The age of onset of this form of familial amyloid polyneuropathy is between 25 and 35 years. The disease progresses slowly and terminates fatally in 10 to 15 or more years. The initial symptoms are usually numbness, paresthesias, and sometimes pain in the feet and lower legs. Weakness is minimal, and the tendon reflexes, although diminished, may be retained early in the course of the illness. Pain and thermal sense are reduced more than tactile, vibratory, and position sense (a “pseudosyringomyelic”) pattern. Autonomic involvement is another important characteristic—loss of pupillary light reflexes and miosis, anhidrosis, vasomotor paralysis with orthostatic hypotension, alternating diarrhea and constipation, and erectile dysfunction. These autonomic changes tend to be more extensive than the sensory ones. Difficulty in walking also develops and has its basis in a combination of faulty position sense and mild muscle weakness. Later, tendon reflexes are abolished and the legs become thin. The nerves are not enlarged. Cranial nerve involvement (facial weakness and numbness, loss of taste) is a late manifestation and occurs in only a few cases.
The clinical details vary somewhat from case to case, even within a family. Cardiac enlargement and irregularities in cardiac rhythm as a result of bundle-branch or atrioventricular (AV) block occur early in some and late in others. A few patients have had severe amyloid cardiomyopathy from the onset (Ikeda et al). Weight loss may be pronounced owing to anorexia and disordered bowel function and the later development of a malabsorption syndrome. The liver may become enlarged (as it may in the acquired form). Vitreous opacities (veils, specks, and strands) may progress to blindness but this has been rare; in a few, there has been an impairment of hearing. Involvement of the CNS—manifest as behavioral abnormalities, cerebellar ataxia, and bilateral corticospinal signs—has also been reported in a few cases but their nature and pathologic basis is controversial (Ikeda et al). A nephrotic syndrome and uremia terminate life in some patients. The CSF may be normal or the protein content may be increased (50 to 200 mg/dL); the blood is normal except for anemia caused by amyloidosis of the bone marrow. This is probably the most common transthyretin mutation–derived amyloidosis.
2. Familial amyloidosis with carpal tunnel syndrome (Swiss type). Falls and coworkers, in 1955, and later Rukavina and associates described a large group of patients of Swiss stock living in Indiana who developed, in their fourth and fifth decades, a syndrome of acroparesthesias in the hands as a result of deposition of amyloid in the connective tissues and beneath the carpal ligaments. Similar kindreds of German descent were recognized in Maryland. There were sensory loss and atrophic muscle weakness in the distribution of the median nerves, which were compressed. Section of the carpal ligaments relieved the symptoms. In some of the patients, other nerves of the arms were said to have become involved later. Vitreous deposits have been observed frequently in this form of the disease. As with the Portuguese type, an abnormal transthyretin is the basis of the deposition of amyloid.
3. Iowa type. In 1969, van Allen described an Iowa kindred with onset, in their thirties, of a fairly severe sensorimotor neuropathy, involving the legs and then the arms. There was amyloid deposition in the testes, adrenal glands, and kidneys (the usual cause of death), as well as a high incidence of peptic ulcer disease. The amyloid in this disease is derived from a mutated apolipoprotein A1, in which there is an amino acid substitution.