Familial Dysautonomia

Also known as: Riley-Day syndrome; Hereditary sensory and autonomic neuropathy type III

Familial Dysautonomia (FD) is a neurodegenerative disorder affecting the development and survival of sensory, sympathetic, and parasympathetic neurons. Affected individuals have a progressive ataxic gait and, optic nerve atrophy, corneal anesthesia, alacrima, decreased perception for pain and temperature, neurogenic dysphagia, aspiration into the airway, gastrointestinal dysfunction, chronic kidney disease, spine curvature, anxiety, and cardiovascular instability due to afferent baroreflex failure. Episodes of autonomic crisis occur in the majority of patients and are characterised by profound hypertension, tachycardia, nausea and vomiting (retching if the patient has a fundoplication) and often sweating, drooling, and personality changes. Evidence of the disorder is present  from birth, although neurological deterioration progresses with age.

FD is seen almost exclusively in people of Ashkenazi Jewish extraction; however, several cases exist in Mexico and therefore diagnosis should not be ruled out completely without genetic testing in patients with clinical signs and symptoms consistent with the diagnosis.

It is an autosomal recessive condition, expressed from birth, with complete penetrance, but variable expression.

Presentation

Although the diagnostic signs may be present at birth, considerable variation exists in the expression of the disease at any time.

Clinical features of FD may include:

  • Feeding difficulties with uncoordinated swallowing and poor suck in infants and risk of aspiration pneumonia throughout the lifespan; all patients with familial dysautonomia are at risk for aspiration due to neurogenic dysphagia with the three sources of aspiration being saliva, oral nutrition and/or hydration and gastroesophageal reflux. Pooling of saliva and food stasis in the esophagus can contribute to aspiration during sleep or when supine.
  • Hypotonia in infancy, contributing to a delay in motor milestones
  • Diminished tears with lack of overflow tears with emotional crying may be noted after 7 months of age when infants normally show evidence of tear production. Lack of tears and corneal anesthesia can lead to corneal abrasions, infections, scarring and potentially blindness. Optic nerve atrophy is progressive and leads to blindness.
  • Decreased or absent deep tendon reflexes
  • Decreased taste and absence of fungiform papillae of the tongue, giving it a smooth pale appearance.
  • Difficulty performing rapid movements and maintaining balance while changing direction. The gait ataxia of FD is uncoordinated and unbalanced with a broad stance, veering with ambulation and extreme unsteadiness with turning. They have a positive Romberg test.
  • Autonomic crises occur in almost all patients with FD at least once during the lifespan, and approximately 50-60% of patients have autonomic crisis on a recurrent basis.
  • The gait and optic nerve atrophy deteriorate with time, and it is likely that the neurogenic dysphagia worsens.
  • Sleep related death is the main cause of death in familial dysautonomia and almost all patients with FD have sleep disordered breathing.
  • Chronic kidney disease, which can progress to end stage renal failure, is present in most patients and likely in part related to the paroxysmal hypertension that is present from birth causing ongoing renal damage.
  • Spinal curvature is present in over 83% of patients by the age of 20 years.

Please click on the titles to open and close the following information sections.

  • FD is caused by a point mutation in the IKBKAP gene that affects the splicing of the elongator-1 protein (ELP-1 or IKAP). ELP-1 is located in most cells throughout the body, particularly neurones in the central nervous system.
  • These mutations cause a marked reduction in non-myelinated neuronal populations, as well as reduction in small diameter myelinated axons.
  • The reduction seems to indicate a developmental arrest in the sensory and autonomic systems and, in the later, principally in the sympathetic fibres.
  • Sympathetic ganglia have been found to be one third of the normal size, and the neuronal population has been found to be one tenth of the normal number.
  • During physical and emotional stress, plasma norepinephrine and dopamine are elevated and autonomic storms or ‘crises’ may develop.
  • Approximately 1:30 of the Ashkenazi Jewish (AJ) population is a carrier.
  • In the AJ population, disease incidence is estimated to be 1:3600 live births.
  • FD almost exclusively affects people of AJ extraction.

Gene Specific:

  • Clinical diagnosis can be confirmed by genetic testing for mutations in the IKBKAP gene.
  • One mutation, a founder mutation accounts for more than 99% of mutant alleles in individuals with FD of AJ descent.

Other supporting evidence

  • There are no specific MRI abnormalities (may be generalized atrophy)
  • Schirmer test – to establish decreased tears
  • Absence of axon flare response after intradermal histamine injection
  • Neurological exam always shows lack of deep tendon reflexes, ataxia, decreased sensation to pain and temperature

Management is symptomatic and supportive, and includes:

  • Maintenance of adequate hydration
  • Measures to avoid aspiration and prevent bronchiectasis
  • Treatment of gastroesophageal reflux
  • Aggressive chest physiotherapy
  • Treatment of orthostatic hypotension (pressure stockings, leg exercises, hydration)
  • Blood pressure management should be addressed throughout the lifespan in order to prevent end-organ damage.
  • Avoiding heat and humidity and ensuring appropriate hydration in order to prevent exacerbation of orthostatic hypotension and possible loss of consciousness.
  • Eye care with artificial tears and gel to prevent corneal damage.

Family members should be offered genetic counselling and testing. Carrier testing and pre-natal testing is available for this condition.

  • FD is a potentially life-threatening disorder with a high mortality rate and has been associated with a high incidence of sudden death, particularly during sleep or respiratory illness.
  • The probability of an individual with FD reaching 40 years of age has increased to 50% due to improved supportive treatment, and some patients are now living past 60 years of age.
  • The main causes of death are primarily respiratory related. Sleep related deaths account for 21% of deaths, all respiratory related deaths represent 30% with pneumonias accounting for 17%, sepsis 6% and unexplained deaths are approximately 14%.
  • Many adults with FD have been able to achieve independent function and some have reproduced.
  • For children exhibiting features of Familial Dysautonomia (FD), suggested initial referral would be to a paediatrician. For Jewish patients, it is important to note the child’s ancestry and higher prevalence of FD in the Jewish population.
  • For patients that have received a positive FD diagnosis with genetic testing:
    • On-going management is usually under the care of a paediatrician with other specialist input as appropriate.
    • Families may benefit from referral to a clinical genetics department to establish carrier status in other family members as appropriate.
    • A referral to the NYU Dysautonomia Center is available to any patient with confirmed genetic testing. The NYU Dysautonomia Center is the only Center in the world that manages patients with FD across the lifespan in collaborations with local physicians and specialists with the goal of improving quality of life and longevity. The NYU Dysautonomia Center also provides ongoing research opportunities to the patients with familial dysautonomia with the hope of improving quality of life and extending the lifespan.
Familial Dysautonomia UK (FDUK)

Formerly known as DSGB. The only UK based charity dedicated to alleviating the suffering from FD. It helps provide specialized equipment, medication, support and respite for FD patients and families; facilitates access to international FD specialists and expertise; raises public awareness of FD and promotes screening for the disorder.

Dysautonomia Foundation (USA)

This USA based charity supports medical treatment, research, public awareness and social services for the benefit of people affected by FD. It has established the world’s only two FD treatment centers and is the largest single source of funding for research and treatment specifically for the benefit of people with FD.

FDUK On Facebook

An international support group on Facebook for people with Bloom syndrome.

Jane’s Story

Click on the ‘Jane’s Story’ link above to see a short video of Jane Pearl sharing her family’s personal story of having a child affected by Familial Dysautonomia.

Article On Current Treatment In FD

Open access article in PubMed from the New York School of medicine on current treatment options.

GeneReviews: www.ncbi.nlm.nih.gov/books/NBK1180

OMIM: #223900

Written by: Dr Jacky Megitt, Jnetics researcher.
Approved by: Dr. Horacio Kaufmann, Professor of Dysautonomia Research, The NYU Dysautonomia Center, NYU School of Medicine and Christy Spalink, Acute Care Nurse Practitioner, The NYU Dysautonomia Center, NYU School of nursing.
Last review: 09.07.2018

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