Congenital Myasthenic Syndrome Treatment Heterogeneity Makes Diagnosis and Treatment Challenging

NEUROMUSCULAR DISORDERS Congenital Myasthenic Syndrome Treatment Heterogeneity makes diagnosis and treatment challenging. By Stanley Jones P. Iyadurai, MD, PhD, FAAN

Congenital myasthenic syndromes (CMS) worldwide.3 As more individuals with CMS are reported, comprise a rare heterogeneous group of dis- appropriate treatment strategies may be identified and eases that impair neuromuscular transmission refined to maximize benefit. Although this appears to be a (NMT) and are characterized by fatigability noble goal, there are no FDA-approved treatments for CMS and transient or permanent weakness of ocu- patients. Historically, several medications have been used to lar, facial, bulbar, or limb muscles. Symptoms treat (and shown clinical improvement) people with CMS. are often present from birth or early childhood, although, Although there is no specific treatment option available or more rarely, may develop in adolescence or adulthood. The favored, some neuromuscular clinicians favor an algorithmic CMS have a wide range of phenotypes and severity—from approach to currently used therapeutic options. This review mild weakness to permanent disabling muscle weakness to summarizes pharmacologic treatments reported to have respiratory failure. been helpful. Caused by genetic mutations in any of the numerous genes encoding for components of the neuromuscular Definition and Diagnosis junction (NMJ), CMS are classified by where in the NMJ Clinical phenotypes of CMS overlap with other neuromus- the mutated component is located: presynaptic, synaptic, cular diseases, most notably myasthenia gravis (MG), an auto- or postsynaptic. An additional category of CMS includes immune disease also characterized by weakness, fatigability, mutations in glycosylation-related genes that encode pro- and ptosis (1 or both eyelids). Caused by autoantibodies to the teins that help stabilize the NMJ through glycosylation. acetylcholine receptor (AChR), muscle-specific tyrosine kinase Taken together, mutations in 30 genes have been impli- (MuSK), or low-density lipoprotein receptor-related protein 4 cated in CMS phenotype. Because of the large number of (LRP4), MG typically has adult onset.4 It is possible that prior gene mutations that can cause CMS, clinical features, age reports termed familial myasthenia gravis were CMS.5,6 of onset, symptoms, and response to treatment vary widely Clinically, MG and CMS can be differentiated by findings and can make diagnosis difficult. Of people diagnosed with of myasthenic symptoms present since birth that persisted CMS, only 50% to 70% have a confirmed genetic diagnosis.1 into childhood.7 This must be distinguished from MG in neo- Advances in genetic testing have made genetic diagnosis nates, termed congenital myasthenia gravis, which results from faster and more cost effective, which is imperative because maternal autoantibodies and resolves with treatment within the location of the defect in the NMJ based on the underly- weeks to months as maternal antibodies dissipate.8 ing causative mutation has implications for differences in Differentiating CMS from MG is critical to avoid unnecessary response to treatment. treatment with immunosuppressant drugs or thymectomy.4 In Prevalence of CMS is estimated at 9.2 per 1,000,000 chil- extremely rare cases, MG and CMS have been observed in the dren less than age18 years2; however, the prevalence is likely same patient. In a pair of twins with CMS due to a mutation in underestimated as many cases of CMS remain misdiagnosed the gene encoding the e subunit of the AChR, 1 sister’s clinical or go undetected in people with mild symptoms. In addi- manifestations deteriorated at age 34 when she was found to tion, although less common, due to extensive use of gene have serum anti-AChR antibodies, the hallmark of MG.9 After sequencing panel-based testing, more and more adults are being described and studied as a distinct disease entity,10 the being diagnosed with CMS (specifically, the group of “sero- first causative genetic mutation of CMS was in the e subunit of negative myasthenia gravis” patients). Despite the rarity AChR (CHRNE).11 Since this initial discovery, over 30 additional and diagnostic challenges of CMS, over 1,000 independent mutations causative for CMS have been found.12 kinships have been identified carrying pathogenic variants Diagnosis of CMS is established with clinical and electrodi-

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agnostic features and identification of a causative mutation. bulbar, facial, axial, limb, or respiratory muscles with early In some instances, a clinical diagnosis can be made without childhood onset finding a causative gene (eg, individuals who exhibit fatigable • Family history of CMS clinical symptoms, especially if con- weakness, especially of ocular and other cranial muscles, at sistent with autosomal dominant or recessive inheritance birth or early childhood. Clinical diagnosis may rely on his- • Clinical similarity to MG with negative findings for antibod- tory, clinical exams, blood tests, incremental or decremental ies to AChR, MuSK, or LRP4 responses or abnormal single-fiber EMG (SF-EMG) study • Lack of response to immunosuppressive therapy; results, lung function tests, polysomnography, the Tensilon • Symptomatic response to acetylcholinesterase inhibitors test, and muscle biopsy. In rarer cases when symptoms mani- (AChEIs) (eg, intravenous edrophonium chloride [Tensilon fest in adolescence or adulthood, symptom presentation may test], nonspecific potassium channel blockers [3,4-DAP], or differ from that seen in infants and young children and can a supervised trial of oral medication include proximal and axial muscle weakness associated with a • Exclusion of alternate diagnoses with muscle biopsy decremental response requiring prolonged stimulation.13 The most common causes of CMS are mutations in genes Electrodiagnostic Features encoding subunits of the AChR (ie, CHRNA1, CHRNB1, The CMS are distinguished electrodiagnostically by defec- CHRND, or CHRNE), which account for approximately 50% tive NMT. The safety margin of NMT is the difference of cases. Mutations in RAPSN, COLQ, and DOK7 comprise between postsynaptic depolarization caused by the endplate another 35% to 50% of cases.13,14 Clinical features and EMG potential and depolarization required to activate postsynaptic findings may suggest which mutation is present and linkage voltage-gated Nav1.4 channels to trigger an action potential. analysis may suggest a chromosomal locus of interest if there Endplate potential amplitude is determined by the number of are a sufficient number of informative relatives. This strategy acetylcholine (ACh) molecules in individual synaptic vesicles; is most effective in populations with founder mutations or activity of acetylcholinesterase (AChE) in the synaptic space; inbreeding (eg, those of European Roma descent or from and the density, distribution, and AChR properties.13 the Maghreb).14 Alternatively, exome analysis of an affected Electrophysiologic investigation of NMT is carried out with individual and his or her parents (trio analysis) can identify a LF-RNS and high-frequency RNS (HF-RNS). For LF-RNS, a relevant mutation. Unequivocal genetic diagnosis of CMS is motor nerve is briefly stimulated at 2 or 3 Hz (and 5 Hz or 7 Hz confirmed when heterozygous or biallelic pathogenic variants or 10 Hz or 15 Hz, in some cases) and the compound muscle are found in a known gene causative for CMS.12,14 action potential (CMAP) that is evoked is recorded with an electrode placed on the muscle surface. The amplitude of this Clinical Features potential is proportionate to the number of muscle fibers acti- The commonality amongst all CMS is muscle weakness that vated by the nerve impulse. If NMT is deficient, the endplate worsens with physical exertion. Other neuromuscular features potential is not great enough to trigger an action potential in may include ptosis, ophthalmoparesis, facial weakness, bulbar all NMJs. As the number of junctions with insufficient endplate weakness, axial weakness, limb weakness, hypotonia, dyspnea, potentials increases, the CMAP progressively decreases. A or reduced tendon reflexes. Muscle wasting or atrophy of decrease of more than 10% from the first evoked CMAP to the skeletal muscles is possible.12-14 Facial dysmorphism may be fourth evoked CMAP indicates a defect in NMT. Usually tested present, including long face, hypertelorism, narrow jaw, or in 2 limb muscles, RNS can also be tested in facial muscles if microcephaly.15-17 Spinal curvature or scoliosis may be pres- results appear normal after testing 2 distal and 2 proximal ent,18-21 and foot deformities, including pes cavus, pes planus, muscles. If certain mutations (eg, SCN4A) are present, however, hammertoes, and club feet, have been observed.17,22 Rarely, the LF-RNS response may be normal and require higher stimu- CMS may result in mild to severe cognitive dysfunction or lus rates before exhibiting a decremental response.31 neurodevelopmental delay.16,23-25 Epilepsy may be associated Using 5 or 10 Hz stimulation, rather than 2 or 3 Hz, in with CMS.26,27 Respiratory insufficiency is common, including HF-RNS can differentiate certain subtypes of CMS. Results of nocturnal hypoventilation and apnea, and stridor.1,20,28-30 HF-RNS usually show an increment and only rarely a decre- The clinical features of CMS are wide-ranging and differ ment (eg, CMS associated with a RAPSN mutation).32 Some among subtypes, the gene that is mutated, and individuals individuals return to baseline 2 to 3 minutes after RNS; how- with the same genetic mutation. Even cases of CMS within ever, for some subtypes (eg, CHAT mutations) recovery may the same family with the exact same pathogenic variants, may take 5 to 15 minutes.33 Higher frequency stimulation, followed present with widely varying symptoms and disease course. Yet, by monitoring the CMAP amplitude for 5 minutes of stimula- some subtype- or gene-specific clinical features exist (Table 1). tion, then monitoring for another 10 to 15 minutes, may be The following observations are suggestive of CMS. performed; HF-RNS for 5 to 10 minutes requires anesthesia. • Fatigability or permanent weakness, involving ocular, Unmasking an abnormal decrement may require that 10 Hz

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TABLE 1. CONGENITAL MYASTHENIC SYNDROME FEATURES ASSOCIATED WITH SPECIFIC MUTATIONS. Subtype Presynaptic Synaptic Postsynaptic Glycosylation Feature Gene Mutation Weakness VAMP1 LAMA5 AGRN, CHRND, PREPL, SLC25A1 ALG14 Bulbar weakness COL13A1 AGRN, CHRNE, MUSK, SCN4A ALG2, GFPT1 Facial weakness COL13A1 AGRN, CHRNB1, CHRNG, MUSK, RAPSN Limb muscle CHAT, SLC5A7, SYT2 COL13A1, LAMB2 CHRNB1, CHRNE, DOK7, LRP4, MUSK, GFPT1, GMPPB weakness MYO9A Hypotonia CHAT, MUNC13-1, CHRNB1, MYO9A, SLC25A1 ALG14, ALG2 SLC5A7, VAMP1 Muscle wasting AGRN, CHRNA1, CHRNB1, LRP4 Contractures CHAT, MUNC13-1, CHRNA1, CHRNG ALG2 SNAP25, VAMP1 Ptosis CHAT, MUNC13-1, COL13A1, COLQ AGRN, CHRNB1, CHRNE, DOK7, LRP4 SLC18A3, SYT2 MUSK, MYO9A, PREPL, RAPSN, SCN4A Ophthalmoparesis SLC18A3, VAMP1 COL13A1, COLQ AGRN, CHRNB1, CHRNE, MUSK Apnea CHAT, SLC5A7, SLC18A3 MUSK, SLC25A1 Respiratory MUNC13-1, SLC18A3, COL13A1, COLQ, CHRNB1, CHRND, CHRNE, CHRNG, LRP4, insufficiency VAMP1 LAMB2 MUSK, MYO9A, SCN4A Dysphagia CHRNB1, LRP4, MYO9A

Feeding difficulties MUNC13-1, VAMP1 COL13A1 CHRND, DOK7, MYO9A, PREPL, RAPSN Vocal cord paralysis DOK7, MUSK Dysmorphism MUNC13-1 COL13A1 CHRNA1, CHRNG Scoliosis MUNC13-1, VAMP1 CHRNA1, CHRNB1, CHRNE, CHRNG Foot deformities SYT2 CHRNG, SLC25A1 Delayed milestones VAMP1 LAMB2 LRP4 ALG2 Intellectual disability SNAP25 COL13A1 SLC25A1 DPAGT1 Epilepsy SLC25A1 ALG14

RNS be done for 5 to 10 minutes prior to HF-RNS because an a repetitive CMAP that is not affected by edrophonium in abnormal decrement may appear normal even when there the Tensilon test.13 Mutations in a single AChR subunits, in are defects in NMT. Exercise or muscle contractions prior to contrast, cause slow-channel CMS (SCCMS) with prolonged LF-RNS can also reveal these defects. An increment of more endplate currents and endplate potentials.35 Prolonged than 60% after a 10 to 15 second exercise is indicative of CMS. synaptic potentials exceed the absolute refractory period Single-fiber EMG (SF-EMGs) has been used to identify of the muscle fiber, triggering repetitive action poten- defects of NMT, particularly when RNS results appear normal. tials and resulting in Ca2+ accumulation postsynaptically. Results of SF-EMG may show increased jitter, block or both. Physiologically, each prolonged endplate potential arises as a The SF-EMG is more sensitive than RNS, but less specific.34 result of the previous endplate potential, leading to progres- In some cases, repetitive CMAP, in which there is a double sive depolarization block of the postsynaptic membrane. response to a single stimulus may be noted. In CMS with Increases in CMAP amplitude after 10 to 15 seconds of exer- COLQ mutations, AChE is absent from the endplate poten- cise are also indicative of CMS. tial, increasing the lifetime of ACh in the synaptic cleft and Synaptic transmission is a complex cascade of events that thus, the duration of the endplate potential. As the endplate requires fine-tuned expression and function of a number of potential outlasts the absolute refractory period of the NMJ components. Usually a genetic diagnosis is made after muscle fiber, it generates a second action potential, causing electrodiagnostic testing and before treatment commences.

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Treatment ered a suitable first-line option for CMS known not to respond Therapy for CMS is focused on alleviating symptoms and well to pyridostigmine. Albuterol has been effective for treat- typically includes pharmacologic treatment, although non- ing synaptic CMS (eg, COL13A1 or COLQ mutations) and pharmacologic treatment has been reported. Because of the postsynaptic CMS (eg, LRP4, MUSK, and DOK7). Albuterol can rarity of CMS and the heterogeneity (genotypic and phe- also be used for the symptomatic management of CMS due notypic), no standardized treatments have been developed. to other mutations, even those that are usually responsive to Acetylcholinesterase inhibitors (AChEIs) (eg, pyridostigmine) other first-line options. The CMS caused by mutations in genes are the most commonly used drugs for CMS. Although pyr- involved in glycosylation may also respond to albuterol, often idostigmine monotherapy is effective for some individuals, in combination with pyridostigmine and/or 3,4-DAP. others benefit from combination therapy, often in the form of 3,4-diaminopyridine (3,4-DAP), to achieve an effective and/or Ephedrine sustained response. Alternative drugs, either given alone or in Ephedrine is an alkaloid from the group of phenyl-ethyl- combination with an AChEI and/or 3,4-DAP include albuterol, amines that acts as a sympathomimetic agent—an a- and ephedrine, fluoxetine, and quinidine. Combination therapies b-adrenergic agonist—that may also enhance the release of have also been used as a first-line option, particularly in cases norepinephrine. Ephedrine may enhance NMT by stimulat- where CMS subtypes are known to respond negatively or ing b2-adrenergic receptors and stabilizing NMJ structure.38 not at all to AChEI monotherapy (eg, DOK7 mutations) or as Ephedrine is generally well-tolerated and can be used for some second- and third-line options for people with CMS refractory CMS subtypes refractory to AChEI treatment and for symp- to AChEI treatment (Figure). Table 2 shows treatments found tomatic management (eg, COLQ and DOK7). Limited data sug- effective for specific genotypes in some studies. gest ephedrine may be effective for CMS due to RAPSN mutations and presynaptic CMS (eg, CHAT and SLC18A) and other Acetylcholinesterase Inhibitors synaptic CMS (eg, LAMB2 mutations). Of the AChEIs, which are the most commonly used first-line Suspected CMS treatment for CMS, pyridostigmine is most frequently used, First-line followed by neostigmine and ambenonium. The AChEIs are Second-line DOK7, effective for many forms of CMS including CHRNE and RAPSN COLQ, Additional SCS and glycosylation defects. For some subtypes, however, AChEIs features? are ineffective and may worsen symptoms, including mutations in components that act to cluster AChRs at the NMJ (eg, YES NO COLQ, COL13A1, LAMB2, DOK7, LRP4, and MUSK). Among rarer forms of CMS (< 1% of CMS), efficacy of AChEIs is not Avoid pyridostigmine Start pyridostigmine yet known. In people with CMS with infections, AChEIs may DOK7 COLQ SCS Rapsyn AChR N-Glyc SCN4A ChAT Other be given prophylactically with antibiotics to prevent episodic Albuterol/Ephedrine Fluoxetine Add 3,4 DAP 36,37 Add apnea and respiratory insufficiency. ACZ Add Quinidine Add 3,4-Diaminopyridine 3,4 DAP Albuterol Ephedrine Amifampridine, or 3,4-DAP, is the most frequently used alternative to AChEIs and is also often given in combination with AChEIs. The mechanism of action of 3,4-DAP is to Consider Other Treatments increase the amount of ACh in the synaptic cleft by prolonging Figure. Treatment algorithm for the most common congenital the time calcium channels are open via potassium channel myasthenic syndromes. Treatment shown for DOK7 can be blockade. It is possible that 3,4-DAP also modulates postsyn- used for all subtypes associated with the AChR-clustering complex, and in these subtypes, 3,4-DAP should be used only aptic potassium channels, although how this might contribute after first- and second-line treatments and with great caution. to improved muscle function is unclear. As an adjunct to Other options reported to have benefit are prednisone (CHRNE pyridostigmine or as stand-alone therapy, 3,4-DAP is generally CMS), neostigmine methyl sulfate (CHAT CMS), amiloride, effective in presynaptic and some postsynaptic CMS or CMS spironolactone, and theophylline (DOK7 CMS), although the with glycosylation defects. There is no evidence of 3,4-DAP effi- benefit/risk of these treatments is not clear. Abbreviations: 3,4 cacy for synaptic COL13A1 or COLQ mutations. DAP, 3,4-diaminopyridine; AChR, acetylcholine receptor; ACZ, acetazolamide; ChAT, choline acetyltransferase; CMS, congenital myasthenic syndromes; COLQ, collagen-like tail subunit of Albuterol asymmetric acetylcholinesterase; DOK7, docking protein 7; Albuterol, also known as salbutamol, is a b2 agonist that N-Glyc, N-glycosylation pathway; SCN4A, sodium channel type 4 stimulates intracellular potassium uptake and has been consid- subunit alpha; SCS, slow-channel syndrome.

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TABLE 2. RESPONSE TO TREATMENT BY GENOTYPE Pyridostigmine 3,4-Diaminopyridine Albuterol Ephedrine Fluoxetine Others Presynaptic CHAT, MUNC13-1, MYO9A, MUNC13-1, SLC18A3, CHAT CHAT, SLC18A3, VAMP1 SNAP25, SYT2 SLC18A3 Synaptic LAMA5 LAMA5 COL13A1, COLQ COLQ, COLQ LAMB2 Postsynaptic CHRNA1, CHRND, CHRNE, CHRNE, DOK7, MUSK, CHRNE, DOK7, CHRNE, CHRNA1, RAPSN (acetazol- PREPL, RAPSN, FCCMS RAPSN LRP4, MUSK, DOK7, CHRNB1, amide), SCN4A RAPSN, FCCMS RAPSN CHRNE, (acetazolamide), MUSK DOK7 (amiloride, spironolactone, theophylline), CHRNE (prednisone) Slow channel Does not respond Unclear Responds Responds positively positively positively Glycosyl- ALG14, ALG2, DPAGT1, DPAGT1, GFPT1, DPAGT1, GFPT1, ation GFPT1, GMPPB GMPPB GMPPB Unspecified Generally positive Generally positive Generally Generally positive negative Note: A genotype is listed as responsive to a treatment when >50% of studies reported >50% of patients with positive response. If a genotype is not listed, it may be that a positive response was seen or that there are no reports of this treatment for the genotype. Fluoxetine to treat MG. In other case reports, however, 2 people treated Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), with prednisone and pyridostigmine did not respond well,39 has variable effects in CMS. Fluoxetine blocks muscle and and 1 person with DOK7 mutations treated with azathioprine, neuronal AChRs in a noncompetitive and voltage-dependent prednisone, and pyridostigmine did not respond positively.40 manner and is an accepted first-line treatment for SCCMS. In In a case study, a person with a DOK7 mutation treated with addition, this author has reported significant improvement in amiloride and spironolactone to correct serum potassium muscle strength with fluoxetine in 12 individuals from 3 dif- level and theophylline to treat possible asthma had complete ferent families (unpublished results). Although not used as recovery (ie, no lower limb deficit, running with ease, no ptosis, frequently as other treatments, fluoxetine is often used as first- dysphagia, or phonation difficulties. This was in contrast to line treatment for SCCMS in adults or when AChEI are inef- ineffective or partially effective treatment with pyridostigmine, fective. Fluoxetine is not always effective for SCCMS, however, corticosteroids, immunoglobulins, and 3,4-DAP.41 and side effects may prohibit use. Quinidine, a long-lasting open-channel AChR blocker that increases action potential duration, has been used to success- Other Treatments fully treat SCCMS.42,43 Quinidine is a stereoisomer of quinine There are a few reports of other treatments, including that acts as a class I antiarrhythmic and is preferentially used acetazolamide, amiloride, spironolactone, theophylline, aza- to treat SCCMS in children and adolescents as an alternative thioprine, prednisone, and quinidine. Quinidine was given to to fluoxetine, which has been associated with psychiatric side treat CMS; the others were given after misdiagnoses as MG effects (eg, suicidal thinking during titration).3,39 Although or for symptomatic treatment. Acetazolamide is a diuretic quinidine is well-tolerated and has been used as first- or reversible carbonic anhydrase inhibitor that reduces hydrogen second-line treatment in people with AChR gene mutations, it ion secretion at the renal tubule and increases renal secretion does not consistently have a positive effect.39 of sodium, potassium, bicarbonate, and water. In a small case Noninvasive, nonpharmacologic treatments include physical series, 1 person with a RAPSN mutation and 1 with a SCN4A therapy, speech therapy, and occupational therapy.12 For peo- mutation responded positively to acetazolamide after being ple with reduced or absent ambulation, orthoses, walkers, and misdiagnosed with MG.38 In another case study, a person wheelchairs may be helpful. For those with respiratory insuffi- initially diagnosed with MG who had CHRNE mutations, had ciency, nasal intermittent positive pressure ventilation (NIPPV) a moderate positive response to combination therapy with may be used either constantly or at night only.44-47 Invasive, prednisone and azathioprine, which are both generally used nonpharmacologic treatments for CMS are also available for

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channel. Proc Natl Acad Sci U S A. 2003;100(12):7377-7382. various symptoms. For dysphagia and feeding difficulties, a 17. Al-Muhaizea MA, Al-Mobarak SB. COLQ-mutant congenital myasthenic syndrome with microcephaly: a unique case percutaneous endoscopic gastrostomy may be needed. For with literature review. Transl Neurosci. 2017;8:65-69. 18. Natera-de Benito D, Bestue M, Vilchez JJ, et al. Long-term follow-up in patients with congenital myasthenic syndrome respiratory insufficiency in which NIPPV is not possible, intuba- due to RAPSN mutations. Neuromuscul Disord. 2016;26(2):153-159. tion and mechanical ventilation may be required. Deformities 19. Pavone P, Pratico AD, Pavone V, Falsaperla R. Congenital familial myasthenic syndromes: disease and course in an affected dizygotic twin pair. BMJ Case Rep. 2013;2013:bcr2012007651 or malformations (eg, scoliosis or foot deformities) may also 20. Tan J-S, Ambang T, Ahmad-Annuar A, et al. Congenital myasthenic syndrome due to novel CHAT mutations in an require corrective surgical procedures. ethnic kadazandusun family. Muscle Nerve. 2016;53(5):822-826. 21. Salpietro V, Lin W, Delle Vedove A, et al. Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome. Ann Neurol. 2017;81(4):597-603. Discussion and Conclusions 22. Brugnoni R, Maggi L, Canioni E, et al. Identification of previously unreported mutations in CHRNA1, CHRNE and RAPSN genes in three unrelated Italian patients with congenital myasthenic syndromes. J Neurol. 2010;257(7):1119-1123. Diagnosis and management of CMS have evolved from 23. Klein A, Robb S, Rushing E, Liu W-W, Belaya K, Beeson D. Congenital myasthenic syndrome caused by mutations in clinical observation, to EMG assessments investigating subcel- DPAGT. Neuromuscul Disord. 2015 Mar;25(3):253-256. 24. O’Connor E, Topf A, Muller JS, et al. Identification of mutations in the MYO9A gene in patients with congenital lular mechanisms of impaired NMT, to genetic assessment myasthenic syndrome. Brain. 2016;139(8):2143-2153. pinpointing specific gene mutations. First-line therapy for CMS 25. Shen XM, Selcen D, Brengman J, Engel AG. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology. 2014;83(24):2247-2255. is typically pyridostigmine, which has been shown effective for 26. Chaouch A, Porcelli V, Cox D, et al. Mutations in the mitochondrial citrate carrier SLC25A1 are associated with impaired symptom management for many. In those with synaptic CMS neuromuscular transmission. J Neuromuscul Dis. 2014;1(1):75-90. 27. Schorling DC, Rost S, Lefeber DJ, et al. Early and lethal neurodegeneration with myasthenic and myopathic features: A or with DOK7, LRP4, or MUSK mutations, however, pyridostig- new ALG14-CDG. Neurology. 2017;89(7):657-664. mine is ineffective and alternative first-line therapies, usually 28. Muller JS, Petrova S, Kiefer R, et al. Synaptic congenital myasthenic syndrome in three patients due to a novel missense mutation (T441A) of the COLQ gene. Neuropediatrics. 2004;35(3):183-189. albuterol, are used. Albuterol may also be combined with 29. Yeung WL, Lam CW, Fung LWE, Hon KLE, Ng PC. Severe congenital myasthenia gravis of the presynaptic type with pyridostigmine and 3,4-DAP, proving effective in some people choline acetyltransferase mutation in a Chinese infant with respiratory failure. Neonatology. 2009;95(2):183-186. 30. Jephson CG, Mills NA, Pitt MC, et al. Congenital stridor with feeding difficulty as a presenting symptom of Dok7 with glycosylation defects. Ephedrine has been reserved for congenital myasthenic syndrome. Int J Pediatr Otorhinolaryngol. 2010;74(9):991-994. CMS refractory to traditional AChEI treatment, but ephedrine 31. Habbout K, Poulin H, Rivier F, Giuliano S, Sternberg D, Fontaine B, et al. A recessive Nav1.4 mutation underlies congenital myasthenic syndrome with periodic paralysis. Neurology. 2016;86(2):161-169. has demonstrated more variable responses compared with 32. LoRusso SJ, Iyadurai SJ. Decrement with high frequency repetitive nerve stimulation in a RAPSN congenital myasthenic other options. There are a few reports of efficacy of fluoxetine syndrome. Muscle Nerve. 2018 Mar;57(3):e106-e108. 33. Durmus H, Shen X-M, Serdaroglu-Oflazer P, et al. Congenital myasthenic syndromes in Turkey: clinical clues and and quinidine as first-line treatment for SCCMS in adults, prognosis with long term follow-up. Neuromuscul Disord. 2018;28(4):315-322. for which AChEI are ineffective, but further study is needed. 34. Mills KR. Specialised electromyography and nerve conduction studies. Neurol Pract. 2005;76(2):36-40. 35. Ohno K, Hutchinson DO, Milone M, et al. Congenital myasthenic syndrome caused by prolonged acetylcholine receptor Appropriate and effective treatment options are not yet estab- channel openings due to a mutation in the M2 domain of the epsilon subunit. Proc Natl Acad Sci USA. 1995;92(3):758-762. lished for the rarer forms of CMS, with some gene mutations 36. Finlayson S, Palace J, Belaya K, et al. Clinical features of congenital myasthenic syndrome due to mutations in DPAGT1. J Neurol Neurosurg Psychiatry. 2013;84(10):1119-1125. reported thus far in only 1 or a small number of patients (eg, 37. Schara U, Della Marina A, Abicht A. Congenital myasthenic syndromes: current diagnostic and therapeutic approaches. SLC5A7, SNAP25, SYT2, SCN4A, and SLC25A1). Neuropediatrics. 2012;43(4):184-193. 38. Lashley D, Palace J, Jayawant S, Robb S, Beeson D. Ephedrine treatment in congenital myasthenic syndrome due to The majority of studies are of small cohorts or single cases, mutations in DOK7. 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