Congenital myasthenic syndrome

Overview

Congenital Myasthenic Syndrome (CMS) is a group of rare, inherited neuromuscular disorders characterized by impaired communication between nerves and muscles at the neuromuscular junction. Unlike autoimmune myasthenia gravis, CMS is present from birth or early infancy and results from genetic mutations affecting proteins involved in transmitting signals from nerve endings to muscles. Individuals with CMS typically experience muscle weakness that worsens with activity (fatigability), affecting mobility, breathing, feeding, and eye movements to varying degrees depending on the subtype.

Causes

CMS is caused by mutations in genes responsible for the development, maintenance, or function of the neuromuscular junction. These genes affect the presynaptic, synaptic, or postsynaptic regions where nerve signals are transmitted to muscle fibers. Known genes associated with CMS include:

• CHRNE: Encodes the epsilon subunit of the acetylcholine receptor

• COLQ: Involved in anchoring acetylcholinesterase at the synapse

• DOK7: Involved in postsynaptic development and maintenance

• RAPSN: Stabilizes acetylcholine receptor clusters

• CHAT: Affects acetylcholine synthesis

CMS is typically inherited in an autosomal recessive pattern, though autosomal dominant and X-linked forms also exist depending on the gene involved.

Symptoms

Symptoms of CMS vary widely depending on the specific genetic mutation, but hallmark features include:

• Muscle weakness: Often worsens with exertion (fatigability)

• Ptosis: Drooping of the upper eyelids, usually bilateral

• Ophthalmoparesis: Weakness of eye muscles, sometimes causing limited eye movement

• Bulbar symptoms: Difficulty in swallowing, chewing, or speaking

• Facial weakness: Reduced facial expressions or difficulty smiling

• Hypotonia: Low muscle tone, especially in infants

• Feeding difficulties: In infancy or early childhood

• Respiratory insufficiency: Can occur in more severe forms

• Delayed motor milestones: Crawling, sitting, or walking may be affected

In some cases, symptoms may remain stable; in others, they can worsen over time or with infections, stress, or certain medications.

Diagnosis

Diagnosis of CMS involves a combination of clinical evaluation, electrophysiological testing, and genetic analysis. Diagnostic steps include:

• Clinical history and physical exam: To assess muscle weakness, fatigability, and family history

• Electromyography (EMG): Repetitive nerve stimulation may show a decremental response typical of neuromuscular junction disorders

• Single-fiber EMG: Measures neuromuscular jitter and blocking

• Genetic testing: Next-generation sequencing panels help identify causative gene mutations

• Acetylcholine receptor antibody testing: Usually negative, helping to differentiate CMS from autoimmune myasthenia gravis

• Muscle biopsy (rarely): Used in complex or unclear cases to evaluate muscle structure

Treatment

Treatment of CMS depends on the underlying genetic subtype, as some medications can help certain types and worsen others. A personalized treatment plan is essential. Common treatment approaches include:

• Acetylcholinesterase inhibitors (e.g., pyridostigmine): Increase acetylcholine availability at the neuromuscular junction; helpful in some types

• Beta-2 agonists (e.g., salbutamol or albuterol): Effective in DOK7 and COLQ mutations

• Ephedrine: Used in some cases to improve neuromuscular transmission

• Avoidance of contraindicated drugs: Certain antibiotics, muscle relaxants, and anesthesia agents can worsen CMS symptoms

• Respiratory support: May be needed in severe cases, especially during infections

• Nutritional support: Including feeding tubes if oral intake is unsafe

• Physical and occupational therapy: To maintain strength, flexibility, and motor function

• Genetic counseling: For affected families to understand inheritance and recurrence risks

Prognosis

The prognosis for individuals with Congenital Myasthenic Syndrome varies depending on the genetic cause and severity of symptoms. With early diagnosis and appropriate treatment, many individuals can lead relatively normal lives and experience improved strength and endurance. Some types of CMS respond very well to specific medications, while others may cause significant disability. Lifelong monitoring, therapy, and supportive care can greatly enhance quality of life and functional independence.