Congenital (hereditary) myasthenic syndrome (CMS) is a group of conditions characterised by fatigable muscle weakness, caused by an inherited disorder affecting the junction between the nerve and the muscle. The muscle weakness typically begins in early childhood but can also appear in adolescence or adulthood.          

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. 

Treatments for CMS

Autosomal recessive inheritance

CMS Type Affected Genes Treatment
AChR Deficiency - postsynaptic CHRNA1, CHRNB1, CHRND, CHRNE Pyridostigmine, 3,4-DAP, Salbutamol* / Ephedrine*
RAPSYN CMS - postsynaptic RAPSN Pyridostigmine, 3,4-DAP
DOK-7 CMS - postsynaptic DOK7

Salbutamol / Ephedrine, 3,4-DAP

ChAT CMS - presynaptic CHAT Pyridostigmine, Salbutamol*
COLQ CMS - synaptic COLQ Salbutamol / Ephedrine
Fast channel CMS - postsynaptic CHRNA1, CHRNB1, CHRND, CHRNE Pyridostigmine, 3,4-DAP, Salbutamol / Ephedrine*
Disorders of glycosylation - postsynaptic GFPT1, DPAGT1, ALG2 / 14, GMPPB Pyridostigmine, 3,4-DAP, Salbutamol / Ephedrine

*Only suitable in some cases

Autosomal dominant inheritance

CMS Type Affected Genes Treatment
Slow channel CMS - postsynaptic CHRNA1, CHRNB1, CHRND, CHRNE Quinidine, Fluoxetine