Familial Dysautonomia - Riley-Day Syndrome

Overview

• Disorder of the autonomic nervous system
• Affects the development / survival of sensory, sympathetic, and some parasympathetic neurons in the autonomic and sensory nervous system
• Symptoms:
1. insensitivity to pain, inability to produce tears, poor growth, and labile blood pressure (episodic hypertension and postural hypotension).
2. 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.
• FD is one example of a group of disorders known as hereditary sensory and autonomic neuropathies (HASN)
• HSAN are characterized by widespread sensory dysfunction and variable autonomic dysfunction caused by incomplete development of sensory and autonomic neurons.
Incidence
Almost exclusively in Ashkenazi Jews
Inherited in an autosomal recessive fashion
Both parents must be carriers in order for a child to be affected.
Carrier frequency in Jewish individuals of Eastern European (Ashkenazi) ancestry is about 1/30
Carrier frequency in non-Jewish individuals is about 1/3000
If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected
Genetic testing is recommended for families who may be carriers of familial dysautonomia.
There have been 590 cases in total
Currently there are 350 people living with this condition worldwide

Etiology
• Familial Dysautonomia, is the result of mutations in IKBKAP gene on chromosome 9
• Chromosome 9 encodes for the IKAP protein
• Three mutations in IKBKAP identified in individuals with FD
• The decreased amount of functional IKAP protein in cells causes Familial Dysautonomia.

Symptoms
Symptoms displayed by a infant / toddler:
1. The most distinctive clinical feature is absence of overflow tears with emotional crying after age 7 months. This symptom can manifest less dramatically as persistent bilateral eye irritation.
2. High prevalence of breech presentation
3. Weak or absent suck and poor tone
4. Poor suck and misdirected swallowing
5. Red blotching of skin
Symptoms in an older child:
1. Delayed speech and walking
2. Unsteady gait
3. Spinal curvature


4. Poor growth
5. Less perception in pain or temperature with nervous system
6. Erratic or unstable blood pressure
7. Red puffy hands
8. Dysautonomia crisis: constellation of symptoms response to physical and emotional stress; usually accompanied by vomiting, increased heart rate, increase in blood pressure, sweating, drooling, blotching of the skin and a negative change in personality.
Clinical Diagnosis 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
• Parents of Ashkenazi Jewish Background

Treatment / Treatment of Symptoms
1. Artificial tears: using eye drop containing artificial tear solutions (methylcellulose)
2. Feeding: Maintenance of adequate nutrition, avoidance of aspiration; thickened formula and different shaped nipples are used for baby.
3. Daily chest physiotherapy (nebulization, bronchodilators, and postural drainage): for Chronic lung disease from recurrent aspiration pneumonia
4. Special drug management of autonomic manifestations such as vomiting: intravenous or rectal diazepam (0.2 mg/kg q3h) and rectal chloral hydrate (30 mg/kg q6h)
5. Protecting the child from injury (coping with decreased taste, temperature and pain perception)
6. Combating orthostatic hypotension: hydration, leg exercise, frequent small meals, a high-salt diet, and drugs such as fludrocortisone.
7. Treatment of orthopedic problems (tibial torsion and spinal curvature)
8. Compensating for labile blood pressures
**no cure for FD and death occurs in 50% of affected individuals by age 30

Therapies Under Investigation

In cell lines derived from heterozygous carriers of FD who display a normal phenotype, there are decreased levels of the normal or wild type IKAP transcript and also functional IKAP protein respectively.

This would suggest that increasing the amount of the wild-type IKAP transcript may improve the manifestation in patients with FD.

Application of tocotrienols in the treatment of FD elevated the expression of IKAP transcripts as well as the amount of induced functional IKAP protein in homozygous cell lines derived from FD patients.

This observed result further suggests the value of therapeutic approaches to lessen suffered symptoms of FD patients by elevating cellular level of functional IKAP which can be induced by tocotrienols

One form of therapy under investigation is electrolyte therapy for refractory seizures common among FD carriers, such as the product Ceralyte.