Clinical manifestations

Presentation and course

The primary abnormality in familial dysautonomia is due to anatomical depletion of sensory and autonomic neurons (76). Signs of the disorder are present from birth, and neurologic function slowly deteriorates with age so that symptoms and problems will vary with time (17; 05; 06; 08).

The diagnosis is considered in an individual who manifests sensory and autonomic dysfunction from infancy. The early history is often positive for feeding difficulties, repeated aspiration, episodes of hypothermia, breath-holding spells, hypotonia, delayed motor development, and repeated vomiting. Because marked variability exists in expression of the disease, the following criteria are used for clinical confirmation of the disorder:

The majority of patients with this disorder have had eastern European Jewish (ie, Ashkenazi Jewish) ancestry (21). The founder population was estimated to be as little as 350 individuals that migrated from the Pale of Settlement region (between the Black and Baltic Seas to Poland in 1500) (29).

Because individuals affected with the other HSANs will also fail to produce an axon flare after intradermal histamine, careful assessment of the other clinical signs and symptoms is necessary in order to distinguish between these disorders (05). Because there can be extreme variability in expression, clinical criteria are not always sufficient, and genetic testing is required. In 1993, the gene for familial dysautonomia was localized to the long arm of chromosome 9 (9q31), and it was appreciated that there was 1 major haplotype for more than 98% of familial dysautonomia chromosomes (26). In spring 2001, the 2 Jewish mutations causing familial dysautonomia were identified (02; 91), allowing definitive diagnosis through DNA analysis and facilitating general population screening in the Ashkenazi Jewish population. In 2003, the first non-Jewish mutation was identified, but it was paired with the common missplicing Jewish mutation (61). These days, most affected infants are born to parents who are unaware of their own Jewish heritage. The most recent cases have been identified in patients descending from families in Central Mexico. These families were unaware of any Jewish ancestry. Whole exome sequencing showed that these cases carried homozygous copies of the founder mutation (74).

Although penetrance is always complete, there is a great deal of variation in expression. Due to the pervasive nature of the autonomic nervous system, protean functional abnormalities are seen. Signs of the disorder are present from birth, and neurologic function slowly deteriorates with age so that symptoms and signs will vary with time, but some clinical features are consistent.

Peripheral involvement of the sensory system is documented by diminished, but not absent, response to painful stimuli. Lower extremities are more affected than upper extremities, and there is usually sparing of palms, soles of feet, neck, and genital areas (21). Temperature appreciation, as documented by sympathetic skin responses and thermotest readings to both hot and cold stimuli, is also affected and is consistent with pathological evidence of decreased dermal innervation (52). As with pain perception, the trunk and lower extremities are more affected (53), and older individuals have greater losses than younger ones (17). Patellar reflexes are depressed. In the older individual, vibration sense and joint position eventually become abnormal, Rombergism appears, and there is progressive gait ataxia. Microneurographic recordings have demonstrated complete absence of functional muscle spindles, which would explain the loss of deep tendon reflexes and a compromised sensorimotor control of locomotion resulting in the ataxic gait (64; Macefield et al 2013). Insensitivity to pain can result in unrecognized fractures and inadvertent trauma to joints, causing Charcot joints and aseptic necrosis (66). Spinal curvature, which can be early and pernicious in its course, requires extreme care in fitting of braces to avoid development of pressure decubiti on insensitive skin (87). Visceral sensation is intact, so patients are able to perceive discomfort with pleuritic or peritoneal irritation.

Central sensory deficits are documented by decreased pain perception along the branches of the trigeminal nerve and diminished corneal reflexes. Optic atrophy is frequent and characterized by predominant loss of papillomacular nerve fibers, a pattern similar to other hereditary optic neuropathies caused by mutations either in nuclear or in mitochondrial DNA, affecting mitochondrial protein function. Defects of eye movements, particularly saccades, also appear to be a feature of patients with familial dysautonomia (65). The sensory branch of the facial nerve is also affected as taste is deficient, especially in recognition of sweet, which corresponds to the absence of fungiform papillae on the tip of the tongue. Hearing is normal.

The frequent finding of hypotonia, especially in the infant and young child, is thought to be due to the combination of central deficits and decreased tone of stretch receptors (38; 64). The gait is mildly ataxic with special difficulties in performing rapid movements or turning. Often the hands are held high without a natural swing. Many patients walk with a forward list and a compensatory increased stiffness in shoulders and neck, leading to protracted shoulders. The gait often deteriorates in older patients, and some adults have had to resort to use of walkers or wheelchairs when outside the home. The disturbances in gait are consistent with findings of significantly decreased fractional anisotropy in the middle cerebellar peduncle on diffusion tensor imaging studies (16).

Gastrointestinal symptoms affect nearly all patients (83). This is an early feature as oropharyngeal incoordination causes feeding difficulty in the infant and may lead to aspiration pneumonia, apnea, or even failure to thrive. Esophageal dysmotility and gastroesophageal reflux are also common, as well as increased risk of aspiration. The most prominent and perhaps the most debilitating manifestation of autonomic dysfunction in familial dysautonomia individuals is the dysautonomic crisis. The dysautonomic crisis consists of a constellation of signs resembling a central sympathetic storm and is associated with increased circulating dopamine (21; 71; 72). Nausea is a consistent feature and is often the first clinical sign of impending crisis. The nausea can escalate to retching or vomiting. In addition, there is hypertension, tachycardia, diffuse sweating, erythematous skin blotching, and even personality change. The personality change is characterized by extreme irritability, withdrawal, negativism, and, occasionally, incessant picking or rubbing that might look like self-mutilation. Difficulties with sleep and oral coordination with difficulty swallowing saliva and reluctance, or inability, to speak may also be present. The dysautonomic crisis can occur intermittently as part of a systemic reaction to physical or emotional stress, or it can occur daily in response to arousal. It can also be triggered in some familial dysautonomia patients by enteral feeds. Because crises are characterized by massive systemic reactions, central autonomic dysfunction is strongly suggested. SPECT scans during crises demonstrate focal areas of hyperperfusion, suggesting that the crisis may reflect autonomic ictal activity in some individuals (24).

Table 1. System Involvement in Familial Dysautonomia

Problems in the respiratory system are primarily the sequelae of repeated aspirations, so many respiratory problems are avoided when gastrointestinal dysfunction is well managed. In addition, lung function in the older patient may be compromised by the development of restrictive lung disease imposed by spinal curvature. Furthermore, chemoreceptor and baroreceptor dysfunction result in an abnormal ventilatory response to hypercapnia and hypoxia, which impedes the familial dysautonomia patient’s ability to respond appropriately to infection or low-oxygen environments such as high altitude (62; 25). Filler and colleagues demonstrated that rebreathing of 12% oxygen for a period of minutes did not result in appropriate increases in minute ventilation causing dramatic falls in oxygen saturation associated with extreme cyanosis, syncope, and even convulsions (41). Edelman and colleagues noted that the response to hypercapnia could be normalized if the patient was maintained hyperoxic (39). However, if familial dysautonomia subjects were hypoxic, there were profound cardiovascular effects. Hypoxia in familial dysautonomia patients causes the heart rate and blood pressure to fall, which is opposite to the normal response, and induces central depression (25). Clinical symptoms referable to abnormal respiratory control responses include hypoxemia during both wakefulness and sleep, increased risk for drowning when swimming underwater, syncope and convulsions during airplane travel and visits to high altitudes, low threshold for cyanosis, and decerebrate posturing with breath-holding (96). Breath-holding occurs mainly during the first 5 years of life; it has occurred at least 1 time in 63% of patients. Patients with familial dysautonomia have a unique autonomic cardiovascular phenotype as their heart rate and blood pressure move in parallel (69).The familial dysautonomia patient is unable to mount appropriate cardiovascular or catecholamine responses to physical stress, including change of position or exercise (21; 11; 98; 69). Upright tilt markedly lowers blood pressure, and there is no compensatory tachycardia. Postural hypotension without compensatory tachycardia can be striking, especially in the adult population. In one study, with tilt, all familial dysautonomia subjects decreased mean blood pressure by more than 24 mm Hg within 5 minutes (22). When patients are agitated or in the supine position, blood pressures are often in the hypertensive range. During upright tilt, plasma norepinephrine levels and vasopressin levels fail to increase appropriately in patients with familial dysautonomia. The failure to modulate sympathetic activity and to release vasopressin by baroreflex-mediated stimuli, together with marked sympathetic activation during cognitive tasks, indicates that patients with familial dysautonomia have selective failure of baroreceptor afference (69).

The cardiovascular perturbations have cutaneous manifestations that become apparent during the examination, especially if the patient is agitated; excessive sweating and blotching can then be noted. The hyperhidrosis and excessive stimulation of sweat glands is often accompanied by seborrheic dermatitis. Distal vasoconstriction in the peripheral skin causes cold, red hands and livid feet when they are dependent.

Sudden death has also been reported in patients with familial dysautonomia (05). Bradyarrhythmias and asystolic events have been documented (88; 22) and have led to insertion of pacemakers (47). Electrocardiographic changes frequently noted are: (1) prolongation of the corrected QT interval and failure of QT to shorten with exercise, (2) prolongation of the tQRS on signal-averaged ECG; and (3) prolongation of the JTc (42; 22). Prolongation of the tQRS appears to be a sensitive but not specific indicator of autonomic dysfunction. QTc prolongation may be an ominous sign. Because there is an increased incidence of syncope in patients with prolonged JTc, this measure may serve as a marker to predict appropriate candidates for pacemaker insertion to avoid sudden death.

The genitourinary system is not severely or universally affected. Although many patients are late in their attainment of day urine control, continence is achieved in over 98%. Nocturnal control is more of a problem, and the average familial dysautonomia patient often is incontinent into adolescence. Nocturia is a frequent occurrence, and many of the women experience urge or stress incontinence (89). Declining renal function, characterized by rising blood urea nitrogen and creatinines, and decreasing creatinine clearances as well as the inability to concentrate urine have been noted in some familial dysautonomia patients and have even led to renal failure and requirement for dialysis (78; 40). Three individuals have had successful renal transplantation (84). The decrease in renal function is not clear but may be related to blood pressure variability and erratic perfusion (70). Pathological studies reveal excess glomerulosclerosis (78). On ultrastructural examination of renal biopsies, vascular innervation is deficient in dysautonomic patients as compared to controls. Although the cause of the progressive renal disease is not certain, increasing evidence implicates abnormal renal hemodynamics as a major factor because the patients who eventually required dialysis had more severe postural hypotension and were less likely to have gastrostomies to assure adequate hydration (40). Both hypotension and hypertension can result in inadequate renal perfusion and may result in ischemic loss of glomerular and tubular integrity. Using Doppler technology to assess renal vascular resistance, renal perfusion has been shown to decrease postexercise and when familial dysautonomia subjects are erect (11). This perturbation in renal hemodynamics may result in ischemic damage with eventual development of renal insufficiency.

Sexual maturation is frequently delayed, but primary and secondary sex characteristics eventually develop in both sexes, and sexual function appears to be normal (21). Women with dysautonomia have conceived and delivered normal infants (81), and males have successfully fathered children. All offspring of familial dysautonomia patients have been phenotypically normal despite their obligatory heterozygote state.

The ophthalmologic problems reflect how the autonomic and sensory systems are both affected in this disorder and how perturbations in 1 system will aggravate the other. Corneal hypoesthesia and alacrima predispose the cornea to neurotrophic corneal ulcerations due to undetected trauma and excessive dryness. The cornea is further compromised if the patient is dehydrated. Optic nerve pathology is reflected in progressive myopia, optic nerve pallor, and reduction of visual fields (86; 65). Patients with familial dysautonomia have a type of optic neuropathy with predominant loss of papillomacular nerve fibers, a pattern similar to other hereditary optic neuropathies caused by mutations either in nuclear or in mitochondrial DNA, affecting mitochondrial protein function (65). Imaging with optical coherence tomography showed progressive and linear reduction in the mean retinal nerve fiber layer and macular ganglion cell and inner plexiform layer thickness (57). A neuroimaging study using diffusion tensor imaging has demonstrated significantly decreased fractional anisotropy in the optic radiation (16).

Although intelligence generally falls within the range of normal (Welton et al 1979), autonomic instability slows down attainment of developmental milestones and modifies emotional reactivity (33). Anxiety levels can be extreme, and obsessive behaviors as well as phobias have been noted. The degree of autonomic dysfunction and lability will influence eventual function and personality. Visual intelligence skills exceed auditory skills, but verbal performance on standardized intelligence tests is more accurate than motor performance due to mild incoordination defects. These individuals tend to be concrete or literal and have difficulty with extrapolation, abstract thinking, and self-motivation. Receptive language usually exceeds expressive abilities, and the familial dysautonomia child can be frustrated by his or her inability to verbally communicate needs or ideas.

Prognosis and complications

About 40% of the known familial dysautonomia population is over 20 years of age. Thus, familial dysautonomia can no longer be considered only a disease of childhood. With greater understanding of the disorder and development of treatment programs, survival statistics have markedly improved so that increasing numbers of patients are reaching adulthood. Survival statistics prior to 1960 reveal that 50% of patients died before 5 years of age (28). Current survival statistics indicate that a newborn with familial dysautonomia has a 50% probability of reaching 40 years of age (05). Still the peak in deaths happens between the ages of 11 and 21 years (74). Earlier statistics indicated that pulmonary infections were the predominant cause of death. As treatment has become more aggressive in this area and as aspirations are being avoided, it is more common for patients to succumb to other causes, such as unexplained sleep deaths or even renal failure (05). The annual incidence rate of sudden unexpected death during sleep in patients with familial dysautonomia was estimated to be 3.4 per 1000 person-years, compared to an annual incidence rate of sudden unexpected death in epilepsy of 0.5 to 1 per 1000 person-years (75).

Clinical vignette

History. In contrast to the typical patient with familial dysautonomia who is usually diagnosed by 18 months of age, RG’s diagnosis was delayed until 16 years of age. The delay in diagnosis was in part due to her relatively benign course and, in particular, the lack of respiratory problems, although she manifested many typical clinical features. She was the first child of parents who were of Ashkenazi Jewish extraction. The family history and pregnancy were unremarkable. She was born at term but was a breech delivery. The adaptability, partnership, growth, affection, and resolve (APGAR) score was 6 (points lost for pallor and low tone), birth weight was 6 lb 6 oz, length was 19.25 inches. In the nursery she was sleepy, hypothermic, and jaundiced. In addition, she did not feed well. Breast feeding was unsuccessful. In the nursery, gavage supplements were required, but at home she was fed small amounts frequently with a syringe and then nipples. Weight gain was suboptimal. At 6 months, she was only 8 lb and was dubbed “failure to thrive.” During this early period, there was frequent vomiting of feeds. Developmental milestones were mildly delayed. She sat at 10 months, walked at 20 months, and started to speak at 24 months. Despite physical therapy for 6 years (from 3 to 9 years of age), her gait remained unsteady. Toe walking was prominent, and she had Achilles tendon lengthening at 5 years of age.

Oral incoordination persisted and probably accounted for tendency to drool excessively. Retention of her primitive suckling pattern contributed to orthodontic problems. At 16 years of age, she still took a long time to chew and would cough occasionally on liquids. There had never been a documented pneumonia, but she had episodes of “bronchitis.” She also complained of a chronic dry cough.

Her short stature led to various consultations. Because she had azotemia, it was speculated that she was growth hormone-resistant due to renal disease. It was also noted that she had labile blood pressures. The hypertensive values were treated with diltiazem and atenolol. She was also symptomatic for orthostatic hypotension:

RG never had overflow tearing. She had experienced blotching with excitement and eating and periodic excessive sweating. She had decreased reaction to painful stimuli.

At 19 months of age, she fractured her right elbow and did not seem uncomfortable. Her parents detected the problem when they noted swelling.

At 14 years of age, she developed bilateral “corneal burns” after swimming in a highly chlorinated pool. Despite the swelling and inflammation of this highly sensitive area, she did not have any discomfort.

She never manifested seizure activity or breath-hold. Although her cognitive functions were normal, her autonomic liability contributed to a high level of anxiety. In fact, she had a tendency to have “panic attacks.” She was able to attend a regular high school and was planning to go to a junior college. Her organizational skills, motivation, and planning were poor, and she was described as socially immature.

Clinical findings. On examination, her posture was poor and there were orthopedic problems including high cervical kyphosis and mild left-thoracic scoliosis, left tibial torsion, and pronated left foot. She had a forward thrust of the head and narrow, over-sloping shoulders.

Her height was 59.5 inches (151 cm), which is in the fifth percentile. Her weight was 89.5 (40.5 Kg), which is slightly less than the fifth percentile.

Her skin was well perfused but clammy due to excessive sweating. As she became anxious, or was supine, erythematous skin blotching appeared around her neck and ears. Other pertinent findings included absent corneal reflex in the left eye but weak reflex in right eye. There were no corneal scars. Visual acuity test revealed severe myopia that was correctable to 20/25 with corrective lenses. There was a right exophoria (divergent strabismus). Excessive cerumen was noted in ear canals. Speech was clear. Balance was fairly good, as she could walk on toes and heels but not tandem. She was able to balance and hop on either foot. There was no tremor or past pointing, and general muscle strength was good. Other than a definite increase in thresholds for appreciation of cold (9.2° C) and hot (8.5° C) (normal is less than 2°C for either), her peripheral sensory examination was normal. Her deep tendon reflexes were absent, and she had bilateral Babinski. Muscle tone was decreased around the ankles. Pain perception on the face was mildly decreased.

Diagnostic tests.

Routine blood chemistries were consistent with chronic dehydration or mild to moderate prerenal azotemia with blood urea nitrogen elevated to 31 mg/dL but serum creatinine of 1 mg/dL. There were no other abnormalities.

Management. Although RG was a mildly affected familial dysautonomia patient who was doing well in a number of areas, she was limited by her orthostatic problems and anxieties. The following recommendations were given:

(1) Increase fluid intake to 2.5 to 3 quarts a day to compensate for excessive losses (including sweating).

(2) Oral coordination and gastrointestinal motility should be assessed with Barium swallow using various consistencies to determine if she was experiencing mini aspirations or having gastroesophageal reflux. The latter can contribute to supine hypertension and also cause a chronic dry cough. Depending on the result, it would be determined if further studies (ie, esophageal pH probe) or treatment, diet modification, use of H2 antagonists, or prokinetics were needed.

(3) Alprazolam should be given twice a day; if particularly anxious and heading into a panic situation, diazepam 5 mg should be given to prevent going into a dysautonomic crisis (ie, excessive drooling, persistent flushing, negative change in personality, and some retching).

(4) Fludrocortisone (0.1 mg in morning and at noon) should be started to promote fluid retention, and lower extremities should be exercised to help promote blood return to the heart and decrease orthostatic hypotension.

(5) Use of artificial tears was also recommended.

RG did not have aspirated swallows or gastroesophageal reflux on her Barium study. The combination of increased fluid intake, fludrocortisone, and exercise improved her stamina and decreased dizzy spells.

Biological basis

Etiology and pathogenesis

It is not known how the mutation in the IKBKAP gene, which codes for the IKAP/ELP1 protein, causes or predisposes to familial dysautonomia. Because IKAP/ELP1 is associated with the human elongator complex that aids in transcriptional elongation (50), it has been suggested that the familial dysautonomia mutations lead to downregulation of genes involved in neuronal migration and function (34; 30), resulting in inadequate development, poor differentiation, or limited survival of unmyelinated and small myelinated neuronal cells that eventually comprise the sympathetic and sensory systems. Supporting this hypothesis is the finding that ELP-1/IKAP protein deficiency in the brain of familial dysautonomia patients resulted in down regulation of 25 genes, 25 of which were involved in oligodendrocyte differentiation and in oligodendroglial myelin formation (32). Using human induced pluripotent stem cells (iPSCs) derived from familial dysautonomia fibroblasts, Lee and colleagues have demonstrated that familial dysautonomia cells have marked defects in neurogenic differentiation and migration behavior (59).

Pathology. To date, neuropathologic examinations have demonstrated diminished neuronal populations in the sensory and autonomic systems consistent with a developmental arrest (01; 49; 79; 80). The epidermal nerve fiber density (EDNF) was found to be severely reduced in the calf and the back sites (52). The sural nerve is reduced in area and contains markedly diminished numbers of nonmyelinated axons as well as diminished numbers of small diameter myelinated axons (01; 76). This reduction in neuronal number has been noted even in very young subjects, as might be expected from the fact that clinical symptoms are present at birth. Consistent with decreased peripheral sensory neuronal populations, the dorsal root ganglia are grossly reduced in size. Within the spinal cord, lateral root entry zones and Lissauer tracts are severely depleted of axons (38). As evidence of slow progressive degeneration, there is a definite trend of increasing age for further depletion of the number of neurons in dorsal root ganglia and of growing abnormal numbers of residual nodules of Nageotte in the dorsal root ganglia. In addition, loss of dorsal column myelinated axons becomes evident in older patients. Neuronal depletion in dorsal root ganglia and the progressive pattern of cord changes correlate well with the clinical observations of worsening pain and vibration sense with age (17).

Neuropathologic findings in the peripheral sympathetic system are similar to those in the peripheral sensory system. The mean volume of superior cervical sympathetic ganglia is reduced to 34% of the normal size, reflecting an actual severe decrease in number of neurons. Despite the diminution in the numbers of sympathetic neurons in familial dysautonomia, staining for tyrosine hydroxylase is enhanced in familial dysautonomia neurons from sympathetic ganglia (77). The anatomical defect in the ganglion cells extends to preganglionic neurons, as the intermediolateral gray columns of the spinal cord also contain low number of neurons (79). Postganglionic sympathetic loss is supported by an ultrastructural study of peripheral blood vessels that demonstrated absence of autonomic nerve terminals (49) and recent cardiac imaging studies that demonstrated noradrenergic hypo-innervation (44). Lack of innervation is consistent with postural hypotension as well as denervation hypersensitivity, as demonstrated by exaggerated responses to sympathomimetic and parasympathomimetic agents (93; 94).

Although patients with familial dysautonomia do not produce overflow tears, and pharmacologic evidence suggests denervation supersensitivity in effector tissues normally supplied by postganglionic parasympathetic nerve terminals, the pathological findings in the parasympathetic system are not impressive. The sphenopalatine ganglia are consistently reduced in size with low total neuronal counts, but the neuronal population is only questionably reduced in other parasympathetic ganglia, such as the ciliary ganglia (80).

Central neuropathology has been poorly defined. However, a neuroimaging study has demonstrated white matter abnormalities and decreased optic radiation and middle cerebellar peduncle fractional anisotropy in familial dysautonomia patients, which suggest compromised myelination and microstructural integrity in familial dysautonomia brains (16). These neuroimaging results are consistent with clinical visual abnormalities and gait disturbance. Furthermore, there was also significantly decreased raw volume in the prefrontal cortex that is consistent with previously reported neuropsychological deficits (Welton et al 1979).

Neurophysiology. Consistent with the decreased sympathetic neuronal population, norepinephrine synthesis and catabolite excretion are reduced (48). Dopamine products continue to be excreted in normal amounts, resulting in abnormal 3-methoxy-4-hydroxymandelic acid to 3-methoxy-4-hydroxyphenylacetic acid ratios. Familial dysautonomia patients, like most other patients with neurogenic orthostatic hypotension, do not have an appropriate increase in plasma levels of norepinephrine and dopamine-beta-hydroxylase with standing, and their supine plasma levels of norepinephrine are normal or elevated (98; 14). In addition, familial dysautonomia patients appear to have a distinctive pattern of plasma levels of catechols, which do not change over time (14; 43). Regardless of posture, plasma levels of DOPA are disproportionately high and plasma levels of DHPG are low, resulting in elevated plasma DOPA:DHPG ratios. The high plasma DOPA levels are consistent with Pearson and colleagues’ description of large amounts of tyrosine hydroxylase in the superior cervical ganglia by monoclonal antibody stains (77).

When familial dysautonomia patients are upright, a strong correlation between blood pressure and plasma dopamine levels exists (14), suggesting that dopamine may be a pressor agent in familial dysautonomia patients. During emotional crises, plasma norepinephrine and dopamine levels are markedly elevated, and vomiting usually coincides with the high dopamine levels (69). Elevated norepinephrine is attributed to peripheral conversion of dopamine by dopamine beta hydroxylase. Diazepam sedates patients in crises and relieves vomiting (07), possibly by enhancing gamma-aminobutyric acid and damping the release of dopamine. Supine early morning plasma renin activity is elevated in familial dysautonomia subjects, and the release of renin and aldosterone is not coordinated (82). In familial dysautonomia individuals with supine hypertension, an increase in plasma atrial natriuretic peptide has also been demonstrated (19; 06). The combination of these factors may serve to explain the exaggerated nocturnal urine volume and increased excretion of salt in some familial dysautonomia individuals (58).

Genetics. Utilizing genetic linkage, the familial dysautonomia gene was localized to the distal long arm of chromosome 9 (q31), with sufficient DNA markers to permit prenatal diagnosis and carrier identification for families in which there had been an affected individual (26). In 2001, mutations were discovered in the IKBKAP gene, with a major haplotype mutation located in the donor splice site of intron 20 (02; 91). This mutation can result in the skipping of exon 20 in the mRNA of patients in specific subsets of cells such as peripheral neurons. The major haplotype accounts for more than 99.5% of the familial dysautonomia chromosomes, corresponding to a founder effect. The second mutation is a missense mutation that affects the phosphorylation of IKAP and has been identified in 4 unrelated patients heterozygous for the major splice mutation (02; 91). In 2003, the first non-Jewish IKBKAP mutation was described (61), which was a proline to leucine missense mutation in exon 26. This mutation was inherited from a parent without Ashkenazi Jewish ancestry. The affected patient was also heterozygous for the major splice mutation that he received from his single Jewish parent.

However, the molecular mechanisms involved in this disease remain elusive. It is assumed that the genetic error in familial dysautonomia leads to an arrested neuronal development and the catecholamine abnormalities are secondary to decreased neuronal number. It is now speculated that the genetic error in familial dysautonomia involves other genes that potentiate transcription of various trophic factors and subsequently the neural crest cell's ability to commit to its ultimate function, resulting in incomplete neuronal development and even apoptosis (34; 30; 32; 59).

Epidemiology

Familial dysautonomia is an autosomal recessive disorder that currently is confined to individuals of Ashkenazi Jewish extraction. Prior to the availability of DNA diagnosis, the carrier rate in the Ashkenazi Jewish population was estimated to be 1 in 32, with a disease frequency of 1 in 4096 live births (63). More studies using molecular diagnosis have cited carrier rates ranging from 1 in 25 to 1 in 42 (36; 95; 60). The highest numbers of patients are encountered in North America (54%) and Israel (34%), with cases also seen in Britain, Argentina, Brazil, South Africa, and Australia. Currently, the population seems to be stable, with around 3 new cases recorded every year (74).

Prevention

Because the 2 Jewish mutations causing familial dysautonomia have been identified (02; 91), DNA diagnosis and general population screening for the Ashkenazi Jewish population are now feasible, and theoretically, the birth of affected children could be avoided.

Differential diagnosis

Familial dysautonomia is 1 example of a group of rare disorders termed hereditary sensory and autonomic neuropathies (14; 05; 06; 51). The hereditary sensory and autonomic neuropathies can be broadly thought of as entities in which normal migration and maturation of neural crest derived cells has been impeded, especially those destined to evolve into the sensory and autonomic populations. Within this classification, familial dysautonomia is termed hereditary sensory and autonomic neuropathy type III.

Table 2. Hereditary Sensory and Autonomic Neuropathies

AD: autosomal dominant; AR: autosomal recessive; ATL1: atlastin GTPase 1; CIP: congenital insensitivity to pain; CIPA: congenital insensitivity to pain with anhidrosis; CMAP: compound muscle action potential; DNMT1: DNA methyltransferase 1; DST: dystonin; ELP1: elongator complex protein 1; FAM134B: family with sequence similarity 134, member B; GERD: gastroesophageal reflux; GI: gastrointestinal; HSN: hereditary sensory neuropathy; HT: histamine test; ID: intellectual disability; IKBKAP: inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein; KIF1A: kinesin family member 1A; NCS: nerve conduction studies; NGFβ: nerve growth factor beta; NTRK1: neurotrophic tyrosine kinase receptor type 1; PRDM12: PR domain zinc finger protein 12; QSART: quantitative sudomotor axon reflex test; QST: quantitative sensory testing; SCN9A: sodium voltage-gated channel alpha subunit 9; SNAP: sensory nerve action potential; SNHL: sensorineural hearing loss; SPTLC1: serine palmitoyletransferase long-chain base unit 1; SSR: sympathetic skin response; UMN: upper motor neuron; WNK1: with no lysine kinase or lysine-deficient protein kinase

(90)

Diagnostic workup

Diagnosis is based on clinical criteria as described above. Skin punch biopsy may show severe reduction in epidermal nerve fiber density (ENFD), mostly in a non-length dependent fashion (52). However, definitive diagnosis is provided by DNA analysis. The proband must either be homozygous for the major mutation or heterozygous for the major and minor mutations.

Management

It has been speculated that by raising the amount of the normal or wild-type protein product, IKAP, the progression of familial dysautonomia will be slowed and the clinical symptoms reduced (03). Four compounds have already been suggested as possible therapeutic agents because of their in vitro efficacy on modifying IKAP’s expression in cell culture: tocotrienols, epigallocatechin gallate, phosphatidylserine, and kinetin (03a; 03b; 92; 54; 59; 56). These compounds have been postulated as therapeutic agents for patients with familial dysautonomia. Although tocotrienol was reported to increase total IKBKAP gene expression (03a), its effectiveness could not be replicated by other studies (59; 56; 31). Epigallocatechin gallate, like kinetin, reportedly modifies mRNA splicing (03b), but its effectiveness in cell lines is modest when compared to kinetin (92; 59). Kinetin’s ability to correct the splicing defect was also demonstrated in olfactory stem cells derived from familial dysautonomia subjects (27). Kinetin was also found to reverse proprioceptive sensory loss in a familial dysautonomia mouse model (67). Phosphatidylserine was shown to increase total IKBKAP expression; however, its effects on IKAP levels in patients with familial dysautonomia are still unknown (56). As a compound that can be purchased over the counter, it is hard to experiment phosphatidylserine in placebo-controlled trials (74). Kinetin is the first of these compounds to be subjected to an objective assessment in humans regarding pharmacokinetics, impact on mRNA splicing, and safety. Because heterozygotes or carriers of the mutant IKBKAP gene have reduced wild-type mRNA IKBKAP in their peripheral white cells (46), kinetin was administered and shown to be effective in modifying, splicing, and raising wild-type mRNA IKBKAP in the peripheral white blood cells (45). Based on these encouraging studies, clinical trials with kinetin were advanced to patient population.

Therefore, treatment of familial dysautonomia remains preventive, symptomatic, and supportive and must be directed toward specific problems. Dysphagia is initially treated by thickening feeds and feeding therapy. However, the insertion of a gastrostomy is frequently required (07). The gastrostomy assures a route to maintain adequate hydration yet avoids aspiration. Esophageal dysmotility and gastroesophageal reflux are also common and increase risk of aspiration. When medical management with prokinetic agents, H2 antagonists, thickening of feeds, and positioning are not successful, then surgical intervention (fundoplication) is performed (23; 15; 07). Failure of medical management is defined as radiographic evidence of lower respiratory disease, hematemesis, apnea, or failure to maintain adequate weight gain, growth, and hydration.

Treatment of the dysautonomic vomiting crisis is perhaps one of the most challenging aspects of care. In addition to treating the precipitating cause, for example, the stress of an infection, the crises are managed with a combination of intravenous or rectally administered diazepam (0.2 mg/kg every 3 hours with a maximum dose of 10 mg) and avoidance of dehydration and aspiration (07). The remarkable response to diazepam is consistent with the hypothesis that the crisis may be a type of autonomic seizure (24). If there is associated refractory hypertension, then clonidine via the gastrostomy or as a transdermal patch may be tried. An α2 adrenergic agonist, dexmedetomidine, has a greater selectivity and a shorter half-life than clonidine. It was found to be safe and effective in treating refractory adrenergic crises in a retrospective study that included 9 familial dysautonomia patients (14 admissions) (35). It can be considered in those who do not respond to clonidine and/or benzodiazepine pharmacotherapy.

In attempts to thwart the cyclical occurrence of nausea, 2 modalities have been tried. The first is the use of pregabalin, as a means of modifying central excitability. Its use on a chronic basis ameliorated the symptom of nausea accompanying morning arousal in a number of patients (09). The second is the use of carbidopa, an inhibitor of dopa-decarboxylase that blocks the synthesis of dopamine outside the brain. In a preliminary study, daily use appears to be effective in decreasing the frequency and intensity of hyperdopaminergic nausea/retching/vomiting attacks (72). High- and low-dose (600 and 300 mg a day, respectively) carbidopa were similarly well tolerated and effective in reducing blood pressure variability in familial dysautonomia patients with afferent baroreflex failure in a randomized placebo-controlled trial that enrolled 22 patients (73).

Postural hypotension can be treated with standard methods such as adequate hydration, lower extremity exercises, elastic stockings, fludrocortisone, and midodrine (18; 07). Aggressive pharmacologic treatment of orthostatic hypotension with fludrocortisone and midodrine has been shown to improve survival statistics (07). Droxidopa (L-threo-dihydroxyphenylserine) was approved by the FDA for neurogenic orthostatic hypotension (55). For more details on the treatment of neurogenic orthostatic hypotension, you can refer to the MedLink articles titled “Treatment of autonomic neuropathy” and “Pure autonomic failure.”

Hypertension is usually transitory, so treatment should be directed to factors precipitating the hypertension such as anxiety or visceral pain. If the hypertension is persistent, diazepam and clonidine have been found to be particularly effective (07). Any patient who experiences a syncopal episode should have Holter monitoring. If there is asystole or prolonged JTc, then the patient should be given a closely monitored trial of disopyramide. If there is a high-grade block or any asystolic episodes, a dual chamber demand pacemaker is indicated (47).

To compensate for alacrima, artificial tears should be instilled on a regular basis. Corneal complications have been decreasing with regular use of artificial tear solutions and maintenance of normal body hydration. In addition, cautery and plugs of the tear duct puncta have been used in refractory situations as they serve to impede drainage from the lacrimal bed. Tarsorrhaphy has been reserved for unresponsive and chronic situations. Soft contact lenses and scleral lenses are also beneficial in promoting corneal healing. Corneal transplants have had limited success.

Outcomes

A 28-day open-label study of kinetin in 8 homozygous patients was performed (20). An increase in splicing efficiency in circulating leukocytes after 8 days of treatment and a further increase after 28 days of exposure were reported. However, subjects started to drop out due to nausea. The small sample size and lack of control group made it hard to draw any meaningful conclusions from these studies (74).

Special considerations

Pregnancy

Women with dysautonomia have conceived and delivered normal infants (81). Although pregnancies were tolerated well, blood pressure lability was marked at delivery due to major hemodynamic shifts. All offspring of familial dysautonomia patients have been phenotypically normal despite their obligatory heterozygote state.

Anesthesia

General anesthesia has caused profound hypotension and cardiac arrest. One of the most important factors in reducing risk is maintaining an adequate circulating volume, as vasodilatation during anesthesia may be extreme. With greater attention to stabilization of the vascular bed by hydrating the patient before surgery and titrating the anesthetic, the risk of these problems has been greatly reduced (10; 68). The patient should be prehydrated the night prior to surgery with intravenous fluids. Arterial blood pressures and blood gases are monitored throughout surgery via an arterial line in long procedures or those associated with changes in intravascular volumes. Hypotension should be corrected by decreasing the percentage of gas anesthetic and administering volume expanders. Phenylephrine hydrochloride or ephedrine is the preferred initial pressor.

Local anesthesia with diazepam as preoperative sedation is preferred whenever possible. Large amounts of epinephrine should not be infiltrated because of the exaggerated response to sympathomimetic drugs. Atropine is also not routinely given preoperatively.

Postoperative management can be extremely challenging. Gastric secretions tend to be copious during excitatory anesthetic phases. To avoid postoperative aspiration, ranitidine can be given, and the stomach should be kept decompressed. This is facilitated if a gastrostomy is present. The stress or pain of the procedure may induce a postoperative vomiting crisis, which will require intravenous diazepam. Visceral pain is appreciated and often causes hypertension, so narcotic pain medication may be required for intraabdominal or intrathoracic procedures. Ophthalmologic cases may require minimal pain medication.