Congenital Myasthenic Syndromes
Congenital myasthenic syndromes (CMS) result from a variety of mutations affecting the neuromuscular junction and are characterized by fatigability and weakness of different muscle groups, commonly including the ocular muscles. CMS is diagnosed via a combination of clinical findings and genetic testing. Pharmacologic treatment is primarily aimed at symptomatic management.
ICD-10-CM code: G70.2
Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders resulting from mutations that affect structures at the neuromuscular junction (NMJ). The prevalence has been estimated at 9.2 per million children (under 18 years old), however there are concerns that figure is under-reported, as some cases are clinically challenging and may be misdiagnosed. There is no known gender predilection. Characteristic features are fatigue and transient or permanent ocular, facial, bulbar, or limb muscle weakness with onset at birth or childhood, however the condition can also present during adolescence or adulthood. CMS differs from acquired myasthenia gravis in that it is not antibody mediated, and therefore immunosuppression is not indicated in the treatment of CMS.
CMS is caused by a wide variety of inherited or de novo mutations in over 30 identified genes affecting presynaptic, synaptic, and postsynaptic components of the NMJ.
The main risk factor for CMS is having a positive family history, but most CMS-associated mutations are inherited in an autosomal recessive pattern and a family history may not be identified. As with all autosomal recessive conditions, the child of two carrier parents with the CMS gene has a 25% chance of having CMS. In contrast, a child has a 50% chance of receiving a CMS-associated mutation that is inherited in an autosomal dominant fashion from an affected parent. X-linked and mitochondrial mutations have not been described in CMS, although some mutations have an unknown inheritance pattern.
Normal neuromuscular transmission involves presynaptic, synaptic, and post synaptic transmission, and CMS can involve pathologies in all three of these components, as well as abnormalities in glycosylation proteins. Pathophysiological mechanisms of CMS involving presynaptic elements include defects in acetylcholine synthesis and acetyltransferase and vesicular transport. Synaptic mechanisms include defects in synaptic vesicles exocytosis. Postsynaptic mechanisms include deficiency in agrin and defects in acetylcholine receptor function, ion channel function, and extracellular matrix proteins that help form motor endplates. Congenital defects in glycosylation, mitochondrial disorders, and congenital myopathies with secondary impairment of neuromuscular transmission can also cause subtypes of CMS. The most common of the 32 genes associated with CMS are CHAT, CHRNE, COLQ, DOK7, GFPT1, and RAPSN. 
If CMS-related mutations are known in a family member, prenatal genetic counseling is recommended, and prenatal tests and preimplantation genetic testing can be conducted.
The diagnosis of CMS is established with characteristic findings on clinical exam, neurophysiological studies, serum studies, poor or good response to acetylcholinesterase inhibitors and immunosuppressive therapeutics, muscle biopsy, and family history in combination with identification of one or more mutations known to be associated with the condition. There are no diagnostic criteria for probable CMS in patients without a genetic mutation.
As in acquired MG, CMS patients tend to present with fatigable ocular (ptosis, diplopia, ophthalmoplegia), bulbar (dysphagia, dysarthria), or limb weakness usually at or near birth. Some patients who appear to have a ‘late’ presentation of CMS in adulthood may have had mild symptoms for which medical attention was not required, or were previously misdiagnosed. A family history of CMS may or may not be present due to a predominantly recessive mode of inheritance.
Physical exam should focus on characterizing weakness of the muscles likely to be affected, including extraocular, bulbar, and limb muscles. A fluctuating pattern of weakness may cause exam to appear normal, especially after a resting period. However, special attention should be paid to the assessment of muscle fatigability, which is the hallmark characteristic of CMS on exam.
Ocular findings are generally seen in CMS, but some CMS subtypes can spare the eye muscles. Fatigable ptosis is the most common ophthalmic sign and is most frequently bilateral. Ophthalmoplegia is also common and typically does not match to a specific cranial nerve distribution given the pathology is NMJ mediated. Signs of bulbar weakness include dysarthria and dysphagia. Axial weakness can manifest as a head drop or a “bent spine” from camptocormia (abnormal thoracolumbar spinal flexion). Neonatal-onset CMS can present with respiratory insufficiency, apnea, cyanosis, weak suck and cry, choking, and arthrogryposis multiplex congenita. Infant stridor can also be a sign of CMS. Facial dysmorphism and skeletal abnormalities can be seen with some subtypes, but cognitive impairment is rarely associated with CMS.
Fatigue is a prominent symptom in CMS. Patients with CMS in late childhood or adulthood may complain of inadequate ability to perform daily activities, such as difficulty with running, climbing stairs, brushing one’s hair, or lifting a glass of water.
CMS should be suspected if a patient has easily fatigable or persistent weakness in ocular, facial, bulbar, limb, axial, or respiratory muscles, especially when onset is at birth or in childhood. Different genetic mutations can have more typical associated features and presentations (including some more affecting limb muscles and some more affecting eye muscles), the details of which are outside the context of this article.
Low- and high-frequency repetitive nerve stimulation (RNS) electrophysiological tests can be used to support a diagnosis of CMS. Low-frequency (2-3 Hz) RNS often reveals a decremental compound muscle action potential (CMAP) response greater than 10%. Typically, limb muscles will be tested first, and if a normal response is seen in two limb muscles, then the facial muscles may be tested. When RNS remains normal in suspected cases of CMS, muscle contractions or exercise before testing or 10 Hz stimulation 5-10 minutes prior to electrophysiological testing can be performed to further assess for abnormalities. Alternatively, single fiber electromyography (EMG) testing may reveal increased jitter or increased block. Similar to adult myasthenia gravis, consideration of edrophonium can be administered intravenously (Tensilon ® test) or pyridostigmine as a trial for symptomatic improvement can be given in accordance with proper protocols. These medications when trialled are given as a high dose, and appropriate monitoring for adverse events in a monitored environment, typically with atropine available in case of bradycardia, is recommended. It is important to note that some subtypes of CMS may be worsened with the administration of acetylcholinesterase inhibitors. Whilst non responsiveness to these medications doesn’t exclude the diagnosis, responsiveness to these medication trials may be supportive of the diagnosis of MG. Skeletal muscle biopsy results are often normal. Given the relatively low prevalence of CMS, workup for other diagnoses is also recommended.
Serum anti-acetylcholine receptor and anti-MuSK antibodies are negative in CMS because it is not an antibody-mediated disease. Creatine kinase can be mildly elevated and is suggestive of endplate myopathy.
Single gene testing, multigene panel testing, or genomic sequencing can be used to identify genetic mutations of CMS. Single gene testing may be performed when a particular mutation is highly suspected based on the phenotypic presentation or the patient’s ethnic origin, or if there is a family member with a known mutation. However, multi-gene panels are increasingly used as first-line tests due to phenotypic heterogeneity, easier availability and choice, and as well as increased identification of pathogenic mutations. Whole exome or genome sequencing can be considered when a mutation is not detected via the multigene panel testing.
The presentation of CMS often resembles acquired myasthenia gravis. Both conditions involve fatigable ocular, bulbar, and limb muscle weakness. CMS usually presents at or near birth while the onset of myasthenia gravis tends to occur during adulthood. However, CMS can also present later in childhood or during adulthood, and some types of myasthenia gravis, such as seronegative autoimmune myasthenia gravis, juvenile myasthenia gravis, and transient neonatal myasthenia gravis, present at birth or during childhood. The most common ocular features in both conditions are ptosis, most often bilateral, and extraocular movement limitation. Strabismus and amblyopia are more likely to be seen in juvenile myasthenia gravis compared to CMS. In addition, CMS does not respond to immunosuppressive therapy, while antibody-mediated, acquired myasthenia gravis typically does respond due to the underlying difference in their etiology (genetic vs. antibody mediated).
Other differential diagnoses of CMS in adults include Kennedy disease, limb girdle muscular dystrophy, mitochondrial disorders, and hereditary neuropathies. Differential diagnoses in infants and children include spinal muscular atrophy, congenital myotonic dystrophy-1, mitochondrial disorders, and botulism. Consideration of these conditions will also affect the workup the patient undergoes.
There are no standardized treatment guidelines for CMS. The rarity of the disease makes it challenging to conduct adequately powered double-blind, placebo-controlled clinical trials. Current treatments aim to improve symptoms, but dosing, duration, treatment combinations, and side effects tend to be poorly specified.
Genetic subtyping should be conducted to inform medical treatment. Non-medical treatment options, such as physical therapy, occupational therapy, speech therapy, orthotics, or non-invasive positive pressure ventilation should also be considered based on a patient’s particular symptoms to optimise their function.
Different subtypes of CMS are likely to have different response to medications, due to the underlying pathology of the disorder. The most common medications taken for CMS are acetylcholinesterase inhibitors, and 3,4-diaminopyridine (3,4-DAP), a potassium channel blocker, is the most common alternative or added pharmacologic treatment. Most patients have a partial beneficial response to one or both medications. However, acetylcholinesterase inhibitors tend to be ineffective in patients with CMS mutations in COLQ, LAMB2, DOK7, MUSK, or LRP4. 3,4-DAP can be ineffective with CHRNE or MUSK mutations. Other medications that may be used to manage symptoms include salbutamol, albuterol, ephedrine, and fluoxetine, depending on the specific CMS subtype.
Medical follow up
Side effects of medications should be monitored carefully. Some medications may exacerbate weakness and precipitate respiratory failure.
Patients with CMS are likely to require regular lifelong follow up to monitor for extent and progression of symptoms as well as efficacy of therapy. Muscle strength and respiratory function should be routinely assessed.
Stressors, such as fever, infection, or strong emotions, may exacerbate weakness and even provoke respiratory insufficiency. Patients with mutations most associated with these risks require prophylaxis with anticholinesterase medication.
The prognosis is highly variable among CMS subtypes. Severity can range from mild weakness to being wheelchair-bound and requiring ventilatory support. In some patients, CMS symptoms can improve with age.
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