Familial dysautonomia

Signs and symptoms of familial dysautonomia usually commence during infancy and worsen with age, and may include gastrointestinal dysmotility (including erratic gastric emptying, gastroesophageal reflux, abnormal esophageal peristalsis, oropharyngeal incoordination),/growth, delayed development (especially walking) and puberty (especially in girls), recurrent aspiration pneumonia (due to inhalation of food or vomitus)), hypotonia, enuresis, arrhythmias, hypertension (including episodic hypertension in response to emotional stress or visceral pain short stature, chronic renal failure (common), visual impairment, variable cognitive ability, characteristic facial features that develop with time, impaired vibration perception, lack of fungiform papilla of the tongue, A lower birth weight as compared to siblings, overflow tearing is absent in neonates and begins to appear only after 2–3 months of age). Affected infants' hands may alternatively appear cool and mottled (from vasoconstriction), or red and swollen (from vasodilation). Red skin blotching is often precipitated by emotional excitement. In older infants and young children, breath-holding spells may occur, possibly leading to cyanosis or fainting. Breath-holding behaviour usually ceases by age 6. Children In school-age children, bed wetting, vomiting episodes, impaired pain, and temperature perception, impaired blood pressure control (including orthostatic hypotension, hypertension during periods of psychological excitement or vomiting), learning disabilities (e.g. short attention span; learning disabilities are present in about a third of those with FD, and may require special education), scoliosis, poor bone quality and bone fractures, and kidney and heart issues may be seen. Adolescence and adulthood Issues that tend to commence during adolescence or early adulthood include lung damage due to multiple respiratory infections, impaired kidney function, and impaired vision (due to atrophy of the optic nerve). By adulthood, difficulties with balance and unaided walking often arise. ==Cause==

Familial dysautonomia is the result of mutations in the IKBKAP gene on chromosome 9, which encodes for the IKAP protein (IkB kinase complex-associated protein). Three mutations in IKBKAP have been identified in individuals with FD. The most common FD-causing mutation occurs in intron 20 of the donor gene. Conversion of T→C in intron 20 of the donor gene resulted in shift splicing that generates an IKAP transcript lacking exon 20. Translation of this mRNA results in a truncated protein lacking all of the amino acids encoded by exons 20–37. Another less common mutation is a G→C conversion resulting in a one-amino-acid mutation in 696, where proline substitutes for normal arginine. The decreased amount of functional IKAP protein in cells causes familial dysautonomia. ==Diagnosis==

Clinical diagnosis inheritance A clinical diagnosis of FD is supported by a constellation of criteria: • No fungiform papillae on the tongue • Decreased deep-tendon reflexes • Lack of an axon flare following intradermal histamine • No overflow tears with emotional crying Genetic testing Genetic testing is performed on a small sample of blood from the tested individual. The DNA is examined with a designed probe specific to the known mutations. The accuracy of the test is above 99%. Dr. Anat Blumenfeld of the Hadassah Medical Center in Jerusalem identified chromosome 9 as the responsible chromosome. Prenatal testing Familial dysautonomia is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. If both parents are shown to be carriers by genetic testing, a 25% chance exists that the child will have FD. For pregnancies at increased risk for FD, preimplantation genetic diagnosis or prenatal diagnosis by amniocentesis (at 15–17 weeks) or chorionic villus sampling (at 10–14 weeks) is possible. ==Management==

No cure for FD has been identified. The only two treatment centers are at New York University Hospital and the Sheba Medical Center in Israel. One is being planned for the San Francisco area. Although the FD-causing gene has been identified and it seems to have tissue-specific expression, no definitive treatment exists at present. A major issue has been aspiration pneumonia. Fundoplications (by preventing regurgitation) and gastrostomy tubes (to preclude oral nutrition) have reduced the frequency of hospitalization. Other issues that can be treated include FD crises, scoliosis, and various eye conditions due to limited or no tears. Treatment of FD remains preventative, symptomatic, and supportive. FD does not express itself in a consistent manner. The types and severity of symptoms displayed vary among patients and even at different ages on the same patients, so patients should have specialized individual treatment plans. Medications are used to control vomiting, eye dryness, and abnormal blood pressure. Common management strategies include artificial tears, appropriate feeding strategy (maintenance of adequate nutrition, avoidance of aspiration (thickened formula and differently shaped nipples for infants)), daily chest physiotherapy (nebulization, bronchodilators, and postural drainage) for chronic pulmonary disease, pharmaceutical management of autonomic features (e.g. intravenous or rectal diazepam, or rectal chloral hydrate), preventing accidental injury, prevention of orthostatic hypotension (hydration, leg exercise, frequent small meals, a high-salt diet, and medication (e.g. with fludrocortisone)), treatment of orthopedic problems, compensating labile blood pressure. Parents and patients should be informed regarding daily eye care and early signs of corneal problems, as well as punctal cautery. Informing patients and caretakers has resulted in decreased corneal scarring and the need for more aggressive surgical measures such as tarsorrhaphy, conjunctival flaps, and corneal transplants. ==Prognosis==

The average age of death is in the third decade of life, but affected persons may live into their 70s. Death occurs in 50% of the affected individuals by age 30. The outlook for patients with FD depends on the particular diagnostic category. Patients with chronic, progressive, generalized dysautonomia in the setting of central nervous system degeneration have a generally poor long-term prognosis. Death can occur from pneumonia, acute respiratory failure, or sudden cardiopulmonary arrest in such patients. The survival rate and quality of life have increased since the mid-1980s, mostly due to a greater understanding of the most dangerous symptoms. At present, FD patients can be expected to function independently if treatment is begun early and if major disabilities are avoided. ==Epidemiology==

Familial dysautonomia is seen almost exclusively in Ashkenazi Jews and is inherited in an autosomal recessive fashion. Both parents must be carriers for a child to be affected. The carrier frequency in Jews of Eastern and Central European (Ashkenazi) ancestry is about one in 30, while the carrier frequency in non-Jews is unknown. If both parents are carriers, a one-in-four chance exists with each pregnancy for an affected child. Genetic counseling and genetic testing are recommended for families who may be carriers of familial dysautonomia. ==Research==

In January 2001, researchers at Fordham University and Massachusetts General Hospital simultaneously reported finding the genetic mutation that causes FD, a discovery that opens the door to many diagnostic and treatment possibilities. Genetic screening subsequently became available in 2001, enabling Ashkenazi Jews to find out if they are carriers. Stem-cell therapy has been proposed as a potential future treatment. Eventually, treatment could be given in utero. Research into treatments is being funded by foundations organized and run by parents of those with FD. No governmental support has been given beyond recognizing those diagnosed with FD as eligible for certain programs. ==See also==