Congenital myasthenic syndromes

The symptoms of the congenital myasthenic syndromes (CMS) vary by the age at which symptoms begin, type of muscle weakness and severity.^[2][3][4] All subtypes involve muscle fatigue and weakness that usually begins at an early age. The most common symptoms of CMS include:

• Muscle weakness that is brought on by activity or exercise
• Eyelid drooping which can come and go
• Facial and throat muscle weakness
• Delay of motor development

Many subtypes of CMS have specific symptoms that help identify them. For example, muscle weakness in the limbs and torso is most often seen in the COLQ, DOK7, and GFPT1 subtypes, and difficulty breathing is seen most often in the CHRNE and CHAT subtypes.^[3][4] 

Congenital myasthenic syndromes are caused by genetic changes in at least 32 genes.  Each gene is associated with a different subtype. The most common genes involved are CHAT, COLQ, RAPSN, CHRNE, DOK7, and GFPT1. Many of the other genes that cause CMS are found in only a few families or individuals.^[3] 

Most subtypes of CMS are inherited in an autosomal recessive manner, including the ones caused by the CHAT, COLQ, RAPSN, CHRNE, DOK7, and GFPT1 genes. A few subtypes are inherited in an autosomal dominant manner.^[1][3]

All individuals inherit two copies of each gene. To have an autosomal recessive condition, a person must have a mutation in both copies of the responsible gene in each cell. People with an autosomal recessive condition inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive disorder typically do not have any signs or symptoms (they are unaffected). When two carriers of an autosomal recessive condition have children, each child has a:

• 25% (1 in 4) chance to have the disorder
• 50% (1 in 2) chance to be an unaffected carrier like each parent
• 25% (1 in 4) chance to be unaffected and not be a carrier

To have an autosomal dominant condition, a person must have a mutation in just one copy of the responsible gene in each cell. The mutation can be inherited from either parent. Some people are born with an autosomal dominant condition due to a new genetic mutation (de novo) and do not have a history of this condition in their family.

Each child of an individual with an autosomal dominant condition has a 50% or 1 in 2 chance of inheriting the mutation and the condition. Offspring who inherit the mutation will have the condition, although they could be more or less severely affected than their parent. Sometimes a person may have a gene mutation for an autosomal dominant condition and show few or no signs or symptoms of the condition. 

Congenital myasthenic syndromes are diagnosed based on clinical examination, symptoms, specialized testing on the muscles and nerves (electrodiagnostic testing) and genetic testing.^[1][2][3] Other diagnostic tests that might be used include:

• Electromyography (EMG) and repetitive nerve stimulation (RNS) tests – which check the health of muscles and nerves 
• Blood testing for antibodies related to muscle disease
• Genetic testing for a gene change associated with CMS

Other testing might include ^[3]:

• Pulmonary function test 
• Sleep study 
• Muscle biopsy

There is no single treatment for congenital myasthenic syndromes. Treatment is based on the symptoms and may be determined by the specific subtype. Medications that have been used to treat CMS include:^[1][3]

• AChE inhibitors
• Potassium channel blockers
• Ephedrine (used for COLQ- and DOK7-associated CMS)
• Albuterol (used for COLQ- and DOK7-associated CMS)
• Others

The response to medication is different from person to person. Genetic diagnosis of the specific sub-type of CMS is important because a medication that benefits one type of CMS can make another type worse.^[3]

Specialists that may be involved in the care of people with CMS include:^[1][3]

• Neurologist
• Pulmonologist
• Physical therapist and occupational therapist
• Speech therapist

Congenital myasthenic syndromes are rare and therefore, the long-term outcome is not well known.^[4] Symptoms may range from minor muscle weakness to severe weakness that makes it difficult to walk. The severity and change in symptoms over time is different between subtypes and can vary from person to person. In some, symptoms are brought on or made worse by fever, infections, or stress ^[3].

The exact number of people with congenital myasthenic syndromes is unknown. Some studies suggest that between 2-12 people per 1,000,000 may have CMS.^[5]