of Neuroscience 2013; Vol. 29 (1) : 64-69

Successful treatment of overactive bladder in a child with myasthenia gravis

Detrusor overactivity in patients with congenital myasthenia gravis is a rare finding. Owing to the underlying disease, anticholinergic treatment is not possible. We present the case of a 6-year-old child in whom a significant improvement was achieved by means of functional electrical stimulation.

Myasthenic Ptosis With Synkinetic Override in a Child With Congenital Oculomotor Nerve Palsy

Congenital myasthenia gravis usually involves the ocular motor system in predictable ways. The purpose of this report is to describe a child who had a congenital oculomotor nerve palsy with aberrant regeneration and fatigable ptosis associated with congenital myasthenia gravis. During periods of levator fatigability, gaze activation of the ipsilateral superior or medial rectus muscles produced instantaneous levator retraction with no fatigability. The ability of this child’s synkinetic neuromuscular connections to override her myasthenic levator fatigability may provide insight into the establishment of normal and abnormal neuromuscular connections in the setting of congenital myasthenia gravis.

Congenital Myasthenia Gravis in Smooth-Haired Miniature Dachshund Dogs

Three 8-week-old Miniature Smooth Haired Dachshund littermates were diagnosed with myasthenia gravis based on clinical signs, results of electrophysiological testing, and response to the short-acting anticholinesterase drug, edrophonium chloride. Congenital myasthenia gravis was confirmed by the demonstration of decreased acetylcholine-receptor density in external intercostal muscle in the absence of demonstrable serum antiacetylcholine receptor antibody or antibodies complexed to acetylcholine receptors in muscle biopsy samples. Unlike most previously reported cases of congenital myasthenia gravis that are relentlessly progressive, clinical signs resolved spontaneously by 6 months of age.

Stimulation of acetylcholine receptor transcription by neuregulin-2 requires an N-box response element and is regulated by alternative splicing

The neuregulin (Nrg) family of growth/differentiation factors is encoded by at least four genes in the mammalian genome: nrg-1, nrg-2, nrg-3 and nrg-4. Nrg-1 and Nrg-2 share the highest homology within the family, and the primary RNA transcripts from their encoding genes are subjected to extensive alternative splicing. Although little is known about the biological function of Nrg-2-4, their structural similarity with Nrg-1 suggests that they could account for some of the activities presently attributed to Nrg-1. Thus, at the neuromuscular junction Nrg-1 has been a favored candidate for the signal that activates selective acetylcholine receptor (AChR) transcription in synaptic myonuclei. However, we have recently shown that like Nrg-1, Nrg-2 can also activate AChR transcription in cultured myotubes and accumulates at the synaptic site. Synapse-specific and Nrg-1-induced AChR transcription require an enhancer sequence, the N-box, which is also mutated in some patients with congenital myasthenia gravis. Here, we show that Nrg-2-induced AChR transcription requires an N-box motif and is regulated by alternative splicing. We also show that unique Nrg-2 isoforms are differentially distributed between spinal cord and skeletal muscle, the tissues that harbor the cellular components of the neuromuscular synapse.

Congenital Myasthenia Gravis in Smooth-Haired Miniature Dachshund Dogs

Three 8-week-old Miniature Smooth Haired Dachshund littermates were diagnosed with myasthenia gravis based on clinical signs, results of electrophysiological testing, and response to the short-acting anticholinesterase drug, edrophonium chloride. Congenital myasthenia gravis was confirmed by the demonstration of decreased acetylcholine-receptor density in external intercostal muscle in the absence of demonstrable serum antiacetylcholine receptor antibody or antibodies complexed to acetylcholine receptors in muscle biopsy samples. Unlike most previously reported cases of congenital myasthenia gravis that are relentlessly progressive, clinical signs resolved spontaneously by 6 months of age.