Familial dysautonomia


Familial dysautonomia is a rare, progressive, recessive genetic disorder of the autonomic nervous system seen primarily in people of Eastern European Jewish descent that affects the development and survival of sensory, sympathetic and some parasympathetic neurons in the autonomic and sensory nervous system.
FD results in variable symptoms, including insensitivity to pain, inability to produce tears, poor growth and labile blood pressure. People with FD have frequent vomiting crises, pneumonia, problems with speech and movement, difficulty swallowing, inappropriate perception of heat, pain and taste as well as unstable blood pressure and gastrointestinal dysmotility.
Originally reported by Drs. Conrad Milton Riley and Richard Lawrence Day in 1949, FD is one example of a group of disorders known as hereditary sensory and autonomic neuropathies. All HSAN are characterized by widespread sensory dysfunction and variable autonomic dysfunction caused by incomplete development of sensory and autonomic neurons. The disorders are believed to be genetically distinct from each other.

Signs and symptoms

Signs and symptoms of familial dyautonomia usually commence during infancy and worsen with age, and may include: gastrointestinal dysmotility, dysphagia and frequent choking/gagging, recurrent vomiting, poor weight gain/growth, delayed development and puberty, recurrent aspiration pneumonia with possible secondary chronic lung disease, absence of overflow tears during crying, corneal ulcers, red skin blotches and excessive sweating, breath-holding spells, slurred speech/nasal voice, tongue ulcers, hyporeflexia, hypotonia, enuresis, arrhythmias, hypertension, hypotension, impaired temperature and pain perception, impaired proprioception, a smooth glossy tongue, scoliosis, abnormal gait, short stature, chronic renal failure, visual impairment, variable cognitive ability, characteristic facial features that develop with time, impaired vibration perception, lack of fungiform papilla of the tongue, and impaired taste perception.
Familial dysautonomia presents with progressive age-specific symptoms.
Though usually not diagnosed until several years of age, generalised signs of FD are present in during the newborn period >80% of those affected.
Dysmorpnic facial features are not directly inherent to the disorder, however, facial asymmetry and a straigntened mouth eventually develop due to abnormal tone and moulding of facial bones.

Perinatal

A very high incidence of breech presentation has been noted among infants with FD. A lower birth weight as compared to siblings, premature birth, and intrauterine growth restriction have also been noted.

Neonatal

During the neonatal period, there may be hypotonia, respiratory insufficiency, poor feeding with difficulty swallowing and aspiration, developmental delay, short stature, scoliosis, and corneal disease.

Infancy

Issues related to the disorder first appear during infancy. Early manifestations include hypotonia, feeding difficulty, poor growth, absence of tears, frequent lung infections, and poor body temperature control. Developmental milestones may or may not be delayed.
In infants with FD, a lack of overflow tears during emotional crying may be noted after the age of 7 months.
Affected infants' hands may alternatively appear cool and mottled, or red and swollen. Red skin blothing 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

Breath-holding behaviour usually resolves by age 6. In school-age children, there may be bed wetting, vomiting episodes, impaired pain and temperature perception, impaired blood pressure control, learning disabilities, scoliosis, poor bone quality and bone fractures, and kidney and heart issues.

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. By adulthood, there are often mounting difficulties with balance and unaided walking.

Cause

Familial dysautonomia is the result of mutations in IKBKAP gene on chromosome 9, which encodes for the IKAP protein. There have been three mutations in IKBKAP 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 one amino acid mutation in 696, where Proline substitutes normal Arginine. The decreased amount of functional IKAP protein in cells causes familial dysautonomia.

Diagnosis

Clinical diagnosis

A clinical diagnosis of FD is supported by a constellation of criteria:
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 number 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, there is a 25% chance that the child will have FD. For pregnancies at increased risk for FD, preimplantation genetic diagnosis or prenatal diagnosis by amniocentesis or chorionic villus sampling is possible.

Management

There is currently no cure for FD. There are only two treatment centers, one at New York University Hospital and one at 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, there is no definitive treatment at present.
A major issue has been aspiration pneumonia. Fundoplications and gastrostomy tubes have reduced the frequency of hospitalization. Other issues which 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 type 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, daily chest physiotherapy for chronic pulmonary disease, pharmaceutical management of autonomic features, preventing accidental injury, prevention of orthostatic hypotension, 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 need for more aggressive surgical measures such as tarsorrhaphy, conjunctival flaps, and corneal transplants.

Prognosis

Average age of death is in the 3rd decade of life, however, affected persons may live into the 7th decade of life. 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 in order for a child to be affected. The carrier frequency in Jewish individuals of Eastern and Central European ancestry is about 1/30, while the carrier frequency in non-Jewish individuals is unknown. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of familial dysautonomia.
Worldwide, there have been approximately 600 diagnoses recorded since discovery of the disease, with approximately 350 of them still living.

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. There is no governmental support beyond recognizing those diagnosed with FD as eligible for certain programs.