Congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders caused by genetic mutations affecting the structure or function of the neuromuscular junction (NMJ)1)2). ICD-10-CM code: G70.2.
The prevalence is estimated at 9.2 per 1 million children (under 18 years). Because clinical diagnosis is difficult and misdiagnosis occurs, the actual prevalence may be higher. No known sex difference.
Characteristic signs are easy fatigability and muscle weakness appearing at birth or in childhood, but some cases onset in adolescence or adulthood. CMS is fundamentally different from antibody-mediated acquired myasthenia gravis (MG), and immunosuppressive therapy is not indicated1).
CMS is caused by structural and functional abnormalities of the NMJ due to genetic mutations, and the immune system is not involved. In contrast, acquired MG is an autoimmune disease caused by anti-acetylcholine receptor antibodies, etc. Therefore, immunosuppressive therapy effective for MG is ineffective for CMS.
Fatigue is the most prominent symptom in CMS.
Ocular symptoms are commonly seen in CMS, but some subtypes may not involve the eye muscles.
Because the pattern of muscle weakness fluctuates, examination findings may appear normal, especially after rest. Careful evaluation is required to assess muscle fatigability.
CMS is caused by mutations in more than 30 genes that affect presynaptic, synaptic cleft, and postsynaptic components of the NMJ. In addition to inherited mutations, sporadic (de novo) mutations also occur.
The six most common genes associated with CMS are as follows:
In addition, congenital defects of glycosylation, mitochondrial diseases, and congenital myopathies with secondary impairment of neuromuscular transmission can also cause CMS subtypes.
The main inheritance patterns of CMS are shown below.
| Inheritance pattern | Probability of disease in child | Notes |
|---|---|---|
| Autosomal recessive | 25% | Most common |
| Autosomal dominant | 50% | Some mutations |
X-linked inheritance and mitochondrial mutations have not been reported in CMS. Most cases are autosomal recessive, so family history is often unclear.
Currently, more than 30 causative genes have been identified, but not all have been elucidated. Even if no genetic mutation is detected, CMS may be suspected based on clinical findings and electrophysiological tests. There are no definitive exclusion diagnostic criteria.
The diagnosis of CMS is established by a comprehensive evaluation of clinical findings, neurophysiological tests, serological tests, drug response, muscle biopsy, family history, and genetic testing.
Repetitive Nerve Stimulation
Low-frequency RNS (2-3 Hz): A decremental response of the compound muscle action potential (CMAP) exceeding 10% is observed.
Procedure: First, examine the limb muscles; if normal in two muscles, then examine the facial muscles.
When RNS is normal: Perform exercise before the test, or administer 10 Hz stimulation 5-10 minutes prior and repeat the test.
Single-Fiber Electromyography
Increased jitter: Reflects instability of neuromuscular junction transmission.
Increased blocking: An indicator for assessing the degree of transmission impairment.
CMS is not an antibody-mediated disease, so the following antibodies are negative.
Evaluate symptom improvement with intravenous edrophonium (Tensilon test) or pyridostigmine administration. Prepare atropine for bradycardia and perform under monitoring.
This is the most important test for confirming the diagnosis of CMS.
Skeletal muscle biopsy results are often normal.
The clinical presentation of CMS is similar to acquired MG, but there are several distinguishing features. In acquired MG, 50–85% of patients present initially with ocular symptoms 3). Ptosis accounts for about 70% and diplopia for about 50% of initial MG symptoms. In the ice pack test (evaluating improvement of ptosis by applying an ice pack to the eyelid), ptosis due to MG improves, but congenital ptosis including CMS does not. Strabismus and amblyopia are more common in juvenile MG than in CMS.
Other differential diagnoses by age are shown below.
CMS is not antibody-mediated, so anti-AChR and anti-MuSK antibodies are both negative. CMS cannot be definitively diagnosed by blood test; genetic testing (e.g., multi-gene panel testing) is required for definitive diagnosis.
There are currently no standardized treatment guidelines for CMS. This is due to the rarity of the disease, which makes it difficult to conduct randomized controlled trials with sufficient power. Treatment is individualized based on identification of the genetic subtype.
Depending on symptoms and functional impairment, combine the following.
First-line drugs
Acetylcholinesterase (AChE) inhibitors: The most commonly used drugs in CMS. They inhibit the breakdown of acetylcholine at the NMJ and improve neuromuscular transmission.
Note: Ineffective in CMS with COLQ, LAMB2, DOK7, MUSK, and LRP4 mutations.
Alternative and additional drugs
3,4-Diaminopyridine (3,4-DAP): A potassium channel blocker. It enhances the release of acetylcholine from presynaptic terminals. It is the most common alternative or add-on medication.
Note: May be ineffective in CHRNE or MUSK mutations.
Most patients show partial benefit from either AChE inhibitors or 3,4-DAP, or both. Depending on the specific subtype, the following medications may also be used.
Stressors such as fever, infection, and strong emotions can worsen muscle weakness and cause respiratory failure. Regularly assess respiratory function with pulmonary function tests, arterial blood gas analysis, and polysomnography.
Prognosis varies greatly depending on the subtype of CMS. It ranges from mild muscle weakness to severe cases requiring wheelchair use or ventilator support. In some patients, symptoms may improve with age.
It is ineffective. The response to medication differs depending on the genetic subtype of CMS. For example, AChE inhibitors are ineffective for CMS with COLQ or DOK7 mutations and may even worsen symptoms. Therefore, identifying the genetic subtype is important for determining the treatment strategy.
In normal neuromuscular transmission, when an action potential reaches the presynaptic terminal, acetylcholine (ACh) is released, diffuses across the synaptic cleft, and binds to acetylcholine receptors (AChR) on striated muscle. This depolarizes the postsynaptic membrane, leading to muscle contraction. In CMS, one or more steps in this transmission process are genetically impaired.
Presynaptic
ACh synthesis disorder: Mutation in the CHAT gene reduces the function of choline acetyltransferase.
Vesicle transport disorder: Filling and transport of ACh into synaptic vesicles are impaired.
Synaptic cleft
Exocytosis disorder: Release of ACh from synaptic vesicles (exocytosis) is impaired.
Cholinesterase abnormality: Mutation in the COLQ gene impairs the anchoring of AChE to the endplate.
Postsynaptic
AChR dysfunction: Mutations in CHRNE and others reduce the function of the AChR itself.
Ion channel dysfunction: In slow-channel syndrome, the AChR channel open time is prolonged.
Endplate formation defect: Mutations in DOK7, RAPSN, and others impair the construction of the motor endplate.
Extraocular muscles are particularly susceptible to damage. The twitch fibers of extraocular muscles require a higher frequency of synaptic firing than limb muscles, making them more vulnerable to NMJ transmission defects. Additionally, the tonic fibers needed for sustained gaze have fewer AChRs and are vulnerable to receptor loss or damage.
Other causes of CMS subtypes include congenital defects in glycosylation (e.g., GFPT1), mitochondrial diseases, and secondary impairment of neuromuscular transmission due to congenital myopathies.
