Congenital myastenic syndrome (CMS)
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Congenital myasthenia is an inherited condition that typically emerges at or shortly after birth, or during early childhood. It involves muscle weakness and fatigue due to issues with the release and reception of neurotransmitters, which are chemicals that transmit signals between nerve cells and muscles.
There are different types of congenital myasthenia, each linked to specific gene mutations, and symptoms can vary depending on the type and age of onset:
- In babies: Infants affected by congenital myasthenia often struggle with muscle control and may experience challenges in achieving developmental milestones such as rolling over or sitting up.
- In older children: This condition manifests as weakness during physical activities. Additionally, they may encounter issues like drooping eyelids, a “lazy eye,” or double vision (diplopia), along with difficulties related to speech and swallowing.
Types of Congenital Myasthenia Syndromes (CMS) include:
- Presynaptic CMS: This involves inadequate release of acetylcholine (ACh), a crucial chemical for muscle function. It often presents as CMS with episodic apnea (CMS–EA), which begins in infancy and causes weakness in facial muscles, as well as those used for swallowing and speech. It can also lead to temporary breathing difficulties.
- Postsynaptic CMS — ACh receptor deficiency (Fast–Channel CMS): This is caused by missing or short–lived ACh receptors. In infants, it may result in severe weakness, feeding and breathing problems, and delayed motor development (sitting, crawling, walking). In childhood and adulthood, it may cause drooping eyelids and fatigue but usually doesn’t significantly hinder daily activities.
- Postsynaptic CMS — slow–channel CMS: This occurs when ACh receptors remain open for extended periods. Infant–onset cases can lead to severe weakness, potentially causing mobility loss and breathing issues in adolescence. Adult–onset cases are typically less disabling.
- Synaptic CMS: This arises from a deficiency of acetylcholinesterase, an enzyme that breaks down ACh. It results in severe weakness, feeding and breathing difficulties from birth or early childhood. Weakness can delay motor milestones and may lead to reduced mobility and scoliosis (spine curvature).
Congenital myasthenia typically worsens with activity and improves with rest. Treatment involves medications to enhance nerve–muscle communication.
Symptoms
Symptoms of CMS vary in severity depending on the specific type but typically include weakness, fatigue, and ptosis (droopy eyelids). Generally, the earlier CMS begins, the more severe the symptoms tend to be.
Causes
Congenital myasthenic syndrome (CMS) results from gene mutations, primarily in CHRNE, RAPSN, CHAT, COLQ, and DOK7 genes. These genes control proteins crucial for neuromuscular junction function, affecting muscle movement signaling. Mutations lead to muscle weakness and developmental motor delays, including respiratory muscle issues. A few CMS cases involve less–known genes, and some remain genetically unexplained.
Diagnosis
If such symptoms are present, consult a neurologist. They will ask questions and perform a physical exam to assess the extent of weakness. To check for increased weakness with exertion, patients may be asked to perform tasks like sustaining an upward gaze, holding out their arms, or climbing steps.
- Blood test: To check for Myasthenia Gravis (MG), a blood test can detect antibodies to the ACh receptor. A negative result can suggest CMS, but not always.
- Electrodiagnostic testing: Electrodes are used to measure muscle electrical signals. Surface electrodes deliver small nerve shocks, and others record muscle responses. This helps assess muscle function.
- Edrophonium test: In some cases, the neurologist may administer an intravenous injection of edrophonium. A temporary strength increase following this test is indicative of CMS.
- Family history: While a family history of myasthenic symptoms supports a CMS diagnosis, it’s not always present. Genetic and muscle tissue tests may be required for some CMS types to provide a definitive diagnosis.
- Genetic test: In cases where a conclusive genetic diagnosis is needed, further testing may be required.
Treatment
Cholinesterase inhibitors, which are commonly used to manage myasthenia gravis (MG), offer benefits in specific cases of congenital myasthenic syndrome (CMS) but can pose risks in others. It’s crucial to understand that CMS, unlike autoimmune conditions, does not react to therapies targeting the immune system, such as immunosuppressant drugs.
Cholinesterase Inhibitors:
Anticholinesterase drugs, also called cholinesterase inhibitors, have been used to treat myasthenia gravis (MG). They provide rapid relief from symptoms, with pyridostigmine (Mestinon) being the most common option.
These drugs increase acetylcholine (ACh) levels, a crucial chemical for proper muscle function, not only at the neuromuscular junction but also in the autonomic nervous system, which controls involuntary bodily functions. Occasionally, they can cause diarrhea, abdominal cramps, or excessive saliva. To mitigate these side effects, the doctor may lower the dose or prescribe atropine, which blocks ACh receptors on nerve cells.
Cholinesterase inhibitors are effective for:
- Presynaptic CMS
- Postsynaptic CMS with ACh receptor deficiency (fast–channel CMS). In addition to cholinesterase inhibitors, amifampridine–containing drugs are used to enhance ACh release.
Cholinesterase inhibitors do not work for:
- Postsynaptic CMS with slow–channel CMS. Quinidine or fluoxetine is used to block ACh receptors.
- Synaptic CMS. Unfortunately, there are currently no drug treatments available for this type of CMS.
