INVITED REVIEW ABSTRACT: Familial dysautonomia (FD) is a neurodevelopmental genetic

disorder within the larger classification of hereditary sensory and autonomic

neuropathies, each caused by a different genetic error. The FD gene has
been identified as IKBKAP. Mutations result in tissue-specific expression of
mutant I␬B 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-fiber neurons. Clinical features reflect
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 pa-
tients 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, definitive 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 auto-
nomic perturbations, as well as small-fiber sensory
dysfunction.3,4,8,24,29,77 It is now appreciated that FD
is one member of a group of rare neurodevelopmen-
tal disorders termed hereditary sensory and auto-
nomic neuropathies (HSAN)3,4 and thus has also
been termed HSAN type III.32 The complexity of the
autonomic nervous system and its intimate relation-
ship with sensory function is especially well illus-
trated in these disorders. As the phenotypic and
neuropathological differences of the HSAN are be-
ing described, specific genetic mutations are being
identified, providing further insight into mecha-
nisms affecting development and survival of the au-
tonomic and sensory nervous systems.4
Abbreviations: ANP, atrial natriuretic peptide; DA, dopamine; D␤H, dopam-
ine-beta-hydroxylase; DHPG, dihydroxyphenylglycol; DOPA, dihydroxyphe-
nylalanine; FD, familial dysautonomia; HSAN, hereditary sensory and auto-
nomic neuropathy; HVA, homovanillic acid; IKAP, I␬B kinase-associated
protein; JNK, c-Jun N-terminal kinase; NE, norepinephrine; VMA, vanillylman-
delic acid
Key words: familial dysautonomia; hereditary sensory and autonomic neu-
ropathy; IKBKAP gene; neurodevelopmental disorder; Riley-Day syndrome
Correspondence to: F.B. Axelrod; e-mail: Felicia.Axelrod@ccmail.med.
nyu.edu
© 2003 Wiley Periodicals, Inc.
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 con-
firmation in questionable cases supported by neuro-
pathological data from sural nerve biopsy specimens.
However, with the recent identification of the ge-
netic mutations causing the disorder, DNA diagnosis
is now available.2,80 The fact that over 99% of af-
fected FD individuals share one common mutation
confirms the genetic homogeneity of the population
but leaves many questions regarding phenotypic di-
versity. 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 af-
fected, there is a pervasive effect on the functioning
of other systems. However, with supportive treat-
ments 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 in-
dividuals of Ashkenazi, or Eastern European, Jewish
extraction. The other HSANs do not have the same
ethnic bias as FD.3,4 Initial epidemiological studies

352 Familial Dysautonomia MUSCLE & NERVE March 2004

had estimated that the carrier rate for FD ranged
from 1 in 100 to 1 in 30.24,64 However, with the
identification of specific genetic mutations and
launching of population screening, the carrier fre-
quency of the most common mutation in the Ash-
kenazi 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 sufficient DNA markers to permit prena-
tal diagnosis and carrier identification 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 ap-
parent decrease in splicing efficiency that produces
variable skipping of exon 20 in the IKBKAP message,
producing truncated IKAP (I␬B kinase-associated
protein). A second FD mutation, a single G–C
change in exon 19, was identified in four FD indi-
viduals of Ashkenazi Jewish extraction who were het-
erozygous 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 ap-
pear to disrupt phosphorylation.61,80
Interestingly, despite the fact that FD is a reces-
sive disease, homozygous mutant cells are capable of
expressing wild-type mRNA and protein and there is
tissue-specific 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 neu-
ronal cells are less capable of compensating for the
missplicing.
Because all of the HSANs affect neuronal devel-
opment, mechanisms causing disease may involve
genes that encode neurotrophins, their receptors, or
any proteins that might participate in a neurotro-
phin-related signal transduction pathway. For exam-
ple, 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 I␬B 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 findings provide a
structural basis for many of the biochemical and
clinical features of the disease and help to distin-
guish 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 findings
indicate that within the peripheral sensory and au-
tonomic systems, individuals affected with FD suffer
from incomplete neuronal development as well as
progressive neuronal degeneration.70 –72
Sensory Nervous System. Intrauterine development
and postnatal maintenance of sensory neurons are
affected, with the greatest impact on the nonmyeli-
nated small-fiber populations. The dorsal root gan-
glia are grossly reduced in size due to decreased
neuronal population.71,72 Within the spinal cord, lat-
eral root entry zones and Lissauer’s tracts are se-
verely depleted of axons. As evidence of slow pro-
gressive degeneration, there is a definite 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 dorsal-
column 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 fas-
cicular area and contains markedly diminished num-
bers of nonmyelinated axons, as well as diminished
numbers of small-diameter myelinated axons.1,7,71
The sural nerve findings are sufficiently characteris-
tic 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 immunoreac-
tive findings support the electron microscopic find-
ings.
MUSCLE & NERVE March 2004 353
Autonomic Nervous System. Consistent with an ac-
tual decrease in neuronal numbers, the mean vol-
ume of superior cervical sympathetic ganglia is re-
duced 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 gan-
glia.73 Decreased numbers of neurons in the inter-
mediolateral gray columns of the spinal cord sug-
gests 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 sympathomi-
metic and parasympathomimetic agents.21,28,88,89
Other than the sphenopalatine ganglia, which
are consistently reduced in size with low total neu-
ronal counts, parasympathetic ganglia, such as the
ciliary ganglia, do not seem to be affected.69
NEUROPHYSIOLOGY
Chemoreceptor and Baroreceptor Dysfunction. De-
nervation extending to chemoreceptors and barore-
ceptors 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 pressur-
ized airplane cabins. During hypoxia (12% O2), pa-
tients with FD initially increase ventilation but, with
continued hypoxia, ventilation decreases.20,34,35
FIGURE 1. Histograms of neuron distribution in sympathetic ganglia in patients with familial dysautonomia (FD) and controls. (Repro-
duced from Pearson and Pytel70 with permission from Elsevier.)
354 Familial Dysautonomia
These observations suggest that patients with FD
have normal peripheral chemoreceptors but an in-
ordinate central depression of ventilation by hypoxia
(Fig. 2). Furthermore, hypoxia induces profound
circulatory responses consistent with sympathetic de-
nervation, resulting in bradyarrhythmia and hypo-
tension which can lead to syncope and even respira-
tory arrest (Fig. 3).
Studies of forearm blood flow 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 in-
crease with either stimulus. It is now well recognized
that individuals with FD consistently manifest ortho-
static hypotension without compensatory tachycar-
dia.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
Catecholamine Metabolism. 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 ra-
tios.40,81,85,86 These findings are consistent with stud-
ies demonstrating exaggerated responses to both
sympathomimetic and parasympathomimetic agents
and neuropathological descriptions of a decreased
sympathetic neuronal population.28,70,83,88,89 Al-
MUSCLE & NERVE March 2004

FIGURE 2. Chemoreflex 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
chemoreflex 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 significantly dif-
ferent 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
sion, do not have an appropriate increase in
plasma levels of NE and dopamine beta-hydroxy-
lase (D␤H) 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 sub-
jects 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 emo-
tional 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 D␤H.
FIGURE 3. Ventilatory and cardiovascular responses to the re-
breathing 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 repre-
sents 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)
MUSCLE & NERVE March 2004 355
 treatment is supportive and oriented to the involved
systems.

Diagnosis. The diagnosis should be suspected by

history and physical examination, which can provide
much of the essential information.3,4,8 However, be-
cause there can be extreme variability in expression,
the clinical diagnosis of FD is based upon the pres-
ence of five relatively invariable “cardinal” criteria,
i.e., absence of overflow emotional tears, absent lin-
gual fungiform papillae (Fig. 5), depressed patellar
reflexes, lack of an axon flare following intradermal
histamine (Fig. 6), and documentation of Ashkenazi
Jewish extraction.3,4,62,82,87 Because individuals af-
fected with the other HSANs will also fail to produce
an axon flare after intradermal histamine, it is ad-
vised that DNA molecular diagnosis be performed in
questionable cases.

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.

Frequency
FIGURE 4. Supine catechol values for 10 familial dysautonomia System Common symptoms (%)
(FD) and 8 control (C) subjects. FD values are averages from two
Ocular Decreased tears ⬎99
to three testing sessions. Control values are absolute values.
Corneal analgesia NA
Horizontal bars are means. (A) Catecholamines: DA, dopamine;
Optic atrophy NA
NE, norepinephrine; EPI, epinephrine. (B) Catechol metabolites:
DOPA, dihydroxyphenylalanine; DOPAC, dihydroxy-phenylacetic Gastrointestinal Dysphagia ⬎60
acid; DHPG, dihydroxyphenylglycol. (Reproduced with permis- dysfunction Esophageal and gastric ⬎60
sion from Axelrod et al.16) dysmotility
Gastroesophageal reflux 67
Vomiting crises 40
Other Vascular Modulators. Supine early morning Pulmonary Aspirations NA
plasma renin activity is elevated in FD subjects and Insensitivity to hypoxia NA
the release of renin and aldosterone is not coordi- Restrictive lung disease NA
nated.76 In FD individuals with supine hypertension, Orthopedic Spinal curvature 85
an increase in plasma atrial natriuretic peptide Asceptic necrosis 15
(ANP) has also been demonstrated.15 The combina- Vasomotor Postural hypotension 99
tion of these factors may serve to explain the exag- Blotching 99
gerated nocturnal urine volume and increased ex- Excessive sweating 99
cretion of salt in some FD individuals especially Hypertensive crises ⬎60
during stress and hypertension. Neurological Decreased deep tendon reflexes 95
Decreased pain and temperature NA
CLINICAL FEATURES AND MANAGEMENT sensation
Decreased vibration (after 13 NA
Although FD is a neurological disorder with pertur- years)
bations that can be attributed to sensory and auto- Progressive ataxia (in adults NA
years)
nomic dysfunction, the clinical features are pervasive
and involve many other systems (Table 1). Therefore NA, percentages not available.

356 Familial Dysautonomia MUSCLE & NERVE March 2004

 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 sub-
jects.9 In the older individual, vibration sense, and
occasionally joint position, become abnormal and a
positive Romberg sign may be noted.9,46 Visceral sen-
sation is intact so patients are able to perceive discom-
fort with pleuritic or peritoneal irritation.
Peripheral sensory deprivation makes the FD pa-
tient 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 fitting of braces
to avoid development of pressure decubiti on insen-
sitive skin. Central sensory deficits include decreased
pain perception along the branches of the trigemi-
nal nerve, diminished corneal reflexes, and de-
creased taste perception, especially in recognition of
sweet, which corresponds to the absence of fungi-
form 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 deficits and decreased tone
of stretch receptors. The older patients have diffi-
culty in maintaining independent ambulation. The
gait becomes broad-based and ataxic.4,8
Autonomic Dysfunction. Pervasive autonomic dys-
function results in protean functional abnormalities.
As the disorder has variable expression, there are
individual variations. Some of these manifestations
Familial Dysautonomia
are apparent at birth and others become more
prominent and problematic with age.
Gastrointestinal System. Oropharyngeal incoordina-
tion is one of the earliest signs of FD. Poor suck or
discoordinated swallow is observed in 60% of in-
fants.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 aspi-
rated. Cineradiographic swallowing studies may doc-
ument the level of functional ability.25,43,58,66 If dys-
phagia impedes maintenance of nutrition or causes
respiratory problems, then gastrostomy is recom-
mended.6
The most prominent manifestation of gastrointes-
tinal 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 hyperten-
sion, tachycardia, diffuse sweating, and even person-
FIGURE 6. Histamine test. Dysautonomic reaction (forearm on
top) demonstrates a narrow areola surrounding the wheal. Nor-
mal reaction (lower forearm) displays diffuse axon flare around a
central wheal.
MUSCLE & NERVE March 2004 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 figure
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 phenom-
enon like an autonomic seizure6,18 (Fig. 7). Because
hypertension may be extreme, clonidine is a useful
adjunct.
Gastroesophageal reflux is another common prob-
lem. If it is identified, medical management includ-
ing prokinetic agents and H2-antagonists should be

358 Familial Dysautonomia MUSCLE & NERVE March 2004

tried. However, if pneumonia, hematemesis, or ap-
nea occur, then surgical intervention (fundoplica-
tion) is recommended.6,10,13,91 After surgery, dysau-
tonomic crises may continue. Although overt emesis
is prevented, the patient may continue to have pro-
longed retching.
Respiratory System. Aspiration is the major cause
of lung infections. Most lung damage occurs during
infancy and early childhood when oral incoordina-
tion is extremely poor and the diet contains mostly
liquids. If gastroesophageal reflux is present, the risk
for aspiration increases.
The ventilatory response to lung infection is of-
ten altered due to insensitivity to hypoxia and hyper-
carbia.20,34,35,65 Hypoxia does not induce appropriate
increases in minute ventilation and can result in
syncope as a consequence of hypotension and bra-
dycardia. Situations where the partial pressure of
oxygen is decreased, such as high altitudes or pres-
surized airplane cabins, can be potentially hazard-
ous. 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. (Re-
produced with permission from Axelrod et al.14)
Familial Dysautonomia
can result in profound desaturations and may con-
tribute 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, with-
out appropriate compensatory increases in heart
rate4,8,14,15,93(Fig. 8). Clinical manifestations of pos-
tural 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 mic-
turition or bowel movement, or with gastric disten-
sion from large meals. Symptoms referable to hypo-
tension become more prominent in the adult years
and can limit function and mobility. Postural hypo-
tension is treated by increasing plasma volume with
oral hydration, increased dietary salt, and fludrocor-
tisone. Other useful measures include lower-extrem-
ity 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 stabi-
lization of the vascular bed by hydrating the patient
before surgery and titrating the anesthetic to contin-
uously 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 oc-
cur 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 hyper-
tension is not usually treated as it is usually transitory
and appears to be better tolerated than hypotension.
Although FD subjects consistently exhibit ortho-
static instability, they have variable electrocardiographic
findings.17,38,39,63,79 As part of the progressive nature
of FD, there is further diminution of sympathetic
function and development of heightened parasym-
pathetic dysfunction. Heart rate variability studies,
using power spectral analysis, indicate that with ex-
ertion, there is inappropriate persistence of parasym-
pathetic 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-
MUSCLE & NERVE March 2004 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 ap-
pears 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 significant
ischemic-type glomerulosclerosis and deficient vas-
cular 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 pos-
tural hypotension appears to be justified.
Ophthalmological Disorders. Individuals with FD
do not cry with overflow tears.59,62,77 Corneal hypes-
thesia also affects the ocular status, as it results in
decreased blink frequency and indifference to cor-
neal trauma. Epithelial erosions of the exposed cor-
nea and conjunctiva are the hallmarks of dry-eye
states. These lesions may become confluent, leading
to patchy areas of de-epithelialization. Early treat-
ment of corneal epithelial erosions includes in-
creased frequency of application of tear substitutes,
attention to the general state of hydration, and
search for precipitating systemic factors that might
have disturbed the patient’s 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 environ-
ment for the graft.
Other ophthalmological features include hyper-
reactivity 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 curva-
tures.78 Left thoracic curves occur more frequently
than in idiopathic scoliosis. In addition to contribut-
ing to short stature, kyphoscoliosis causes restrictive
chest deformities that further compromise pulmo-
nary function.
360 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, in-
volves weight-bearing joints.60,68
Central Nervous System Features. Emotional labil-
ity has been considered one of the prominent fea-
tures of FD and was stressed in its original descrip-
tion.26,36,77 It is now appreciated that the behavioral
abnormalities tend to be part of the central auto-
nomic dysfunction, which intensify during crisis. Us-
ing a functional neuroimaging technique to assess
cerebral perfusion, i.e., Tc-99m ethylene cysteine
dimer (ECD) SPECT, hyperperfusion of the tempo-
ral and frontal areas during crisis was demonstrat-
ed.18 In addition, the ameliorating effect of benzo-
diazepines supports this hypothesis.6
Most affected individuals are of normal intelli-
gence. 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 difficulty extrap-
olating, 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 exces-
sive salt wasting during hot weather due to uncom-
pensated 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 postur-
ing, and may represent a type of seizure activity.
Breath-holding is frequent in the early years, occur-
ring at least once in 63% of patients. This phenom-
enon 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 im-
proving 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 cur-
rent 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-
MUSCLE & NERVE March 2004
tion. Both men and women with FD have married
and reproduced. All offspring have been phenotyp-
ically 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 difficulty in concentrating. They are prone
to depression, anxieties, and even phobias.26 With
increasing age, sympathovagal balance becomes
more precarious with worsening of orthostatic hypo-
tension, development of supine hypertension, and
even occasional bradyarrhythmias.17,19
Causes of death are less often related to pulmo-
nary complications, indicating that aggressive treat-
ment of aspirations has been beneficial.5,19 Of recent
concern have been the patients who have suc-
cumbed 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 identification of the FD gene should
provide insight into the molecular mechanisms of
FD, as well as help to understand the processes in-
volved in normal development and maintenance of
the sensory and autonomic nervous systems. Further-
more, it is anticipated that this information will help
in differentiating FD from the other HSANs, lead to
definitive treatments for individuals affected with
FD, and foster innovative treatment approaches for
other autonomic and sensory disorders.
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