Congenital myasthenic syndrome (CMS)

What is congenital myasthenic syndrome?

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.

Is CMS the same as myasthenia gravis (MG)?

No. When most people talk about myasthenia, they mean myasthenia gravis, a more common condition which is 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. Certain other treatments which are suitable for MG, should be avoided in people with CMS.

How is CMS inherited?

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 condition. Children who have inherited an autosomal recessive type of CMS will pass on one copy of the faulty gene to their child. They themselves are unlikely to have affected children, unless they marry a blood relative.

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.

Diagnosis

In recent years, medical research has identified most of the gene faults that cause CMS. For some people who have had unexplained symtoms all of their lives, recent advancements has made diagnosis possible.

Before a diagnosis is made, a neurologist will review the medical history before deciding whether or not to undertake a series of tests:

  • An electromyogram (EMG) tests muscle responses to electrical nerve stimulation.
  • DNA test - to look for faulty genes.
  • A blood test or muscle biopsy may be needed to exclude other causes of similar symptoms.

Once a diagnosis has been made, families should be referred to a specialist genetics centre for a full discussion on the diagnosis.

Symptoms

Symptoms of CMS vary from person to person and fluctuate throughout the day and they can also overlap with other muscular disorders. The following symptoms may be noticed in someone with CMS:

  • babies: decreased movement inside the mother's womb before birth, a weak suck and cry, difficulty feeding and swallowing, reduced movements after birth, breathing difficulties and episodic apnoeic attacks
  • children and adults: may get frequent chest infections, droopy eyelids when tired, reduced eye movement with double vision, unclear or nasal speech, may start walking late, fatigue and may struggle with walking, sport, exertion or activities of daily living, scoliosis (curvature of the spine), tendency to fall easily. Sometimes they may have distinctive facial features such as a prominent lower jaw, high arched palate and misalignment or crowding of the teeth (maloclusion), stiffness in fingers and wrists, weak neck and people with CMS may be unable to hold their arms above the head for long.

Outcomes for people with CMS

If CMS is diagnosed early, then it can be treated and prevented to some extent with medication. Most people with CMS will be able to walk independently and CMS does not affect intellect in any way. In some cases, CMS is so mild that it is only diagnosed in late childhood, adolescence or even adulthood.

Breathing support, physiotherapy, speech and language therapy (including feeding advice) may be needed at different stages.

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 (acetylcholine receptors) 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 of 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 a problem is at the gap between the muscle and the nerve.

Treatments for CMS

Treatment of CMS depends on the type of condition. Below is a list of the main treatments and their possible side effects.

Pyridostigmine (Mestinon®)

Some types of CMS are helped by pyridostigmine, an enzyme blocking drug. This drug boosts the ACh effect on the muscle by blocking its breakdown. Possible side effects at higher doses may include stomach cramps or loose stools. These effects can often be relieved with the help of other medication. Pyridostigmine can make some types of CMS worse.

3,4-Diaminopyridine (3,4-DAP)

This boosts the release of ACh from the nerve ending. 3,4-DAP has to be used carefully, but it is sometimes helpful when combined with pyridostigmine. Possible side effects include tingling around the mouth or in the fingers and toes, anxiety, over-excitement and, very rarely, epileptic fits. However, these side effects are very rare within the normal dosage commonly used. 3,4-DAP can also make some types of CMS worse.

Click here to read our 3,4-DAP information sheet.

Ephedrine and Salbutamol

Ephedrine and salbutamol are from the same family of medications and are believed to help with clustering the AChRs. In some cases, it can take weeks or months of treatment before the medication fully takes effect. The most common side effects are fine tremor, anxiety, headaches, muscle cramps, dry mouth and palpitations. You can read the story of myaware member Jimmy, who successfully trialled salbutamol here.

Quinidine and fluoxetine

These drugs may help AChRs to close sooner in slow channel CMS. Careful monitoring is essential as there may be cardiac side effects and fluoxetine may cause depression in young people.

Non-invasive ventilation

Some children and adults with CMS may need help with night time breathing difficulties. This might include non-invasive ventilation in bed with the use of a mask to support breathing and give the muscles a rest.

Pregnancy and CMS

Many women with CMS have successful pregnancies and deliver healthy babies. However, extra rest and careful monitoring are likely to be necessary before, during and after the pregnancy.

If pregnant women with CMS need a Caesarean section, a planned epidural anaesthetic is preferable. This should be discussed with the midwife and obstetrician early in the pregnancy.

It is strongly recommended that women planning pregnancy should consult with their neurologist to obtain specialist advice, regarding their care and relating to the suitability of their medication during pregnancy and breastfeeding.

You can find more information on pregnancy and myasthenia here.

Guidelines for medications to avoid

Certain medications should be avoided by people with CMS. Medications to be avoided or used with caution include:

  • many types of antibiotics
  • some drugs used for blood pressure or the heart (especially beta-blockers)
  • some drugs used in psychiatric conditions
  • pyridostigmine (Mestinon®) can make some types of CMS worse

A full list of medications that can make myasthenia worse can be seen here.

People with CMS should never start new medications without consultation with their doctor.

Where to go for more information

Apart from your doctor and hospital specialist, there are specialist nurses at some UK centres who will offer help, advice and support to a family. Ask your GP or hospital specialist whether such a service exists in your area.

Myaware is always here for you and we have a Kids support group that meets every year and is invaluable to us.

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