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Familial dysautonomia (a.k.a Riley-Day syndrome) is a disorder caused by defects in the autonomic and sensory nervous systems. The autonomic system is the part of the nervous system responsible for controlling involuntary actions, while the sensory system controls activities related to the senses. Affected people have a range of symptoms including poor muscle tone, feeding problems, infections, difficulty maintaining a stable body temperature and an inability to feel pain.
What are the Symptoms of Familial Dysautonomia?
The neurons (nerve cells) in the autonomic and sensory nervous systems of familial dysautonomia patients do not develop correctly or survive for the normal period. The autonomic nervous system is important for controlling essential involuntary actions, like breathing, digestion, heart rate, and the regulation of blood pressure and body temperature. The sensory nervous system controls and processes sensory information, including the systems for vision, hearing, touch, taste and smell.
Familial dysautonomia is a debilitating disease present from birth and progressive neuronal degeneration continues throughout life. The early signs of this disorder include poor growth and muscle tone, feeding and swallowing difficulties, blotchy red skin, frequent lung infections, a lack of tears and an inability to maintain a stable body temperature. Further symptoms develop as the affected infant grows, including holding their breath for an extended period, sometimes to the point of fainting. Luckily this breath-holding behavior usually stops by age 6. Developmental delays (e.g. learning to walk and talk) can occur in some children and some have learning disabilities (e.g. a short attention span), but this disorder generally does not affect intelligence.
Digestive problems cause frequent vomiting episodes and other symptoms associated with gastrointestinal dysmotility. Bed-wetting, poor balance, an abnormal gait, and curvature of the spine occur in affected school-age children and frequent bone fractures can happen due to poor bone quality and an inability to feel normal pain levels. Affected people lack the normal senses of heat, pain and taste, so injuries and burns commonly occur without any awareness. Blood pressure is not maintained effectively and can drop rapidly upon standing, (leading to dizziness, blurred vision or fainting), or increase when nervous or excited or during vomiting episodes.
By adolescence, many patients have lung damage from repeated infections, reduced kidney function, and increasing balance and coordination difficulties. A lack of tear production and damage to the optic nerve cause vision deterioration. Familial dysautonomia is a potentially life-threatening disorder and is associated with a high incidence of sudden death, mainly due to pulmonary or respiratory issues and sepsis.
What Causes Familial Dysautonomia?
Familial dysautonomia is caused by genetic defects in the IKBKAP gene, which encodes the IKK complex-associated protein (IKAP). IKAP is found in a variety of cells but its exact role is currently unknown. The mutations in IKBKAP that cause familial dysautonomia result in decreased levels of IKAP. Interestingly this reduction in IKAP only occurs in certain cells, while other cell types appear to have normal IKAP levels. The cells affected in familial dysautonomia patients are predominantly cells of the autonomic and sensory nervous systems. The reduction of IKAP in these cells, reduces their normal functions and activities, leading to the typical symptoms of this disorder.
How is Familial Dysautonomia Diagnosed?
Familial dysautonomia is diagnosed by molecular genetic analysis to identify the mutations in the IKBKAP gene. Two mutations, IVS20+6T>C (a.k.a c.2204+6T>C) and R696P (a.k.a c.2087G>C), are found in almost 99% of the familial dysautonomia patients of Ashkenazi Jewish descent.
How is Familial Dysautonomia Treated?
There is no cure for familial dysautonomia, however effective treatment and management of symptoms can improve the quality and the length of a patient’s life.
Feeding problems are treated to maintain adequate nutrition. An aversion to feeding and failure to thrive are frequently managed by a percutaneous endoscopic gastrostomy. This involves placing a flexible feeding tube through the abdominal walls into the stomach allowing nutrition and fluids to be directly passed into the stomach. Gastroesophageal reflux is managed through upright positioning for feeds, medication that helps control acid reflux (prokinetic agents), H2 antagonists to treat and prevent intestinal ulcers, drugs that reduce gastric acid production (proton pump inhibitors) or a gastrostomy. Vomiting crises are treated with diazepam or chloral hydrate, along with IV fluids to prevent dehydration. Other medications used include transdermal clonidine patches to provide stable blood pressure levels, and carbidopa to reduce the frequency and severity of hypertensive vomiting.
Chronic lung disease is treated with daily chest physiotherapy. Early diagnoses of pneumonia and infections are important, as individuals with familial dysautonomia are prone to viral respiratory infections, along with bacterial infections. Orthostatic hypotension or postural hypotension (head rush) caused by low blood pressure can be managed through hydration, elastic stockings and leg exercises to increase muscle tone and reduce pooling of blood in the veins of the legs. Counter-maneuvers like squatting and bending forward improve orthostatic blood pressure by increasing cardiac output, however the effectiveness varies between individuals.
Patients with familial dysautonomia also have a tendency to hypoventilate during sleep, because of an insensitivity to hypoxia and elevated carbon dioxide levels (hypercapnia). Noninvasive assisted ventilation is recommended during sleep to prevent hypoventilation. Chronic renal failure is common and can be delayed by controlling blood pressure. Renal tubular acidosis commonly occurs and requires treatment with bicarbonate. Hyperkalemia, (higher than normal potassium levels), is treated with a low potassium diet.
The absence of tears can be treated with the use of a tear substitute and is important in maintaining the integrity of the cornea and the membrane surfaces and to reduce incidents of inflammation and infection. Soft contact lenses can also promote corneal healing if damage has already occurred. A surgical procedure to partially sew the eyelids together to narrow the eyelid opening (tarasorrhaphy) is used when the above preventative measures are inadequate to treat corneal injuries.
Due to the number of complex symptoms associated with familial dysautonomia routine assessments are very important. Periodic evaluation of chronic respiratory disease, regular monitoring of blood pressure and optimal management of blood pressure, routine monitoring of other cardiovascular problems, monitoring of adequate hydration by measuring blood urea nitrogen levels, screening for sleep-disordered breathing, periodic eye examinations and annual examinations of the spine are all highly recommended for increasing the length and quality of the life with individuals with familial dysautonomia.
Recommended Links: Ferreira JC, Schreiber-Agus N, Carter SM, Klugman S, Gregg AR, Gross SJ. (2014) Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze. Am J Obstet Gynecol. 211(3): 197-204.
Shohat M, Weisz Hubshman M. (2003) [Updated 2014 Dec 18]. Familial Dysautonomia. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.