Congenital Myasthenic Syndrome

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by a primary defect in the transmission of signals from nerve cells to muscles.

These disorders are characterized by muscle weakness that worsens with exertion. The age of onset, severity of symptoms, and distribution of muscle weakness may vary among individual patients. In specific subtypes, a wide range of additional symptoms affecting other organ systems may be present. The severity can range from mild symptoms, such as slight exercise intolerance, to severe, disabling forms. Most CMS are inherited in an autosomal recessive pattern; several specific subtypes are inherited in an autosomal dominant manner. Genetic diagnosis of these disorders is important, as treatment that is beneficial for one type of CMS may worsen another type.

Types of CMS:

•  presynaptic
•  associated with the synaptic basal lamina
•  acetylcholine receptor defects
•  defects in the development and maintenance of endplates
•  congenital disorders of glycosylation
•  other myasthenic syndromes

CMS involve the neuromuscular junction, which is a synapse where signals from motor nerves are transmitted to muscle fibers and instruct them when to contract.

A normal neuromuscular junction consists of a presynaptic region, a synaptic space, and a postsynaptic region. The presynaptic region contains the end of the motor nerve cell, known as the motor nerve terminal. The motor nerve terminal overlies a specialized region of the muscle fiber called the postsynaptic region. The space between the motor nerve terminal and the postsynaptic region is called the synaptic space or synaptic cleft. The postsynaptic region contains multiple folds, known as junctional folds. The motor nerve terminal contains small vesicles filled with the neurotransmitter acetylcholine (ACh), which acts as a chemical “messenger” carrying instructions for muscle contraction.

The process by which motor nerve endings communicate with muscle fibers is highly specialized, and a genetic defect that impairs this communication can result in a congenital myasthenic syndrome. Understanding this process helps in understanding myasthenic disorders.

Diagnosis

Congenital myasthenic syndromes are caused by a change (mutation) in a specific gene, resulting in an abnormal protein or loss of protein. The abnormal protein (disease-causing protein) may be located in the motor nerve terminal or at the synapse.

The general diagnosis of CMS can be established on clinical grounds based on a history of fatigable weakness involving ocular muscles, bulbar muscles (muscles of the face and those used for speech and swallowing), and limb muscles from infancy or early childhood, a history of similarly affected relatives, and various tests. These tests include EMG and negative tests for antibodies against the acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK). However, in many patients with CMS, the family history is negative; in others, onset may be delayed, EMG abnormalities are not present in all muscles or are only intermittent, and weakness may have a limited distribution.

Electromyography (EMG) records electrical activity in skeletal muscles at rest and during contraction. A decremental EMG response is measured by stimulating the motor nerve to the muscle at a rate of 2–3 times per second; the evoked electrical responses from the muscle, known as compound muscle action potentials (CMAPs), are recorded by electrodes placed on the skin over the stimulated muscle. The response is abnormal if the fourth evoked CMAP is more than 10% smaller than the first. Single-fiber EMG is a more sensitive but less specific test for myasthenic disorders. In this test, individual intramuscular nerve fibers are repeatedly stimulated, and action potentials from single muscle fibers are recorded simultaneously from 2 to 4 fibers. Abnormally increased variability in the timing of these action potentials is an early indicator of impaired neuromuscular transmission.

A specific diagnosis of CMS depends on identifying the disease gene and the pathogenic mutations in that gene. Commercially available tests can readily detect mutations in previously identified types of CMS. Mutations in previously unrecognized types can be detected by whole-exome or whole-genome sequencing, although bioinformatic analysis of the results remains challenging.

Genetic diagnosis of CMS is important, as therapy that benefits one type of CMS may worsen another.

Treatment

There are currently no standardized treatment protocols or guidelines. 

Due to the rarity of CMS as a whole and the fact that some subtypes have been identified only in a small number of individuals, no large-scale clinical trials have been conducted. Various therapies have been reported in the medical literature as part of individual case reports or small patient series. Treatment trials would be highly beneficial in determining the long-term safety and effectiveness of specific drugs and therapeutic approaches for individuals with CMS.

As noted above, it is critically important to identify the specific subtype in each individual, as medications that are effective for one type of CMS may be ineffective or even harmful in another. More detailed information on the treatment of specific CMS subtypes is provided in the section “Signs and Symptoms” above for the individual subtypes.

Current therapies for CMS include medications known as cholinergic agonists, such as pyridostigmine or amifampridine (3,4-diaminopyridine), long-acting open-channel blockers such as fluoxetine and quinidine acting on the acetylcholine receptor, and adrenergic agonists such as salbutamol and ephedrine.

• muscle weakness (provoked or worsened by exertion) – so-called fatigable weakness
• sometimes double vision
• facial weakness
• ptosis (drooping of the eyelids)
• sometimes slurred or unclear speech
• difficulty swallowing
• occasional weakness of limb and trunk muscles
• in some cases, developmental delay, epileptic seizures, varying degrees of intellectual disability, or other metabolic abnormalities of different organs