This disorder, inherited as an autosomal recessive trait, affects predominantly children of Ashkenazic Jewish heritage. Familial dysautonomia is usually manifested soon after birth (poor sucking, failure to thrive, unexplained fever, episodes of pneumonia). Hyporeflexia and impairment or loss of pain and temperature sensation, with relative preservation of pressure and tactile sense, are the main manifestations. Motor fibers are probably involved as well, but only to a slight degree; this is shown more effectively by reduced motor conduction velocity in peripheral nerves than it is by weakness. At a later age, the neuropathy becomes overshadowed by other manifestations of the disease, notably repeated infections and abnormalities of the autonomic nervous system—lack of tears, corneal ulceration, fixed pupils, blotchiness of the skin, defective temperature control, cold hands and feet, excessive sweating, lability of blood pressure, postural hypotension, difficulty in swallowing, esophageal and intestinal dilation, emotional instability, recurrent vomiting, and stunted growth. The tongue lacks fungiform papillae.
Nerve biopsy reveals a diminution of small myelinated and unmyelinated fibers, which explains the impairment of pain and temperature sensation. In autopsy material, sympathetic and parasympathetic ganglion cells and, to a lesser extent, nerve cells in the sensory ganglia are diminished in number. Patients excrete increased amounts of homovanillic acid and decreased amounts of vanillylmandelic acid and methoxyhydroxyphenylglycol.
Weinshilboum and Axelrod demonstrated a decrease in serum dopamine β-hydroxylase, the enzyme that converts dopamine to norepinephrine. The disease is caused by a mutation in a gene that expresses a kinase-associated protein (see HSAN3 in Table 43-6). There is no treatment for the disease except to provide symptomatic relief of gastrointestinal symptoms and orthostatic fainting.
Other examples of congenital polyneuropathy with absence of autonomic function, probably differing from the Riley-Day dysautonomia, have been reported. Some of these develop transient episodes of reflex sympathetic dystrophy. A congenital failure of development of neural elements derived from the neural crest has been postulated.
Ataxia-telangiectasia and Chédiak-Higashi disease are other genetic diseases with a recognized metabolic abnormality that may cause a polyneuropathy. They are described in Chap. 36, with the hereditary metabolic disorders.
Other Forms of Inherited Sensory Neuropathy
Included here are numerous disorders similar to the ones described in the preceding pages but caused by different mutations; neuropathy with cerebellar degeneration; and the neuropathies in which there are recognized metabolic abnormalities, including familial amyloidosis. Some years ago a young man and woman with universal anesthesia affecting head, neck, trunk, and limbs came to attention (Adams et al); all forms of sensation were absent. The patients were areflexic but retained nearly full motor power; their movements were ataxic. Autonomic functions were impaired but not abolished. In a sural nerve biopsy, nearly all fibers—large and small, myelinated and unmyelinated—had disappeared. Surprisingly, there were no trophic changes of any kind. Donaghy and coworkers and others have described a variant of the recessively inherited form of sensory neuropathy in which there was an associated neurotrophic keratitis and a selective loss of small myelinated fibers in sural nerve biopsies. We continue to observe variant and unclassifiable cases of purely motor, sensory, or mixed types in which genetic testing does not reveal a mutation such as these every year.