Congenital myasthenic syndromes (CMS) comprise a rare heterogeneous group of diseases that impair neuromuscular transmission (NMT) and are characterized by fatigability and transient or permanent weakness of ocular, facial, bulbar, or limb muscles. Symptoms are often present from birth or early childhood, although, more rarely, may develop in adolescence or adulthood. The CMS have a wide range of phenotypes and severity—from mild weakness to permanent disabling muscle weakness to respiratory failure.

Caused by genetic mutations in any of the numerous genes encoding for components of the neuromuscular junction (NMJ), CMS are classified by where in the NMJ the mutated component is located: presynaptic, synaptic, or postsynaptic. An additional category of CMS includes mutations in glycosylation-related genes that encode proteins that help stabilize the NMJ through glycosylation. Taken together, mutations in 30 genes have been implicated in CMS phenotype. Because of the large number of gene mutations that can cause CMS, clinical features, age of onset, symptoms, and response to treatment vary widely and can make diagnosis difficult. Of people diagnosed with CMS, only 50% to 70% have a confirmed genetic diagnosis.1 Advances in genetic testing have made genetic diagnosis faster and more cost effective, which is imperative because the location of the defect in the NMJ based on the underlying causative mutation has implications for differences in response to treatment.

Prevalence of CMS is estimated at 9.2 per 1,000,000 children less than age18 years2; however, the prevalence is likely underestimated as many cases of CMS remain misdiagnosed or go undetected in people with mild symptoms. In addition, although less common, due to extensive use of gene sequencing panel-based testing, more and more adults are being diagnosed with CMS (specifically, the group of “seronegative myasthenia gravis” patients). Despite the rarity and diagnostic challenges of CMS, over 1,000 independent kinships have been identified carrying pathogenic variants worldwide.3 As more individuals with CMS are reported, appropriate treatment strategies may be identified and refined to maximize benefit. Although this appears to be a noble goal, there are no FDA-approved treatments for CMS patients. Historically, several medications have been used to treat (and shown clinical improvement) people with CMS. Although there is no specific treatment option available or favored, some neuromuscular clinicians favor an algorithmic approach to currently used therapeutic options. This review summarizes pharmacologic treatments reported to have been helpful.

Definition and Diagnosis

Clinical phenotypes of CMS overlap with other neuromuscular diseases, most notably myasthenia gravis (MG), an autoimmune disease also characterized by weakness, fatigability, and ptosis (1 or both eyelids). Caused by autoantibodies to the acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK), or low-density lipoprotein receptor-related protein 4 (LRP4), MG typically has adult onset.4 It is possible that prior reports termed familial myasthenia gravis were CMS.5,6

Clinically, MG and CMS can be differentiated by findings of myasthenic symptoms present since birth that persisted into childhood.7 This must be distinguished from MG in neonates, termed congenital myasthenia gravis, which results from maternal autoantibodies and resolves with treatment within weeks to months as maternal antibodies dissipate.8

Differentiating CMS from MG is critical to avoid unnecessary treatment with immunosuppressant drugs or thymectomy.4 In extremely rare cases, MG and CMS have been observed in the same patient. In a pair of twins with CMS due to a mutation in the gene encoding the ε subunit of the AChR, 1 sister’s clinical manifestations deteriorated at age 34 when she was found to have serum anti-AChR antibodies, the hallmark of MG.9 After being described and studied as a distinct disease entity,10 the first causative genetic mutation of CMS was in the ε subunit of AChR (CHRNE).11 Since this initial discovery, over 30 additional mutations causative for CMS have been found.12

Diagnosis of CMS is established with clinical and electrodiagnostic features and identification of a causative mutation. In some instances, a clinical diagnosis can be made without finding a causative gene (eg, individuals who exhibit fatigable weakness, especially of ocular and other cranial muscles, at birth or early childhood. Clinical diagnosis may rely on history, clinical exams, blood tests, incremental or decremental responses or abnormal single-fiber EMG (SF-EMG) study results, lung function tests, polysomnography, the Tensilon test, and muscle biopsy. In rarer cases when symptoms manifest in adolescence or adulthood, symptom presentation may differ from that seen in infants and young children and can include proximal and axial muscle weakness associated with a decremental response requiring prolonged stimulation.13

The most common causes of CMS are mutations in genes encoding subunits of the AChR (ie, CHRNA1, CHRNB1, CHRND, or CHRNE), which account for approximately 50% of cases. Mutations in RAPSN, COLQ, and DOK7 comprise another 35% to 50% of cases.13,14 Clinical features and EMG findings may suggest which mutation is present and linkage analysis may suggest a chromosomal locus of interest if there are a sufficient number of informative relatives. This strategy is most effective in populations with founder mutations or inbreeding (eg, those of European Roma descent or from the Maghreb).14 Alternatively, exome analysis of an affected individual and his or her parents (trio analysis) can identify a relevant mutation. Unequivocal genetic diagnosis of CMS is confirmed when heterozygous or biallelic pathogenic variants are found in a known gene causative for CMS.12,14

Clinical Features

The commonality amongst all CMS is muscle weakness that worsens with physical exertion. Other neuromuscular features may include ptosis, ophthalmoparesis, facial weakness, bulbar weakness, axial weakness, limb weakness, hypotonia, dyspnea, or reduced tendon reflexes. Muscle wasting or atrophy of skeletal muscles is possible.12-14 Facial dysmorphism may be present, including long face, hypertelorism, narrow jaw, or microcephaly.15-17 Spinal curvature or scoliosis may be present,18-21 and foot deformities, including pes cavus, pes planus, hammertoes, and club feet, have been observed.17,22 Rarely, CMS may result in mild to severe cognitive dysfunction or neurodevelopmental delay.16,23-25 Epilepsy may be associated with CMS.26,27 Respiratory insufficiency is common, including nocturnal hypoventilation and apnea, and stridor.1,20,28-30

The clinical features of CMS are wide-ranging and differ among subtypes, the gene that is mutated, and individuals with the same genetic mutation. Even cases of CMS within the same family with the exact same pathogenic variants, may present with widely varying symptoms and disease course. Yet, some subtype- or gene-specific clinical features exist (Table 1).

The following observations are suggestive of CMS.

  • Fatigability or permanent weakness, involving ocular, bulbar, facial, axial, limb, or respiratory muscles with early childhood onset
  • Family history of CMS clinical symptoms, especially if consistent with autosomal dominant or recessive inheritance
  • Clinical similarity to MG with negative findings for antibodies to AChR, MuSK, or LRP4
  • Lack of response to immunosuppressive therapy;
  • Symptomatic response to acetylcholinesterase inhibitors (AChEIs) (eg, intravenous edrophonium chloride [Tensilon test], nonspecific potassium channel blockers [3,4-DAP], or a supervised trial of oral medication
  • Exclusion of alternate diagnoses with muscle biopsy

Electrodiagnostic Features

The CMS are distinguished electrodiagnostically by defective NMT. The safety margin of NMT is the difference between postsynaptic depolarization caused by the endplate potential and depolarization required to activate postsynaptic voltage-gated Nav1.4 channels to trigger an action potential. Endplate potential amplitude is determined by the number of acetylcholine (ACh) molecules in individual synaptic vesicles; activity of acetylcholinesterase (AChE) in the synaptic space; and the density, distribution, and AChR properties.13

Electrophysiologic investigation of NMT is carried out with LF-RNS and high-frequency RNS (HF-RNS). For LF-RNS, a motor nerve is briefly stimulated at 2 or 3 Hz (and 5 Hz or 7 Hz or 10 Hz or 15 Hz, in some cases) and the compound muscle action potential (CMAP) that is evoked is recorded with an electrode placed on the muscle surface. The amplitude of this potential is proportionate to the number of muscle fibers activated by the nerve impulse. If NMT is deficient, the endplate potential is not great enough to trigger an action potential in all NMJs. As the number of junctions with insufficient endplate potentials increases, the CMAP progressively decreases. A decrease of more than 10% from the first evoked CMAP to the fourth evoked CMAP indicates a defect in NMT. Usually tested in 2 limb muscles, RNS can also be tested in facial muscles if results appear normal after testing 2 distal and 2 proximal muscles. If certain mutations (eg, SCN4A) are present, however, the LF-RNS response may be normal and require higher stimulus rates before exhibiting a decremental response.31

Using 5 or 10 Hz stimulation, rather than 2 or 3 Hz, in HF-RNS can differentiate certain subtypes of CMS. Results of HF-RNS usually show an increment and only rarely a decrement (eg, CMS associated with a RAPSN mutation).32 Some individuals return to baseline 2 to 3 minutes after RNS; however, for some subtypes (eg, CHAT mutations) recovery may take 5 to 15 minutes.33 Higher frequency stimulation, followed by monitoring the CMAP amplitude for 5 minutes of stimulation, then monitoring for another 10 to 15 minutes, may be performed; HF-RNS for 5 to 10 minutes requires anesthesia. Unmasking an abnormal decrement may require that 10 Hz RNS be done for 5 to 10 minutes prior to HF-RNS because an abnormal decrement may appear normal even when there are defects in NMT. Exercise or muscle contractions prior to LF-RNS can also reveal these defects. An increment of more than 60% after a 10 to 15 second exercise is indicative of CMS.

Single-fiber EMG (SF-EMGs) has been used to identify defects of NMT, particularly when RNS results appear normal. Results of SF-EMG may show increased jitter, block or both. The SF-EMG is more sensitive than RNS, but less specific.34

In some cases, repetitive CMAP, in which there is a double response to a single stimulus may be noted. In CMS with COLQ mutations, AChE is absent from the endplate potential, increasing the lifetime of ACh in the synaptic cleft and thus, the duration of the endplate potential. As the endplate potential outlasts the absolute refractory period of the muscle fiber, it generates a second action potential, causing a repetitive CMAP that is not affected by edrophonium in the Tensilon test.13 Mutations in a single AChR subunits, in contrast, cause slow-channel CMS (SCCMS) with prolonged endplate currents and endplate potentials.35 Prolonged synaptic potentials exceed the absolute refractory period of the muscle fiber, triggering repetitive action potentials and resulting in Ca2+ accumulation postsynaptically. Physiologically, each prolonged endplate potential arises as a result of the previous endplate potential, leading to progressive depolarization block of the postsynaptic membrane. Increases in CMAP amplitude after 10 to 15 seconds of exercise are also indicative of CMS.

Synaptic transmission is a complex cascade of events that requires fine-tuned expression and function of a number of NMJ components. Usually a genetic diagnosis is made after electrodiagnostic testing and before treatment commences.

Treatment

Therapy for CMS is focused on alleviating symptoms and typically includes pharmacologic treatment, although nonpharmacologic treatment has been reported. Because of the rarity of CMS and the heterogeneity (genotypic and phenotypic), no standardized treatments have been developed. Acetylcholinesterase inhibitors (AChEIs) (eg, pyridostigmine) are the most commonly used drugs for CMS. Although pyridostigmine monotherapy is effective for some individuals, others benefit from combination therapy, often in the form of 3,4-diaminopyridine (3,4-DAP), to achieve an effective and/or sustained response. Alternative drugs, either given alone or in combination with an AChEI and/or 3,4-DAP include albuterol, ephedrine, fluoxetine, and quinidine. Combination therapies have also been used as a first-line option, particularly in cases where CMS subtypes are known to respond negatively or not at all to AChEI monotherapy (eg, DOK7 mutations) or as second- and third-line options for people with CMS refractory to AChEI treatment (Figure). Table 2 shows treatments found effective for specific genotypes in some studies.

Figure. Treatment algorithm for the most common congenital myasthenic syndromes. Treatment shown for DOK7 can be used for all subtypes associated with the AChR-clustering complex, and in these subtypes, 3,4-DAP should be used only after first- and second-line treatments and with great caution. Other options reported to have benefit are prednisone (CHRNE CMS), neostigmine methyl sulfate (CHAT CMS), amiloride, spironolactone, and theophylline (DOK7 CMS), although the benefit/risk of these treatments is not clear. Abbreviations: 3,4 DAP, 3,4-diaminopyridine; AChR, acetylcholine receptor; ACZ, acetazolamide; ChAT, choline acetyltransferase; CMS, congenital myasthenic syndromes; COLQ, collagen-like tail subunit of asymmetric acetylcholinesterase; DOK7, docking protein 7; N-Glyc, N-glycosylation pathway; SCN4A, sodium channel type 4 subunit alpha; SCS, slow-channel syndrome.

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Figure. Treatment algorithm for the most common congenital myasthenic syndromes. Treatment shown for DOK7 can be used for all subtypes associated with the AChR-clustering complex, and in these subtypes, 3,4-DAP should be used only after first- and second-line treatments and with great caution. Other options reported to have benefit are prednisone (CHRNE CMS), neostigmine methyl sulfate (CHAT CMS), amiloride, spironolactone, and theophylline (DOK7 CMS), although the benefit/risk of these treatments is not clear. Abbreviations: 3,4 DAP, 3,4-diaminopyridine; AChR, acetylcholine receptor; ACZ, acetazolamide; ChAT, choline acetyltransferase; CMS, congenital myasthenic syndromes; COLQ, collagen-like tail subunit of asymmetric acetylcholinesterase; DOK7, docking protein 7; N-Glyc, N-glycosylation pathway; SCN4A, sodium channel type 4 subunit alpha; SCS, slow-channel syndrome.

Acetylcholinesterase Inhibitors

Of the AChEIs, which are the most commonly used first-line treatment for CMS, pyridostigmine is most frequently used, followed by neostigmine and ambenonium. The AChEIs are effective for many forms of CMS including CHRNE and RAPSN and glycosylation defects. For some subtypes, however, AChEIs are ineffective and may worsen symptoms, including mutations in components that act to cluster AChRs at the NMJ (eg, COLQ, COL13A1, LAMB2, DOK7, LRP4, and MUSK). Among rarer forms of CMS (< 1% of CMS), efficacy of AChEIs is not yet known. In people with CMS with infections, AChEIs may be given prophylactically with antibiotics to prevent episodic apnea and respiratory insufficiency.36,37

3,4-Diaminopyridine

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 increase the amount of ACh in the synaptic cleft by prolonging the time calcium channels are open via potassium channel blockade. It is possible that 3,4-DAP also modulates postsynaptic potassium channels, although how this might contribute to improved muscle function is unclear. As an adjunct to pyridostigmine or as stand-alone therapy, 3,4-DAP is generally effective in presynaptic and some postsynaptic CMS or CMS with glycosylation defects. There is no evidence of 3,4-DAP efficacy for synaptic COL13A1 or COLQ mutations.

Albuterol

Albuterol, also known as salbutamol, is a β2 agonist that stimulates intracellular potassium uptake and has been considered a suitable first-line option for CMS known not to respond well to pyridostigmine. Albuterol has been effective for treating synaptic CMS (eg, COL13A1 or COLQ mutations) and postsynaptic CMS (eg, LRP4, MUSK, and DOK7). Albuterol can also be used for the symptomatic management of CMS due to other mutations, even those that are usually responsive to other first-line options. The CMS caused by mutations in genes involved in glycosylation may also respond to albuterol, often in combination with pyridostigmine and/or 3,4-DAP.

Ephedrine

Ephedrine is an alkaloid from the group of phenyl-ethyl-amines that acts as a sympathomimetic agent—an α- and β-adrenergic agonist—that may also enhance the release of norepinephrine. Ephedrine may enhance NMT by stimulating β2-adrenergic receptors and stabilizing NMJ structure.38 Ephedrine is generally well-tolerated and can be used for some CMS subtypes refractory to AChEI treatment and for symptomatic management (eg, COLQ and DOK7). Limited data suggest ephedrine may be effective for CMS due to RAPSN mutations and presynaptic CMS (eg, CHAT and SLC18A) and other synaptic CMS (eg, LAMB2 mutations).

Fluoxetine

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has variable effects in CMS. Fluoxetine blocks muscle and neuronal AChRs in a noncompetitive and voltage-dependent manner and is an accepted first-line treatment for SCCMS. In addition, this author has reported significant improvement in muscle strength with fluoxetine in 12 individuals from 3 different families (unpublished results). Although not used as frequently as other treatments, fluoxetine is often used as first-line treatment for SCCMS in adults or when AChEI are ineffective. Fluoxetine is not always effective for SCCMS, however, and side effects may prohibit use.

Other Treatments

There are a few reports of other treatments, including acetazolamide, amiloride, spironolactone, theophylline, azathioprine, prednisone, and quinidine. Quinidine was given to treat CMS; the others were given after misdiagnoses as MG or for symptomatic treatment. Acetazolamide is a diuretic reversible carbonic anhydrase inhibitor that reduces hydrogen ion secretion at the renal tubule and increases renal secretion of sodium, potassium, bicarbonate, and water. In a small case series, 1 person with a RAPSN mutation and 1 with a SCN4A mutation responded positively to acetazolamide after being misdiagnosed with MG.38 In another case study, a person initially diagnosed with MG who had CHRNE mutations, had a moderate positive response to combination therapy with prednisone and azathioprine, which are both generally used to treat MG. In other case reports, however, 2 people treated with prednisone and pyridostigmine did not respond well,39 and 1 person with DOK7 mutations treated with azathioprine, prednisone, and pyridostigmine did not respond positively.40

In a case study, a person with a DOK7 mutation treated with amiloride and spironolactone to correct serum potassium level and theophylline to treat possible asthma had complete recovery (ie, no lower limb deficit, running with ease, no ptosis, dysphagia, or phonation difficulties. This was in contrast to ineffective or partially effective treatment with pyridostigmine, corticosteroids, immunoglobulins, and 3,4-DAP.41

Quinidine, a long-lasting open-channel AChR blocker that increases action potential duration, has been used to successfully treat SCCMS.42,43 Quinidine is a stereoisomer of quinine that acts as a class I antiarrhythmic and is preferentially used to treat SCCMS in children and adolescents as an alternative to fluoxetine, which has been associated with psychiatric side effects (eg, suicidal thinking during titration).3,39 Although quinidine is well-tolerated and has been used as first- or second-line treatment in people with AChR gene mutations, it does not consistently have a positive effect.39

Noninvasive, nonpharmacologic treatments include physical therapy, speech therapy, and occupational therapy.12 For people with reduced or absent ambulation, orthoses, walkers, and wheelchairs may be helpful. For those with respiratory insufficiency, nasal intermittent positive pressure ventilation (NIPPV) may be used either constantly or at night only.44-47 Invasive, nonpharmacologic treatments for CMS are also available for various symptoms. For dysphagia and feeding difficulties, a percutaneous endoscopic gastrostomy may be needed. For respiratory insufficiency in which NIPPV is not possible, intubation and mechanical ventilation may be required. Deformities or malformations (eg, scoliosis or foot deformities) may also require corrective surgical procedures.

Discussion and Conclusions

Diagnosis and management of CMS have evolved from clinical observation, to EMG assessments investigating subcellular mechanisms of impaired NMT, to genetic assessment pinpointing specific gene mutations. First-line therapy for CMS is typically pyridostigmine, which has been shown effective for symptom management for many. In those with synaptic CMS or with DOK7, LRP4, or MUSK mutations, however, pyridostigmine is ineffective and alternative first-line therapies, usually albuterol, are used. Albuterol may also be combined with pyridostigmine and 3,4-DAP, proving effective in some people with glycosylation defects. Ephedrine has been reserved for CMS refractory to traditional AChEI treatment, but ephedrine has demonstrated more variable responses compared with other options. There are a few reports of efficacy of fluoxetine and quinidine as first-line treatment for SCCMS in adults, for which AChEI are ineffective, but further study is needed. Appropriate and effective treatment options are not yet established for the rarer forms of CMS, with some gene mutations reported thus far in only 1 or a small number of patients (eg, SLC5A7, SNAP25, SYT2, SCN4A, and SLC25A1).

The majority of studies are of small cohorts or single cases, attributable to the rarity of CMS and the heterogeneity of the population. This heterogeneity has also resulted in a lack of standardization of treatment. The more we understand the gene functions underlying CMS, the greater are the chances of identifying novel treatments for this rare disorder.

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SPJI reports that he is the vice president of clinical affairs for Catalyst Pharmaceuticals.