Alpha 2-adrenergic receptor in familial amyloidotic polyneuropathy.

alpha 2-Adrenergic receptor binding has been studied in platelet membranes from 16 patients with type 1 familial amyloidotic polyneuropathy (FAP) at various clinical stages and 15 normal subjects. Binding of the radioligand [3H]yohimbine to platelet membranes was used to examine alpha 2-adrenergic receptors. The number of alpha 2-adrenergic receptors were significantly lower in patients of the early stage than in normal subjects. Then, the numbers tended to be higher than those of normal subjects in the intermediate stage, and they were higher in the single advanced-stage patient studied. The reduction in alpha 2-adrenergic receptor numbers in platelet membranes from patients of the early stage might be explained by the down-regulation of the receptors in vascular smooth muscle, but it remains uncertain whether a high number of alpha 2-adrenergic receptors observed in the single advanced-stage patient might be explained by the up-regulation of the receptors.

Disturbed function of the pineal gland in familial amyloid polyneuropathy.

In order to estimate the function of the pineal gland, the sympathetic nervous system and the adrenal medulla in patients with familial amyloid polyneuropathy relative to healthy subjects, we have quantified urinary 6-hydroxymelatonin, normetanephrine and metanephrine. Urinary 6-hydroxymelatonin level correlated with neither of two O-methylated catecholamine levels in healthy subjects. The excretion of both 6-hydroxymelatonin and metanephrine were reduced in the patient group as compared with the control group, and the normal daily rhythm of 6-hydroxymelatonin was undetectable in the most of the patients. This finding indicates that the function of the pineal gland is disturbed in familial amyloid polyneuropathy.

Genetic studies of familial amyloid polyneuropathy in the Arao district of Japan: I. The genealogical survey.

A genealogical survey of familial amyloid polyneuropathy in the Arao district of Japan was undertaken, and the data were analysed statistically. The survey revealed 92 patients (46 males and 46 females) in 9 families. Thirty-one of the patients (16 males and 15 females) are alive. For 44 patients, the mean age of onset was 34.1 years (range 20-46 years). The penetrance corrected for late onset was 83.5% by Morton's method. The segregation ratio of 18 sibships in which one of the parents was affected was 36 +/- 6% for single ascertainment and 46 +/- 5% for complete ascertainment; the corresponding figures of 14 sibships in which neither parent was affected was 30 +/- 7% for single ascertainment and 40 +/- 6% for complete ascertainment. The results of the analysis were consistent with the assumption of an autosomal dominant mode of inheritance.

Pharmacokinetic studies of oral L-threo-3,4-dihydroxyphenylserine in normal subjects and patients with familial amyloid polyneuropathy.

The pharmacokinetics of oral L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) was studied in 7 normal subjects and 7 patients with familial amyloid polyneuropathy. Each person swallowed a single 300 mg dose in the fasting state, and L-threo-DOPS in plasma and urine was determined by high performance liquid chromatography with an electrochemical detector after separation on a boric acid gel column. L-threo-DOPS was slowly absorbed by normal subjects; the maximum plasma concentration occurred 3 h after administration and 20% of the oral dose was recovered unchanged in the urine within 12 h. It induced a substantial elevation of plasma norepinephrine levels, the peak being attained at 5 h, but without any change in blood pressure. In the patients, the absorption and metabolism of L-threo-DOPS were delayed, and a prolonged pressor response was observed, with a peak after 8 h. It was concluded that the effects on plasma norepinephrine and blood pressure of oral L-threo-DOPS were essentially equal to those of twice as large a dose of DL-threo-DOPS.

Orthostatic hypotension in familial amyloid polyneuropathy: treatment with DL-threo-3,4-dihydroxyphenylserine.

We measured plasma norepinephrine levels in patients with familial amyloid polyneuropathy. Patients with orthostatic hypotension had low basal plasma norepinephrine levels, which did not increase after postural change. On the basis of biochemical findings that suggest depletion of peripheral norepinephrine, DL-threo-3,4-dihydroxyphenylserine, an immediate precursor of norepinephrine, was given orally. Six hundred mg of this drug induced substantial and sustained elevation of blood pressure for several hours, and plasma norepinephrine content increased. Daily administration for 4 weeks improved postural dizziness and syncope, and daily activity increased.

Effect of infused L-threo-3,4-dihydroxyphenylserine on adrenergic activity in patients with familial amyloid polyneuropathy.

L-threo-3,4-dihydroxyphenylserine (DOPS), an immediate precursor amino acid of (-)-norepinephrine, was used as a pharmacological tool to investigate the pathophysiology of the peripheral sympathetic nervous system in Type 1 familial amyloid polyneuropathy. Patients with the well-established disorder showed an enhanced pressor response to L-threo-DOPS under conditions that produced no change in normal subjects. While octopamine induced a brisk pressor response, L-threo-DOPS produced a slow and prolonged change in blood pressure, with a marked concomitant increase in urinary excretion of norepinephrine. A slight increase in urinary excretion of total metanephrine was observed in both groups, but there was no significant increase in serum dopamine-beta-hydroxylase activity. Since infusion of dilute norepinephrine into patients also produced a markedly hypersensitive response, the characteristic pressor response to L-threo-DOPS was indicative of denervation supersensitivity of adrenergic receptors to norepinephrine formed enzymatically from L-threo-DOPS.

Catecholamine metabolism in familial amyloid polyneuropathy.

In order to evaluate the involvement of the peripheral autonomic nervous system in the pathogenesis of type 1 familial amyloid polyneuropathy, the urinary excretion rates of catecholamines and serum dopamine-beta-hydroxylase (DB/) activity were examined in 22 patients at various clinical stages. Changes in both indices were closely linked to the progression of the illness; urinary excretion rates of catecholamines were first decreased in patients suffering from moderate autonomic dysfunction, while serum DBH activity was significantly reduced only in patients with far advanced disease. These findings suggested that patients with advanced disease might be suffering from a chronic deficiency of catecholamines in the peripheral sympathetic nerves. Administration of L-dopa, however, failed to improve the clinical manifestations.

Pharmacological studies of the pupils in familial amyloid polyneuropathy.

Pharmacological studies of the pupils of 7 patients with familial amyloid polyneuropathy (FAP) were performed in order to demonstrate the site of the lesion. Supersensitivity to 1.25% epinephrine was observed frequently, but not to 2.5% methacholine. The lesions of the sympathetic nervous system, judging from the epinephrine and tyramine tests, were regarded as preganglionic in 2 patients and postganglionic in 4. Among 3 patients reexamined six months later, 1 had developed signs of sympathetic postganglionic disturbance and another showed a peripheral parasympathetic disturbance associated with progress of a sympathetic preganglionic disturbance. From these results it was suggested that in FAP, sympathetic abnormalities involve the pupils more often than parasympathetic disturbances, and pharmacological studies can detect the autonomic dysfunction before it becomes clinically apparent.