An Overview of Familial Dysautonomia

Familial dysautonomia (FD) is a serious and rare genetic condition that affects the survival of specific nerve cells, primarily parts of the autonomic nervous system and sensory neurons. This affects the body’s control of involuntary actions, such as breathing, digesting, making tears, salivating, and regulating blood pressure and temperature. Reduced sensitivity to pain and temperature is another major problem.

The condition was first described in 1949 by two researchers, Riley and Day, and it is sometimes called Riley-Day syndrome. Type III hereditary sensory and autonomic neuropathy (HSAN type III) also refers to the same medical problem. The condition occurs primarily in people of Ashkenazi Jewish ancestry. In this group, it affects about one person in 3,700.

Symptoms

Familial dysautonomia is a debilitating disease that can cause many different symptoms. These appear early in infancy, and might first show up as low muscle tone, absence of tears, and difficulty maintaining body temperature.

Additional symptoms may appear, such as:

• Difficulty swallowing
• Poor growth
• Frequent lung infections
• Excessive saliva
• Episodes of vomiting
• Delays in reaching physical milestones
• Gastroesophageal reflux disease
• Bedwetting
• Abnormal heart rhythms
• Dry eyes, which can lead to corneal abrasions
• Other eye problems, like strabismus
• Decreased taste sensation
• Breathing issues during sleep
• Abnormal curving of the spine (scoliosis)
• Poor balance and broad gait that worsens over time

Poor regulation of blood pressure is also a common problem. This might cause orthostatic hypotension, a lowering of blood pressure when standing, which might trigger dizziness or fainting. The periodic increases in blood pressure also tend to cause kidney problems over the long-term.

Insensitivity to pain and temperature is another problem. This can contribute to injury, for example, if an affected person doesn’t notice to remove their hand from a very hot object.

Many people with FD have normal intelligence, but some people have learning issues such as attention deficit problems.

People with FD also have a decreased life expectancy, on average. Some people with the condition die from complications from pneumonia. Others suffer from sudden unexplained death during sleep or from other disease complications.

Causes

The symptoms of familial dysautonomia make sense when you learn about the part of the body that’s affected by the disease. The disease seems to affect mostly neurons.

The autonomic neurons of the body seem particularly prone to problems. These are the neurons that help regulate the autonomic nervous system. This system helps regulate many automatic functions of your body, such as breathing, blood pressure, sweating, salivating, regulating temperature, and digesting. That’s why these parts of the body seem particularly prone to problems.

The disease also affects some sensory neurons, which is why sensations of temperature and pain are impaired.

Some of the other problems of FD result from complications of these issues. For example, people with FD suffer from periods of very high blood pressure. This, in turn, can damage the kidneys over the long-term.

Genetic Mutation

There are other medical issues that can cause problems with the autonomic nervous system. But in familial dysautonomia, these problems are caused by mutations in a single gene. Specifically, mutations in a gene called “ELP1” (also known as IKAP) cause the disease.

This gene makes a protein whose function isn’t completely understood. However, we do know that it seems to be important in the proper development of the nervous system.

When a person has a genetic mutation in ELP1, the body can’t make enough of the functional protein where it’s needed. This is particularly true for certain cells in the nervous system. This is what causes the problems with parts of the nervous system that lead to symptoms.

FD is one of a group of related disorders, the hereditary sensory and autonomic neuropathies (HSANs). These disorders are all inherited genetically, and they all can affect both sensory and autonomic neurons. However, they have slightly different genetic causes, and thus have somewhat different (though overlapping) symptoms. All the other disorders in this group, including FD, cause some sensory and autonomic symptoms.

How the Disease is Inherited

Familial dysautonomia is an autosomal recessive genetic condition. That means that a person with FD received an affected gene from both of their parents.

People who carry only one copy of the gene (called carriers) don’t have any symptoms. If a couple has had one child with FD, there is a 25% chance that another child of theirs would also have the disease.

Diagnosis

The diagnostic process begins with a history and a thorough medical exam. Family history is also important, though an infant may be the first person known in a family to have the disease. Clinicians try to get as much information to evaluate the possible diagnoses. This can even begin in-utero with an accuracy greater than 99%. Since prenatal screening for the familial dysautonomia gene became available in 2001, the rate of babies born with the disease has decreased in the US.

FD is a rare condition, and there are many other problems that can cause some of the symptoms of FD. For example, other neurological syndromes and or other hereditary and sensory neuropathies might cause some similar problems. It’s important to rule out these other possible causes.

Taken together, certain clues can help a practitioner make the correct diagnosis. These include the presence of the following:

• Low muscle tone in infancy
• Absent or decreased deep tendon reflexes
• Smooth, pale appearing tongue
• Absence of tears
• Ashkenazi Jewish genetic background

Testing is also an important part of the diagnostic process. A wide array of tests will be done initially as clinicians try to get an idea of what is going on. These might include general tests, like blood tests and a complete metabolic panel.

Other tests to assess the nervous system might be important, like brain imaging tests or electroencephalography. Initial tests might vary depending on how symptoms first appear.

There are a couple of specific tests that can help diagnosis FD if a clinician suspects it. One is the response to a subcutaneous injection of histamine. People with FD show a very specific skin response (called “lack of axon flare”).

Another test uses eye drops of the medication methacholine (which affects the autonomic nervous system). The pupil of someone with FD will shrink in size dramatically after these drops.

It is often helpful to work with a clinician with experience in rare genetic diseases when trying to find the exact diagnosis.

Treatment

There is currently no treatment approved by the U.S. Food and Drug Administration (FDA) that can directly address the disease and its progression. However, there are many interventions that can help address the disease’s problems and help prevent complications.

Some of these are only needed temporarily, such as to address a crisis of increased blood pressure or a pneumonia infection. Others are needed more long-term. These treatments will be specifically tailored to the individual’s needs.

Some possible treatments might include:

• Gastronomy tube (g-tube) to maintain nutrition
• Medications for gastroesophageal reflux disease (like omeprazole)
• IV fluids for vomiting crises
• Chest physiotherapy, to help prevent lung infections
• Antibiotics for lung infection
• Pacemaker for fainting or orthostatic hypotension
• Elastic stockings and leg maneuvers to help with orthostatic hypotension
• Drugs like diazepam to treat hypertensive episodes and vomiting crises
• Drugs like midodrine, to treat orthostatic hypotension
• Drugs like ACE-inhibitors, for kidney disease
• Drugs like glycopyrrolate, to decrease saliva production
• Artificial tears for protection of the cornea
• Surgery or orthopedic devices for scoliosis
• Positive airway pressure (CPAP or BiPAP) for disordered breathing during sleep

Treatments Under Development

Researchers are working to find treatments that might directly treat the disease itself.

One promising treatment is a compound called phosphatidylserine, which is approved by the FDA as an over-the-counter food supplement. Some scientific research suggests that this food supplement may slow the course of the disease by increasing levels of ELP1. Currently, clinical trials of the compound are ongoing that will provide more information about its safety and effectiveness.

Clinical trials are also ongoing for another potential treatment called “kinetin.” Potentially, it may also increase the levels of functioning ELP1.

Hopefully, FDA approval of one or more of these investigational treatments will improve the lives of people with FD. It remains to be seen whether these treatments might help slow or reverse the disease process. Other potential treatments are also under development.

Monitoring

Regular monitoring is also an important part of managing the disease. This is important because certain symptoms of the disease can worsen over time.

• For example, people with FD may need to receive:
• Regular assessments for chronic respiratory disease
• Regular monitoring of blood pressure and cardiovascular problems
• Regular eye exams
• Screening for disordered breathing during sleep
• Regular exams of the spine

Coping

Certain situations can temporarily worsen certain symptoms of FD. When possible, these situations should be avoided in people with the condition. These might include:

• Being out in hot and humid weather
• Having an overly full bladder
• Taking long car rides
• Experiencing emotional stress or pain

It’s also important for caregivers to take care of themselves. When dealing with a chronic and severe condition like familial dysautonomia, it’s important to reach out to others.

As a family, it will take major adjustments to accommodate your child’s best care. But it is easier than ever before to network with other families who have experience with the disease. The Familial Dysautonomia Foundation provides many resources for support.

A Word From Verywell

It can be devastating to learn that your child has a major medical condition like familial dysautonomia. Give yourself time to take in the news.

Fortunately, newer and better treatments may be on the way. With time, education, and the support of your healthcare team, you will continue to learn about the best way to advocate for your loved one.