Congenital myasthenic syndromes

Alternate names

CMS; Congenital Myasthenia; Congenital myasthenic syndrome

Definition

Congenital myasthenic syndrome is a group of conditions characterized by muscle weakness (myasthenia) that worsens with physical exertion. The muscle weakness typically begins in early childhood but can also appear in adolescence or adulthood.

Epidemiology

• The prevalence of congenital myasthenic syndrome is unknown. At least 600 families with affected individuals have been described in the scientific literature.
• Some studies suggest that between 2-12 people per 1,000,000 may have CMS.

Cause

• Mutations in many genes can cause congenital myasthenic syndrome.
• Mutations in the CHRNE gene are responsible for more than half of all cases. A large number of cases are also caused by mutations in the RAPSN, CHAT, COLQ, and DOK7 genes.
• All of these genes provide instructions for producing proteins that are involved in the normal function of the neuromuscular junction. The neuromuscular junction is the area between the ends of nerve cells and muscle cells where signals are relayed to trigger muscle movement.

Gene mutations

• Gene mutations lead to changes in proteins that play a role in the function of the neuromuscular junction and disrupt signaling between the ends of nerve cells and muscle cells.
• Disrupted signaling between these cells results in an impaired ability to move skeletal muscles, muscle weakness, and delayed development of motor skills.
• The respiratory problems in congenital myasthenic syndrome result from impaired movement of the muscles of the chest wall and the muscle that separates the abdomen from the chest cavity (the diaphragm).
• Mutations in other genes that provide instructions for proteins involved in neuromuscular signaling have been found to cause some cases of congenital myasthenic syndrome, although these mutations account for only a small number of cases.
• Some people with congenital myasthenic syndrome do not have an identified mutation in any of the genes known to be associated with this condition.

Inheritance

Autosomal recessive inheritance, a 25% chance

• This condition is most commonly inherited in an autosomal recessivepattern, which means both copies of the gene in each cell have mutations.
• The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
• Rarely, this condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
• In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Signs and symptoms

The symptoms of the congenital myasthenic syndromes (CMS) vary by the age at which symptoms begin, type of muscle weakness and severity. 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.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Dysphagia(Poor swallowing)
• Fatigable weakness
• Frontalis muscle weakness(Weakness of forehead muscle)
• Intermittent episodes of respiratory insufficiency due to muscle weakness
• Neck muscle weakness(Floppy neck)
• Poor suck(Poor sucking)
• Proximal muscle weakness(Weakness in muscles of upper arms and upper legs)
• Ptosis(Drooping upper eyelid)
• Sudden episodic apnea

30%-79% of people have these symptoms

• Apneic episodes precipitated by illness, fatigue, stress
• Arthrogryposis multiplex congenita
• Ataxia
• Bulbar palsy
• Central sleep apnea
• Choking episodes
• Cyanosis(Blue discoloration of the skin)
• Decreased fetal movement(Less than 10 fetal movements in 12 hours)
• Difficulty walking(Difficulty in walking)
• Easy fatigability
• EMG: impaired neuromuscular transmission
• Episodic respiratory distress(Episodic difficulty breathing)
• Generalized muscle weakness
• Intellectual disability(Mental deficiency)
• Muscle fiber atrophy(Muscle fiber degeneration)
• Nasal regurgitation
• Nasal speech(Nasal voice)
• Ophthalmoplegia(Eye muscle paralysis)
• Recurrent respiratory infections(Frequent respiratory infections)
• Spinal deformities

Diagnosis

Congenital myasthenic syndromes are diagnosed based on clinical examination, symptoms, specialized testing on the muscles and nerves (electrodiagnostic testing) and genetic testing. 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 :

• Pulmonary function test
• Sleep study
• Muscle biopsy

Treatment

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:

• 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.

Prognosis

• Congenital myasthenic syndromes are rare and therefore, the long-term outcome is not well known.
• 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 .

NIH genetic and rare disease info

• NIH info on Congenital myasthenic syndromes

Congenital myasthenic syndromes is a rare disease.

Congenital myasthenic syndromes Resources
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