Familial dysautonomia
Familial dysautonomia | |
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Other names | Riley–Day syndrome[1] and Hereditary sensory and autonomic neuropathy type III (HSAN-III) |
Facial features of a patient with familial dysautonomia over time: Note flattening of upper lip. By age 10, prominence of the lower jaw is apparent and by age 19 a mild erosion of right nostril occurs due to inadvertent self-mutilation. | |
Specialty | Neurology |
Familial dysautonomia (FD), also known as Riley-Day syndrome, is a rare,
FD results in variable symptoms, including
Originally reported by Drs. Conrad Milton Riley and Richard Lawrence Day in 1949,
Signs and symptoms
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),
- Autonomic crises - In children with FD, recurrent episodes of vomiting may occur. Such episodes may be triggered by physical (e.g. infection) or emotional stress, may occur every 15–20 minutes for over 24 hours, and may be accompanied by significant hypertension, drenching sweat, breathing issues,[6] fever, tachycardia, aspiration pneumonia,[8] skin blotches, drooling, and negative personality change.[citation needed]
- Pain insensitivity - Insensitivity or indifference to painful stimuli may lead to frequent/progressive self-mutilation, burns, and ulcers. There may be self-mutilation of the tongue (especially in toddlers during teething), lips, and cheeks, or loss of teeth. Compulsive oral biting may result in ulcers, or tumour-like masses (Riga-Fede disease).[8]
Progression
Familial dysautonomia presents with progressive,[3] age-specific symptoms.
Though usually not diagnosed until several years of age, generalised signs of FD are present during the newborn period in more than 80% of those affected.[8] Dysmorpnic facial features are not directly inherent to the disorder, but facial asymmetry and a straightened mouth eventually develop due to abnormal tone and molding of facial bones.[8][3]
Perinatal
A very high incidence of
Neonatal
During the neonatal period, hypotonia, respiratory insufficiency, poor feeding with difficulty swallowing and aspiration, developmental delay, short stature, scoliosis, and corneal disease may occur.[8]
Infancy
Issues related to the disorder first appear during infancy. Early manifestations include hypotonia, feeding difficulty (impaired swallowing and suckling[2]), poor growth, absence of tears, frequent lung infections, and poor body-temperature control (infants may display cold hands and feet[2]). Developmental milestones (e.g. walking, speech) may or may not be delayed.[7]
In infants with FD, a lack of overflow tears during emotional crying may be noted after the age of 7 months (until this age, overflow emotional tearing may also not occur in unaffected infants;[12] overflow tearing is absent in neonates and begins to appear only after 2–3 months of age[8]).[12]
Affected infants' hands may alternatively appear cool and mottled (from vasoconstriction), or red and swollen (from vasodilation).[8] Red skin blotching is often precipitated by emotional excitement.[8]
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.[7]
Children
Breath-holding behaviour usually resolves by age 6. In school-age children, bed wetting, vomiting episodes, impaired pain and temperature perception, impaired blood pressure control (including orthostatic hypotension, a 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.[7]
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).[7] By adulthood, difficulties with balance and unaided walking often arise.[7]
Cause
Familial dysautonomia is the result of mutations in the
Diagnosis
Clinical diagnosis
A clinical diagnosis of FD is supported by a constellation of criteria:[citation needed]
- 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 number 9 as the responsible chromosome.[citation needed]
Prenatal testing
Familial dysautonomia is inherited in an autosomal
Management
No cure for FD has been identified. The only two treatment centers are at
A major issue has been aspiration pneumonia. Fundoplications (by preventing regurgitation) and gastrostomy tubes (to preclude oral nutrition) have reduced the frequency of hospitalization.[citation needed] Other issues that can be treated include FD crises, scoliosis, and various eye conditions due to limited or no tears.[citation needed]
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
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
Prognosis
Average age of death is in the third decade of life, but affected persons may live into their 70s.[3] 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.[citation needed]
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.[citation needed]
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.[citation needed]
Worldwide, about 600 diagnoses have been recorded since discovery of the disease, with around 350 of them still living.[16]
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.[17][18] Genetic screening subsequently became available in 2001, enabling Ashkenazi Jews to find out if they are carriers.[citation needed]
Stem-cell therapy has been proposed as a potential future treatment. Eventually, treatment could be given in utero.[citation needed] 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.[19]
See also
- Dysautonomia
- Medical genetics of Ashkenazi Jews
References
- ^ pediatriconcall.com Archived 2007-04-30 at the Wayback Machine
- ^ a b c d e "Dysautonomia, Familial". NORD (National Organization for Rare Disorders). Retrieved 2020-05-31.
- ^ a b c d e f g h i j k "Orphanet: Familial dysautonomia". www.orpha.net. Retrieved 2020-05-31.
- S2CID 245200408.
- S2CID 44306353.
- ^ a b c d e f Publishing, Harvard Health (21 December 2018). "Familial Dysautonomia". Harvard Health. Retrieved 2020-05-30.
- ^ a b c d e f g h Reference, Genetics Home. "Familial dysautonomia". Genetics Home Reference. Retrieved 2020-05-30.
- ^ )
- PMID 29698477.
- ^ PMID 12119926.
- S2CID 21579907.
- ^ a b "Familial Dysautonomia Workup: Laboratory Studies". emedicine.medscape.com. Retrieved 2020-05-31.
- ^ Dysautonomia Treatment and Evaluation Center Archived 2006-01-14 at the Wayback Machine
- ^ Sheba Medical Center
- ^ "San Francisco To Get a Genetics Center - Forward.com". 5 August 2005. Retrieved 2007-11-02.
- ^ "FD History & Statistics - Dysautonomia Foundation - Familial Dysautonomia (FD)". Archived from the original on 2009-04-18. Retrieved 2009-04-02.
- PMID 11179021.
- PMID 11179008.
- ^ Benefits for people with FD Archived 2011-07-26 at the Wayback Machine – from Dysautonomia foundation
Further reading
- Axelrod FB, Hilz MJ (2003). "Inherited autonomic neuropathies". Semin Neurol. 23 (4): 381–90. S2CID 260317729.
- Axelrod FB (2004). "Familial dysautonomia". Muscle Nerve. 29 (3): 352–63. S2CID 222032372.
- Slaugenhaupt SA, Gusella JF (2002). "Familial dysautonomia". Curr Opin Genet Dev. 12 (3): 307–11. PMID 12076674.
- Felicia B Axelrod; Gabrielle Gold-von Simson (October 3, 2007). "Hereditary sensory and autonomic neuropathies: types II, III, and IV". Orphanet Journal of Rare Diseases. 2 (39): 39. PMID 17915006.