Form Of Congenital Myasthenic Syndrome Research Articles

Alteration of actin cytoskeletal organisation in fetal akinesia deformation sequence

Fetal akinesia deformation sequence (FADS) represents the severest form of congenital myasthenic syndrome (CMS), a diverse group of inherited disorders characterised by impaired neuromuscular transmission. Most CMS originate from defects in the muscle nicotinic acetylcholine receptor, but the underlying molecular pathogenesis is only poorly understood. Here we show that RNAi-mediated silencing of FADS-related proteins rapsyn and NUP88 in foetal fibroblasts alters organisation of the actin cytoskeleton. We show that fibroblasts from two independent FADS individuals have enhanced and shorter actin stress fibre bundles, alongside with an increased number and size of focal adhesions, with an otherwise normal overall connectivity and integrity of the actin-myosin cytoskeleton network. By proximity ligation assays and bimolecular fluorescence complementation, we show that rapsyn and NUP88 localise nearby adhesion plaques and that they interact with the focal adhesion protein paxillin. Based on these findings we propose that a respective deficiency in rapsyn and NUP88 in FADS alters the regulation of actin dynamics at focal adhesions, and thereby may also plausibly dictate myofibril contraction in skeletal muscle of FADS individuals.

Congenital Myasthenic Syndromes

Congenital myasthenic syndromes (CMS) are characterized by congenital defects in the neuromuscular signal transmission and are caused by pathogenic variants in 36 genes. Recently identified forms of CMS include TOR1AIP1-CMS, CHD8-CMS, PURA-CMS, and TEFM-CMS. Most forms of CMS are caused by autosomal recessive variants, whereas four forms of CMS are caused by autosomal dominant variants, in which adult-onset cases are not rare. As myasthenic features are not always observed and muscle hypotrophy is sometimes observed, CMS should be considered in differential diagnosis of congenital myopathies and other neuromuscular diseases. Low- and high-frequency repetitive nerve stimulation is essential to diagnose CMS for patients who develop muscle weakness at less than 2 years of age. Tubular aggregates are observed in muscle biopsy in four forms of CMS, and serum CK levels are elevated in some forms of CMS. As rational therapies are available for most forms of CMS, identification of causative gene variants by genetic analysis is required.

Congenital myasthenic syndromes: beta adrenergic receptor agonist treatment

Acetylcholinesterase inhibitors, such as pyridostigmine, are the standard symptomatic treatment for myasthenia gravis, and so have naturally been applied to the genetic forms of myasthenia, termed congenital myasthenic syndromes (CMS). Although effective for many CMS in others there was no clear response and in some it was positively harmful. Now, with greater understanding of the mutations and molecular mechanisms underlying CMS, treatments can be tailored for the specific syndrome and depending on diseases severity and patient response this can include utilizing different combinations of the drugs. In CMS, over the last 15-20 years b2-adrenergic receptor agonists have moved from occasional use to a mainstream medication. Many cases show life-transforming improvement both when the b2-adrenergic receptor agonists are used alone or in combination. Here we feature how the identification of DOK7-CMS first highlighted the consistent benefit of b2-adrenergic receptor agonists as medication and how it’s application to many different CMS subtypes evolved. The molecular pathogenic mechanisms for many CMS subtypes are now established and this report will also discuss a hypothetical rationale for which forms of CMS are likely to benefit from the b2-adrenergic receptor agonists.

The longest reported sibling survivors of a severe form of congenital myasthenic syndrome with the ALG14 pathogenic variant

Congenital myasthenic syndromes (CMS) is a group of diseases that causes abnormalities at the neuromuscular junction owing to genetic anomalies. The pathogenic variant in ALG14 results in a severe pathological form of CMS causing end-plate acetylcholine receptor deficiency. Here, we report the cases of two siblings with CMS associated with a novel variant in ALG14. Immediately after birth, they showed hypotonia and multiple joint contractures with low Apgar scores. Ptosis, low-set ears, and high-arched palate were noted. Deep tendon reflexes were symmetrical. They showed worsening swallowing and respiratory problems; hence, nasal feeding and tracheotomy were performed. Cranial magnetic resonance imaging scans revealed delayed myelination and cerebral atrophy. Exome sequencing indicated that the siblings had novel compound heterozygous missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon 4 of ALG14. Repetitive nerve stimulation test showed an abnormal decrease in compound muscle action potential. After treatment with pyridostigmine, the time off the respirator increased. Their epileptic seizures were well controlled by anti-epileptic drugs. Their clinical course is stable even now at the ages of 5 and 2 years, making them the longest reported survivors of a severe form of CMS with the ALG14 variant thus far.

New recessive mutations in SYT2 causing severe presynaptic congenital myasthenic syndromes.

ObjectiveTo report the identification of 2 new homozygous recessive mutations in the synaptotagmin 2 (SYT2) gene as the genetic cause of severe and early presynaptic forms of congenital myasthenic syndromes (CMSs).MethodsNext-generation sequencing identified new homozygous intronic and frameshift mutations in the SYT2 gene as a likely cause of presynaptic CMS. We describe the clinical and electromyographic patient phenotypes, perform ex vivo splicing analyses to characterize the effect of the intronic mutation on exon splicing, and analyze the functional impact of this variation at the neuromuscular junction (NMJ).ResultsThe 2 infants presented a similar clinical phenotype evoking first a congenital myopathy characterized by muscle weakness and hypotonia. Next-generation sequencing allowed to the identification of 1 homozygous intronic mutation c.465+1G>A in patient 1 and another homozygous frameshift mutation c.328_331dup in patient 2, located respectively in the 5′ splice donor site of SYT2 intron 4 and in exon 3. Functional studies of the intronic mutation validated the abolition of the splice donor site of exon 4 leading to its skipping. In-frame skipping of exon 4 that encodes part of the C2A calcium-binding domain of SYT2 is associated with a loss-of-function effect resulting in a decrease of neurotransmitter release and severe pre- and postsynaptic NMJ defects.ConclusionsThis study identifies new homozygous recessive SYT2 mutations as the underlying cause of severe and early presynaptic form of CMS expanding the genetic spectrum of recessive SYT2-related CMS associated with defects in neurotransmitter release.

MYASTHENIA & RELATED DISORDERS: P.31 Identification of new recessive mutations in synaptotagmin-2 responsible for severe and early presynaptic forms of congenital myasthenic syndrome

Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of inherited disorders caused by defective synaptic transmission at the neuromuscular junction (NMJ) and characterized by fluctuation of muscle weakness and fatigability. Recently, many mutations encoding presynaptic proteins have been identified as responsible for increasingly complex CMS phenotypes of CMS. Among them, the autosomal dominant mutations in Synaptotagmin2 (SYT2) C2B domain that have been linked to described as responsible for presynaptic CMS combined to Lambert-Eaton myasthenic syndromes and motor neuropathy forms.

Null variants in AGRN cause lethal fetal akinesia deformation sequence

We present a case of lethal fetal akinesia deformation sequence (FADS) caused by a frameshift variant in trans with a 148 kbp deletion encompassing 3-36 exons of AGRN. Pathogenic variants in AGRN have been described in families with a form of congenital myasthenic syndrome (CMS), manifesting in the early childhood with variable fatigable muscle weakness. To the best of our knowledge, this is the first case of FADS caused by defects in AGRN gene. FADS has been reported to be caused by pathogenic variants in genes previously associated with CMS including these involved in endplate development and maintenance: MuSK, DOK7, and RAPSN. FADS seems to be the most severe form of CMS. None of the reported in the literature CMS cases associated with AGRN had two null variants, like the case presented herein. This indicates a strong genotype-phenotype correlation.

John Newsom-Davis. 18 October 1932—24 August 2007

John Newsom-Davis (‘JND’) was a neurologist who played an important role in the discovery of the causes of, and treatments for, myasthenia gravis (MG), and of other diseases of the nerve–muscle junction. He started his career at the National Hospital in London, becoming director of the Batten Unit there, with an interest in respiratory physiology. He began to work on MG in collaboration with Ricardo Miledi (FRS 1970) at University College London and in 1978, after performing the first study on plasma exchange in that disease, he established an MG research group at the Royal Free Hospital, subsequently identifying the role of the thymus in this disease and demonstrating an autoimmune basis for the Lambert–Eaton myasthenic syndrome and ‘seronegative’ myasthenia. He was awarded the first Medical Research Council Clinical Research Professorship in 1979 but moved to Oxford in 1987 when he was elected Action Research Professor of Neurology. While at Oxford he continued to run a very successful multidisciplinary group, and began the molecular work that identified the genetic basis for many forms of congenital myasthenic syndrome. He also helped to establish the Functional Magnetic Resonance Imaging of the Brain (FMRIB) Centre. Meanwhile he was also involved in university and college governance and contributed widely to the Medical Research Council, government committees, and the Association of British Neurologists (ABN). Among many honours, he was appointed Commander of the Order of the British Empire in 1996 and made a Foreign Associate Member of the Institute of Medicine (now the National Academy of Medicine) in the USA in 2001. Following retirement from Oxford, he was President of the ABN and Editor ofBrain, and led a National Institutes of Health-funded international trial of thymectomy.

Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions.

Congenital myasthenic syndromes (CMS) form a heterogeneous group of rare diseases characterized by fatigable muscle weakness. They are genetically-inherited and caused by defective synaptic transmission at the cholinergic neuromuscular junction (NMJ). The number of genes known to cause CMS when mutated is currently 30, and the relationship between fatigable muscle weakness and defective functions is quite well-understood for many of them. However, some of the most recent discoveries in individuals with CMS challenge our knowledge of the NMJ, where the basis of the pathology has mostly been investigated in animal models. Frontier forms between CMS and congenital myopathy, which have been genetically and clinically identified, underline the poorly understood interplay between the synaptic and extrasynaptic molecules in the neuromuscular system. In addition, precise electrophysiological and histopathological investigations of individuals with CMS suggest an important role of NMJ plasticity in the response to CMS pathogenesis. While efficient drug-based treatments are already available to improve neuromuscular transmission for most forms of CMS, others, as well as neurological and muscular comorbidities, remain resistant. Taken together, the available pathological data point to physiological issues which remain to be understood in order to achieve precision medicine with efficient therapeutics for all individuals suffering from CMS.

Phenotypic heterogeneity in two large Roma families with a congenital myasthenic syndrome due to CHRNE 1267delG mutation. A long-term follow-up

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders. Mutations in CHRNE are one of the most common cause of them and the ɛ1267delG frameshifting mutation is described to be present on at least one allele of 60% of patients with CHRNE mutations. We present a comprehensive description of the heterogeneous clinical features of the CMS caused by the homozygous 1267delG mutation in the AChR Ɛ subunit in nine members of two large Gipsy kindreds. Our observations indicate that founder Roma mutation 1267delG leads to a phenotype further characterized by ophthalmoplegia, bilateral ptosis, and good response to pyridostigmine and 3,4-DAP; but also by facial weakness, bulbar symptoms, neck muscle weakness, and proximal limb weakness that sometimes entails the loss of ambulation. Interestingly, we found in our series a remarkable proportion of patients with a progressive or fluctuating course of the disease. This finding is in some contrast with previous idea that considered this form of CMS as benign, non progressive, and with a low impact on the capacity of ambulation.

What's in the Literature?

One of the first questions asked by patients and family members when a diagnosis of amyotrophic lateral sclerosis is made is "what about stem cells?" The term "stem cells" has attractiveness to it, with the assumption that stem cell treatment (stem nerve cells) can replace lost nerve cells. There are perhaps 2 types of stem cell trials, those that are vetted by the Food and Drug Administration and those that have no official oversight and whose results are infrequently published. The issue of the latter was discussed in the last edition of this column. The results of one of the formal stem cell trials now in the United States have been reported. Spinal muscular atrophy is a form of motor neuron disease affecting children and has a genetic cause, which has led to a feasibility study giving antisense oligonucleotides, and the results have also been reported. Biomarkers of amyotrophic lateral sclerosis are being sought, and the presence of neurofilaments is promising. Inflammatory neuropathies are an important group because they are treatable. Intravenous immune globulin is a commonly used agent, but a number of questions persist: one is efficacy among brands, another is the probability of a response, and a third is optimum dosing and taper schedules. A number of recent articles address these issues. The predictive value of single-fiber electromyography in determining which patients with ocular myasthenia will develop generalized disease, the risk of crisis after thymectomy, and 2 papers discussing new forms of congenital myasthenic syndrome are discussed. The risk of brain tumors, quality of life, and the assessment of trunk muscle strength in patients with type 1 myotonic dystrophy is reviewed. An article describing the discovery of mutations in SCN4A as a cause of congenital myopathy is discussed, as is one describing the occurrence of rhabdomyolysis in a group of patients subsequently discovered to have various forms of muscular dystrophy. Finally, articles describing the features of patients with inflammatory myopathies and Jo-1 and either 3-hydroxy-3-methylglutaryl-conezymea reductase or to signal recognition particle antibodies are reviewed.

ID 429 – Clinical and electrophysiological follow-up study of a patient with congenital myasthenic syndrome (CMS) associated with mutations in the gen of the agrin (AGRN)

We describe the clinical and electrophysiological findings of a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations in the gene encoding agrin (AGRN). A 43 year-old-man, born after a normal pregnancy at term, presented with generalized hypotonia in the first months of life. He walked at 12 months but soon developed ptosis, neck and truncal muscle weakness progressed slowly. There was arreflexia with flexor plantar responses. He never had sensory symptoms. Parents were normal; an older brother with a similar condition died at15. Electrophysiological investigations were performed on many occasions; blood count and chemistries of serum and CSF were normal. Antibodies against AChR, MuSK, and P/Q voltage-gated were negative. NCS were normal. RNS (3 Hz) of the median nerve induced a 40% decrement in the Thenar CMAP that improved markedly after exercise and Neostigmine. SFEMG showed increased jitter and blocking. Ultrastructure of muscle showed small nerve terminals, simplified postsynaptic folds, and disruption of their architecture. Genetic analysis revealed a nonsense and a missense mutations in the gene encoding agrin (AGRN). These findings demonstrate that the AGRN mutations can cause a disruption of the architecture of the neuromuscular junction that results in a severe CMS.

Mice with a Null Allele for NaV1.4 Exhibit Pseudo-Myasthenia, but are not Susceptibile to Periodic Paralysis

Functional analysis of disease-associated mutant NaV1.4 channels have revealed defects that often provide a mechanistic basis for derangements in sarcolemma excitability to produce the clinical phenotype. Loss-of-function mutations are less common and the pathogenic basis for muscle dysfunction is less clear than for the gain-of-function NaV1.4 mutations associated with myotonia, paramyotonia congenita or hyperkalemic periodic paralysis. Loss-of-function via enhanced inactivation (both fast and slow) accompanies other channel defects in hypokalemic periodic paralysis (HypoKPP) and is the primary defect in a rare form of congenital myasthenic syndrome. We explored whether a NaV1.4 loss-of-function created in a mouse would produce features of HypoKPP or myasthenia.A null allele of NaV1.4 was generated by excision of exon 12 (174 bp which encodes DIIS2-DIIS4). Heterozygous (+/-) mice were viable, but homozygous nulls (-/-) did not survive beyond P2. Spontaneous movement, feeding, and reproduction were normal in (+/-) mice. Voltage-clamp studies of dissociated fibers showed a 50% reduction of Ina in (+/-) animals. The Na current was completely blocked by 200 nM TTX, suggesting there was no compensatory upregulation of NaV1.5. In vitro contraction testing showed a right shift of the force- stimulus intensity curve and a prominent sag from the early peak force for submaximal stimulus intensities in (+/-) mice. Repetitive nerve stimulation did not elicit a decremental response in the compound muscle AP (CMAP) at baseline, but exposure to low-dose curare (0.5 uM) revealed a larger decrement for (+/-) than WT. These features are consistent with mild myasthenia. Challenge with low K did not diminish maximal tetanic force, nor did insulin & glucose infusion cause a decrease of CMAP amplitude, both of which were observed in our R669H HypoKPP mice.

Anticholinesterase Therapy Worsening Head Drop and Limb Weakness Due to a Novel DOK7 Mutation

Dok-7 myasthenia is an autosomal recessive congenital myasthenic syndrome due to DOK7 mutations. Anticholinesterase therapy is ineffective and may worsen the weakness in patients with Dok-7 myasthenia or few other forms of congenital myasthenic syndromes. We describe a 31-year-old man previously diagnosed with seronegative myasthenia gravis. Repetitive stimulation of the right spinal accessory nerve showed 51% decrement. Needle electromyography revealed myopathic changes in clinically affected muscles. Muscle biopsy was normal. The patient was referred to us for worsening weakness after taking pyridostigmine. We searched for DOK7 mutations and identified compound heterozygous mutations of a common c.1124_1127dupTGCC mutation and a novel splice site mutation, c.772+2_+4delinsCCGGGCAGGCGGGCA. Discontinuation of pyridostigmine improved weakness. He further regained strength with oral albuterol therapy and decrement was reduced to 25%. Worsening of symptoms with anticholinesterase therapy in patients with "seronegative myasthenia gravis" should prompt clinicians to consider a possibility of congenital myasthenic syndromes to avoid unnecessary use of immunosuppressive therapy. Patients with Dok-7 myasthenia respond well to oral albuterol treatment.

A COLQ Missense Mutation in Sphynx and Devon Rex Cats with Congenital Myasthenic Syndrome.

An autosomal recessive neuromuscular disorder characterized by skeletal muscle weakness, fatigability and variable electromyographic or muscular histopathological features has been described in the two related Sphynx and Devon Rex cat breeds (Felis catus). Collection of data from two affected Sphynx cats and their relatives pointed out a single disease candidate region on feline chromosome C2, identified following a genome-wide SNP-based homozygosity mapping strategy. In that region, we further identified COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase) as a good candidate gene, since COLQ mutations were identified in affected humans and dogs with endplate acetylcholinesterase deficiency leading to a synaptic form of congenital myasthenic syndrome (CMS). A homozygous c.1190G>A missense variant located in exon 15 of COLQ, leading to a C397Y substitution, was identified in the two affected cats. C397 is a highly-conserved residue from the C-terminal domain of the protein; its mutation was previously shown to produce CMS in humans, and here we confirmed in an affected Sphynx cat that it induces a loss of acetylcholinesterase clustering at the neuromuscular junction. Segregation of the c.1190G>A variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant. Genotyping of a panel of 333 cats from 14 breeds failed to identify a single carrier in non-Sphynx and non-Devon Rex cats. Finally, the percentage of healthy carriers in a European subpanel of 81 genotyped Sphynx cats was estimated to be low (3.7%) and 14 control Devon Rex cats were genotyped as wild-type individuals. Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G>A missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds. The presently available DNA test will help owners avoid matings at risk.

G.P.139: Congenital myasthenic syndrome due to novel choline acetyltransferase (ChAT) gene mutations in Kadazandusun family from Borneo

Pathogenic mutations of the choline acetyltransferase (ChAT) gene alters its function and causes reduced synthesis of acetylcholine and its depletion in synaptic vesicles. This results in a rare presynaptic form of congenital myasthenic syndrome which presents at birth or in infancy characterised by apnoeic attacks. We present Kadazandusun family, an ethnic group native to Sabah, in north Borneo, with ChAT deficiency in which 5 of 6 siblings of non-consanguineous parents were affected. 2 died in their infancy from apnoeic atatacks while another sibling died at the age of 12 years from a severe apnoeic episode after an intercurrent infection. We reviewed 2 brothers, the eldest and the 4th at 24 and 18 years of age respectively, although both had presented in infancy with bilateral ptosis and limb weakness. The elder brother had episodes of apnoea and weakness on exposure to cold well water in their village. A congenital myasthenic syndrome was suspected and both brothers were treated on pyridostigmine after positive Tensilon tests and negative acetylcholine receptor antibody tests. On review, both had muscle weakness after moderate to severe exertion and repetitive nerve stimulation test of the abductor digiti minimi, which was normal at rest, showed sustained decremental response after prolonged 5 min stimulation at 10 Hz. Screening of the ChAT gene showed compound heterozygous mutation in both brothers, c.1069G>C and c.2263_2265delTCT in exons 6 and 15 respectively. Each parent was heterozygous for one of the mutations, which were not seen in any of 50 normal controls obtained from the native population of Sabah. In summary, we present a Kadazandusun family with ChAT deficiency congenital myasthenic syndrome, in which, 3 affected siblings died from apnoeic episodes, while another 2 survived to adulthood. This variable severity could be attributed to treatment with pyridostigmine as well as recognised improvement with age in this condition.

P1030: Clinical and electrophysiological follow-up study of a patient with congenital myasthenic syndrome (CMS) associated with mutations in the gene of the agrin (AGRN)

Objective We describe the clinical and electrophysiological findings of a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations in the gene encoding agrin (AGRN). Patient and methods A 43 year-old-man, born after a normal pregnancy at term, presented with generalized hypotonia in the first months of life. He walked at 12 months but soon developed ptosis, neck and truncal muscle weakness progressed slowly. There was arreflexia with flexor plantar responses. He never had sensory symptoms. Parents were normal; an older brother with a similar condition died at15. Electrophysiological investigations were performed on many occasions; blood count and chemistries of serum and CSF were normal. Antibodies against AChR, MuSK, and P/Q voltage-gated were negative. Results NCS were normal. RNS (3 Hz) of the median nerve induced a 40% decrement in the Thenar CMAP that improved markedly after exercise and Neostigmine. SFEMG showed increased jitter and blocking. Ultrastructure of muscle showed small nerve terminals, simplified postsynaptic folds, and disruption of their architecture. Genetic analysis revealed a nonsense and a missense mutations in the gene encoding agrin (AGRN). Conclusion These findings demonstrate that the AGRN mutations can cause a disruption of the architecture of the neuromuscular junction that results in a severe CMS.

Clinical features of congenital myasthenic syndrome due to mutations in DPAGT1

BackgroundA newly defined congenital myasthenic syndrome (CMS) caused by DPAGT1 mutations has recently been reported. While many other CMS-associated proteins have discrete roles localised to the neuromuscular junction, DPAGT1 is...

Recurrent COLQ Mutation in Congenital Myasthenic Syndrome

Congenital myasthenic syndromes comprise clinically and genetically heterogeneous disorders resulting from presynaptic, synaptic, or postsynaptic defects. Mutations in the COLQ gene result in acetylcholinesterase deficiency and cause a rare, autosomal recessive synaptic form of congenital myasthenic syndrome, with variable age of onset and clinical severity. We present four unrelated patients with a homozygous W148X mutation in the COLQ gene. Signs began at birth in all, but subsequent severity ranged from independent ambulation to wheelchair use during childhood. Treatment was partly effective; one patient was asymptomatic with 3,4-diaminopyridine treatment. These cases illustrate the clinical features and treatment results associated with this particular genotype, which appears to be relatively frequent among Turkish patients with congenital myasthenic syndrome.

Congenital Myasthenic Syndrome: A Brief Review

Congenital myasthenic syndromes comprise heterogeneous genetic diseases characterized by compromised neuromuscular transmission. Congenital myasthenic syndromes are classified as presynaptic, synaptic, or postsynaptic, depending on the primary defect's location within the neuromuscular junction. Presynaptic forms are the rarest, affecting an estimated 7-8% of patients; synaptic forms account for approximately 14-15% of patients; and the remaining 75-80% are attributable to postsynaptic defects. Clinical manifestations vary by congenital myasthenic syndrome subtype. Electrophysiologic, morphologic, and molecular descriptions of various forms of congenital myasthenic syndromes have led to an enhanced understanding of clinical manifestations and disease pathophysiology. Although congenital myasthenic syndromes are indicated by clinical manifestations, family history, electrophysiologic studies, and responses to acetylcholinesterase inhibitors, overlap in some presentations occurs. Therefore, genetic testing may be necessary to identify specific mutations in CHAT, COLQ, LAMB2, CHRNA, CHRNB, CHRND, CHRNE, CHRNG, RAPSN, DOK7, MUSK, AGRN, SCN4A, GFPT1, or PLEC1 genes. The identification of congenital myasthenic syndromes subtypes will prove important in the treatment of these patients. Different drugs may be beneficial, or should be avoided because they are ineffective or worsen some forms of congenital myasthenic syndromes. We explore the classification, clinical manifestations, electrophysiologic features, genetics, and treatment responses of each congenital myasthenic syndrome subtype.