Familial Dysautonomia Health Article

Definition

Familial dysautonomia (FD) is a rare inherited disorder in which affected individuals experience multiple malfunctions of the autonomic nervous system (the part of the nervous system that regulates heart muscle, smooth muscle, and glands) as well as the sensory, motor, and central components of the nervous system. The disorder is progressive with a continual loss of nerve cells of the sensory and autonomic nervous systems.

Description

Familial dysautonomia is an inherited disorder that occurs almost exclusively in people of Eastern European (Ashkenazi) Jewish descent. FD is one of a larger group of at least five hereditary sensory and autonomic neuropathies (HSANs), meaning conditions that stem from abnormalities of the nervous system. FD was first described in 1949 by pediatricians Conrad Riley and Richard Day. They reported five children, all Jewish, who had an unusual set of reactions to mild anxiety, attributed to a disturbance of the autonomic nervous system. FD is also known as HSAN type III or Riley-Day syndrome. Decades of studies have determined the cause to be a genetic abnormality that causes poor development of nerve cells in the fetus, leading to a progressive loss of nerve cells of the autonomic and sensory nervous systems. The depletion of nerve cells in the autonomic system causes problems with unstable heart rate, blood pressure, and body temperature, as well as gastrointestinal dysfunction, poor motor coordination, and emotional instability. Abnormal development of the sensory nervous system results in poor perception of pain, heat, and cold. This causes affected individuals to injure themselves without being aware of it. This deterioration of the nervous system worsens throughout life and causes multiple health problems that lead to the death of 50% of those affected by adulthood.

Genetic profile

FD is caused by mutations (genetic errors) in the IKBKAP gene that is found on human chromosome 9, specifically located at region 9q31. The disease is inherited as an autosomal recessive trait. This means that both parents have one copy of the mutant gene but do not have the disease. For these parents, there is a 25% chance with each pregnancy that the child will have the disease.

The IKBKAP gene has two known mutations, which together account for 100% of the Ashkenazi Jewish (AJ) cases of FD. There is also a third mutation causing FD that is rarely seen in the non-AJ population. This mutation's gene location has not yet been determined.

Demographics

The abnormal gene causing FD is rare in the general population but has a fairly high incidence in the Ashkenazi Jewish population, originating from Eastern Europe. Both males and females are affected. In the at-risk group, one in 30 people is thought to be a carrier of the abnormal gene, with a disease frequency of one in 3,600 live births. Rare non-Jewish individuals affected with FD have been reported.

Signs and symptoms

Sensory and autonomic nervous systems fail to develop properly in the fetus. Newborn babies with FD have poor or decreased muscle tone and have poor sucking and swallowing reflexes that make feeding difficult. Affected babies are prone to periods of abnormally low body temperature and are unable to produce adequate tears when crying.

Although symptoms vary markedly, by adolescence affected children have a 90% likelihood of spinal curvature and experience weakness and leg cramping. They have difficulty concentrating and undergo personality changes including negativism, depression, irritability, and insomnia. Forty percent of affected people have regular vomiting crises in response to either emotional or physical stress. A crisis typically involves one to three days of compulsive vomiting, rapid heart rate, high blood pressure, profuse sweating, and red, blotchy skin.

Between crises, affected individuals may experience low blood pressure when rising to a standing position. They often have unexplained fevers and may have convulsions in response to even mild infections. Uncoordinated swallowing, reflux of stomach contents, and a poor gag reflex result in food or fluids being misdirected into the trachea and lungs. Aspiration pneumonia (lung infections) often follows. Kidney function may deteriorate with age. Affected people have an abnormal response to low oxygen or high carbon dioxide in their blood. They do not experience the expected "air hunger," or urge to breathe, and may faint or have a seizure. Lack of tears, decreased blink frequency, and insensitivity of the eye to pain from foreign objects can cause inflammation and ulcers of the cornea.

A characteristic sign in those affected with familial dysautonomia is a lack of the sense of taste. This is due to the absence of taste buds on the tongue. Other sensory problems include an inability to feel pain or distinguish between hot and cold temperatures; sensory loss increases with age. Deep tendon reflexes in affected individuals are decreased. Poor speech and motor coordination result in abnormal gait, unsteadiness, tongue thrusting, and abnormal rhythmic facial movements. Growth is stunted, with an average adult height of 5 ft (1.5 m). Puberty is delayed in both sexes. However, fertility and offspring of affected individuals are normal.