INVITED REVIEW

ABSTRACT: Familial dysautonomia (FD) is a neurodevelopmental genetic

disorder within the larger classication of hereditary sensory and autonomic
neuropathies, each caused by a different genetic error. The FD gene has
been identied as IKBKAP. Mutations result in tissue-specic expression of
mutant IB kinase-associated protein (IKAP). The genetic error probably
affects development, as well as maintenance, of neurons because there is
neuropathological and clinical progression. Pathological alterations consist
of decreased unmyelinated and small-ber neurons. Clinical features reect
widespread involvement of sensory and autonomic neurons. Sensory loss
includes impaired pain and temperature appreciation. Autonomic features
include dysphagia, vomiting crises, blood pressure lability, and sudomotor
dysfunction. Central dysfunction includes emotional lability and ataxia. With
supportive treatment, prognosis has improved greatly. About 40% of patients are over age 20 years. The cause of death is usually pulmonary
failure, unexplained sudden deaths, or renal failure. With the discovery of the
genetic defect, denitive treatments are anticipated.
Muscle Nerve 29: 352-363, 2004

FAMILIAL DYSAUTONOMIA
FELICIA B. AXELROD, MD
Departments of Pediatrics and Neurology, New York University Medical Center,
530 First Avenue, New York, New York 10016, USA
Accepted 6 August 2003

Familial dysautonomia (FD), originally termed the

Riley-Day syndrome (R-D), is an autosomal recessive
disorder with extensive central and peripheral autonomic perturbations, as well as small-ber sensory
dysfunction.3,4,8,24,29,77 It is now appreciated that FD
is one member of a group of rare neurodevelopmental disorders termed hereditary sensory and autonomic neuropathies (HSAN)3,4 and thus has also
been termed HSAN type III.32 The complexity of the
autonomic nervous system and its intimate relationship with sensory function is especially well illustrated in these disorders. As the phenotypic and
neuropathological differences of the HSAN are being described, specic genetic mutations are being
identied, providing further insight into mechanisms affecting development and survival of the autonomic and sensory nervous systems.4
Abbreviations: ANP, atrial natriuretic peptide; DA, dopamine; DH, dopamine-beta-hydroxylase; DHPG, dihydroxyphenylglycol; DOPA, dihydroxyphenylalanine; FD, familial dysautonomia; HSAN, hereditary sensory and autonomic neuropathy; HVA, homovanillic acid; IKAP, IB kinase-associated
protein; JNK, c-Jun N-terminal kinase; NE, norepinephrine; VMA, vanillylmandelic acid
Key words: familial dysautonomia; hereditary sensory and autonomic neuropathy; IKBKAP gene; neurodevelopmental disorder; Riley-Day syndrome
Correspondence to: F.B. Axelrod; e-mail: Felicia.Axelrod@ccmail.med.
nyu.edu
2003 Wiley Periodicals, Inc.

352

Familial Dysautonomia

Although FD is the most prevalent of the HSAN

and has been the most intensely studied, for over 50
years diagnosis relied on clinical criteria, with conrmation in questionable cases supported by neuropathological data from sural nerve biopsy specimens.
However, with the recent identication of the genetic mutations causing the disorder, DNA diagnosis
is now available.2,80 The fact that over 99% of affected FD individuals share one common mutation
conrms the genetic homogeneity of the population
but leaves many questions regarding phenotypic diversity. The genetic defect affects prenatal neuronal
development so that symptoms are present from
birth, but individual expression varies widely.3,4,11
Because the entire autonomic nervous system is affected, there is a pervasive effect on the functioning
of other systems. However, with supportive treatments of its various manifestations, the prognosis for
affected individuals has improved and a growing
number of individuals affected with FD are surviving
into adulthood.5,19
GENETICS

FD is transmitted as an autosomal recessive disorder

and has a remarkably high carrier frequency in individuals of Ashkenazi, or Eastern European, Jewish
extraction. The other HSANs do not have the same
ethnic bias as FD.3,4 Initial epidemiological studies

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had estimated that the carrier rate for FD ranged

from 1 in 100 to 1 in 30.24,64 However, with the
identication of specic genetic mutations and
launching of population screening, the carrier frequency of the most common mutation in the Ashkenazi Jewish population has been reported to be
between 1 in 27 to 1 in 32.31,90
Using genetic linkage, in 1993 the gene was
mapped to the distal long arm of chromosome 9
(q31) with sufcient DNA markers to permit prenatal diagnosis and carrier identication for families in
which there was an affected individual.22 Recently, a
single noncoding mutation in the gene IKBKAP was
shown to cause 99.5% of all cases of FD.1,80 This
common FD mutation is a single base-change in the
donor splice site of intron 20. The result is an apparent decrease in splicing efciency that produces
variable skipping of exon 20 in the IKBKAP message,
producing truncated IKAP (IB kinase-associated
protein). A second FD mutation, a single GC
change in exon 19, was identied in four FD individuals of Ashkenazi Jewish extraction who were heterozygous for the intron splice mutation.1,80 A third
FD mutation, a proline to leucine missense mutation
in exon 26, has been seen only in one individual who
was also heterozygous for the common mutation but
inherited the missense mutation from a non-Jewish
parent.61 Both the second and third mutations appear to disrupt phosphorylation.61,80
Interestingly, despite the fact that FD is a recessive disease, homozygous mutant cells are capable of
expressing wild-type mRNA and protein and there is
tissue-specic expression.27,80 RNA isolated from FD
lymphoblast cell lines is primarily wild-type, whereas
RNA isolated from postmortem brain samples from
FD patients is primarily mutant, suggesting that neuronal cells are less capable of compensating for the
missplicing.
Because all of the HSANs affect neuronal development, mechanisms causing disease may involve
genes that encode neurotrophins, their receptors, or
any proteins that might participate in a neurotrophin-related signal transduction pathway. For example, HSAN type IV has been shown to result from
mutations in the gene that encodes a neurotrophin
receptor, NTRK1, which is located on chromosome
1.57 In FD, it is not known how the mutation in
IKBKAP causes or predisposes to this disease. Initial
studies suggested that IKAP, the protein encoded by
IKBKAP, was part of the IB kinase complex or
associated with the human Elongator complex in
transcriptional elongation.44 Recently, studies have
demonstrated that the IKAP protein is involved in
the regulation and activation of stress response

Familial Dysautonomia

through the c-Jun N-terminal kinase (JNK) signaling

pathway.42,56 Deletion of the c-terminal portion of
IKAP reduces c-Jun phosphorylation.56 It is possible
that the FD mutations in the c-terminal portion of
the IKBKAP gene alter the interaction of IKAP with
JNK and results in misregulation of JNK, leading to
inadequate development, poor differentiation, or
limited survival of neuronal cells.
NEUROPATHOLOGY

Consistent neuropathological ndings provide a

structural basis for many of the biochemical and
clinical features of the disease and help to distinguish this disorder from the other hereditary sensory
neuropathies; however, they leave unexplained the
dysfunctions of the higher central nervous system
that are clinically apparent.71 Pathological ndings
indicate that within the peripheral sensory and autonomic systems, individuals affected with FD suffer
from incomplete neuronal development as well as
progressive neuronal degeneration.70 72
Intrauterine development
and postnatal maintenance of sensory neurons are
affected, with the greatest impact on the nonmyelinated small-ber populations. The dorsal root ganglia are grossly reduced in size due to decreased
neuronal population.71,72 Within the spinal cord, lateral root entry zones and Lissauers tracts are severely depleted of axons. As evidence of slow progressive degeneration, there is a denite trend with
increasing age for further depletion of the number of
neurons in dorsal root ganglia and an increase in the
abnormal numbers of residual nodules of Nageotte in
the dorsal root ganglia.33,72 In addition, loss of dorsalcolumn myelinated axons becomes evident in older
patients. Neuronal depletion in dorsal root ganglia and
spinal cord correlate well with the clinical observations
of worsening pain and vibration sense with age.9
The sural nerve is reduced in its transverse fascicular area and contains markedly diminished numbers of nonmyelinated axons, as well as diminished
numbers of small-diameter myelinated axons.1,7,71
The sural nerve ndings are sufciently characteristic for familial dysautonomia to differentiate it from
other sensory neuropathies.3,4,7
Diminution of primary substance P axons in the
substantia gelatinosa of spinal cord and medulla has
been demonstrated using immunohistochemistry.75
Because substance P may be involved in synaptic
transmission of sensory neurons, the immunoreactive ndings support the electron microscopic ndings.
Sensory Nervous System.

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353

Consistent with an actual decrease in neuronal numbers, the mean volume of superior cervical sympathetic ganglia is reduced to 34% of the normal size (Fig. 1),70 yet
staining for tyrosine hydroxylase is enhanced in the
neurons that remain present in the sympathetic ganglia.73 Decreased numbers of neurons in the intermediolateral gray columns of the spinal cord suggests involvement of preganglionic neurons.70
Furthermore, autonomic nerve terminals cannot be
demonstrated on peripheral blood vessels.41 Lack of
innervation is consistent with postural hypotension,
as well as exaggerated responses to sympathomimetic and parasympathomimetic agents.21,28,88,89
Other than the sphenopalatine ganglia, which
are consistently reduced in size with low total neuronal counts, parasympathetic ganglia, such as the
ciliary ganglia, do not seem to be affected.69
Autonomic Nervous System.

These observations suggest that patients with FD

have normal peripheral chemoreceptors but an inordinate central depression of ventilation by hypoxia
(Fig. 2). Furthermore, hypoxia induces profound
circulatory responses consistent with sympathetic denervation, resulting in bradyarrhythmia and hypotension which can lead to syncope and even respiratory arrest (Fig. 3).
Studies of forearm blood ow have described
inappropriate arteriolar and venous tone responses
to both upright positioning and cold stimuli.23,49,53,54,67
In individuals with FD, vascular resistance did not increase with either stimulus. It is now well recognized
that individuals with FD consistently manifest orthostatic hypotension without compensatory tachycardia.14,15,17,93 Furthermore, transcranial Doppler study
in FD patients shows impaired cerebral autoregulation
and paradoxical cerebral vasoconstriction during
head-upright tilt.47,48,55

NEUROPHYSIOLOGY

Denervation extending to chemoreceptors and baroreceptors has never been demonstrated pathologically
but is strongly suggested by physiological studies and
severely compromises the ability of FD patients to
cope with respiratory infections and other potential
causes of hypoxia, such as high altitudes or pressurized airplane cabins. During hypoxia (12% O2), patients with FD initially increase ventilation but, with
continued hypoxia, ventilation decreases.20,34,35
Chemoreceptor and Baroreceptor Dysfunction.

Early studies of urinary

catecholamine metabolites demonstrated that FD
patients had elevated levels of homovanillic acid
(HVA) and normal to low levels of vanillylmandelic
acid (VMA), resulting in elevated HVA:VMA ratios.40,81,85,86 These ndings are consistent with studies demonstrating exaggerated responses to both
sympathomimetic and parasympathomimetic agents
and neuropathological descriptions of a decreased
sympathetic neuronal population.28,70,83,88,89 Al-

Catecholamine Metabolism.

FIGURE 1. Histograms of neuron distribution in sympathetic ganglia in patients with familial dysautonomia (FD) and controls. (Reproduced from Pearson and Pytel70 with permission from Elsevier.)

354

Familial Dysautonomia

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sion, do not have an appropriate increase in

plasma levels of NE and dopamine beta-hydroxylase (DH) with standing.14,16,93 In addition, FD
patients appear to have a distinctive pattern of
plasma levels of catechols (Fig. 4). Regardless of
posture, plasma levels of dihydroxyphenylalanine
(DOPA) are disproportionately high and plasma
levels of dihydroxyphenylglycol (DHPG) are low,
resulting in elevated plasma DOPA:DHPG ratios
that are not seen in other disorders associated with
neurogenic orthostatic hypotension.16 The high
plasma DOPA levels are consistent with FD subjects having an increased proportion of tyrosine
hydroxylase in superior cervical ganglia.73
When FD subjects are supine, there is a strong
correlation between mean blood pressure and
plasma levels of NE, but when they are upright, the
correlation is seen only with plasma dopamine (DA)
levels, suggesting that in FD patients DA may serve to
maintain upright blood pressure.16 During emotional crises, plasma NE and DA levels are markedly
elevated, and vomiting usually coincides with the
high dopamine levels. The elevation of plasma NE is
attributed to peripheral conversion of DA by DH.

FIGURE 2. Chemoreex sensitivity. Average regression lines of

the relationship between ventilation (VE), corrected for body
surface area (BSA), and oxygen saturation (SaO2) or end-tidal
CO2 (CO2-ET) in subjects with familial dysautonomia (FD) and
controls (C). The slopes of the regression lines indicate the
chemoreex sensitivity to either O2 or CO2. The regression lines
have different slopes (p 0.002) for the response to changes in
oxygen saturation, whereas the slopes are not signicantly different for the response to changes in CO2, indicating that the
threshold for starting ventilation in response to a change in CO2
is reset to a higher value in FD subjects.

though supine plasma levels of norepinephrine

(NE) are normal or elevated, FD patients, like most
other patients with neurogenic orthostatic hypoten-

Familial Dysautonomia

FIGURE 3. Ventilatory and cardiovascular responses to the rebreathing of 100% and 12% oxygen by six dysautonomic and six
normal subjects. Left hand points: 100% O2; right hand points:
12% O2. Upper panel: ventilatory response to CO2 expressed as
increase in ventilation per mmHg increase in PaCO2 normalized
for body surface area. Middle panel: each point represents the
change in mean systemic blood pressure from the beginning to
the end of a rebreathing period. Lower panel: each point represents the change in heart rate from the beginning to the end of a
rebreathing period. In contrast to control subjects, rebreathing
12% O2 by dysautonomia subjects resulted in a lower ventilatory
response to CO2 than during 100% rebreathing, bradycardia, and
a substantial fall in systemic blood pressure. (Reproduced with
permission from Edelman et al.34)

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355

treatment is supportive and oriented to the involved

systems.
The diagnosis should be suspected by
history and physical examination, which can provide
much of the essential information.3,4,8 However, because there can be extreme variability in expression,
the clinical diagnosis of FD is based upon the presence of ve relatively invariable cardinal criteria,
i.e., absence of overow emotional tears, absent lingual fungiform papillae (Fig. 5), depressed patellar
reexes, lack of an axon are following intradermal
histamine (Fig. 6), and documentation of Ashkenazi
Jewish extraction.3,4,62,82,87 Because individuals affected with the other HSANs will also fail to produce
an axon are after intradermal histamine, it is advised that DNA molecular diagnosis be performed in
questionable cases.
Diagnosis.

Sensory System. In the younger patient, sensory

abnormalities appear limited to the unmyelinated
neuronal population, but, in the older patient, there
is progressive involvement of myelinated neurons of
the dorsal column tracts.9,84 Although pain sensation

Table 1. Clinical features of familial dysautonomia.

FIGURE 4. Supine catechol values for 10 familial dysautonomia
(FD) and 8 control (C) subjects. FD values are averages from two
to three testing sessions. Control values are absolute values.
Horizontal bars are means. (A) Catecholamines: DA, dopamine;
NE, norepinephrine; EPI, epinephrine. (B) Catechol metabolites:
DOPA, dihydroxyphenylalanine; DOPAC, dihydroxy-phenylacetic
acid; DHPG, dihydroxyphenylglycol. (Reproduced with permission from Axelrod et al.16)

Other Vascular Modulators. Supine early morning

plasma renin activity is elevated in FD subjects and
the release of renin and aldosterone is not coordinated.76 In FD individuals with supine hypertension,
an increase in plasma atrial natriuretic peptide
(ANP) has also been demonstrated.15 The combination of these factors may serve to explain the exaggerated nocturnal urine volume and increased excretion of salt in some FD individuals especially
during stress and hypertension.
CLINICAL FEATURES AND MANAGEMENT

Although FD is a neurological disorder with perturbations that can be attributed to sensory and autonomic dysfunction, the clinical features are pervasive
and involve many other systems (Table 1). Therefore

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Familial Dysautonomia

System

Common symptoms

Frequency
(%)

Ocular

Decreased tears
Corneal analgesia
Optic atrophy

99
NA
NA

Gastrointestinal
dysfunction

Dysphagia
Esophageal and gastric
dysmotility
Gastroesophageal reux
Vomiting crises

60
60
67
40

Pulmonary

Aspirations
Insensitivity to hypoxia
Restrictive lung disease

NA
NA
NA

Orthopedic

Spinal curvature
Asceptic necrosis

85
15

Vasomotor

Postural hypotension
Blotching
Excessive sweating
Hypertensive crises

Neurological

Decreased deep tendon reexes

Decreased pain and temperature
sensation
Decreased vibration (after 13
years)
Progressive ataxia (in adults
years)

99
99
99
60
95
NA
NA
NA

NA, percentages not available.

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FIGURE 5. (A) Normal tongue with fungiform papillae present on the tip. (B) Dysautonomic tongue.

is decreased, it is not completely absent and there is

usually sparing of the palms, soles of feet, neck, and
genital areas, with these areas often being exquisitely
sensitive. Temperature appreciation, as documented
by sympathetic skin responses and quantitative analysis
of warm and cold thresholds, is also affected.46,50 52
With both pain and temperature perceptions, the
trunk and lower extremities are more affected and
older individuals have greater losses than younger subjects.9 In the older individual, vibration sense, and
occasionally joint position, become abnormal and a
positive Romberg sign may be noted.9,46 Visceral sensation is intact so patients are able to perceive discomfort with pleuritic or peritoneal irritation.
Peripheral sensory deprivation makes the FD patient prone to self-injury. Inadvertent trauma to
joints and long bones can cause avascular necrosis
and unrecognized fractures.60,68 Treatment of spinal
curvature requires extreme care in tting of braces
to avoid development of pressure decubiti on insensitive skin. Central sensory decits include decreased
pain perception along the branches of the trigeminal nerve, diminished corneal reexes, and decreased taste perception, especially in recognition of
sweet, which corresponds to the absence of fungiform papillae on the tip of the tongue.87
Motor problems are most apparent in the very
young child and the older patients. The child with
FD is frequently hypotonic, which may be due to a
combination of central decits and decreased tone
of stretch receptors. The older patients have difculty in maintaining independent ambulation. The
gait becomes broad-based and ataxic.4,8
Pervasive autonomic dysfunction results in protean functional abnormalities.
As the disorder has variable expression, there are
individual variations. Some of these manifestations
Autonomic Dysfunction.

Familial Dysautonomia

are apparent at birth and others become more

prominent and problematic with age.
Gastrointestinal System. Oropharyngeal incoordination is one of the earliest signs of FD. Poor suck or
discoordinated swallow is observed in 60% of infants.6,8 Oral incoordination may persist in the older
patient and be manifested as a tendency to drool and
a preference for soft foods. Liquids are often aspirated. Cineradiographic swallowing studies may document the level of functional ability.25,43,58,66 If dysphagia impedes maintenance of nutrition or causes
respiratory problems, then gastrostomy is recommended.6
The most prominent manifestation of gastrointestinal dysmotility in FD individuals is the propensity to
vomit. Vomiting can occur intermittently as part of a
systemic reaction to physical or emotional stress or it
can occur daily in response to the stress of arousal.
Because vomiting is often associated with hypertension, tachycardia, diffuse sweating, and even person-

FIGURE 6. Histamine test. Dysautonomic reaction (forearm on

top) demonstrates a narrow areola surrounding the wheal. Normal reaction (lower forearm) displays diffuse axon are around a
central wheal.

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357

FIGURE 7. Tc-99m ECD SPECT studies in one patient with familial dysautonomia (FD). Representative SPECT slices through the areas
of interest during crisis (A) and at baseline when not in crisis (B). In each set, a transverse slice is in the top panel, a coronal slice is in
the middle, and a sagittal slice is on the bottom. Transverse and coronal images are displayed so that the right hand of the gure
corresponds to the left side of the brain. Images obtained during crisis (A) show foci of increased uptake in the left temporal lobe and the
left medial insular cortex which is best appreciated on coronal and sagittal views (arrows). On images from the baseline scan (B), these
areas are no longer hyperperfused. (Reproduced with permission from Axelrod et al.14)

ality change, this constellation of signs has been

termed the dysautonomic crisis.3,4,6,8 Diazepam is the
most effective antiemetic for the dysautonomic crisis,
suggesting that the crisis may be a central phenomenon like an autonomic seizure6,18 (Fig. 7). Because

358

Familial Dysautonomia

hypertension may be extreme, clonidine is a useful

adjunct.
Gastroesophageal reux is another common problem. If it is identied, medical management including prokinetic agents and H2-antagonists should be

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tried. However, if pneumonia, hematemesis, or apnea occur, then surgical intervention (fundoplication) is recommended.6,10,13,91 After surgery, dysautonomic crises may continue. Although overt emesis
is prevented, the patient may continue to have prolonged retching.
Respiratory System. Aspiration is the major cause
of lung infections. Most lung damage occurs during
infancy and early childhood when oral incoordination is extremely poor and the diet contains mostly
liquids. If gastroesophageal reux is present, the risk
for aspiration increases.
The ventilatory response to lung infection is often altered due to insensitivity to hypoxia and hypercarbia.20,34,35,65 Hypoxia does not induce appropriate
increases in minute ventilation and can result in
syncope as a consequence of hypotension and bradycardia. Situations where the partial pressure of
oxygen is decreased, such as high altitudes or pressurized airplane cabins, can be potentially hazardous. Furthermore, sleep architecture is frequently
abnormal with central apneas and hypopnea that

FIGURE 8. Hemodynamic response to change in position and

exercise in controls and familial dysautonomia (FD) subjects.
Columns represent mean blood pressures with 1 SD bars. (Reproduced with permission from Axelrod et al.14)

Familial Dysautonomia

can result in profound desaturations and may contribute to the increased incidence of death in
sleep.5,19,37
Cardiovascular Irregularities. Consistent with
sympathetic dysfunction, patients exhibit rapid and
severe orthostatic decreases in blood pressure, without appropriate compensatory increases in heart
rate4,8,14,15,93(Fig. 8). Clinical manifestations of postural hypotension include episodes of lightheadedness
or dizzy spells. Some patients complain of weak
legs. On occasion, there may be syncope. Symptoms
tend to be worse in the morning, in hot or humid
weather, or with vagal stimuli such as following micturition or bowel movement, or with gastric distension from large meals. Symptoms referable to hypotension become more prominent in the adult years
and can limit function and mobility. Postural hypotension is treated by increasing plasma volume with
oral hydration, increased dietary salt, and udrocortisone. Other useful measures include lower-extremity exercises to increase muscle tone and promote
venous return, elastic stockings, and midodrine, an
alpha-adrenergic agonist.
General anesthesia has the potential for inducing
severe hypotension. With greater attention to stabilization of the vascular bed by hydrating the patient
before surgery and titrating the anesthetic to continuously monitored arterial blood pressure, anesthetic
risk has been greatly reduced.12
In older patients, supine hypertension may become
prominent despite the retention of severe responses
to orthostatic challenge. Hypertension may also occur intermittently in response to emotional stress or
visceral pain or as part of the crisis constellation. The
hypertension will respond to the same medications
recommended for crisis management, i.e., diazepam
and clonidine. Hypertension may also exist without
any other symptoms. Because the blood pressure is
so labile in individuals with FD, asymptomatic hypertension is not usually treated as it is usually transitory
and appears to be better tolerated than hypotension.
Although FD subjects consistently exhibit orthostatic instability, they have variable electrocardiographic
ndings.17,38,39,63,79 As part of the progressive nature
of FD, there is further diminution of sympathetic
function and development of heightened parasympathetic dysfunction. Heart rate variability studies,
using power spectral analysis, indicate that with exertion, there is inappropriate persistence of parasympathetic activity and failure to enhance sympathetic
activity.63 Prolongation of the QTc occurs in some
patients and may be an ominous sign.38,39 Patients
have been shown to have arrhythmias, and pacemak-

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359

ers have been required for documented asystolic

episodes.79
Renal Problems. Azotemia is frequently prerenal
in origin. Although clinical signs of dehydration may
not be present, blood urea nitrogen values often can
be reduced by simple hydration. Renal function appears to deteriorate with advancing age, so that
about 20% of adult patients have reduced renal
function.8 Renal biopsies performed on individuals
with uncorrectable azotemia revealed signicant
ischemic-type glomerulosclerosis and decient vascular innervation.74 Renal hypoperfusion secondary
to cardiovascular instability has been suggested as
the cause of the progressive renal disease.14 This
hypothesis was supported by studies utilizing the
technique of renal artery Doppler blood velocity
waveform analysis, which demonstrated decreased
renal systolic velocity when FD patients were upright
and exercised. Thus, aggressive treatment of postural hypotension appears to be justied.
Ophthalmological Disorders. Individuals with FD
do not cry with overow tears.59,62,77 Corneal hypesthesia also affects the ocular status, as it results in
decreased blink frequency and indifference to corneal trauma. Epithelial erosions of the exposed cornea and conjunctiva are the hallmarks of dry-eye
states. These lesions may become conuent, leading
to patchy areas of de-epithelialization. Early treatment of corneal epithelial erosions includes increased frequency of application of tear substitutes,
attention to the general state of hydration, and
search for precipitating systemic factors that might
have disturbed the patients fragile catecholamine
homeostasis. Persistent erosions or ulcerations may
require a therapeutic soft contact lens, occlusion of
the lacrimal puncta, or small lateral tarsorrhaphies
that limit the area exposed to surface evaporation.
Corneal grafts generally have not been successful as
the dry anesthetic cornea is an unfavorable environment for the graft.
Other ophthalmological features include hyperreactivity to sympathetic and parasympathetic agents
as well as a tendency to myopia, strabismus, and
optic atrophy.30,62,88
Orthopedic Problems. There is a high incidence
of juvenile scoliosis in familial dysautonomia and this
can be pernicious in its course.45,78 By age 10 years,
85% of FD patients exhibit structural spine curvatures.78 Left thoracic curves occur more frequently
than in idiopathic scoliosis. In addition to contributing to short stature, kyphoscoliosis causes restrictive
chest deformities that further compromise pulmonary function.

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Familial Dysautonomia

There are also a number of nonspinal orthopedic

problems that limit function including tibial torsion
and a high frequency of unrecognized fractures and
aseptic necrosis that usually, but not exclusively, involves weight-bearing joints.60,68
Central Nervous System Features. Emotional lability has been considered one of the prominent features of FD and was stressed in its original description.26,36,77 It is now appreciated that the behavioral
abnormalities tend to be part of the central autonomic dysfunction, which intensify during crisis. Using a functional neuroimaging technique to assess
cerebral perfusion, i.e., Tc-99m ethylene cysteine
dimer (ECD) SPECT, hyperperfusion of the temporal and frontal areas during crisis was demonstrated.18 In addition, the ameliorating effect of benzodiazepines supports this hypothesis.6
Most affected individuals are of normal intelligence. In one study, 38% of FD patients had less
than average intelligence but correlation with other
systemic problems was not available.92 In general,
patients tend to be literal and have difculty extrapolating, visual intellect exceeds verbal intellect, and
executive planning skills are poor.
Seizures have been seen as a result of hypoxia or
metabolic perturbations such as a low serum sodium
level. The hyponatremia can be secondary to excessive salt wasting during hot weather due to uncompensated losses from sweating or excessive free water
intake. Hyponatremia can also accompany crises as a
result of prolonged hypertension and concomitant
excessive ANP and DA production.15 Prolonged
breath-holding with crying can be severe enough to
result in cyanosis, syncope, and decerebrate posturing, and may represent a type of seizure activity.
Breath-holding is frequent in the early years, occurring at least once in 63% of patients. This phenomenon probably is a manifestation of insensitivity to
hypoxia. It can become a manipulative maneuver
with some children. In our experience, the episodes
are self-limited, cease by 6 years of age, and have
never been fatal.8
PROGNOSIS

With greater understanding of the disorder and the

development of treatment programs, survival is improving for patients with familial dysautonomia.5,19,24
Survival statistics prior to 1960 reveal that 50% of
patients died before 5 years of age.24 The most current survival statistics indicate that a newborn with
FD now has a 50% probability of reaching 40 years of
age.19 Quality of life has also improved. Many FD
adults have been able to achieve independent func-

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tion. Both men and women with FD have married

and reproduced. All offspring have been phenotypically normal despite their obligatory heterozygote
state.
However, the presence of an adult FD population
has provided evidence for the progressive nature of
the disorder. Adult FD patients do not appear to
appreciate the decline in their sensory abilities but
they frequently complain of poor balance, unsteady
gait, and difculty in concentrating. They are prone
to depression, anxieties, and even phobias.26 With
increasing age, sympathovagal balance becomes
more precarious with worsening of orthostatic hypotension, development of supine hypertension, and
even occasional bradyarrhythmias.17,19
Causes of death are less often related to pulmonary complications, indicating that aggressive treatment of aspirations has been benecial.5,19 Of recent
concern have been the patients who have succumbed to unexplained deaths that may have been
the result of unopposed vagal stimulation or a sleep
abnormality.19 A few adult patients have died of
renal failure.
FUTURE GOALS

The recent identication of the FD gene should

provide insight into the molecular mechanisms of
FD, as well as help to understand the processes involved in normal development and maintenance of
the sensory and autonomic nervous systems. Furthermore, it is anticipated that this information will help
in differentiating FD from the other HSANs, lead to
denitive treatments for individuals affected with
FD, and foster innovative treatment approaches for
other autonomic and sensory disorders.

REFERENCES
1. Aguayo AJ, Nair CPV, Bray GM. Peripheral nerve abnormalities in the Riley-Day syndrome, ndings in sural nerve biopsy.
Arch Neurol 1971;24:106 116.
2. Anderson SL, Coli R, Daly IW, Kichula EA, Volpi SA, Ekstein
J, Rubin BY. Familial dysautonomia is caused by mutations in
the IKAP gene. Am J Hum Genet 2001;68:753758.
3. Axelrod FB. Autonomic and sensory disorders. In: Emory
AEH, Rimoin DL, editors. Principles and practice of medical
genetics, 3rd ed. Edinburgh: Churchill Livingstone; 1996. p
397 411.
4. Axelrod FB. Hereditary sensory and autonomic neuropathies:
familial dysautonomia and other HSANs. Clin Auton Res
2002;12(Suppl 1):214.
5. Axelrod FB, Abularrage JJ. Familial dysautonomia. A prospective study of survival. J Pediatr 1982;101:234 236.
6. Axelrod FB, Maayan C. Familial dysautonomia. In: Burg FD,
Ingelnger JR, Wald ER, Polin RA, editors. Gellis and Kagens
current pediatric therapy, 16th ed. Philadelphia: WB Saunders; 1999. p 466 469.

Familial Dysautonomia

7. Axelrod FB, Pearson J. Congenital sensory neuropathies. Diagnostic distinction from familial dysautonomia. Am J Dis
Child 1984;138:947954.
8. Axelrod FB, Nachtigall R, Dancis J. Familial dysautonomia:
diagnosis pathogenesis and management. In: Schulman I,
editor. Advances in pediatrics, Vol 21. Chicago: Yearbook;
1974. p 7596.
9. Axelrod FB, Iyer K, Fish I, Pearson J, Sein ME, Spielholz N.
Progressive sensory loss in familial dysautonomia. Pediatrics
1981;65:517522.
10. Axelrod FB, Schneider KM, Ament ME, Kutin ND,
Fonkalsrud EW. Gastroesophageal fundoplication and gastrostomy in familial dysautonomia. Ann Surg 1982;195:253
258.
11. Axelrod FB, Porges RF, Sein ME. Neonatal recognition of
familial dysautonomia. J Pediatr 1987;110:946 948.
12. Axelrod FB, Donnenfeld R, Danziger F, Turndorf H. Anesthesia in familial dysautonomia. Anesthesiology 1988;68:631
635.
13. Axelrod FB, Gouge TH, Ginsburg HB, Bangaru BS, Hazzi C.
Fundoplication and gastrostomy in familial dysautonomia.
J Pediatr 1991;118:388 394.
14. Axelrod FB, Glickstein JS, Weider J, Gluck MC, Friedman D.
The effects of postural change and exercise on renal haemodynamics in familial dysautonomia. Clin Auton Res 1993;3:
195200.
15. Axelrod FB, Krey L, Clickstein JS, Freidman D, Weider J,
Metakis L, Porges VM, Mineo M, Notterman. Atrial natriuretic peptide and catecholamine response to orthostatic
hypotension and treatments in familial dysautonomia. Clin
Auton Res 1994;4:311318.
16. Axelrod FB, Goldstein DS, Holmes C, Berlin D, Kopin I.
Pattern of plasma catechols in familial dysautonomia. Clin
Auton Res 1996;6:205209.
17. Axelrod FB, Putman D, Berlin D, Rutkowski M. Electrocardiographic measures and heart rate variability in patients with
familial dysautonomia. Cardiology 1997;88:133140.
18. Axelrod FB, Zupanc M, Hilz MJ, Kramer EL. Ictal SPECT
during autonomic crisis in familial dysautonomia. Neurology
2000;55:122125.
19. Axelrod FB, Goldberg JD, Ye XY, Maayan C. Survival in familial dysautonomia: impact of early intervention. J Pediatr 2002;
141:518 523.
20. Bernardi L, Hilz M, Stemper B, Passino C, Welsch G, Axelrod
FB. Respiratory and cerebrovascular responses to hypoxia and
hypercapnia in familial dysautonomia. Am J Respir Crit Care
Med 2002;167:141149.
21. Bickel A, Axelrod FB, Schmetz M, Marthal H, Hilz MJ. Dermal
microdialysis provides evidence for hypersensitivity to noradrenaline in patients with familial dysautonomia. J Neurol
Neurosurg Psychiatry 2002;73:299 302.
22. Blumenfeld A, Slaugenhaupt SA, Axelrod FB, Lucente DE,
Maayan C, Lieberg CB, Ozelius LJ, Trofatter JA, Haines JL,
Breakeeld XO, Gusella JF. Localization of the gene for
familial dysautonomia on chromosome 9 and denition of
DNA markers for genetic diagnosis. Nat Genet 1993;4:160
164.
23. Brown CM, Stemper B, Welsch G, Brys M, Axelrod FB, Hilz
MJ. Orthostatic challenge reveals impaired vascular resistance
control but normal venous pooling and capillary ltration in
familial dysautonomia. Clin Sci 2003;104:163169.
24. Brunt PW, McKusick VA. Familial dysautonomia. A report of
genetic and clinical studies with a review of the literature.
Medicine 1970;48:343374.
25. Brunt PW, Margulies SI, Coburn WM, Donner MW, Hendrix
TR. The esophagus in dysautonomia: a manometric and cineuorographic study. Gut 1967;8:636 637.
26. Clayson D, Welton W, Axelrod FB. Personality development
and familial dysautonomia. Pediatrics 1980;65:269 274.
27. Cuajungco MP, Leyne M, Gill SP, Mull J, Lu W, Zagzag D,
Axelrod FB, Gusella JF, Maayan C, Slaugenhaupt SA. Tissuespecic reduction in splicing efciency of IKBKAP due to the

MUSCLE & NERVE

March 2004

361

28.
29.
30.
31.

32.

33.

34.

35.
36.
37.
38.

39.

40.
41.
42.
43.
44.

45.
46.
47.

48.

362

major mutation associated with familial dysautonomia. Am J

Hum Genet 2003,72:749 758.
Dancis J. Altered drug reponses in familial dysautonomia.
Ann NY Acad Sci 1968;151:876 879.
Dancis J, Smith AA. Familial dysautonomia. N Engl J Med
1966;274:207209.
Diamond GA, DAmico RA, Axelrod FB. Optic nerve dysfunction in familial dysautonomia. Am J Ophthalmol 1987;104:
645 648.
Dong J, Edelmann L, Bajwa AM, Kornreich R, Desnick R.
Familial dysautonomia: detection of the IKBKAP IVS206T3 C
and R696P mutations and frequencies among Ashkenazi Jews.
Am J Med Genet 2002;110:253257.
Dyck PJ. Neuronal atrophy and degeneration predominantly
affecting peripheral sensory and autonomic neurons. In:
Dyck PJ, Thomas PK, Grifn JW, Low PA, Poduslo JF, editors.
Peripheral neuropathy. Philadelphia: WB Saunders; 1993. p
10651093.
Dyck P, Kawamura Y, Low PA, Shimono M. The numbers and
sizes of reconstructed peripheral anatomic sensory and motor
neurons in a case of dysautonomia. J Neuropathol Exp Neurol 1978;37:741755.
Edelman NH, Cherniack NS, Lahiri S, Richards E, Fishman
AP. The effects of abnormal sympathetic nervous function
upon the ventilatory response to hypoxia. J Clin Invest 1970;
41:11531165.
Filler J, Smith AA, Stone S, Dancis J. Respiratory control in
familial dysautonomia. J Pediatr 1965;66:509 516.
Freedman AM, Helme W, Havel J, Eustis MJ, Riley C, Langford WS. Psychiatric aspects of familial dysautonomia. Am J
Orthopsychiatry 1957;27:96 106.
Gadoth N, Sokol J, Lavie P. Sleep structure and nocturnal
disordered breathing in familial dysautonomia. J Neurol Sci
1983;60:117125.
Glickstein JS, Schwartzman D, Friedman D, Rutkowski M,
Axelrod F. Abnormalities of the corrected QT interval in
familial dysautonomia: an indicator of autonomic dysfunction. J Pediatr 1993;122:925928.
Glickstein JS, Axelrod FB, Friedman D. Electrocardiographic
repolarization abnormalities in familial dysautonomia: an indicator of autonomic dysfunction. Clin Auton Res 1999;9:109:
112.
Goodall G, Gitlow SE, Alton H. Decreased noradrenaline
synthesis in FD. J Clin Invest 1971;50:2734 2740.
Grover-Johnson N, Pearson J. Decient vascular innervation
in familial dysautonomia, an explanation for vasomotor instability. J Neuropathol Appl Neurobiol 1976;2:217224.
Gupta S, Campbell D, Derijard B, Davis RJ. Transcription
factor ATF2 regulation by the JNK signal transduction pathway. Science 1995;267:389 393.
Gyepes MT, Linde LM. Familial dysautonomia: the mechanism of aspiration. Radiology 1968;91:471 475.
Hawkes NA, Otero G, Winkler GS, Marshall N, Dahmus ME,
Krappmann D, Scheidereit C, Thomas CL, Schiavo G, Erdjument-Bromage H, Tempst P, Svejstrup JQ. Purication and
characterization of the human elongator complex. J Biol
Chem 2002;277:30473052.
Hayek S, Laplaza J, Axelrod FB, Burke SW. Spinal deformity
in familial dysautonomia: prevalence and results of brace
management. J Bone Joint Surg (Am) 2000;82:1558 1562.
Hilz MJ, Axelrod FB. Quantitative sensory testing of thermal
and vibratory perception in familial dysautonomia. Clin Auton Res 2000;10:177183.
Hilz MJ, Axelrod FB, Haertl U, Sauer P, Steingrueber M,
Braeske K, Neundorfer B. Transcranial Doppler sonography
during tilt test in familial dysautonomia. Clin Auton Res
1996;6:272.
Hilz MJ, Axelrod FB, Sauer P, Russo H, Heckman JG, Neundorfer B. TCD in familial dysautonomia patients shows impaired cerebral autoregulation and paradoxic cerebral vasoconstriction during head-upright tilt. J Neuroimaging 1997;
7:240.

Familial Dysautonomia

49. Hilz MJ, Axelrod FB, Sauer P, Hagler A, Russo H, Neundorfer

B. Cold pressor test demonstrates peripheral sympathetic failure in familial dysautonomia despite impaired thermal perception. Clin Auton Res 1998;8:42 43.
50. Hilz MJ, Kolodny EH, Neuner I, Stemper B, Axelrod FB.
Highly abnormal thermotest in familial dysautonomia suggests increased cardiac autonomic risk. J Neurol Neurosurg
Psychiatry 1998;65:338 343.
51. Hilz MJ, Axelrod FB, Schweibold G, Kolodny EH. Sympathetic
skin response following thermal, electrical, acoustic and inspiratory gasp stimulation in familial dysautonomia patients
and healthy persons. Clin Auton Res 1999;9:165177.
52. Hilz MJ, Stemper B, Axelrod FB. Sympathetic skin response
differentiates hereditary sensory autonomic neuropathies
types III and IV. Neurology 1999;52:16521657.
53. Hilz MJ, Stemper B, Sauer P, Haertl U, Singer W, Axelrod FB.
Cold face stimulation demonstrates parasympathetic dysfunction in familial dysautonomia. Am J Physiol 1999;276:R1833
R1839.
54. Hilz MJ, Axelrod FB, Braeske K, Stemper B. Cold pressor test
demonstrates residual sympathetic cardiovascular activation
in familial dysautonomia. J Neurol Sci 2002;196:81 89.
55. Hilz MJ, Axelrod FB, Steingrueber M, Stemper B. Valsalva
maneuver suggests increased rigidity of cerebral resistance
vessels in familial dysautonomia. Clin Auton Res 2002;12:385
392.
56. Holmberg C, Katz S, Lerdrup M, Herdegen T, Jaattela M,
Aronheim A, Kallunki T. A novel specic role for IB kinase
complex-associated protein in cytosolic stress signaling. J Biol
Chem 2002;277:31918 31928.
57. Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano
T, Mitsubuchi H, Tonoki H, Awaya Y, Matsuda I. Mutations in
the NTRKA/NGF receptor gene in patients with congenital
insensitivity to pain with anhidrosis. Nat Genet 1996;13:485
488.
58. Krausz Y, Maayan C, Faber J, Marciano R, Mogle P, Wynchank
S. Scintigraphic evaluation of esophageal transit and gastric
emptying in familial dysautonomia. J Radiol 1994;18:5256.
59. Kroop IG. The production of tears in familial dysautonomia:
preliminary report. J Pediatr1956;58:328 329.
60. Laplaza J, TurajaneT, Axelrod FB, Burke SW. Non-spinal
orthopaedic problems in familial dysautonomia. J Pediatric
Orthop 2001;21:229 232.
61. Leyne M, Mull J, Gill SP, Cuajungco MP, Oddoux C, Blumenfeld A, Maayan C, Gusella JF, Axelrod FB, Slaugenhaupt SA.
Identication of the rst non-Jewish mutation in familial
dysautonomia. Am J Med Genet 2003;118A:305308.
62. Liebman SD. Ocular manifestations of Riley-Day syndrome.
Arch Ophthalmol 1956;56:719 725.
63. Maayan C, Axelrod FB, Axselrod S, Carley DW, Shannon CD.
Evaluation of autonomic dysfunction in familial dysautonomia by power spectral analysis. J Auton Nerv Syst 1987;21:51
58.
64. Maayan C, Kaplan E, Shachar S, Peleg O, Godfrey S. Incidence of familial dysautonomia in Israel 19771981. Clin
Genet 1987;32:106 108.
65. Maayan C, Carley DW, Axelrod FB, Grimes J, Shannon DC.
Respiratory system stability and abnormal carbon dioxide
homeostasis. J Appl Physiol 1992;72:1186 1193.
66. Margulies SI, Brunt PW, Silbiger ML. Familial dysautonomia:
a cineradiographic study of the swallowing mechanism. Radiology 1968;90:107112.
67. Mason DT, Kopin IJ, Braunwald E. Abnormalities in reex
control of the circulation in familial dysautonomia. Am J Med
1966;41:898 909.
68. Mitnick J, Axelrod FB, Genieser N, Becker M. Aseptic necrosis
in familial dysautonomia. Radiology 1982;142:89 91.
69. Pearson J, Pytel B. Quantitative studies of ciliary and sphenopalatine ganglia in familial dysautonomia. J Neurol Sci 1978;
39:123130.

MUSCLE & NERVE

March 2004

70. Pearson J, Pytel B. Quantitative studies of sympathetic ganglia

and spinal cord intermedio-lateral gray columns in familial
dysautonomia. J Neurol Sci 1978;39:4759.
71. Pearson J, Axelrod FB, Dancis J. Current concepts of dysautonomia: neurological defects. Ann NY Acad Sci 1974;228:
288 300.
72. Pearson J, Pytel B, Grover-Johnson N, Axelrod FB, Dancis J.
Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia.
J Neurol Sci 1978;35:7797.
73. Pearson J, Brandeis L, Goldstein M. Tyrosine hydroxylase
immunohistoreactivity in familial dysautonomia. Science
1979;206:7172.
74. Pearson J, Gallo G, Gluck M, Axelrod F. Renal disease in
familial dysautonomia. Kidney Int 1980;17:102112.
75. Pearson J, Brandeis L, Cuello AC. Depletion of substance
P-containing axons in substantia gelatinosa of patients with
diminished pain sensitivity. Nature 1982;295:61 63.
76. Rabinowitz D, Landau H, Rosler A, Moses SW, Rotem Y,
Freier S. Plasma renin activity and aldosterone in familial
dysautonomia. Metabolism 1974;23:15.
77. Riley CM, Day RL, Greely DMcL, Langford WS. Central autonomic dysfunction with defective lacrimation. Report of 5
cases. Pediatrics 1949;3:468 477.
78. Rubery PT, Spielman JH, Hester P, Axelrod FB, Burke SW,
Levine DB. Scoliosis in familial dysautonomia. J Bone Joint
Surg 1995;77:13621369.
79. Rutkowski M, Axelrod FB, Danilowicz D. Transient thirddegree atrioventricular block in a 4-year-old-child with familial dysautonomia. Pediatr Cardiol 1992;13:184 186.
80. Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J,
Cuajungo MP, Liebert CB, Chadwick B, Idelson M, Reznik L,
Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella JF. Tissue-specic
expression of a splicing mutation in the IKBKAP gene causes
familial dysautonomia. Am J Hum Genet 2001;68:598 605.

Familial Dysautonomia

81. Smith AA, Dancis J. Physiologic studies in familial dysautonomia. J Pediatr 1963;63:838 840.
82. Smith AA, Dancis J. Response to intradermal histamine in
familial dysautonomia: a diagnostic test. J Pediatr 1963;63:
889 894.
83. Smith AA, Dancis J. Exaggerated response to infused norepinephrine in familial dysautonomia. N Engl J Med 1964;270:
704 707.
84. Smith AA, Dancis J. Peripheral sensory decits in familial
dysautonomia. J Pediatr 1964;65:10351036.
85. Smith AA, Dancis J. Catecholamine release in familial dysautonomia. N Engl J Med 1967;277;61 64.
86. Smith AA, Taylor T, Wortis SB. Abnormal catecholamine
metabolism in familial dysautonomia. N Engl J Med 1963;268:
705707.
87. Smith AA, Farbman A, Dancis J. Absence of taste bud papillae
in familial dysautonomia. Science 1965;147:1040 1041.
88. Smith AA, Dancis J, Breinin G. Ocular responses to autonomic drugs in familial dysautonomia. Invest Ophthalmol
1965;4:358 361.
89. Smith AA, Hirsch JI, Dancis J. Responses to infused methacholine in familial dysautonomia. Pediatrics 1965;36:225230.
90. Sugarman EA, Allitto BA. Familial dysautonomia mutation
frequency: clinical testing of greater than 2700 specimens
conrms high frequency in Ashkenazi Jews. Am J Hum Genet
2002;71(Suppl):387.
91. Udassin R, Seror D, Vinograd I, Zamir O, Godfrey S, Nissan S.
Nissen fundoplication in the treatment of children with familial dysautonomia. Am J Surg 1992;164:332336.
92. Welton W, Clayton D, Axelrod F, Levine D. Intellectual development in familial dysautonomia. Pediatrics 1979;63:708
712.
93. Ziegler MG, Lake RC, Kopin IJ. Decient sympathetic nervous
system response in familial dysautonomia. N Engl J Med
1976;294:630 633.

MUSCLE & NERVE

March 2004

363