Two sibling patients with late-onset familial amyloidotic polyneuropathy and atypical clinical manifestations]

Brothers (case 1 and case 2) had familial amyloidotic polyneuropathy type 1 (FAP type 1) confirmed with sural nerve biopsy and DNA analysis. Both patients were unique in that their ages at onset were 56 and 52, and that their only manifestation was sensori-motor polyneuropathy, without clinically apparent autonomic involvements such as orthostatic hypotension, sweat dysfunction and sphincter dysfunction, or severe organ involvement such as gastrointestinal features and myocardial involvement after the onset. They are also unique in that their parents were healthy. The initial manifestation was sensori-motor polyneuropathy starting in the lower extremities. These atypical manifestations made the diagnosis of FAP type 1 difficult in the present cases. Based on reports in the literature and the present cases, there might be a tendency that in patients with late-onset FAP type 1 the clinical manifestations are generally mild and autonomic involvement and organ disturbance are absent or mild. In the etiological diagnosis of polyneuropathy, FAP type 1 should be considered especially in steadily progressive patients.     

Transthyretin-related familial amyloidotic polyneuropathy

Transthyretin-related familial amyloidotic polyneuropathy (FAP) is a fatal hereditary amyloidosis. Until 20 years ago, FAP was thought to be restricted to endemic occurrence in certain areas. However, owing to progress in biochemical and molecular genetic analyses, FAP is now believed to occur worldwide. As of today, reports of about 100 different points of single or double mutations, or a deletion in the transthyretin gene, have been published, and several different phenotypes of FAP have been documented, even for the same mutation in the transthyretin gene. We present herein the current clinicopathological, biochemical, molecular genetic, and epidemiological aspects of transthyretin-related FAP, and we introduce a new diagnostic procedure for the disease.     

Autonomic neuropathy in familial amyloidotic polyneuropathy

Familial amyloidotic polyneuropathy (FAP) is characterized by both sensimotor and autonomic dysfunction. Autonomic disturbance involving the gastrointestinal tract, the urinary bladder, the cardiac conduction system, and the peripheral circulation has been described. In this study simple, non-invasive tests of autonomic function based on heart rate variability were applied to 12 patients with FAP and 12 healthy volunteers. The heart rate variation during normal breathing, deep breathing and during tilt from recumbent to standing position was measured. All tests showed significantly less heart rate variation in patients than in controls and the heart rate variation decreased with increasing severity of neurological disability, but the small number of patients in our study does not allow any further comparison between subgroups. Our study thus indicates impaired cardiovascular autonomic function in patients with FAP and we believe that these findings might also be of importance in other forms of systemic amyloidosis.     

Genetic expression of a transthyretin mutation in typical and late-onset Portuguese families with familial amyloidotic polyneuropathy

Two studies were conducted to explore questions concerning the expression of a mutant transthyretin (TTR) gene, found in Portuguese patients with familial amyloidotic polyneuropathy (FAP). In a kindred with typical onset of the disease, complete agreement between genotype and phenotype was seen for all carriers of the variant TTR with a methionine-for-valine substitution at position 30 (TTR[Met30]). In another study involving a FAP kindred with a late onset of clinical disease, TTR(Met30) was found in plasma in asymptomatic persons with ages above the usual age of onset of the disease. No evidence was obtained for the existence of a different mutation in TTR or for repression of the expression of the mutant TTR gene in this kindred. The factors responsible for the delay in the development of clinical manifestations in late-onset patients are not known and warrant further study.     

Endothelium-dependent vasodilatation in patients with familial amyloidotic polyneuropathy

We examined endothelium-dependent vasodilatation in 15 familial amyloidotic polyneuropathy (FAP) amyloidogenic transthyretin (ATTR) Valine30Methionine (Val30Met) patients and 12 healthy volunteers. Using ultrasonography, we measured the radial artery diameters under both baseline and hyperemic conditions. Endothelium-dependent vasodilatation was expressed as a percent increase in the diameters of the radial artery after induced hyperemia. Endothelium-dependent vasodilatation tended to decrease in the patients, compared with healthy volunteers. Responses were not elicited at all in patients with disease of more than 9 years' duration. Linear negative correlation was observed between endothelium-dependent vasodilatation and disease duration (P < 0.01). Correlation between endothelium-dependent vasodilatation and degree of autonomic dysfunction was significant (P = 0.0524) and for age was close to significance (P = 0.051). These results suggest that the peripheral vasomotor dysfunction in FAP patients may predominantly depend on the amount of amyloid deposition around the vessels through the course of illness.     

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.     

Gene analysis of Japanese patients with familial amyloidotic polyneuropathy type IV]

Familial amyloidotic polyneuropathy type IV (FAP IV) is clinically characterized by slowly progressive cranial neuropathy and corneal lattice dystrophy. More than 300 cases were clustered in the Finnish population. Recent biochemical studies have demonstrated that the amyloid fibril protein in FAP IV is related to Asn-187 variant gelsolin, and the corresponding missense mutation, a G to A substitution at nucleotide 654 of plasma gelsolin cDNA, cosegregates with the disease phenotype in Finnish families. Here we analyzed the gelsolin gene of the Japanese family with FAP IV which we described as the first Japanese case. Direct sequence analysis of PCR-amplified DNA fragments spanning the codon 187 of plasma gelsolin cDNA from the 2 affected family members demonstrated a single base substitution, G to A at nucleotide 654, which is identical to the mutation of Finnish FAP IV. Restriction analysis using a modified PCR revealed that three unaffected family members and three unrelated healthy controls were homozygous for the normal allele, whereas the seven affected family members were heterozygous for the normal and the mutated alleles. This indicates the cosegregation of the mutation with the disease phenotype in this Japanese family, suggesting that the mutation causes the FAP IV phenotype regardless of ethnic background.     

Variant transthyretin in cerebrospinal fluid in familial amyloidotic polyneuropathy

Structurally abnormal transthyretin is a precursor protein of amyloid fibrils in type I familial amyloidotic polyneuropathy (FAP). This variant transthyretin has an amino acid substitution of methionine for valine at position 30. The purpose of this study was to clarify whether this variant transthyretin also circulates in the cerebrospinal fluid (CSF) of patients with type I FAP. CSF transthyretin of the patients was purified and its primary structure determined. Sequence determination indicated that transthyretin consisted of a mixture of normal and variant transthyretin. Variant transthyretin was present in the CSF of all 5 Japanese FAP patients studied. The CSF concentration of variant transthyretin was high (0.72 +/- 0.15 mg/dl, mean +/- S.D.), suggesting that variant transthyretin is synthesized in the choroid plexus. Variant transthyretin was not present in any of 20 controls. The CSF concentration of total transthyretin in FAP patients was 1.74 +/- 0.42 mg/dl, which was not significantly different from controls.     

Abnormal transthyretin in asymptomatic relatives in familial amyloidotic polyneuropathy

Familial amyloidotic polyneuropathy (FAP) has been biochemically and genetically proven to be an inherited molecular disorder of transthyretin. (The term transthyretin has been suggested by the Nomenclature Committee of the international Union of Biochemistry and the International Union of Pure and Applied Chemistry for the protein that has heretofore been called prealbumin.) We have experienced three cases that included typical clinical, electrophysiologic, and neuropathologic manifestations of FAP, and yet no known family history of the disorder. The patients and members of their families were studied by radioimmunoassay for a variant transthyretin with a methionine-for-valine substitution at position 30. All three patients had the variant transthyretin in the serum, at concentrations of 54.5, 87.9, and 105.9 mg/L (5.45, 8.79, and 10.59 mg/dL). Although parents and siblings had neither neurologic nor electromyographic evidence of FAP, some of these family members had serum concentrations of variant transthyretin as high as those of the propositi. It was from these asymptomatic parents that the "nonfamilial" patients inherited the gene for FAP. Further study is needed to define the mechanisms retarding or preventing, as well as those promoting, the clinical development of FAP when the variant transthyretin is present in the serum at a high level.     

Bleeding manifestations in 24 patients with familial amyloidotic polyneuropathy

Focal or generalized hemorrhage is a commonly encountered complication in patients with many kinds of amyloidosis. We studied 24 patients (18 males, 6 females) with familial amyloidotic polyneuropathy and found that five had experienced one or more bleeding episodes. In four of these five patients, bleeding occurred in the terminal stage. The incidence of hemorrhage in familial amyloidotic polyneuropathy is lower than that of other types of amyloidosis or that which has been reported in this disease. In our experience clotting abnormalities were rare; clotting factor deficiency appeared not to exist in familial amyloidotic polyneuropathy.     

Studies of protease and protease inhibitors in familial amyloidotic polyneuropathy

Serum levels of 6 protease inhibitors, alpha 1-antitrypsin, Cl inactivator, alpha 2-macroglobulin, antithrombin-3, alpha 1-antichymotrypsin and inter-alpha-trypsin inhibitor were measured in patients with familial amyloidotic polyneuropathy (FAP) and a control group without neurologic disease. No significant differences were observed between the 2 groups. The proteolytic effect of brinase, an enzyme from Aspergillus oryzae, on amyloid tissue sections from patients with FAP was also evaluated. Amyloid fibrils were degraded by brinase, while the tissue structure remained fairly intact.