Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0152025 (polyneuropathy)
 7,862 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial amyloidotic polyneuropathy (FAP) is a genetic disease characterized by systemic amyloid deposition particularly in the peripheral nervous system. These deposits are composed mainly of a mutant form of the serum protein transthyretin (TTR) having a methionine for valine substitution at position 30-TTR Met 30. The factors involved in the formation of these deposits are unknown. The existence of animal models for FAP should allow elucidation of these factors. As one approach to the development of animal models for amyloidogenesis in FAP, we have constructed recombinant retrovirus vectors, carrying the full length human cDNA for either TTR or TTR Met 30 under the control of the Moloney murine leukemia virus (MoMLV) LTR element. After transfection of the packaging cell line, psi 2, viral stocks were used to infect a rat hepatoma cell line, H56, mouse fibroblast cell line, NIH3T3, and mouse primary fibroblasts. H56 cells efficiently secreted both TTR and TTR Met 30 as assessed by immunoprecipitation and ELISA, whereas NIH3T3 fibroblasts appeared not to release these proteins under the conditions tested. Primary fibroblasts secreted the mutant protein as assessed by ELISA. These genetically modified cells can be grafted into animals for in vivo study of amyloidogenesis, as well as be used in culture to investigate factors that might regulate the rate of amyloid deposition.
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PMID:Retrovirus-mediated gene transfer of transthyretin and transthyretin-methionine 30: a potential tool for the study of amyloidogenesis. 826 24

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary type of lethal amyloidosis involving single (or double) amino acid substitutions in the amyloidogenic protein transthyretin (TTR). The most common type of FAP (Type I, or Portuguese) is characterized by a Val-->Met substitution at position 30. The Met30 variant of TTR has been produced by recombinant methods, crystallized in a form isomorphous with native TTR, subjected to X-ray analysis and compared structurally with the wild-type protein. The comparison shows that the effect of the substitution at position 30 is transmitted through the protein core to Cys10, the only thiol group in the TTR subunit, which becomes slightly more exposed. The variant TTR molecule is otherwise in a near-native state. Use of computer graphics has shown that it is possible to model a linear aggregate of TTR molecules, each linked to the next by a pair of disulphide bonds involving Cys10 residues. Formation of these disulphide bonds involves a small number of slightly short molecular contacts with native TTR molecules, most of which are relieved in the Met30 variant. We propose this model as a possible basis for a molecular description of the FAP amyloid fibrils.
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PMID:Structure of Met30 variant of transthyretin and its amyloidogenic implications. 838 10

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disease due to mutations in the transthyretin (TTR) gene. Valine30-->methionine (TTR M30) is by far the most common mutation in patients with FAP. In a sample of 11 North American unrelated patients, we previously found that 6 had TTR M30. By utilizing double PASA, we could perform haplotype analysis despite the absence of DNA samples on relatives. The results indicate that at least four of the six patients with TTR M30 have different haplotypes, an observation that is surprising for North American patients in which the ostensible symptoms generally begin after the reproductive years. It is suggested that the most likely explanation is rapid selection against TTR M30 mutations by one of four possible mechanisms.
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PMID:The high frequency of TTR M30 in familial amyloidotic polyneuropathy is not due to a founder effect. 840 13

We measured the serum apolipoprotein levels in patients with familial amyloidotic polyneuropathy (FAP). The serum apolipoprotein AII levels were much lower than those of the control subjects, while the levels in asymptomatic carriers of the FAP gene were normal. Other plasma apolipoprotein levels, such as apolipoproteins AI, B, CII, CIII, and E, were all within normal ranges. The decrease of apolipoprotein AII in the plasma of FAP patients correlated with the progression of the disease. In a transgenic mice model of FAP carrying human variant transthyretin gene (Met-30), serum apolipoprotein AII levels were decreased in 1.5-year-old mice compared with control mice, while the 3-month-old mice had normal levels. These results suggest that apolipoprotein AII may play an important role in lipid metabolism or amyloid formation in patients with FAP.
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PMID:Low plasma apolipoprotein AII levels in human and mouse amyloidosis with mutant transthyretin (Met-30) gene. 849 27

Four unrelated French cases of familial amyloid polyneuropathy are reported. Clinical onset ranged from the sixth to the ninth decade. Sensory signs were predominant initially in the lower limbs; motor changes, and in one case autonomic involvement, appeared later. Amyloid disease was clinically limited to the peripheral nervous system. In two cases, there was no evidence of familial disease. DNA analysis was performed in these four patients and in two children of Patient 1. Restriction analysis of amplification products of exon 2 of the transthyretin gene was positive for the valine 30 to methionine mutation. These four unrelated patients live in different areas of France. Further studies are needed to determine whether these mutations have a common origin and whether they are related to the Portuguese mutation.
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PMID:Late-onset familial amyloid polyneuropathy with the TTR Met 30 mutation in France. 850 Feb 60

We report a 69-year-old woman of Mexican origin with a 6-year history of progressive paresis, mild peripheral neuropathy, and recent onset of fluctuating mental status. Head and spinal MRI revealed contrast enhancing thickened meninges which on biopsy disclosed amyloid deposition. Immunohistochemistry identified the amyloid as transthyretin (TTR), and polymerase chain reaction/restriction fragment length polymorphism analysis of blood revealed a Val30Met mutation in one of her TTR genes. This mutation causes familial (hereditary) amyloidotic polyneuropathy of the Portuguese type (FAP 1). However, unlike FAP 1, in which peripheral neuropathy is a dominant feature, our patient's clinical manifestations, which included communicating hydrocephalus and myelopathy, were more suggestive of familial oculoleptomeningeal amyloidosis (FOLMA). In summary, the clinical presentation of TTR Met 30 mutation is more varied than previously suspected, and leptomeningeal amyloidosis should be considered in the differential diagnosis of obscure conditions involving meninges.
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PMID:Massive leptomeningeal amyloidosis associated with a Val30Met transthyretin gene. 885 32

Amyloid fibrils derived from the Japanese, Portuguese, and Swedish types of familial amyloidotic polyneuropathy all consist of a variant transthyretin (TTR) with a substitution of methionine for valine at position 30 (TTR Met 30). In an attempt to establish an animal model of TTR Met-30-associated homozygous familial amyloidotic polyneuropathy and to study the structural and functional properties of human TTR Met 30, we generated a mouse line carrying a null mutation at the endogenous ttr locus (ttr-/-) and the human mutant ttr gene (6.0-hMet 30) as a transgene. In these mice, human TTR Met-30-derived amyloid deposits were first observed in the esophagus and stomach when the mice were 11 months of age. With advancing age, amyloid deposits extended to various other tissues. Because no significant difference was detected in the onset, progression, and tissue distribution of amyloid deposition between the ttr-/- and ttr+/+ transgenic mice expressing 6.0-hMet 30, endogenous normal mouse TTR probably does not affect the deposition of human TTR Met-30-derived amyloid in mice. TTR is a tetramer composed of four identical subunits that binds thyroxine (T4) and plasma retinol-binding protein. The introduction of 6.0-hMet 30 into the ttr-/- mice significantly increased their depressed serum levels of T4 and retinol-binding protein, suggesting that human TTR Met 30 binds T4 and retinol-binding protein in vivo. The T4-binding ability of human TTR Met 30 was confirmed by the analysis of T4-binding proteins in the sera of ttr-/- transgenic mice expressing 6.0-hMet 30. The T4-binding studies also demonstrated the presence of hybrid tetramers between mouse and human TTR subunits in the ttr+/+ transgenic mice expressing 6.0-hMet 30.
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PMID:Analysis of amyloid deposition in a transgenic mouse model of homozygous familial amyloidotic polyneuropathy. 909 4

We identified three different missense mutations of the transthyretin (TTR) gene in three Japanese patients with familial amyloidotic polyneuropathy by analysis of their DNAs extracted from formalin-fixed and paraffin-embedded tissues. Patient 1 carried the TTR methionine-30 (Met) mutation (G to A transition at position 1679). DNA sequencing analysis of the TTR gene from patient 2 showed a G to T transversion at position 3830 in exon 3, resulting in an amino acid replacement of serine-50 (Ser) with isoleucine (Ile). Patient 3 had the novel mutation (G to T transversion at position 7314) in exon 4, resulting in an amino acid replacement of alanine-109 (Ala) with Ser. We established DNA diagnostic methods for detecting TTR Ile50 by polymerase chain reaction (PCR)-induced mutation restriction analysis and for TTR Ser109 by PCR-restriction fragment length polymorphism. Gene analysis of archival paraffin-embedded tissues is useful for the precise diagnosis of FAP and for clarifying its molecular pathogenesis in patients for whom fresh genomic DNA is not available.
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PMID:Detection of three transthyretin gene mutations in familial amyloidotic polyneuropathy by analysis of DNA extracted from formalin-fixed and paraffin-embedded tissues. 926 42

Familial amyloidotic polyneuropathy (FAP)--Portuguese type, is an autosomal dominant polyneuropathy related with an abnormal transthyrretin (TTR Met 30). In males, the first complaint can be sexual dysfunction. Fifteen FAP patients, mean age 37 +/- 7.7 years, mean disease duration 5.2 +/- 2.2 years, all males, complaining of sexual dysfunction were studied with pudendal evoked potentials (PEP), bulbocavernous reflex (BCR) and sympathetic skin response (SSR). PEP and BCR reflect the central somatosensory pathways and sacral arch functioning; SSR relates with autonomic pathways. The aims of this study were: to correlate clinical and EMG scores with somatic and autonomic fibres involvement; to evaluate the timing of somatic and autonomic nerves lesion in disease evolution. Results showed: that PEP and BCR abnormalities have a statistically significant correlation with clinical and EMG scores; abnormal SSR in the plant precede other clinical or EMG abnormalities in the present study.
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PMID:Neurophysiological evaluation of sexual dysfunction in familial amyloidotic polyneuropathy--Portuguese type. 930 69

Familiar Amyloid Polyneuropathy (FAP), an autosomal dominant inherited multisystemic disorder was first observed by Corino de Andrade, a Portuguese neurologist, in 1939. This disease of Portuguese origin was probably spread by fishermen, mainly to Sweden and Japan. It is characterized by a progressive peripheral polyneuropathy and autonomic neuropathy (erectile sexual disfunction, gastrointestinal disfunction, bladder dysfunction and cardio vascular disease) and malnutrition. There are neural and systemic amiloid deposits. Type I FAP, of Portuguese origin, is the most common variety. The amyloid protein is the variant transthyretin (TTR) in which methionine (MET) is a substitute for valine in position 30 (TTR MET 30). It is mainly produced by the liver (90%) and, in small amounts, by the choroidal plexus. Symptoms usually start in the 3rd and 4th decade of life and the patients usually die within 10-15 years. From the therapeutic options--plasmapheresis, immunoadsorption and liver transplantation; the latter seems to be the only one, which stops the production of TTR MET 30 in a permanent way, by means of the liver. The lack of any other effective therapy and the success of the first liver transplantation performed in Sweden arouse great hope. So far, around 300 patients have been transplanted all over the world. A hundred and thirty of them were transplanted in Portugal. A Kaplan Meier survival curve of the Portuguese patients shows a survival rate of 78% at 5 years. However, in spite of the progression of the disease being halted, the irreversibility of some neurological lesions seems to persist. This fact raises the problem of the timing of the transplantation. It seems that the patients should be transplanted as soon as the symptoms start, since mortality and severe morbidity seems to mainly involve those in whom symptomatic disease has lasted longer than six years. As the explanted liver is a morphologic normal liver, a sequential (domino) transplant has been carried out in 16 cases so far done--by one of the authors (ALF) on patients with either hepatocellular carcinoma or liver metastatic disease.
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PMID:Liver transplantation for familial amyloid polyneuropathy. 984 68


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