Congenital myasthenic syndromes

Congenital myasthenic syndromes are a group of rare hereditary conditions caused by a gene change that results in muscle weakness, which worsens with physical activity. Any muscles used for movement can be affected, including muscles that control speaking, chewing and swallowing, seeing and blinking, breathing, and walking.

There are many types of congenital myasthenic syndromes, depending on which gene is affected. The changed gene also determines many of the signs and symptoms and severity of the condition.

Congenital myasthenic syndromes are usually identified at birth or early childhood and are lifelong conditions.

There is no cure for congenital myasthenic syndromes. Medications are generally an effective treatment for muscle weakness symptoms. Which medication works depends on which gene is identified as the cause of the congenital myasthenic syndrome. Rarely, some children may have a mild form that doesn't need treatment.

Congenital myasthenic syndromes are typically identified at birth. But if signs and symptoms are mild, the condition may not be identified until childhood, or rarely, early adulthood.

Depending on the type of congenital myasthenic syndrome, the severity of signs and symptoms vary greatly, from minor weakness to the inability to move. Some symptoms can be life-threatening.

Common to all congenital myasthenic syndromes is muscle weakness that worsens with physical activity. Any muscles used for movement can be affected, but the most commonly affected muscles are those that control movement of the eyelids and eyes and chewing and swallowing.

During infancy and early childhood, progressive loss of essential voluntary muscle activity occurs with muscle use. Impaired muscle weakness can result in:

• Droopy eyelids and poor eye control, often with double vision.
• Difficulty chewing and swallowing.
• Weakness of facial muscles.
• Weak cry.
• Slurring or nasal speech.
• Delayed crawling and walking.
• Delayed development of wrist, hand and finger skills, such as brushing teeth or combing hair.
• Trouble supporting the head in an upright position.
• Problems breathing, such as feeling short of breath and having short pauses in breathing, sometimes worsened by infection, fever or stress.

Depending on the type of congenital myasthenic syndrome, other signs and symptoms can include:

• Skeletal deformities, such as joint, spine or foot deformities.
• Unusual facial features, such as narrow jaw or wide-set eyes.
• Hearing loss.
• Weakness, numbness and pain, usually in hands and feet.
• Seizures.
• Kidney problems.
• Cognitive impairment, rarely.

When to see a doctor

Talk to your doctor if you observe any signs listed above in your child or if you have concerns about your own signs or symptoms.

Caused by any one of more than 30 identified genes, the type of congenital myasthenic syndrome depends on which gene is affected.

Congenital myasthenic syndromes are classified by which location is affected in the neuromuscular junction ― the area that provides signals (impulses) between the nerve cells and the muscle cells to trigger movement (synapses). Disrupted signals that cause loss of muscle function can occur in different locations:

• Nerve cells where the impulse starts (presynaptic).
• Space between your nerve and muscle cells (synaptic).
• Muscle cells where the impulse is received (postsynaptic), the most common location.

Some types of congenital myasthenic syndromes are the result of congenital disorders of glycosylation. Glycosylation is a complex chemical process that plays a role in regulating communication between cells. Glycosylation defects can adversely affect the transmission of signals from nerve cells to muscles.

Congenital myasthenic syndromes are most commonly inherited in an autosomal recessive pattern. That means both parents must be carriers, but they do not typically show signs of the condition. The affected child inherits two copies of the abnormal gene — one from each parent. If children inherit only one copy, they won't develop the syndrome, but they'll be carriers and possibly pass the gene to their own children.

Rarely, congenital myasthenic syndromes can be inherited in an autosomal dominant pattern, meaning that only one parent passes on the affected gene. In some cases, the affected gene occurs randomly and is not inherited. In other cases, no gene can be identified.

A child is at risk of a congenital myasthenic syndrome if both parents are carriers of a gene known to cause the syndrome. The child then inherits two copies of the gene. Children who inherit only one copy of the gene from one parent typically won't develop the syndrome but will be carriers.

Your doctor will do a physical examination ― including a neurological exam ― and review symptoms and medical history to check for signs of a congenital myasthenic syndrome. Your doctor may also order tests to exclude other conditions with similar symptoms.

The following tests can help diagnose a congenital myasthenic syndrome and determine how severe the disorder is.

• Blood tests. A blood test might reveal the presence of abnormal antibodies that disrupt signals between your nerves and your muscles. Other blood tests may be helpful to rule out other conditions that may have similar symptoms.
• Electromyography (EMG). EMG is a diagnostic procedure to assess the health of muscles and the nerve cells that control them, called motor neurons. EMG results can reveal nerve dysfunction, muscle dysfunction or problems with signal transmission between the nerves and muscles.
• Repetitive nerve stimulation. In this nerve conduction study, electrodes are attached to your skin over the muscles to be tested. Small pulses of electricity are sent through the electrodes to measure the nerve's ability to send a signal to your muscle. The nerve is tested repeatedly to see if its ability to send signals worsens with fatigue.
• Genetic testing. This can identify the specific affected gene that's responsible for the congenital myasthenic syndrome and which treatments may be beneficial.
• Cholinesterase challenge test. Cholinesterase inhibitor medication, such as pyridostigmine, is given to determine if improvement in muscle fatigue occurs with repetitive movement.
• Other tests. These may include lung function tests to assess breathing and oxygenation, a sleep study to assess breathing and apnea during sleep, or a muscle biopsy to look at muscle fibers.

Genetic testing

Genetic testing involves examining your DNA, the chemical database that carries instructions for your body's functions. Genetic testing can reveal changes, sometimes called mutations, in genes that cause congenital myasthenic syndromes. Genetic testing may also be recommended for family members.

Talking to your doctor, a medical geneticist or a genetic counselor about why the test is being done and how the results may affect you is an important step in the process of genetic testing.

Rarely, some children with mild congenital myasthenic syndromes may not need treatment.

Medication

Medications aren't a cure, but they can improve muscle contraction and muscle strength in people with congenital myasthenic syndromes. Which medications are effective depends on the type of affected gene. Medications that are effective for one type of syndrome may be ineffective for another type, so genetic testing is recommended before starting medications.

Medication treatment options may include:

• Acetazolamide
• 3,4-diaminopyridine (3,4-DAP), marketed as amifampridine (Firdapse, Ruzurgi)
• Albuterol
• Ephedrine
• Fluoxetine (Prozac)
• Neostigmine (Bloxiverz)
• Pyridostigmine (Mestinon, Regonol)

Supportive treatments

Supportive treatments depend on the type and severity of the congenital myasthenic syndrome. Options may include:

• Therapies. Physical, speech and occupation therapies may help maintain function. Therapy also can offer supportive devices, such as wheelchairs, walkers, and hand and arm supports.
• Breathing support. Some congenital myasthenic syndromes may result in pauses in breathing, called apnea. Using an apnea monitor may be recommended. Noninvasive positive-pressure ventilation, such as a continuous positive airway pressure (CPAP) mask and machine, may be used to support breathing and oxygenation. In some cases, intubation and use of mechanical ventilation may be needed.
• Feeding support. Problems with chewing and swallowing may require additional nutrition. Enteral nutrition, also known as tube feeding, is a way of delivering nutrition directly into the stomach or small intestine. Your doctor may recommend a procedure to place a tube through the skin on the abdomen and into the stomach (gastrostomy) or into the small intestine (jejunostomy).
• Surgery. For severe orthopedic deformities, such as in the spine or feet, surgical correction may be needed.

Ongoing care

Regular follow-up appointments with a team of medical professionals provides ongoing care and may help prevent certain complications. Your health care team can link you with appropriate support for home, school or work.

Pregnancy can worsen symptoms of congenital myasthenic syndromes, so close monitoring during and after pregnancy is required.

Caring for a child or family member with a congenital myasthenic syndrome can be stressful and exhausting. You may not know what to expect, and you may worry about your ability to provide the care needed.

Consider these steps to prepare yourself:

• Learn about the disorder. Learn as much as you can about congenital myasthenic syndromes. Then you can make the best choices and be an advocate for yourself or your child.
• Find a team of trusted professionals. You'll need to make important decisions about care. Medical centers with specialty teams can offer you information about the disorder, coordinate your care among specialists, help you evaluate options and provide treatment.
• Seek out other families. Talking to people who are dealing with similar challenges can provide you with information and emotional support. Ask your doctor about support groups in your community. If a group isn't for you, maybe your doctor can put you in touch with a family who has dealt with the disorder. Or you may be able to find a group or individual support online.
• Consider support for caregivers. Ask for or accept help in caring for your loved one when needed. Options for additional support can include asking about sources of respite care, asking for support from family and friends, and taking time for your own interests and activities. Counseling with a mental health professional may help with adjustment and coping.

Make an appointment with your doctor if you notice signs or symptoms common to congenital myasthenic syndromes. After the initial evaluation, you may be referred to a doctor trained in evaluating and treating these conditions.

Here's some information to help you prepare for your appointment, as well as what to expect from your doctor.

What you can do

You may want to prepare answers to these questions:

• What symptoms do you notice?
• When did the symptoms start?
• Does anything make the symptoms better or worse?
• Has anyone in your family ever had a congenital myasthenic syndrome?

What to expect from your doctor

After getting detailed information about the symptoms and your family's medical history, your doctor may order tests to help with diagnosis and plan treatment.