Project Description

Congenital Myasthenia Fast Facts

Congenital myasthenia is a neurological disorder that causes muscle weakness that gets worse during periods of exertion. It is also known as congenital myasthenic syndrome (CMS).

The first signs of CMS usually appear in early childhood but may not emerge until later in childhood or adulthood.

The severity of CMS symptoms varies greatly. Some cases may cause only mild symptoms, but in some cases, the symptoms can be debilitating.

The disorder is caused by problems in communication between nerve cells and muscles.

The first signs of CMS usually appear in early childhood but may not emerge until later in childhood or adulthood.

What is Congenital Myasthenia?

Congenital myasthenia, also called congenital myasthenic syndrome (CMS), is a neurological disorder that causes muscle weakness. The condition is caused by dysfunction in the communication between nerve cells and muscles; the impaired communication results in muscles that don’t respond correctly when triggered by the nervous system.

In the most common type of myasthenia, myasthenia gravis, the immune system attacks healthy muscle cells and makes them unable to detect nerve impulses. In CMS, genetic mutations cause imbalances in proteins vital to nerve-muscle communication. In all forms of myasthenia, the common feature is that muscle weakness worsens during periods of exertion, and strength can only be regained through rest.

Symptoms of CMS

CMS symptoms usually begin in early childhood, but the symptoms may be mild and go unnoticed until later in childhood. In some cases, symptoms don’t emerge until adolescence or adulthood.

Common symptoms of CMS include:

  • Delays in motor development
  • Muscle weakness triggered by exercise or that becomes worse with exertion
  • Weakness in the muscles of the face or throat
  • Drooping eyelids
  • Breathing difficulties

What Causes Congenital Myasthenia?

CMS is caused by abnormal changes (mutations) in many different genes. Mutations in different genes cause different subtypes of the disorder. Mutations in the CHRNE gene are the most common cause of CMS.

Other genes commonly associated with CMS include:

  • CHAT
  • COLQ
  • RAPSN
  • DOK7
  • GFPT1

These genes contain instructions for making proteins crucial in the biochemical process of transmitting signals from nerves to muscles. Abnormal production of these proteins can disrupt the process and cause the symptoms of CMS.

Is Congenital Myasthenia Hereditary?

Most cases of CMS are inherited in an autosomal recessive pattern. This means a child will develop the disorder only if they inherit two copies of the CMS mutation, one from each parent. A person with only one copy of the mutated gene will not develop the disorder but may pass the mutation on to their children.

When both parents have the CMS mutation, each of their children has a 25 percent chance of developing the disorder. Each child has a 50 percent chance of inheriting only one mutated gene and being a carrier. Each child has a 25 percent chance of inheriting two normal genes and being unaffected.

Some types of CMS are inherited in an autosomal dominant pattern. In these cases, a child can develop the disorder when they inherit just one copy of the mutated gene from either parent.

Some cases of CMS result from mutations that occur spontaneously in the development of sperm or egg cells or the early development of the embryo. In these cases, neither parent carries the disorder-causing mutation.

How Is Congenital Myasthenia Detected?

Early diagnosis of CMS can be difficult because early symptoms may go unnoticed. In some cases, visible signs don’t emerge at all until later in childhood.

Early signs of CMS may include:

  • Limp or floppy muscles in infancy
  • Delays in achieving skills such as sitting, rolling over, or crawling
  • Choking
  • Brief interruptions in breathing
  • Difficulty running or walking in toddlerhood
  • Difficulty speaking or swallowing
  • Drooping eyelids or facial muscles

How Is Congenital Myasthenia Diagnosed?

The process of diagnosing CMS usually includes evaluating the child’s medical history, physical and neurological exams, and tests to rule out other causes or confirm a diagnosis of CMS.

Diagnostic steps often include:

  • Electromyography (EMG), a test that measures the electrical activity in muscles
  • Blood tests to look for antibodies that interfere with nerve-muscle communication
  • Genetic testing to look for the specific gene mutations that cause CMS

When diagnosing CMS, it is essential to identify the particular subtype of the disorder. Different subtypes often cause correspondingly different symptoms and may respond to different specific treatments.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Congenital Myasthenia Treated?

CMS has no cure, but some medications may be effective at improving communication between nerves and muscles. The type of medication used depends on the subtype of CMS, and different people respond differently to the medicines.

Medications that may be used to control CMS symptoms include:

  • Pyridostigmine
  • Fluoxetine
  • Ephedrine
  • Amifampridine
  • Quinidine
  • Salbutamol
  • Albuterol

How Does Congenital Myasthenia Progress?

The long-term progression of CMS varies significantly from case to case. In cases where symptoms are mild, the disorder might cause no significant complications or impairments. In more severe cases, muscle weakness might be so profound that the ability to walk is lost. In many instances, symptoms don’t worsen over time, and in at least one subtype, muscle weakness may eventually improve.

Among the most severe complications are respiratory issues or problems swallowing caused by weakness in the neck, throat, or chest muscles. In these cases, susceptibility to potentially life-threatening respiratory infections is a concern. With other forms of the syndrome, people with CMS have a normal life expectancy.

How Is Congenital Myasthenia Prevented?

There is no known way to prevent CMS. Parents with a family history of the disorder or who have had another child with CMS are advised to consult a genetic counselor to assess their risk if they plan to have another child.

Congenital Myasthenia Caregiver Tips

  • Understand your child’s disease. CMS is not a single disease with a consistent set of symptoms. Learn about your child’s specific type of CMS so you can better understand its effects and the kinds of treatments that are most likely to help.
  • Be open about the disorder. CMS is a difficult condition to understand. Your child’s experience living with the disorder will be better if important people in your child’s life understand the challenges of CMS.
  • Get the resources you need to be an effective, healthy caregiver. The Myasthenia Gravis Foundation of America has put together a collection of support resources for patients, families, and caregivers.  

Congenital Myasthenia Brain Science

CMS affects the biochemical process in the area where nerve cells connect to muscle fibers. This area is called the neuromuscular junction. The junction consists of a part of the nerve cell where signals for movement originate, a space between the cells (called a synapse), and a part of the muscle cell where the signal is received.

When a person wants to move a muscle voluntarily, a signal moves from the brain through the nervous system to the neuromuscular junction. There it passes from the nerve cell, through the synapse, and into the muscle cell via a complex process involving several different chemical reactions. CMS causes abnormalities of proteins (or complete absence of specific proteins) in the neuromuscular junctions that interfere with the process and inhibit the transmission of signals from nerve cells to muscle cells.

Congenital Myasthenia Research

Title:  Efficacy of Albuterol in the Treatment of Congenital Myasthenic Syndromes

Stage: Completed

Principal investigator: Andrew G. Engel, MD

Mayo Clinic

Rochester, MN

The study tests the notion that patients suffering from certain types of congenital myasthenic syndromes benefit from the use of albuterol at doses used in clinical practice.

The proposal aims to evaluate the effects of albuterol, an adrenergic agonist, in the treatment of congenital myasthenic syndromes (CMS). Over the past two decades, some CMS patients refractory to or worsened by cholinergic agonists, namely those suffering from defects in acetylcholinesterase (AChE) or Dok-7, respond to ephedrine, a medication used for over half a century in the treatment of autoimmune myasthenia gravis. After ephedrine became unavailable, the same type of patients were treated with albuterol in doses ranging from 4 mg daily to twice daily for adults; the dose for children 6 to 12 years is 2 mg two or three times daily; the dose for children 2 to 6 years is 0.1 mg/kg/day (maximum 2 mg) three times daily.

 

Title: Treatment Use of 3,4 Diaminopyridine in Congenital Myasthenia and Lambert-Eaton Syndrome

Stage: Available

Contact: Ricardo Maselli, MD

University of California, Davis Medical Center

Sacramento, CA

Congenital myasthenia and LEMS are potentially lethal disorders, which, even with careful management, significantly impede participation in normal daily functions. Currently approved therapies have had little impact on promoting a normal quality of life activity in these patients. The goal is to systematically examine the effect of 3,4-DAP on the natural course of this disease, and to gain additional experience in titrating 3,4-DAP with other available therapies to maximize clinical function and development in this patient population.

The specific aim of this study is to evaluate the use of 3,4 Diaminopyridine (DAP) on selected patients proven by genetic or serum antibody testing to have Congenital Myasthenic Syndrome (CMS) or Lambert-Eaton Myasthenic Syndrome (LEMS). We will evaluate the patient for CMS or LEMS, prescribe 3,4 DAP, and then clinically evaluate the response.

The subject population will consist of selected patients proven by genetic testing, muscle biopsy, or antibody testing to have CMS or LEMS. Consideration for entry in our clinical study will require a referral from a treating pediatrician or neurologist. Dr. Maselli will examine patients and deem which are appropriate for neurophysiologic examinations at the University of California, Davis Medical Center. In vitro neuromuscular recordings of anconeus muscle biopsy material (as well as standard light and electron morphologic analysis) or documentation of a genetic mutation associated with congenital myasthenia will be required in some patients to confirm CMS diagnosis.

 

Title: Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes

Stage: Completed

Contact: Thomas Crawford, MD

Johns Hopkins Pediatric Neurology

Baltimore, MD

This randomized, double-blind, controlled, outpatient two-period, two-treatment crossover study is designed to evaluate the efficacy and safety of amifampridine phosphate in patients (ages two and above) diagnosed with certain genetic subtypes of CMS and demonstrated open-label (amifampridine phosphate) or history of sustained amifampridine benefit from treatment.

Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to (4) weeks until stable dose and frequency of amifampridine phosphate is achieved for seven days. After this phase, blinded treatment effect will be assessed in a randomized fashion of continuation or cessation of drug (Placebo) starting with Period I (duration seven days). Following experimental Period 1, patients will be returned to the stable dose administered at the end of the open-label run-in period for approximately two weeks, followed by cross-over treatment in Period 2 dosing for seven days. After completion of Period 2, patients will be eligible for expanded access with restoration of open-label amifampridine phosphate at the same dose and frequency as established in the run-in phase of the study.

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