Pathology

This disease of the peripheral nervous system is characterized pathologically by a reduced number of small unmyelinated nerve fibers that carry pain, temperature, and taste sensations and that mediate autonomic functions. Large myelinated afferent nerve fibers that relay impulses from muscle spindles and Golgi tendon organs also are deficient. The degree of demonstrable anatomic change in peripheral and especially autonomic nerves is variable. Fungiform papillae of the tongue (taste buds) are absent or reduced in number. The number of parasympathetic ganglion cells in the myenteric plexuses is reduced. There is terminal vessel hyperperfusion in tissues, despite an overall hypoperfusion of organs and extremities.

Clinical Manifestations

The disease is expressed in infancy by poor sucking and swallowing. Aspiration pneumonia can occur. Feeding difficulties remain a major symptom throughout childhood. Vomiting crises can occur. Apart from dysphagia, esophageal dysmotility can contribute to these symptoms. Episodic somnolence can occur in infants. Excessive sweating and blotchy erythema of the skin are common, especially at mealtime or when the child is excited. Infants are vulnerable to heatstroke. Episodic hyperhidrosis is due to chemical hypersensitivity of the remaining reduced number of sudomotor axons rather than of the sweat gland secretory cells. Breath-holding spells followed by syncope are common in the first 5 years of life.

As affected children become older, insensitivity to pain becomes evident and traumatic injuries are frequent. Corneal ulcerations are common. Newly erupting teeth cause tongue ulcerations. Walking is delayed or clumsy or appears ataxic because of poor sensory feedback from muscle spindles. The ataxia is probably related more to deficient muscle spindle feedback and to vestibular nerve dysfunction than to cerebellar involvement. Tendon stretch reflexes are absent. Scoliosis is a serious complication in the majority of patients and usually is progressive. Overflow tearing with crying does not normally develop until 2-3 mo of age but fails to develop after that time or is severely reduced in children with familial dysautonomia. There is an increased incidence of urinary incontinence. Bradycardia and other cardiac arrhythmias can occur, and some patients require a cardiac pacemaker.

About 40% of patients have generalized major motor seizures, some of which are associated with acute hypoxia during breath holding, some with extreme fevers, but most without an apparent precipitating event. Body temperature is poorly controlled; both hypothermia and extreme fevers occur. Impaired intellectual function is not secondary to epilepsy. Emotional lability and learning disabilities are common in school-age children with the disorder. Puberty is often delayed, especially in girls. Short stature can occur, but growth velocity can be accelerated by treatment with growth hormone. Speech is often slurred or nasal.

After 3 yr of age, autonomic crises begin, usually with attacks of cyclic vomiting lasting 24-72 hr or even several days. Retching and vomiting occur every 15-20 min and are associated with hypertension, profuse sweating, blotching of the skin, apprehension, and irritability. Prominent gastric distention can occur, causing abdominal pain and even respiratory distress. Hematemesis can complicate pernicious vomiting.

Allgrove syndrome is a clinical variant, involving alacrima, achalasia, autonomic dysfunction with orthostatic hypotension and altered heart rate variability, and sensorimotor polyneuropathy, usually manifesting in adolescence. Cholinergic dysfunction may be demonstrated.

Laboratory Findings

Electrocardiography discloses prolonged correcting QT intervals with lack of appropriate shortening with exercise, a reflection of the aberration in autonomic regulation of cardiac conduction. Chest radiographs show atelectasis and pulmonary changes resembling cystic fibrosis. Urinary vanillylmandelic acid level is decreased, and homovanillic acid level is increased. Plasma level of dopamine β-hydroxylase (the enzyme that converts dopamine to epinephrine) is diminished. Sural nerve biopsy shows a decreased number of unmyelinated fibers. Electroencephalography is useful for evaluating seizures.

Diagnosis

Slow IV infusion of norepinephrine produces an exaggerated pressor response. The hypotensive response to infusion of methacholine is increased. Intradermal injection of 1 : 1,000 histamine phosphate fails to produce a normal axon flare, and local pain is absent or diminished. Because the skin of a normal infant reacts more intensely to histamine, a 1 : 10,000 dilution should be used. Instillation of 2.5% methacholine into the conjunctival sac produces miosis in patients with familial dysautonomia and no detectable effect on a normal pupil; this is a nonspecific sign of parasympathetic denervation due to any cause. Methacholine is applied to only 1 eye in this test, with the other eye serving as a control; the pupils are compared at 5-min intervals for 20 min. A test for the genetic marker in blood is available in selected centers around the USA and Israel for definitive diagnostic testing.

Treatment

Symptomatic treatment includes special attention to the respiratory and GI systems to prevent aspiration and malnutrition, methylcellulose eye drops or topical ocular lubricants to replace tears and prevent corneal ulceration, orthopedic management of scoliosis and joint problems, and appropriate anticonvulsants for epilepsy. Chlorpromazine is an effective antiemetic and may be given as rectal suppositories during autonomic crises. It also reduces apprehension and lowers the blood pressure. Diazepam also is effective in some cases. Dehydration and electrolyte disturbances should be anticipated. Bethanechol may be an alternative drug for cyclic vomiting. It is also useful for enuresis, another common complication, and augments tear production. Protection from injuries is important because of the lack of pain as a protective mechanism. Scoliosis often requires surgical treatment. Antiepileptic drugs may be required. A cardiac pacemaker may be required by some children. Blood pressure monitoring may be important in some cases. A promising genetic approach to treatment, which corrects the splicing defect, is the use of oral kinetin to regulate the expression of IKBKAP transcripts. Tocotrienols also have a theoretical value in treating familial dysautonomia.

Prognosis

Sixty percent of patients die in childhood before the age of 20 yr, usually of chronic pulmonary failure or aspiration. Treatment in a center familiar with the diverse complications greatly extends the life expectancy; some have survived by age 40 yr. Prevention of aspiration with fundoplication, gastrostomy, and tube feeding reduces the risk of aspiration.

Myenteric Plexus Neuropathies

Aganglionic megacolon (Hirschsprung disease) is a failure of embryonic development of parasympathetic neurons in the submucosal and myenteric plexuses of segments of the colon and rectum. Nerves between the longitudinal and circular layers of smooth muscle of the gut wall are hypertrophic; ganglion cells are absent (Chapter 324).

Congenital Insensitivity to Pain and Anhidrosis

Congenital insensitivity to pain and anhidrosis is a hereditary disorder of uncertain genetic transmission. It affects many more boys than girls and manifests in early infancy. Patients have episodes of high fever related to warm environmental temperatures because they do not perspire. Frequent burns and traumatic injuries result from apparent lack of pain perception. Intelligence is normal. Nerve biopsy reveals an almost total absence of unmyelinated nerve fibers that convey impulses of pain, temperature, and autonomic functions. Some cases of hypomyelinating neuropathy manifest clinically as congenital insensitivity to pain (Chapter 605.8). The sympathetic skin response as an electrophysiologic study is a reliable diagnostic test in cases associated with a mutation at the TrKA receptor for nerve growth factor.

Reflex Sympathetic Dystrophy

Reflex sympathetic dystrophy is a form of local causalgia, usually involving a hand or foot but not corresponding to the anatomic distribution of a peripheral nerve (Chapter 162.2). A continuous burning pain and hyperesthesia are associated with vasomotor instability in the affected zone, resulting in increased skin temperature, erythema, and edema due to vasodilatation and hyperhidrosis. In the chronic state, atrophy of skin appendages, cool and clammy skin, and disuse atrophy of underlying muscle and bone occur. More than 1 extremity is occasionally involved. The pain is disabling and is exacerbated by the movement of an associated joint, although no objective signs of arthritis are seen; immobilization provides some relief. The most common preceding event is local trauma in the form of a contusion, laceration, sprain, or fracture that occurred days or weeks earlier.

Several theories of pathogenesis have been proposed to explain this phenomenon. The most widely accepted is reflexive overactivity of autonomic nerves in response to injury, and regional sympathetic blockade often affords temporary relief. Physiotherapy also is helpful. Some cases resolve spontaneously after weeks or months, but others continue to be symptomatic and require sympathectomy. A psychogenic component is suspected in some cases but is difficult to prove.