Familial dysautonomia is a genetic disorder that affects the development and survival of certain nerve cells. The disorder disturbs cells in the autonomic nervous system, which controls involuntary actions such as digestion, breathing, production of tears, and the regulation of blood pressure and body temperature. It also affects the sensory nervous system, which controls activities related to the senses, such as taste and the perception of pain, heat, and cold. Familial dysautonomia is also called hereditary sensory and autonomic neuropathy, type III.

Problems related to this disorder first appear during infancy. Early signs and symptoms include poor muscle tone (hypotonia), feeding difficulties, poor growth, lack of tears, frequent lung infections, and difficulty maintaining body temperature. Older infants and young children with familial dysautonomia may hold their breath for prolonged periods of time, which may cause a bluish appearance of the skin or lips (cyanosis) or fainting. This breath-holding behavior usually stops by age 6. Developmental milestones, such as walking and speech, are usually delayed, although some affected individuals show no signs of developmental delay.

Additional signs and symptoms in school-age children include bed wetting, episodes of vomiting, reduced sensitivity to temperature changes and pain, poor balance, abnormal curvature of the spine (scoliosis), poor bone quality and increased risk of bone fractures, and kidney and heart problems. Affected individuals also have poor regulation of blood pressure. They may experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting. They can also have episodes of high blood pressure when nervous or excited, or during vomiting incidents. About one-third of children with familial dysautonomia have learning disabilities, such as a short attention span, that require special education classes. By adulthood, affected individuals often have increasing difficulties with balance and walking unaided. Other problems that may appear in adolescence or early adulthood include lung damage due to repeated infections, impaired kidney function, and worsening vision due to the shrinking size (atrophy) of optic nerves, which carry information from the eyes to the brain.

Mutations in the ELP1 gene cause familial dysautonomia. The ELP1 gene provides instructions for making a protein that is found in a variety of cells throughout the body, including brain cells.

Nearly all individuals with familial dysautonomia have two copies of the same ELP1 gene mutation in each cell. This mutation can disrupt how information in the ELP1 gene is pieced together to make a blueprint for the production of ELP1 protein. As a result of this error, a reduced amount of normal ELP1 protein is produced. This mutation behaves inconsistently, however. Some cells produce near normal amounts of the protein, and other cells—particularly brain cells—have very little of the protein. Critical activities in brain cells are probably disrupted by reduced amounts or the absence of ELP1 protein, leading to the signs and symptoms of familial dysautonomia.

Normal Function

The ELP1 gene provides instructions for making a protein called elongator complex protein 1 (ELP1). This protein is found in a variety of cells throughout the body, including brain cells. It is part of a six-protein complex called the elongator complex. The elongator complex plays a key role in transcription, the process that transfers information in genes to the cell machinery that makes proteins. Researchers believe that the elongator complex is important for the transcription of proteins that affect the cell's structural framework (the cytoskeleton) and cell movement (motility). The cytoskeleton and cell motility are essential for the growth and development of cells. For example, the cytoskeleton plays a critical role in the growth of nerve cells, particularly the specialized extensions called axons and dendrites that are required for the transmission of nerve impulses. Cell motility is crucial for the movement of nerve cells to their proper locations in the brain.

Health Conditions Related to Genetic Changes

Familial dysautonomia

Nearly all individuals with familial dysautonomia have two copies of the same mutation in each cell. This mutation can disrupt how information in the ELP1 gene is spliced together during transcription. As a result of this splicing error, a reduced amount of ELP1 protein is produced. This mutation behaves inconsistently, however. Some cells produce near normal amounts of ELP1 protein, and other cells—particularly brain cells—have very little of the protein.

In a small number of reported familial dysautonomia cases, researchers have identified other mutations that change one of the protein building blocks (amino acids) in the ELP1 protein. In these cases, the amino acid arginine is replaced by the amino acid proline at position 696 (written as Arg696Pro), or the amino acid proline is replaced by the amino acid leucine at position 914 (written as Pro914Leu). People with one of these improper amino acid substitutions also have the splicing mutation. Together, these mutations impair the ELP1 protein.

It is unclear how ELP1 gene mutations lead to the signs and symptoms of familial dysautonomia. Reduced amounts of ELP1 protein may impair the growth and development of nerve cells by disrupting the cytoskeleton and cell motility.

Other Names for This Gene

• DYS
• ELP1_HUMAN
• IKAP
• IKBKAP
• IKI3
• inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein
• TOT1

Genomic Location

• Difficulty swallowing and feeding
• Low muscle tone (hypotonia)
• Absence of tears
• Poor control of breathing, especially during sleep
• Trouble regulating blood pressure and body temperature
• Insensitivity to pain
• Unsteady gait
• Vomiting episodes
• Frequent pneumonia

Familial dysautonomia occurs primarily in people of Ashkenazi (central or eastern European) Jewish descent. It affects about 1 in 3,700 individuals in Ashkenazi Jewish populations. Familial dysautonomia is extremely rare in the general population.