Diagnosis Of Congenital Myasthenic Syndromes Research Articles

Can Scoliosis Help the Early Diagnosis of Congenital Myasthenic Syndrome?

Background Congenital myasthenic syndromes (CMS) are a group of hereditary diseases of the neuromuscular junction. CMS are extremely rare diseases that cause hypotonia; however, scoliosis may theoretically be helpful in early diagnosis of CMS. The objective of this studywas to emphasize the clinical features of the patients we followed up with the diagnosis of CMS and demonstrate that scoliosis is an important finding in the diagnosis of CMS in the presence of hypotonia/weakness. Materials and methods In this retrospective study, data were retrieved by examining the digital files of the patients who presented to Aydın Maternity and Children's Hospital and Elazığ Fethi Sekin City Hospital Pediatric Neurology Clinics between 2018 and 2023. The diagnosis of CMS was strongly supported by a combination of clinical characteristics, neurophysiological studies, genetic tests, AChR antibodies, and serum creatine kinase measurement. The presence of scoliosis was evaluated by an orthopedics and traumatology specialist. Results Eleven CMS patients with accompanying scoliosis were included in the study. The mean age of the patients was 69.4±39.28 months. The age of the patients at the time of diagnosis was 42.7±35.19 months. Among the patients, eight were males (72.7%), and three were females (27.2%). Seven patients (63.6%) had COLQ mutations. Electromyography was conducted on eight patients, with one of them showing no pathological findings, while seven exhibited decremental responses. All patients had ptosis, while six (54.5%) had bulbar signs. Ten patients (90.9%) had weakness. Nine patients (81.8%) experienced frequent recurrent lower respiratory tract infections. Both the patient with CHAT mutation and RAPSN mutation had arthrogryposis. Conclusion In this study, CMS stands out as an essential consideration in the differential diagnosis, particularly when scoliosis accompanies early-onset muscle weakness.

Delayed Diagnosis of Congenital Myasthenic Syndromes Erroneously Interpreted as Mitochondrial Myopathies.

Congenital myasthenic syndromes (CMSs) and primary mitochondrial myopathies (PMMs) can present with ptosis, external ophthalmoplegia, and limb weakness. Our method involved the description of three cases of CMS that were initially characterized as probable PMM. All patients were male and presented with ptosis and/or external ophthalmoplegia at birth, with proximal muscle weakness and fatigue on physical exertion. After normal repetitive nerve stimulation (RNS) studies performed on facial muscles, a muscle biopsy (at a median age of 9) was performed to rule out congenital myopathies. In all three cases, the biopsy findings (COX-negative fibers or respiratory chain defects) pointed to PMM. They were referred to our neuromuscular unit in adulthood to establish a genetic diagnosis. However, at this time, fatigability was evident in the physical exams and RNS in the spinal accessory nerve showed a decremental response in all cases. Targeted genetic studies revealed pathogenic variants in the MUSK, DOK7, and RAPSN genes. The median diagnostic delay was 29 years. Treatment resulted in functional improvement in all cases. Early identification of CMS is essential as medical treatment can provide clear benefits. Its diagnosis can be challenging due to phenotypic overlap with other debilitating disorders. Thus, a high index of suspicion is necessary to guide the diagnostic strategy.

Congenital myasthenic syndromes (CMS) a rare cause of uncommon fatigue

Introduction and purpose:
 Muscle weakness in newborns, infants and young children can be caused by disorders of the neuromuscular junction (NMJ). Congenital myasthenic syndromes (CMS) are a group of rare genetic diseases whose symptoms resemble the clinical picture of autoimmune myasthenia gravis. There are many mutations that can disrupt the neuromuscular transmission leading to pathology. The diagnosis of CMS is based on genetic testing. The aim of this study is to draw clinicians' attention to the symptoms and present current forms of CMS diagnosis and management.
 State of knowledge:
 An increasing number of genetic changes are associated with CMS pathology. They are divided, depending on the location in the NMJ of the encoded protein, into presynaptic, synaptic and postsynaptic. The most common disorder is the mutation of CHRNE, which is responsible for the expression of one of the subunits in the structure of the acetylcholine receptor. Regardless of the type of disease, the characteristic symptom is uncommon fatigue of skeletal muscles. It may present as ptosis of one or both eyelids or gait disturbance. The interview, laboratory tests and EMG are helpful in the diagnosis, but genetic tests play a key role. They can target specific mutations or cover the entire genome comprehensively. Currently used drugs alleviate the course of CMS by increasing the release of acetylcholine or increasing the concentration of acetylcholine in the synaptic cleft.
 Conclusion:
 Because of its rarity and variability, many CMS patients may be misdiagnosed. It is important to implement extensive genetic diagnostics and early implementation of treatment. There is a need for long-term studies of CMS cases and implementation of therapies targeted at specific mutations.

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.

OTHER NMDs: EP.349 GFPT1-related myopathy overlapping with autophagic vacuolar myopathy. A case report

Autophagic vacuolar myopathies are a heterogeneous group of muscle diseases with a common denominator of altered autophagy and defective protein quality control. Pathogenic variants in GFPT1 cause limb-girdle congenital myasthenic syndrome. Muscle biopsies from affected patients usually show characteristic tubular aggregates, fiber disproportion, and in limited reports, autophagic vacuoles. A 27-year-old female born to non-consanguineous parents, presented with a progressive axial and limb-girdle weakness from 22 months of age, without cognitive impairment. She developed a progressive dorsolumbar scoliosis and restrictive respiratory pattern from 4 years of age. CK levels were normal and EMG without RNS revealed a myopathic pattern. The muscle biopsy showed variable fiber size and large numbers of fibres containing single or multiple cytoplasmic vacuoles containing cellular debris. Oxidative activity was increased in those fibers. Muscle MRI revealed generalized atrophy predominantly in axial and limb-girdle muscles. Trio-WES analysis failed to find pathogenic variants in genes related to autophagic vacuolar myopathy, but research-based reanalysis identified a homozygous pathogenic variant in GFPT1 (NM_001244710.1 c.686-2A>G). RNS revealed a mild and inconstant area decrement at trapezius muscle and SFEMG a pathological jitter with blocks at extensor digitorum communis, consistent with the diagnosis of congenital myasthenic syndrome. Treatment with pyridostigmine and 2,4-diaminopyrimidine was initiated with mild improvement. She is now able to walk independently indoors holding her head, without respiratory or oropharyngeal concerns. The initial diagnosis of autophagic vacuolar myopathy based on the presence of autophagic vacuoles delayed the genetic diagnosis and treatment in this case. We propose the inclusion of GFPT1 under the umbrella of autophagic vacuolar myopathies and encourage a deeper study of the GFPT1 function in autophagy.

Congenital myasthenic syndrome: Ten years clinical experience from a quaternary care south-Indian hospital

BackgroundTo ascertain the frequency, clinical spectrum and outcome of congenital myasthenic syndrome (CMS) patients who reported to the neuromuscular division of our quaternary medical center during the past ten years. MethodsWe performed a retrospective analysis of all the CMS patients who reported to us during the study period. ResultsTwenty-one patients of CMS attended our quaternary hospital over the past ten years. The median follow-up was 24 (IQR: 16.5–67.3) months. All the patients showed an overall improvement in the last follow up. The diagnosis of CMS could be genetically confirmed in seven cases. Four patients had COLQ mutation, two had CHRNε mutation and one had MUSK mutation. All the cases of COLQ mutation and one case of MUSK mutation had a limb-girdle (LG) presentation. Our study and review of literature imply that CMS should be suspected in cases of seronegative myasthenia gravis cases if the onset is at less than 20 years and strongly so if the onset is within the first two years of life. In addition, a positive family history, delayed motor milestones, and a poor response to immune-modulators should be actively sought for as indicators of CMS.

Study of Rare Cases of Congenital Myasthenic Syndrome in Bangladesh

Congenital myasthenic syndromes (CMS) comprise a heterogeneous group of rare inherited diseases in which the neuromuscular transmission in the motor plate is compromised by one or more genetic pathophysiological specific mechanisms are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. The diagnosis of CMS is based on clinical findings, a decremental EMG response of the compound muscle action potential (CMAP) on low-frequency (2- 3 Hz) stimulation, absence of anti-acetylcholine receptor (AChR) and anti-MuSK antibodies in the serum, a positive response to acetylcholinesterase (AchE) inhibitors and lack of improvement of clinical symptoms with immunosuppressive therapy. Pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of CMS. The most commonly associated genes include: CHAT, CHRNE, COLQ, DOK7, GFPT1 and RAPSN. We studied on a sibling presented with progressive fatigability and fluctuating ptosis with frequent exacerbations of muscle weakness during infections since infancy. On both cases CT scan of chest were negative for thymoma, antibodies against the acetylcholine receptor (AChR) and the muscle specific kinase (MuSK) were negative and decremental response on electrophysiological study of Repetitive nerve stimulation (RNS) and EMG were consistent with disease of neuromuscular junction (post synaptic) and they were only on pyridostigmine for long time with marked improvement of symptoms and signs. Considering all scenario both of our cases mostly fits with the autosomal recessive, post synaptic CMS associated with Rapsyn deficiency.
 Objective : As in Bangladesh, there is inadequate data on the epidemiological profile of CMS, our aim is to describe these cases for their rarity and the difficulty encountered in diagnosis as they are easily confused with Juvenile Myasthenia Gravis (JMG) and familial myopathies. As both the cases are very rare, it should be an original article.
 Bangladesh Journal of Neuroscience 2019; Vol. 35 (2): 95-103

P.077 Utility of a next generation sequencing in the diagnosis of Congenital Myasthenic Syndromes

Background: Congenital Myasthenic Syndromes (CMS) are heterogeneous disorders caused by genetically determined structural or functional differences in proteins involved with the neuromuscular junctions. Clinical and molecular genetics studies of CMS patients have revealed significant locus heterogeneity; there are 21 known genes related to CMS, but other genes may mimic the phenotype, justifying the use of a multi-gene panel for genetic testing Methods: Our group developed custom sequence capture probes designed to flank 27 different genes associated with CMS, including enrichment for all coding exons as well the flanking intronic regions. We enrolled 20 patients from the paediatric and adult neuromuscular clinic with a clinical phenotype of CMS. Using custom analytical, we -assessed the sequence variants and exon-level CNVs for each patient. Results: Thirteen male and seven female patients with median age of 12.25 years (range 1.5-39y) were assessed. We identified missense and CNVs in 17 patients, including established pathogenic mutations confirming the diagnosis in 5 patients Conclusions: The use of Next Generation Sequence with CNV for CMS can help determine the underlying causes of most CMS disorders and allow appropriate medical treatment, refined genetic counseling, and improved understanding of prognosis, justifying the implementation in the standard clinical screening of CMS.

The interest of electrophysiological study in the diagnosis of congenital myasthenic syndromes

The interest of electrophysiological study in the diagnosis of congenital myasthenic syndromes

P.333 - Next generation sequencing technologies in the genetic diagnosis of congenital myasthenic syndrome

P.333 - Next generation sequencing technologies in the genetic diagnosis of congenital myasthenic syndrome

Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome.

Congenital myasthenic syndromes are a group of rare and genetically heterogenous disorders resulting from defects in the structure and function of the neuromuscular junction. Patients with congenital myasthenic syndrome exhibit fatigable muscle weakness with a variety of accompanying phenotypes depending on the protein affected. A cohort of patients with a clinical diagnosis of congenital myasthenic syndrome that lacked a genetic diagnosis underwent whole exome sequencing in order to identify genetic causation. Missense biallelic mutations in the MYO9A gene, encoding an unconventional myosin, were identified in two unrelated families. Depletion of MYO9A in NSC-34 cells revealed a direct effect of MYO9A on neuronal branching and axon guidance. Morpholino-mediated knockdown of the two MYO9A orthologues in zebrafish, myo9aa/ab, demonstrated a requirement for MYO9A in the formation of the neuromuscular junction during development. The morphants displayed shortened and abnormally branched motor axons, lack of movement within the chorion and abnormal swimming in response to tactile stimulation. We therefore conclude that MYO9A deficiency may affect the presynaptic motor axon, manifesting in congenital myasthenic syndrome. These results highlight the involvement of unconventional myosins in motor axon functionality, as well as the need to look outside traditional neuromuscular junction-specific proteins for further congenital myasthenic syndrome candidate genes.

P164 – 2586: Congenital myasthenic syndrome in Israel: Genetic and clinical characterization

Objective Congenital myasthenic syndromes (CMS) are a rare heterogeneous group of inherited neuromuscular disorders associated with distinctive clinical, electrophysiological and genetic abnormalities. Mutations in various genes of the neuromuscular junction may cause presynaptic, synaptic or postsynaptic defects. In this study, the genetic and clinical characteristics of Israeli patients with CMS were evaluated. Methods Twentysix patients with CMS from 16 independent families in whom genetic mutation was detected were diagnosed in two Israeli medical centers. Genetic evaluation was initially performed depending on patients' clinical symptoms and known CMS genes were sequenced. Patients of Jewish Iranian or Iraqi ethnic origin were screened directly for a known 38 A-G mutation in RAPSYN. In two patients, whole exome sequencing was analyzed. All patients' medical records were reviewed and their clinical data, electrophysiological studies and outcome were recorded. Results The diagnosis of CMS was confirmed in 26 patients of 16 families. Among these patients, 8 patients of 4 families had recessive mutations in COLQ, eight patients of 5 families, mutations in CHRNE, and eight patients of 5 families, mutations in RAPSN. CHRND was diagnosed in 2 patients from one family. The mean age of onset of clinical symptoms was 6 months. Ptosis, ophthalmoplegia and feeding problems were the most common symptoms. Conclusions RAPSYN and CHRNE are the most common causes of CMS in our cohort. The second most common cause is COLQ. Specific mutations in RAPSYN, CHRNE and COLQ are detected in unique ethnic populations in Israel.

Diagnosis of congenital myasthenic syndromes by target capture/next generation sequencing (P2.023)

Diagnosis of congenital myasthenic syndromes by target capture/next generation sequencing (P2.023)

Delayed diagnosis of congenital myasthenia due to associated mitochondrial enzyme defect

Clinical phenotypes of congenital myasthenic syndromes and primary mitochondrial disorders share significant overlap in their clinical presentations, leading to challenges in making the correct diagnosis. Next generation sequencing is transforming molecular diagnosis of inherited neuromuscular disorders by identifying novel disease genes and by identifying previously known genes in undiagnosed patients. This is evident in two patients who were initially suspected to have a mitochondrial myopathy, but in whom a clear diagnosis of congenital myasthenic syndromes was made through whole exome sequencing. In patient 1, whole exome sequencing revealed compound heterozygous mutations c.1228C > T (p.Arg410Trp) and c.679C > T (p.Arg227*) in collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ). In patient 2, in whom a deletion of exon 52 in Dystrophin gene was previously detected by multiplex ligation-dependent probe amplification, Sanger sequencing revealed an additional homozygous mutation c.1511_1513delCTT (p.Pro504Argfs*183) in docking protein7 (DOK7). These case reports highlight the need for careful diagnosis of clinically heterogeneous syndromes like congenital myasthenic syndromes, which are treatable, and for which delayed diagnosis is likely to have implications for patient health. The report also demonstrates that whole exome sequencing is an effective diagnostic tool in providing molecular diagnosis in patients with complex phenotypes.

The need for careful diagnosis of congenital myasthenic syndromes with secondary complex I disorders

The need for careful diagnosis of congenital myasthenic syndromes with secondary complex I disorders

P.12.1 Diagnostic pitfalls in congenital myasthenic syndromes in children: Clinical experience in an academic neuromuscular centre

Congenital myasthenic syndromes (CMSs) cover a group of heterozygous disorders in which the neuromuscular transmission is affected. As clinical features, like tired- and weakness in a young child, are rather a specific and do not always guide towards a CMS, the diagnostic studies leading to a diagnosis can be very challenging. We describe our diagnostic work up and show our struggles in eight children suffering from tiredness, exhaustion and muscle weakness. Common diagnostic pitfalls, causing delay in diagnosis and treatment, are the lack of specificity of clinical features, false negative elektromyography (EMG) results, non-specific changes in muscle histology and technical drawbacks of invasive testing in young children. We discovered five mutations in the CHRNE gene, two in the RAPSYN gene and one mutation in DPAGT1, so finally DNA confirmed diagnosis of CMS was made. We started with medications what considerably improve the quality of live. Clinicians are urged to perform tailored genetic testing guided by clinical features. CMSs are highly treatable and early initiation of treatment can considerably improve the quality of life of patients with a CMS.

Limb‐girdle myasthenia with tubular aggregates associated with novel GFPT1 mutations

Limb-girdle myasthenia with tubular aggregates (LGM with TAs) is a subtype of congenital myasthenic syndrome caused by recessive mutations of glutamine-fructose-6-phosphate transaminase 1 (GFPT1). Clinical and neurophysiological assessment was made in a Korean boy who had proximal limb muscle weakness. Findings suggested a diagnosis of congenital myasthenic syndrome. Muscle biopsy disclosed numerous TAs in muscle fibers, and DNA sequence analysis disclosed 2 novel missense mutations (p.E256Q and p.M499T) in GFPT1. Treatment with oral cholinesterase inhibitors produced a dramatic improvement in muscle strength. GFPT1 is the key enzyme in the hexosamine biosynthesis pathway, and mutations in GFPT1 cause defective glycosylation in the proteins of the neuromuscular junction. Identification of LGM with TAs among patients with congenital myasthenic syndrome is important because treatment with cholinesterase inhibitors can produce symptomatic improvement.

Diagnosis of congenital myasthenic syndrome with mutation of the RAPSN gene after general anaesthesia

Diagnosis of congenital myasthenic syndrome with mutation of the RAPSN gene after general anaesthesia

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

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

Workshop on the use of stimulation single fibre electromyography for the diagnosis of myasthenic syndromes in children held in the Institute of Child Health and Great Ormond Street Hospital for Children in London on April 24th, 2009

A meeting to discuss the use of stimulation single fibre electromyography (StimSFEMG) to assist diagnosis of congenital myasthenic syndromes (CMS) took place on 24th April 2009 at the Institute of Child Health in London. Seventeen neurophysiologists with a special interest in electromyography from 15 regional centres attended.