Congenital myasthenic syndrome (CMS)

What is congenital myasthenic syndrome (CMS)?

Congenital myasthenic syndrome (CMS) is a group of rare genetic disorders that disrupt communication between nerves and muscles, resulting in muscle weakness and fatigue. CMS affects voluntary muscles, including those controlling movement, speech and breathing.

CMS differs from autoimmune conditions such as myasthenia gravis, even though both affect muscles.

Signs and symptoms of CMS

Depending on the type, CMS symptoms vary from mild to severe. Symptoms include:

• fatigue
• droopy eyelids and poor control of eye movements
• difficulty with chewing and swallowing
• slurred or nasal speech
• muscle weakness in the face, neck and limbs that worsens with physical activity
• delayed motor skills such as crawling or walking in infants
• respiratory issues, including obstructive sleep apnea and shortness of breath, that worsen with respiratory viruses
• skeletal deformities, such as spine or joint deformities

Symptoms can vary greatly from person to person. Not all symptoms will be present in each person, nor will they be experienced in the same way.

CMS is caused by genetic mutations that affect the neuromuscular junction. This is where nerve cells communicate with muscle cells. These mutations affect the production, release or reception of acetylcholine (a neurotransmitter that triggers muscle contraction). The specific gene mutation determines the type and severity of CMS.

Types of neuromuscular junction defects

• Presynaptic defects: Mutations affect the nerve ending. This leads to reduced production or release of acetylcholine. This limits the nerve’s ability to send signals to the muscle.
• Synaptic defects: Mutations disrupt the synaptic space (the gap between nerve and muscle). This makes it difficult for acetylcholine to travel across the gap to reach the muscle.
• Postsynaptic defects: Mutations that affect the surface of the muscle. This affects proper signal reception, reducing the muscle’s response to nerve signals. This is the most common defect in CMS.

Inheritance patterns

CMS is most often inherited in an autosomal recessive pattern. This is where both parents carry a copy of the mutated gene but do not typically show symptoms.

In some cases, CMS can be autosomal dominant, needing only one parent to pass on the mutation.

Rarely, a mutation may occur spontaneously and is not inherited.

CMS is a lifelong condition with symptoms that often worsen with activity or illness but may improve with treatment. Some people may require lifelong medication, while others might see improvements over time with supportive care. Identifying the specific genetic cause is crucial for understanding the condition's progression and selecting targeted treatments.

Diagnosis of CMS

Diagnosing CMS involves several steps to distinguish it from other similar neuromuscular disorders, such as myasthenia gravis (MG), and to confirm the specific type of CMS:

Physical examination and history: A health-care provider will conduct a thorough physical exam to assess muscle strength and fatigue patterns. To observe signs of muscle fatigue, patients may be asked to perform tasks such as looking up without blinking, holding their arms out or climbing stairs.

Electrodiagnostic testing: Electrodiagnostic tests, such as electromyography (EMG) and repetitive nerve stimulation (RNS), are often performed next. Surface electrodes measure muscle responses to small electrical impulses, helping to identify nerve or muscle problems.

Genetic testing: Genetic testing is critical to confirm CMS and identify the specific mutation, which is needed for targeted treatment and understanding the inheritance pattern.

Treatment of CMS

There is no cure for CMS, but treatment aims to manage symptoms and improve muscle function:

• Medications: While medications do not cure CMS, they can help improve muscle strength and contraction, easing symptoms for some people. How well certain medications work varies based on the type of CMS, so genetic testing is often recommended to guide treatment choices. Some common medications used to manage CMS include:
  • Pyridostigmine
  • Albuterol
  • 3,4-diaminopyridine (3,4-DAP)
  • Ephedrine
  • Fluoxetine
  • Neostigmine
• Supportive therapies:
  • Physical therapy is used to help maintain mobility.
  • Speech therapy is used to help with for speech issues.
  • Occupational therapy is used to help with daily tasks.
• Respiratory and feeding support: Breathing devices and feeding tubes may be recommended in severe cases.
• Surgery: Corrective surgery may be necessary for severe orthopedic issues such as scoliosis or joint contractures.

Complications of CMS

• Respiratory complications: Breathing issues, particularly during sleep or with any respiratory illness.
• Orthopedic issues: Includes scoliosis, joint deformities and foot abnormalities due to muscle weakness.
• Nutritional challenges: Swallowing difficulties may require special feeding techniques or the placement of a feeding tube either permanently or temporarily

It is important that CMS not be confused with myasthenia gravis or congenital myasthenia gravis as these are different diseases and are managed differently.

Genetic counselling

Genetic counselling can be a valuable resource for families. A genetic counsellor can provide support by explaining test results and helping families understand the implications of a CMS diagnosis. They can also discuss prenatal testing options if there is a family history of CMS or if a family member has tested positive for a CMS-related mutation. Genetic counselling can be especially useful in planning for future family decisions and managing the impact of CMS on family life.

Support

Connecting with others who have experience with CMS can provide a strong support network for families. Psychological counselling or participation in support groups can be beneficial both before and after a diagnosis, offering emotional support for children with CMS and their families. These resources help families navigate the challenges of CMS and provide a space for shared experiences and guidance.

Regular follow-up is recommended to monitor symptoms, address complications and update care plans.

Take your child to the nearest emergency department

For children with CMS, certain symptoms may indicate a need for urgent medical attention. Take your child to the emergency department if they experience:

• sudden shortness of breath
• rapid or shallow breathing
• pauses in breathing
• any signs of respiratory distress

At SickKids

SickKids has a specialized neuromuscular clinic that focuses on congenital myasthenic syndrome (CMS) and similar conditions. Located within the neurology department, the clinic is staffed by a neurologist, nurse practitioner, and experienced technicians who are dedicated to caring for children with CMS. Our clinic visits range from simple follow-ups to more specialized procedures, such as nerve conduction studies and electromyography. Additionally, we offer access to a professional social worker who can provide support for both you and your child and connect you with relevant support groups if needed. You are not alone in this journey!

https://www.sickkids.ca/en/care-services/clinical-departments/neurology/neuromuscular-program/

Resources

Muscular Dystrophy Association
mda.org

National Organization for Rare Disorders (NORD)
rarediseases.org

References

Abicht A., Müller J.S., & Lochmüller H. (2021). Congenital Myasthenic Syndromes Overview. In M.P. Adam, S. Bick, G.M. Mirzaa, R.A. Pagon, S.E. Wallace, & A. Amemiya (Eds.), GeneReviews [Internet]. University of Washington. https://www.ncbi.nlm.nih.gov/books/NBK1168/

Finsterer J. (2019). Congenital myasthenic syndromes. Orphanet Journal of Rare Diseases. 14(1),57. https://doi.org/10.1186/s13023-019-1025-5