Congenital Myasthenic Syndrome Treatment Heterogeneity Makes Diagnosis and Treatment Challenging
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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- JULY/AUGUST 2019 PRACTICAL NEUROLOGY 67 NEUROMUSCULAR DISORDERS 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