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Familial Dysautonomia

(pronounced "fa-mill-yul dis-auto-no-mia")
(also known as Riley-Day Syndrome)
(abbreviated and commonly called FD)

Familial Dysautonomia is a Jewish genetic disorder that primarily affects the autonomic nervous system and causes impairment of the developmental and survival of sensory, sympathetic, and parasympathetic nerve cells resulting in a variety of possible symptoms: labile blood pressure (episodic hypertension and postural hypotension), vomiting crises, poor growth and development, reduced pain and temperature perception, lack of overflow tears, respiratory and swallowing difficulties, and delays in speech and motor development.




Familial Dysautonomia is an autosomal recessive disorder, which means that every individual that is affected has inherited one copy of the genetic mutation from each of his parents. People who have only one copy of the mutation are known as carriers and since they are unaffected, often are not aware they have the mutation until they have a child with FD. FD has a carrier rate of 1 in 27 Ashkenazi Jews (Jews of Eastern European descent), a rate as common as the better-known Jewish disorder, Tay-Sachs disease. A study of Israeli Jews demonstrated a carrier rate of 1 in 18 Jews of Polish descent. The birth rate for FD is 1 in 3600 babies born to couples of Ashkenazi descent.

At conception, each parent provides one copy of the FD gene. When two FD carriers conceive, the child inherits either the unaffected gene or the mutation from each of his or her parents. Depending on which copy the child inherits, he/she will either be a carrier (2 in 4 chance), an affected individual (1 in 4 chance), or be neither a carrier or affected (1 in 4 chance):

In the following diagram, each parent has a copy of the unaffected gene (X) and a copy of the mutation (x). There are four possible ways a child can inherit these genes:

• A child can inherit two copies of the unaffected gene (XX). They are unaffected and cannot pass the disorder on to their children (1 out of the 4 possibilities; 25% chance).
• A child can inherit a copy of the unaffected gene and a copy of the mutation (Xx or xX). They are
a carrier like his/her parents (2 out of 4; 50% chance).
• A child can inherit two copies of the mutation (xx). This child is affected (1 out of 4; 25% chance).

FD is the result of three known genetic mutations:
1. The main mutation found in every individual with FD and exclusively in the Ashkenazi Jewish population.
2. A second mutation also found in the Ashkenazi population, and
3. A third mutation found in one individual.

99.5% of all individuals with FD have two copies of the main mutation, the remaining 0.5% have one copy of this mutation and one copy of a second mutation. Since carriers (i.e., parents of children with FD) are asymptomatic, a genetic cure of the main mutation will not only treat the majority of patients, but also the patients who have two different mutations, effectively treating all individuals with FD.


Chromosomes are the blueprint for how a body's cells develop and function. Every person has 23 pairs of chromosomes. One chromosome of each pair is inherited from one's mother and the other chromosome is inherited from one's father. Chromosomes are made up of strands of a molecular substance called DNA. Sections of the DNA strands which make proteins are called genes. It is our genes that determine how certain traits will be expressed and tell our body's cells how to function. When there is an error within a portion of a gene's DNA, it is called a mutation and the gene does not function the way it should.

Chromosomes have many different functions. The part of the chromosome that makes up the genes is only a small portion of the total DNA in the chromosomes. These gene sections are called exons. Between the exons are sections of DNA called introns, enhancers, 3'-UTR, promoter, and other regions, which tell the chromosome important things like when to turn a gene on and off. The intron regions, previously thought to be "junk" DNA, are now believed to hold information like how an individual reacts to certain drugs.



In January, 2001, the gene affected in Familial Dysautonomia was identified as the IKBKAP gene on chromosome 9, which encodes for the IKAP protein (IkB kinase complex associated protein). There have been three mutations in IKBKAP identified in individuals with FD. Two of these are found exclusively among individuals of Eastern European descent and a third was found in a single individual.

The Major Mutation:

The most common FD mutation (99.5% of all patients are heterozygous) is found in an intron region of DNA. It controls where the gene product is cut and spliced. The mutation causes an exon (an important piece of DNA) to be cut out of the final protein product. One of the things that makes Familial Dysautonomia unique is that some cells are able to ignore the error message and produce regular, full-length protein. Most cells types are able to do this on a regular basis (although they all still produce abnormal protein some of the time). Unfortunately, nerve cells are more likely to produce the shortened, abnormal protein (although they too are able to produce normal protein some of the time).

This mutation in intron 20 of the donor gene results in the deletion of a coding region of the IKAP protein. Conversion of T-->C in position 6 of intron 20 of the donor gene results 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 in exons 20-37.

When a cell nucleus expresses a gene, it requires an RNA-protein complex to help splice out the intron (non-coding) regions. The U1snRNA is a component of this essential complex that binds with the DNA. The point mutation of the major mutation interrupts the DNA base pairing with U1snRNA. U1 snRNA interacts both with the last three nucleotides of the exon and the first six nucleotides of the downstream intron. The majority of 5’ splice sites interact with seven base pairs of U1 snRNA, and there are at most three mismatches between the 5’ splice site and U1 snRNA. These mismatches are not randomly distributed. They either weaken the exonic portion of the 5’ splice site, which is then compensated by strong binding to the intronic portion, or a weak intronic portion is compensated by a strong exonic portion.

In exon 20 of the IKBKAP gene, the exonic part of the splice site is weak, due to an A at position –1. The T->C mutation weakens the intronic part of the 5’ splice site, which causes exon skipping. Exon 20 usage is susceptible to a weak 5’ splice site, as the exon has a weak 3’ splice site that has an A at the –3 position, and contains several exonic silencer elements.

Array analysis indicates that IKBKAP promotes expression of genes involved in oligodendrocyte and myelin formation, which could explain the demyelination phenotype caused by the loss of IKBKAP.

The Second Mutation:

The second and minor mutation (a G-->C conversion causing a singl amino acid mutation in 696, where Proline substitutes normal Arginine) results in the substitution of an amino acid in an important regulatory region of the protein. Every individual diagnosed with FD to date carries at least one copy of the "major" mutation, which has the carrier rate of 1 in 27. Individuals who have a copy of the second or third mutation are called "heterozygous"; they have two different mutations.

Founder Effect:

The high prevalence of one mutation found in every affected individual and the majority of carriers is due to a genetic principle called the founder effect. The founder effect describes the inheritance of a gene mutation within a relatively small population with a high degree of intermarriage. One person (the founder) is born with a spontaneous mutation of a gene. In the case of FD, this is thought to have occurred approximately 400-500 years ago. When that individual passes the mutation on to his/her children, the mutation begins to be inherited within the population. In the case of FD, this is thought to have occurred among Ashkenazi Jews living near the town of Minsk, Belarus. Eventually, two of the founder’s descendents who have inherited the mutation have a child who inherits the mutation from both of them and the first case of FD is born. All carriers (and therefore all affected individuals) are descendents of this founder and as such share the same portion of DNA.




• Both natural parents of a child with Familial Dysautonomia are carriers (they have one normal
chromosome and one with the IKAP mutation).
• A child with familial dysautonomia has inherited the chromosome containing the FD mutation
from each parent.
• In any future pregnancy, there are four possible outcomes: inheriting mom's normal and dad's
mutation, inheriting mom's mutation and dad's normal, inheriting normal chromosomes from
both, or inheriting the mutation from both. Therefore the chance of having any one of the
above possibilities is one in four (25%).
• Since an unaffected sibling has not inherited the FD mutation from both parents (or else they
would have FD), they have only three possible chromosome combinations (mutation from mom and normal gene from dad; normal gene from mom and mutation from dad; or two normal
genes – see inheritance table above). The unaffected sibling will be a carrier in the first two
cases. Therefore, siblings of individuals with FD have a two in three chance of being a carrier
• The following table states the risk of being an FD carrier for family members of different levels
of relation to an individual with FD.

Brother or Sister
67% (2 in 3)

100% (both are carriers)

Uncle, Aunt, Grandparents
52% (approx. 1 in 2)

First Cousin*
28% (approx. 1 in 4)

First Cousin's Child, Parent's First Cousin
17% (approx. 1 in 6)

Second Cousin**
10% (approx. 1 in 10)

Second Cousin's Child
7% (approx. 1 in 6)

General Population Risk
3.7% (1 in 27)

*uncle or aunt's child
**mother or father's first cousin's child

This table assumes that all relatives are Ashkenazi Jews and therefore includes the baseline 1 in 30 risk from each parent unrelated to the affected individual. If non-Ashkenazi Jews are included in your family tree, then the carrier risk is less.
(N.b.: the reason an aunt or uncle has a higher than 50% chance of being a carrier is that in addition to having a 1 in 2 chance of inheriting the mutation from the grandparent who was the carrier, the other grandparent may have been a carrier as well (1 in 27 chance), and they have a 1 in 2 chance of inheriting that mutation, for an additional 2% risk)

Gene Information:
OMIM entry on Familial Dysautonomia: #223900
OMIM Gene Database # 603722
Gene map locus 9q31



The following is a list of possible symptoms; no patient will have all of these symptoms and many will experience only a few at a given time. For more information see Online Mandolin Inheritance in Man (OMIM) entry 223900. The symptoms experienced by an individual with FD vary over time. Because the symptoms can be varied, the average age that the diagnosis of FD is made is nearly 3 years old, and one case was diagnosed in an adult in her 40s.

At birth, infants:
• are born to parents of Ashkenazi (Eastern European) Jewish descent
• exhibit low muscle tone (hypotonia),
• experience feeding difficulties (problems with suck and swallow that often require the place
ment of a gastrostomy tube and a fundoplication to prevent aspiration of breastmilk/formula
into the lungs)
• are often born in breech presentation (25%)
• have low birth weight compared to siblings,
• experience heart rate difficulties during labor (variable and late decelerations),
• experience temperature instability (especially in the newborn period)
• demonstrate failure to thrive (poor weight gain)
• lack fungiform papilla (the large red-tipped taste buds on the tip of the tongue)
• have absent or decreased deep tendon reflexes
• exhibit tongue thrusting

Children and adults with FD can:
• suffer from episodes of autonomic crisis (periods of cyclical vomiting and/or retching, high
blood pressure, fast heart rate, excessive sweating and drooling, abdominal pain, inability to
sleep, decreased speech, and what is described as a “negative change in personality”)
• experience delays in developmental milestones (walking, talking, fine and gross motor skills)
• have decreased or absent pain and temperature perception (when mild, most notable on the
back) and may experience decreased taste sensation
• have unstable blood pressure:
• high blood pressure when upset, in autonomic crisis, or over time
• low blood pressure when dehydrated, when standing up, with exertion, or with the need to
• experience problems swallowing, worse with liquids. Most individuals with FD require a
gastrostomy tube (a tube that goes directly into the stomach, bypassing the esophagus and
thereby preventing food from being aspirated into the lungs) and a fundoplication procedure
(tightens the entrance of the stomach to prevent reflux into the esophagus)
• develop frequent lung infections (including pneumonia from aspirating saliva as well as food or
• often get red, blotchy, and sweaty when eating (worse with particular foods such as chocolate)
• exhibit poor balance and gait instability
• have short stature (especially compared to parents and siblings)
• exhibit delayed puberty and increased autonomic crises events with puberty
• are unable to cry tears with emotions or pain (seen after 7 months of age)
• have decreased sensation of the cornea of the eye and can develop corneal abrasions and
scarring, leading to impaired vision
• experience breath-holding spells (failure to take a breath in at the end of a long cry which
results in a postural seizure)
• develop scoliosis (curvature of the spine) and kyphosis (hunching of the shoulders)
• experience poor wound healing and increased fractures (which a child with FD may not feel as
pain and therefore take longer to diagnose)
• despite generally normal intelligence, can experience learning difficulties including auditory
processing disorders, problems with writing, apraxia (motor planning), and may appear to be
on the autism spectrum

Familial Dysautonomia is progressive and ultimately fatal. Although predictive studies suggest lifespans of individuals with FD are increasing, based on current numbers, fewer than 50% of individuals with FD live to 30. An estimated 600 children have been diagnosed with FD since the Dysautonomia Center was established at NYU in 1970.

Symptoms by organ systems:

lack of overflow tears (dry eyes)
corneal wounds (with poor healing)
optic atrophy
blepharitis (crusting and infection of eyelids)

lack of fungiform papilla on the tongue
fewer taste buds (may appear as a smooth tongue)
small jaw size with overcrowding of teeth
high arched palate
thin upper lip
early tooth loss (can be due to minor traumas such as bumping teeth on a hard surface)
tongue thrusting
tongue ulcers (sores) due to teeth rubbing

uncoordinated suck and swallow
episodes of cyclic vomiting
reflux (heartburn)
motility problems (constipation, dumping syndrome)

episodes of erratic fast heart rate and high blood pressure
low blood pressure (hypotension) with standing, can cause dizziness, blurred vision or fainting
long QT syndrome
sudden death
paradoxical low blood pressure and heart rate with exercise

Recurrent pneumonias due to aspiration
Inability to tolerate lower oxygen levels
Chronic cough
Poor oxygenation at high altitudes and in airplanes, necessitating the use of oxygen in flight

dehydration with elevated blood urea nitrogen (BUN)
poor kidney blood flow
salt wasting
renal insufficiency or failure
delayed urinary continence (night wetting generally until 11 years old)

Nervous system:
autonomic dysfunction
decreased ability to feel pain or temperature
decreased deep tendon reflexes
ataxia and apraxia
gait disturbances
“autonomic crisis”: (episodes of erratic blood pressure, heart rate, cyclical vomiting, gaseousness, temperature instability, excessive sweating and salivation, anorexia, and apparent discomfort)
seizures (breath-holding spells, febrile seizures, and seizure disorders)
dizziness, passing out

poor stamina
tender knots
tight muscles in shoulders, back, neck

exaggerated lordosis
neuropathic joints
inability to feel fractures
frequent fractures with decreased mineralization in cortical bone

poor wound healing
blotching with eating, excitement, or sleeping
excessive sweating (especially on the head)
seborrhea on the scalp or cradle cap
red, puffy hands

poor attention span
auditory processing problems
repetitive rubbing when in crisis
separation anxiety

breech presentation at birth
low birth weight
variable and late decelerations during labor
temperature instability in the newborn period

delayed puberty
delayed gross motor and fine motor development (late walking, poor handwriting)
delayed speech development
slurred or nasal speech
socially immature for age
short stature
poor weight gain and/or inability to maintain weight

Lab Findings:
elevated BUN
elevated DOPA:DHPG ratio
thrombocytopenia (intermittent and variable)
leukopenia (intermittent and variable)
IKBKAP gene mutation
decreased amounts of normal IKAP protein