Congenital Myasthenic Syndrome (CMS)


Fact: CMS is inherited and there is no cure.

What is it?
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. Facial muscles, including muscles that control the eyelids, muscles that move the eyes, and muscles used for chewing and swallowing, are most commonly affected. However, any of the muscles used for movement (skeletal muscles) can be affected in this condition. Due to muscle weakness, affected infants may have feeding difficulties. 
Development of motor skills such as crawling or walking may be delayed. The severity of the myasthenia varies greatly, with some people experiencing minor weakness and others having such severe weakness that they are unable to walk.
Some individuals have episodes of breathing problems that may be triggered by fevers or infection. Severely affected individuals may also experience short pauses in breathing (apnea) that can lead to a bluish appearance of the skin or lips (cyanosis).

The difference between CMS and myasthenia gravis (MG)
When most people talk about myasthenia, they are referring to myasthenia gravis, which is the most common type of myasthenia caused by the body’s immune system attacking healthy tissue. MG is an autoimmune condition and is treated with steroids, immunosuppressive drugs and sometimes a thymectomy (surgical removal of the thymus gland).
CMS, on the other hand, is a group of genetic conditions where the genes are defected from conception. They do NOT respond to steroids or a thymectomy. Other certain treatments which are suitable for MG, should be avoided in people with CMS.

What are the different types of CMS?
There are lots of different types of CMS caused by errors in genes, some of which we understand whilst others are still unknown.

Presynaptic CMS (nerve side of the junction)
Presynaptic CMS is the least common type of CMS. This is where a problem occurs in the nerve-ending.

Postsynaptic CMS (muscle side of the junction)
Postsynaptic CMS is the most common type of CMS. This is where a problem occurs on the muscle side. There are many types of postsynaptic CMS.

Fast-channel CMS occurs when the AChRs don't stay open long enough.

Slow-channel CMS occurs when the AChRs stay open for too long.

AChR deficiency means that there aren't enough AChRs for the process to work correctly.

Inadequate clustering of AChRs can be caused by deficiencies in proteins including RAPSYN and DOK-7.

Disorders of glycosylation involves the adding to sugars to modify the shape and function of proteins. These are also thought to be involved with inadequate clustering.

Synaptic CMS (the gap between the muscle and the nerve)
Synaptic CMS occurs when the problem is at the gap between the muscle and the nerve.

What are the symptoms of CMS?
Symptoms of CMS vary from person to person and fluctuate throughout the day and they can also overlap with other muscular disorders, although people with CMS may notice the following:
Babies

  • Decreased movements of the baby inside the mother's womb before birth
  • Weak suck and cry
  • Reduced movements
  • Difficulties in feeding and swallowing
  • Breathing difficulties

Children and adults

  • Late walking
  • May struggle with sport, exertion or activities of daily living
  • Difficulty performing repetitive movements
  • Frequent chest infections
  • Stiffness in fingers and wrists
  • Droopy eyelids
  • Double vision
  • Tendency to fall easily


How is CMS diagnosed?
A neurologist will make a clinical diagnosis and carry out tests for CMS.
Further tests will be needed to exclude other causes of the symptoms, including a DNA test from a blood sample, and a muscle biopsy to exclude other conditions.
Once a diagnosis has been made, families should be referred to a specialist genetics centre for a full discussion on the diagnosis.

How is CMS inherited?
CMS is a rare and inherited condition caused by mistakes in one or more genes.
CMS is commonly caused by autosomal recessive inheritance. This means that it has been inherited because both parents carry one faulty gene copy and their affected child has inherited one fault from each parent.

This couple will have a 1 in 4 (25%) chance during every pregnancy of having another child with the same syndrome. Children who have inherited an autosomal recessive type of CMS will pass on one copy of the faulty gene of their child. They themselves are unlikely to have affected children, as the chances of their partner also carrying a faulty gene are very small, unless they 
are a blood relative (e.g. first cousin).

Less commonly, CMS is caused by autosomal dominant inheritance. This means that it has been inherited because one parent carries a faulty gene. In autosomal dominant disorders, only transmission of one copy of the faulty gene will cause the disorder even though the matching gene from the other parent is correct. This couple will have a 1 in 2 (50%) chance during every pregnancy of having another child with the same disorder.

Standard Therapies
Treatment
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the CMS overall and that fact that certain subtypes have only been identified in a handful or fewer individuals, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with CMS.

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

Current therapies for CMS include medications known as cholinergic agonists such as pyridostigmine or amifampridine, long-lived open channel blockers of acetylcholine receptor ion channel fluoxetine and quinidine, and adrenergic agonists such as salbutamol and ephedrine.

Investigational Therapies
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

Want to learn more?

The following are organizations and/or websites dedicated to providing information and education surrounding Congenital Myasthenic Syndrome (CMS). These organizations are dedicated to research, education, awareness, and/or support. They are listed in Alphabetical order without any preference or prejudice. Listing these organizations is not a recommendation or referral in any regard for seeking treatment or consultation or support for treatment.

Mayo Clinic
MDA
MyAware

NIH
NORD

Information on this page taken directly from:
MyAware
NIH
NORD