Congenital myastenic syndrome (CMS)

Overview 

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.