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INVITED REVIEW ABSTRACT: Familial dysautonomia (FD) is a neurodevelopmental geneticdisorder within the larger classification of hereditary sensory and autonomicneuropathies, each caused by a different genetic error. The FD gene hasbeen identified as IKBKAP. Mutations result in tissue-specific expression ofmutant IB kinase-associated protein (IKAP). The genetic error probablyaffects development, as well as maintenance, of neurons because there isneuropathological and clinical progression. Pathological alterations consist

of decreased unmyelinated and small-fiber neurons. Clinical features reflectwidespread involvement of sensory and autonomic neurons. Sensory lossincludes impaired pain and temperature appreciation. Autonomic featuresinclude dysphagia, vomiting crises, blood pressure lability, and sudomotordysfunction. Central dysfunction includes emotional lability and ataxia. Withsupportive treatment, prognosis has improved greatly. About 40% of pa-tients are over age 20 years. The cause of death is usually pulmonaryfailure, unexplained sudden deaths, or renal failure. With the discovery of thegenetic defect, definitive treatments are anticipated.

Muscle Nerve29: 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 theRiley-Day syndrome (R-D), is an autosomal recessivedisorder with extensive central and peripheral auto-nomic perturbations, as well as small-fiber sensorydysfunction.3,4,8,24,29,77 It is now appreciated that FDis one member of a group of rare neurodevelopmen-tal disorders termed hereditary sensory and auto-nomic neuropathies (HSAN)3,4 and thus has alsobeen termed HSAN type III.32 The complexity of theautonomic nervous system and its intimate relation-ship with sensory function is especially well illus-trated in these disorders. As the phenotypic andneuropathological differences of the HSAN are be-ing described, specific genetic mutations are beingidentified, providing further insight into mecha-nisms affecting development and survival of the au-tonomic and sensory nervous systems.4

Although FD is the most prevalent of the HSANand 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 diagnosisis now available.2,80 The fact that over 99% of af-

fected FD individuals share one common mutationconfirms the genetic homogeneity of the populationbut leaves many questions regarding phenotypic di-

versity. The genetic defect affects prenatal neuronaldevelopment so that symptoms are present frombirth, but individual expression varies widely.3,4,11

Because the entire autonomic nervous system is af-fected, there is a pervasive effect on the functioningof other systems. However, with supportive treat-ments of its various manifestations, the prognosis foraffected individuals has improved and a growingnumber of individuals affected with FD are survivinginto adulthood.5,19

GENETICS

FD is transmitted as an autosomal recessive disorderand has a remarkably high carrier frequency in in-dividuals of Ashkenazi, or Eastern European, Jewishextraction. The other HSANs do not have the sameethnic bias as FD.3,4 Initial epidemiological studies

Abbreviations:ANP, atrial natriuretic peptide; DA, dopamine; DH, dopam-ine-beta-hydroxylase; DHPG, dihydroxyphenylglycol; DOPA, dihydroxyphe-

nylalanine; FD, familial dysautonomia; HSAN, hereditary sensory and auto-nomic neuropathy; HVA, homovanillic acid; IKAP, IB kinase-associatedprotein; JNK, c-JunN-terminalkinase; NE, norepinephrine; VMA, vanillylman-delic acidKey words: familial dysautonomia; hereditary sensory and autonomic neu-ropathy;IKBKAPgene; neurodevelopmental disorder; Riley-Day syndromeCorrespondence to: F.B. Axelrod; e-mail: [email protected]

2003 Wiley Periodicals, Inc.

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had estimated that the carrier rate for FD rangedfrom 1 in 100 to 1 in 30.24,64 However, with theidentification of specific genetic mutations andlaunching of population screening, the carrier fre-quency of the most common mutation in the Ash-kenazi Jewish population has been reported to bebetween 1 in 27 to 1 in 32.31,90

Using genetic linkage, in 1993 the gene wasmapped 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, asingle noncoding mutation in the gene IKBKAPwasshown to cause 99.5% of all cases of FD.1,80 Thiscommon FD mutation is a single base-change in thedonor splice site of intron 20. The result is an ap-parent decrease in splicing efficiency that produces

variable skipping of exon 20 in theIKBKAPmessage,producing truncated IKAP (IB kinase-associatedprotein). A second FD mutation, a single GC

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 thirdFD mutation, a proline to leucine missense mutationin exon 26, has been seen only in one individual who

was also heterozygous for the common mutation butinherited the missense mutation from a non-Jewishparent.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 ofexpressing wild-type mRNA and protein and there istissue-specific expression.27,80 RNA isolated from FD

lymphoblast cell lines is primarily wild-type, whereasRNA isolated from postmortem brain samples fromFD patients is primarily mutant, suggesting that neu-ronal cells are less capable of compensating for themissplicing.

Because all of the HSANs affect neuronal devel-opment, mechanisms causing disease may involvegenes that encode neurotrophins, their receptors, orany proteins that might participate in a neurotro-phin-related signal transduction pathway. For exam-ple, HSAN type IV has been shown to result frommutations in the gene that encodes a neurotrophinreceptor, NTRK1, which is located on chromosome

1.57

In FD, it is not known how the mutation inIKBKAPcauses or predisposes to this disease. Initialstudies suggested that IKAP, the protein encoded byIKBKAP, was part of the IB kinase complex orassociated with the human Elongator complex intranscriptional elongation.44 Recently, studies havedemonstrated that the IKAP protein is involved inthe regulation and activation of stress response

through the c-Jun N-terminal kinase (JNK) signalingpathway.42,56 Deletion of the c-terminal portion ofIKAP reduces c-Jun phosphorylation.56 It is possiblethat the FD mutations in the c-terminal portion ofthe IKBKAPgene alter the interaction of IKAP with

JNK and results in misregulation of JNK, leading toinadequate development, poor differentiation, or

limited survival of neuronal cells.

NEUROPATHOLOGY

Consistent neuropathological findings provide astructural basis for many of the biochemical andclinical features of the disease and help to distin-guish this disorder from the other hereditary sensoryneuropathies; however, they leave unexplained thedysfunctions of the higher central nervous systemthat are clinically apparent.71 Pathological findingsindicate that within the peripheral sensory and au-tonomic systems, individuals affected with FD suffer

from incomplete neuronal development as well asprogressive neuronal degeneration.7072

Sensory Nervous System. Intrauterine developmentand postnatal maintenance of sensory neurons areaffected, with the greatest impact on the nonmyeli-nated small-fiber populations. The dorsal root gan-glia are grossly reduced in size due to decreasedneuronal population.71,72Within the spinal cord, lat-eral root entry zones and Lissauers tracts are se-

verely depleted of axons. As evidence of slow pro-gressive degeneration, there is a definite trend withincreasing age for further depletion of the number of

neurons in dorsal root ganglia and an increase in theabnormal numbers of residual nodules of Nageotte inthe dorsal root ganglia.33,72 In addition, loss of dorsal-column myelinated axons becomes evident in olderpatients. Neuronal depletion in dorsal root ganglia andspinal cord correlate well with the clinical observationsof 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 diminishednumbers 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 thesubstantia gelatinosa of spinal cord and medulla hasbeen demonstrated using immunohistochemistry.75

Because substance P may be involved in synaptictransmission of sensory neurons, the immunoreac-tive findings support the electron microscopic find-ings.

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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 yetstaining for tyrosine hydroxylase is enhanced in theneurons 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 bedemonstrated on peripheral blood vessels.41 Lack ofinnervation 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, whichare consistently reduced in size with low total neu-ronal counts, parasympathetic ganglia, such as theciliary 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 pathologicallybut is strongly suggested by physiological studies andseverely compromises the ability of FD patients tocope with respiratory infections and other potentialcauses of hypoxia, such as high altitudes or pressur-ized airplane cabins. During hypoxia (12% O2), pa-tients with FD initially increase ventilation but, withcontinued hypoxia, ventilation decreases.20,34,35

These observations suggest that patients with FDhave normal peripheral chemoreceptors but an in-ordinate central depression of ventilation by hypoxia(Fig. 2). Furthermore, hypoxia induces profoundcirculatory 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 responsesto 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 recognizedthat individuals with FD consistently manifest ortho-static hypotension without compensatory tachycar-dia.14,15,17,93 Furthermore, transcranial Doppler studyin FD patients shows impaired cerebral autoregulationand paradoxical cerebral vasoconstriction duringhead-upright tilt.47,48,55

Catecholamine Metabolism. Early studies of urinarycatecholamine metabolites demonstrated that FDpatients had elevated levels of homovanillic acid(HVA) and normal to low levels of vanillylmandelicacid (VMA), resulting in elevated HVA:VMA ra-tios.40,81,85,86 These findings are consistent with stud-ies demonstrating exaggerated responses to bothsympathomimetic and parasympathomimetic agentsand neuropathological descriptions of a decreasedsympathetic neuronal population.28,70,83,88,89 Al-

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.)



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though supine plasma levels of norepinephrine(NE) are normal or elevated, FD patients, like mostother patients with neurogenic orthostatic hypoten-

sion, do not have an appropriate increase inplasma levels of NE and dopamine beta-hydroxy-lase (DH) with standing.14,16,93 In addition, FDpatients appear to have a distinctive pattern ofplasma levels of catechols (Fig. 4). Regardless ofposture, plasma levels of dihydroxyphenylalanine(DOPA) are disproportionately high and plasma

levels of dihydroxyphenylglycol (DHPG) are low,resulting in elevated plasma DOPA:DHPG ratiosthat are not seen in other disorders associated withneurogenic orthostatic hypotension.16 The highplasma DOPA levels are consistent with FD sub-

jects having an increased proportion of tyrosinehydroxylase in superior cervical ganglia.73

When FD subjects are supine, there is a strongcorrelation between mean blood pressure andplasma levels of NE, but when they are upright, thecorrelation is seen only with plasma dopamine (DA)levels, suggesting that in FD patients DA may serve tomaintain upright blood pressure.16 During emo-

tional crises, plasma NE and DA levels are markedlyelevated, and vomiting usually coincides with thehigh dopamine levels. The elevation of plasma NE isattributed to peripheral conversion of DA by DH.

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 CO2expressed 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% O2by 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)

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.



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Other Vascular Modulators. Supine early morningplasma renin activity is elevated in FD subjects andthe release of renin and aldosterone is not coordi-nated.76 In FD individuals with supine hypertension,an increase in plasma atrial natriuretic peptide(ANP) has also been demonstrated.15 The combina-tion of these factors may serve to explain the exag-gerated nocturnal urine volume and increased ex-cretion of salt in some FD individuals especially

during stress and hypertension.

CLINICAL FEATURES AND MANAGEMENT

Although FD is a neurological disorder with pertur-bations that can be attributed to sensory and auto-nomic dysfunction, the clinical features are pervasiveand involve many other systems (Table 1). Therefore

treatment is supportive and oriented to the involvedsystems.

Diagnosis. The diagnosis should be suspected byhistory and physical examination, which can providemuch 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 patellarreflexes, lack of an axon flare following intradermalhistamine (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 producean axon flare after intradermal histamine, it is ad-

vised that DNA molecular diagnosis be performed inquestionable cases.

Sensory System. In the younger patient, sensory

abnormalities appear limited to the unmyelinatedneuronal population, but, in the older patient, thereis progressive involvement of myelinated neurons ofthe dorsal column tracts.9,84Although pain sensation

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-phenylaceticacid; DHPG, dihydroxyphenylglycol. (Reproduced with permis-

sion from Axelrod et al.16)

Table 1.Clinical features of familial dysautonomia.

System Common symptoms

Frequency

(%)

Ocular Decreased tears 99

Corneal analgesia NA

Optic atrophy NA

Gastrointestinaldysfunction

Dysphagia 60Esophageal and gastric

dysmotility

60

Gastroesophageal reflux 67

Vomiting crises 40

Pulmonary Aspirations NA

Insensitivity to hypoxia NA

Restrictive lung disease NA

Orthopedic Spinal curvature 85

Asceptic necrosis 15

Vasomotor Postural hypotension 99

Blotching 99

Excessive sweating 99

Hypertensive crises 60

Neurological Decreased deep tendon reflexes 95

Decreased pain and temperature

sensation

NA

Decreased vibration (after 13

years)

NA

Progressive ataxia (in adults

years)

NA

NA, percentages not available.



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is decreased, it is not completely absent and there isusually sparing of the palms, soles of feet, neck, andgenital areas, with these areas often being exquisitelysensitive. Temperature appreciation, as documented

by sympathetic skin responses and quantitative analysisof warm and cold thresholds, is also affected.46,5052

With both pain and temperature perceptions, thetrunk and lower extremities are more affected andolder individuals have greater losses than younger sub-

jects.9 In the older individual, vibration sense, andoccasionally joint position, become abnormal and apositive 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 spinalcurvature requires extreme care in fitting of bracesto avoid development of pressure decubiti on insen-sitive skin. Central sensory deficits include decreasedpain perception along the branches of the trigemi-nal nerve, diminished corneal reflexes, and de-creased taste perception, especially in recognition ofsweet, which corresponds to the absence of fungi-form papillae on the tip of the tongue.87

Motor problems are most apparent in the veryyoung child and the older patients. The child withFD is frequently hypotonic, which may be due to acombination of central deficits and decreased tone

of stretch receptors. The older patients have diffi-culty in maintaining independent ambulation. Thegait 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 areindividual variations. Some of these manifestations

are apparent at birth and others become moreprominent 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 olderpatient and be manifested as a tendency to drool anda 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 causesrespiratory problems, then gastrostomy is recom-mended.6

The most prominent manifestation ofgastrointes-tinal dysmotilityin FD individuals is the propensity to

vomit. Vomiting can occur intermittently as part of asystemic 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.

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



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ality change, this constellation of signs has beentermed the dysautonomic crisis.3,4,6,8 Diazepam is themost 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 usefuladjunct.

Gastroesophageal reflux is another common prob-lem. If it is identified, medical management includ-ing prokinetic agents and H2-antagonists should be

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)



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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 emesisis prevented, the patient may continue to have pro-longed retching.

Respiratory System. Aspirationis the major cause

of lung infections. Most lung damage occurs duringinfancy and early childhood when oral incoordina-tion is extremely poor and the diet contains mostlyliquids. If gastroesophageal reflux is present, the riskfor 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 appropriateincreases in minute ventilation and can result insyncope as a consequence of hypotension and bra-dycardia. Situations where the partial pressure ofoxygen is decreased, such as high altitudes or pres-surized airplane cabins, can be potentially hazard-

ous. Furthermore, sleep architecture is frequentlyabnormal with central apneas and hypopnea that

can result in profound desaturations and may con-tribute to the increased incidence of death insleep.5,19,37

Cardiovascular Irregularities. Consistent withsympathetic dysfunction, patients exhibit rapid andsevere orthostatic decreases in blood pressure, with-out appropriate compensatory increases in heart

rate4,8,14,15,93(Fig. 8). Clinical manifestations of pos-tural hypotensioninclude episodes of lightheadednessor dizzy spells. Some patients complain of weaklegs. On occasion, there may be syncope. Symptomstend 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 yearsand can limit function and mobility. Postural hypo-tension is treated by increasing plasma volume withoral 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, analpha-adrenergic agonist.

General anesthesia has the potential for inducingsevere hypotension. With greater attention to stabi-lization of the vascular bed by hydrating the patientbefore surgery and titrating the anesthetic to contin-uously monitored arterial blood pressure, anestheticrisk has been greatly reduced.12

In older patients, supine hypertensionmay becomeprominent despite the retention of severe responsesto orthostatic challenge. Hypertension may also oc-

cur intermittently in response to emotional stress orvisceral pain or as part of the crisis constellation. Thehypertension will respond to the same medicationsrecommended for crisis management, i.e., diazepamand clonidine. Hypertension may also exist withoutany other symptoms. Because the blood pressure isso labile in individuals with FD, asymptomatic hyper-tension is not usually treated as it is usually transitoryand appears to be better tolerated than hypotension.

Although FD subjects consistently exhibit ortho-static instability, they have variableelectrocardiographic

findings.17,38,39,63,79 As part of the progressive natureof 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 sympatheticactivity.63 Prolongation of the QTc occurs in somepatients and may be an ominous sign.38,39 Patientshave been shown to have arrhythmias, and pacemak-

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)



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ers have been required for documented asystolicepisodes.79

Renal Problems. Azotemia is frequently prerenalin origin. Although clinical signs of dehydration maynot be present, blood urea nitrogen values often canbe reduced by simple hydration. Renal function ap-pears to deteriorate with advancing age, so that

about 20% of adult patients have reduced renalfunction.8 Renal biopsies performed on individuals

with uncorrectable azotemia revealed significantischemic-type glomerulosclerosis and deficient vas-cular innervation.74 Renal hypoperfusion secondaryto cardiovascular instability has been suggested asthe cause of the progressive renal disease.14 Thishypothesis was supported by studies utilizing thetechnique of renal artery Doppler blood velocity

waveform analysis, which demonstrated decreasedrenal systolic velocity when FD patients were uprightand exercised. Thus, aggressive treatment of pos-tural hypotension appears to be justified.

Ophthalmological Disorders. Individuals with FDdo not cry with overflow tears.59,62,77 Corneal hypes-thesia also affects the ocular status, as it results indecreased blink frequency and indifference to cor-neal trauma. Epithelial erosions of the exposed cor-nea and conjunctiva are the hallmarks of dry-eyestates. These lesions may become confluent, leadingto 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, andsearch for precipitating systemic factors that might

have disturbed the patients fragile catecholaminehomeostasis. Persistent erosions or ulcerations mayrequire a therapeutic soft contact lens, occlusion ofthe lacrimal puncta, or small lateral tarsorrhaphiesthat limit the area exposed to surface evaporation.Corneal grafts generally have not been successful asthe dry anesthetic cornea is an unfavorable environ-ment for the graft.

Other ophthalmological features include hyper-reactivity to sympathetic and parasympathetic agentsas well as a tendency to myopia, strabismus, andoptic atrophy.30,62,88

Orthopedic Problems. There is a high incidence

of juvenile scoliosis in familial dysautonomia and thiscan 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 frequentlythan in idiopathic scoliosis. In addition to contribut-ing to short stature, kyphoscoliosis causes restrictivechest deformities that further compromise pulmo-nary function.

There are also a number of nonspinal orthopedicproblems that limit function including tibial torsionand a high frequency of unrecognized fractures andaseptic 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 behavioralabnormalities tend to be part of the central auto-nomic dysfunction, which intensify during crisis. Us-ing a functional neuroimaging technique to assesscerebral perfusion, i.e., Tc-99m ethylene cysteinedimer (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 lessthan 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, andexecutive planning skills are poor.

Seizures have been seen as a result of hypoxia ormetabolic perturbations such as a low serum sodiumlevel. The hyponatremia can be secondary to exces-sive salt wasting during hot weather due to uncom-pensated losses from sweating or excessive free waterintake. Hyponatremia can also accompany crises as aresult of prolonged hypertension and concomitantexcessive ANP and DA production.15 Prolongedbreath-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 tohypoxia. It can become a manipulative maneuver

with some children. In our experience, the episodesare self-limited, cease by 6 years of age, and havenever 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% ofpatients died before 5 years of age.24 The most cur-rent survival statistics indicate that a newborn withFD now has a 50% probability of reaching 40 years ofage.19 Quality of life has also improved. Many FDadults have been able to achieve independent func-



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tion. Both men and women with FD have marriedand reproduced. All offspring have been phenotyp-ically normal despite their obligatory heterozygotestate.

However, the presence of an adult FD populationhas provided evidence for the progressive nature ofthe disorder. Adult FD patients do not appear to

appreciate the decline in their sensory abilities butthey frequently complain of poor balance, unsteadygait, and difficulty in concentrating. They are proneto depression, anxieties, and even phobias.26 Withincreasing age, sympathovagal balance becomesmore precarious with worsening of orthostatic hypo-tension, development of supine hypertension, andeven 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 recentconcern have been the patients who have suc-cumbed to unexplained deaths that may have been

the result of unopposed vagal stimulation or a sleepabnormality.19 A few adult patients have died ofrenal failure.

FUTURE GOALS

The recent identification of the FD gene shouldprovide insight into the molecular mechanisms ofFD, as well as help to understand the processes in-

volved in normal development and maintenance ofthe sensory and autonomic nervous systems. Further-more, it is anticipated that this information will helpin differentiating FD from the other HSANs, lead to

definitive treatments for individuals affected withFD, and foster innovative treatment approaches forother autonomic and sensory disorders.

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1. Aguayo AJ, Nair CPV, Bray GM. Peripheral nerve abnormali-ties in the Riley-Day syndrome, findings in sural nerve biopsy.

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J, Rubin BY. Familial dysautonomia is caused by mutations inthe IKAP gene. Am J Hum Genet 2001;68:753758.

3. Axelrod FB. Autonomic and sensory disorders. In: EmoryAEH, Rimoin DL, editors. Principles and practice of medicalgenetics, 3rd ed. Edinburgh: Churchill Livingstone; 1996. p

397411.4. Axelrod FB. Hereditary sensory and autonomic neuropathies:

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