Familial Dysautonomia Clinical Presentation

Although the diagnostic signs may be evident at birth, considerable variation exists in the expression of the disease at any time.^{[1, 2]} The earliest signs are feeding difficulties with uncoordinated swallowing and risk of aspiration pneumonia. The lack of tears with emotional crying may be noted after age 7 months when infants normally show evidence of tear production. Additionally, the affected child may show severe reactions to physical and emotional stress termed dysautonomic crises. These events are characterized by intractable vomiting, sweating, tachycardia, hypertension, and personality changes. During these episodes, parents of young patients may notice flushing of the skin and profuse drooling, as well as conjunctival congestion, loss of corneal luster, or corneal opacification. Older patients report loss of vision without pain when the integrity of the ocular surface is compromised.

• Ocular findings

  • Absence of overflow tears with emotional crying is noted in all cases.
  • Baseline moisture and reflex tearing varies among individuals and even in the same individual at different periods, although the overall tear volume usually is reduced. This reduction places the integrity of the corneal epithelium at greater risk in the presence of fever or dehydration or in an overly dry environment.
  • Corneal anesthesia usually is present, increases susceptibility to minor trauma, and may delay repair when epithelial defects occur.
  • Diffuse punctate conjunctival and corneal epithelial staining with vital dyes, such as fluorescein or rose bengal, is a common finding, and it is particularly increased during crisis episodes.
  • During crisis periods the blink rate, which usually is reduced, is slowed further.
  • The palpebral fissure often is widened, possibly due to unopposed activity of the lid retractors, increasing the surface drying.
  • Incomplete lid closure during sleep also may cause erosions of the inferior cornea. Persistent epithelial erosions lead to progressive corneal thinning and repair by fibrovascular scaring.
  • Neurotrophic corneal ulcers are usually circular or horizontally oval in contour with rolled epithelial edges and located in the central or inferior cornea. The surrounding inflammatory reaction as well as the anterior chamber reaction may be mild, and a border of hazy epithelium usually surrounds the defect.
  • Stromal opacification due to edema and degenerative changes in the collagen as well as calcium deposition in the bed can occur.
  • Superinfection must of course be guarded against but has been less frequent in familial dysautonomia than might be anticipated, possibly because of the irrigating effect of frequent tear instillations and excellent family support.^{[19, 20]} When bacterial superinfection occurred, staphylococci were the most common agents.
  • However, resistant strains and gram-negative contamination must be considered when patients are hospitalized for respiratory complications.
  • Herpes simplex and herpes zoster infections have not been noted, raising speculation of a relationship to the reduction in the neuronal population of the ganglia.
  • Exotropia and myopia have been noted more commonly in familial dysautonomia than in the general population.
  • Optic neuropathy characterized by nerve pallor and decrease in best corrected visual acuity is frequent and increases with age. It can be detected in the early stage by abnormal visual-evoked potential (VEP) and later by generalized visual field depression particularly in the cecocentral region.^{[21, 22]}
• Systemic findings

  • The diagnosis is confirmed by ascertaining the presence of 5 cardinal criteria.
    • Absence of overflow emotional tears
    • Absent lingual fungiform papillae
    • Depressed patellar reflexes
    • Lack of an axon flare following intradermal histamine
    • Documentation of Ashkenazi Jewish extraction
  • Further supportive evidence is provided by findings of decreased response to pain and temperature, orthostatic hypotension, periodic erythematous blotching of the skin, and increased sweating.
  • In addition, cineesophagrams may reveal delay in cricopharyngeal closure, tertiary contractions of the esophagus, gastroesophageal reflux, and delayed gastric emptying.
  • Other clinical signs include manifestations of sensory and autonomic nervous system dysfunction.
• Sensory system

  • Although pain sensation is decreased, it is not completely absent, and palms, soles of feet, neck, and genital areas usually are spared; these areas often are exquisitely sensitive.
  • Temperature appreciation is affected with decreased responses to both hot and cold.
  • Pain and temperature perceptions are more affected in the trunk and lower extremities, and older individuals have greater losses than younger individuals.
  • In the older individual, vibration sense and occasionally joint position become abnormal and rombergism may be noted.
  • Visceral sensation is intact, so patients are able to perceive discomfort with pleuritic or peritoneal irritation.
  • Peripheral sensory deprivation makes the patient with familial dysautonomia prone to self-injury.
  • In addition to inadvertent trauma to joints and long bones causing Charcot joints, aseptic necrosis, and unrecognized fractures, some patients self-mutilate by picking at their fingers to the point of bleeding.
  • Spinal curvature abnormality can be early and pernicious in its course.
  • Central sensory deficits include decreased pain perception along the branches of the trigeminal nerve, diminished corneal reflexes, and decreased taste perception, especially in recognition of sweet, which corresponds to the absence of fungiform papillae on the tip of the tongue.
  • Although the motor system is spared, the young child with familial dysautonomia is frequently hypotonic, which may be due to a combination of central deficits and decreased tone of stretch receptors.
  • Older patients are not weak but develop a broad-based and mildly ataxic gait with special difficulties in performing rapid movements or turning. Gait abnormalities can be severe enough to require use walkers or wheelchairs.
• Autonomic dysfunction: Pervasive autonomic dysfunction results in protean functional abnormalities affecting other systems and yielding a myriad of clinical manifestations. As the disorder has variable expression, individual variations exist. Some of these manifestations are apparent at birth and others become more prominent and problematic as a function of age.

  • Gastrointestinal system
    • Oropharyngeal incoordination is one of the earliest signs of familial dysautonomia. Poor suck or uncoordinated swallow is observed in 60% of infants in the neonatal period.
    • Oral incoordination also results in tendency to drool.
    • Liquids are more apt to be aspirated.
    • If nutrition cannot be maintained or respiratory problems persist, then gastrostomy is recommended.
    • The most prominent manifestation of abnormal gastrointestinal dysmotility in individuals with familial dysautonomia 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 often is associated with hypertension, tachycardia, diffuse sweating, and even personality change, this constellation of signs has been termed the dysautonomic crisis.
    • Gastroesophageal reflux (GER) is another common problem and should be considered in individuals with familial dysautonomia who frequently vomit.
  • Respiratory system
    • Aspiration is the major cause of lung infections and is due to oral incoordination and or gastroesophageal reflux.
    • Ventilatory response to lung infection often is altered because of insensitivity to hypoxia and hypercapnia.^{[23, 24]}
    • Low oxygen saturations do not stimulate tachypnea and can cause syncope as hypoxia induces both hypotension and bradycardia.
    • Dysautonomic patients must be cautious in settings where the partial pressure of oxygen is decreased, such as at high altitudes or during airplane travel. When the airplane's altitude exceeds 39,000 feet, the cabin pressure will be equivalent to more than 6000 feet, and supplemental oxygen probably will be necessary.
    • Diving and underwater swimming can be potential hazards.
  • Cardiovascular irregularities
    • Consistent with sympathetic dysfunction, patients exhibit rapid and severe orthostatic decreases in blood pressure, without appropriate compensatory increases in heart rate.
    • Clinical manifestations of postural hypotension include episodes of lightheadedness or dizzy spells.
    • Some patients complain of weak legs.
    • On occasion, syncope may occur. Symptoms tend to be worse in the morning, in hot or humid weather, when the bladder is full, before a large bowel movement, after a long car ride, coming out of a movie theater, or with fatigue.
    • Symptoms referable to hypotension become more prominent in the adult years and can limit function and mobility.
    • General anesthesia has the potential for inducing severe hypotension. With greater attention to stabilization of the vascular bed by hydrating the patient before surgery and titrating the anesthetic to continuously monitored arterial blood pressure, anesthetic risk has been reduced greatly.
    • In older patients, supine hypertension can become prominent despite the retention of severe orthostatic hypotension, which increases treatment challenge.
    • Hypertension also can occur intermittently in response to emotional stress or visceral pain or as part of the crisis constellation. The hypertension responds to the same medications recommended for crisis management.
    • Hypertension also can exist without any other symptoms. Because blood pressure is so labile in individuals with familial dysautonomia, asymptomatic hypertension usually is not treated because the hypertension usually is transitory and appears to be better tolerated than hypotension.
    • As part of the progressive nature of familial dysautonomia, worsening of sympathetic dysfunction and development of parasympathetic dysfunction occurs.
  • Renal problems
    • Azotemia is frequently prerenal in origin.
    • Although clinical signs of dehydration may not be present, blood urea nitrogen values often can be reduced by simple hydration.
    • Renal function appears to deteriorate with advancing age, so that about 20% of adult patients have reduced renal function.^[11]
    • Renal biopsies performed on individuals with noncorrectable azotemia revealed significant ischemic-type glomerulosclerosis and deficient vascular innervation.
    • Renal hypoperfusion secondary to cardiovascular instability has been suggested as the cause of the progressive renal disease.
  • Central nervous system features (intelligence/emotion/seizures)
    • Emotional lability has been considered one of the prominent features of familial dysautonomia and was emphasized in its original description. Now, behavioral abnormalities are acknowledged as part of the crisis constellation and may be secondary to periodic catecholamine imbalance. The prompt normalization of personality in response to benzodiazepines supports this hypothesis.
    • Most affected individuals are of normal intelligence.^[14]
    • About 25% of patients with familial dysautonomia have abnormal EEGs but less than 10% actually have a true seizure disorder.
    • Prolonged breath-holding with crying can be severe enough to result in cyanosis, syncope, and decerebrate posturing and has been believed to represent a type of seizure activity.
    • Breath-holding is frequent in the early years, occurring at least one time in 63% of patients. This phenomenon probably is a manifestation of insensitivity to hypoxia and hypercapnia. It can become a manipulative maneuver with some children. The episodes are self-limited, cease by age 6 years, and have never been fatal.
    • Metabolic seizures, induced by hyponatremia, have been observed during extremely hot weather when fluid and salt intake have failed to compensate for the excessive sweating manifested by these patients.
    • Hyponatremic seizures also have occurred with severe infections.

Familial dysautonomia is an autosomal recessive genetic disorder caused by mutations in the IKBKAP gene.^{[4, 6]}