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)

Transthyretin (TTR) is a plasma protein in which most of the coding region is constituted of three exons, each one of approximately 200 bp. Several TTR variants have been reported in association with familial amyloid polyneuropathy (FAP) and the characterization of the mutations is crucial for understanding the process of amyloidogenesis. In order to simplify mutation screening and DNA sequencing studies, a method of exon scanning was developed employing duplex amplification of exon 2/3 and individual amplification of exon 4 followed by single strand conformation polymorphism analysis (SSCPs) on acrylamide gels and silver staining. In this work, 22 different known TTR mutations were discriminated and studies on 210 samples from patients with peripheral neuropathies detected one polymorphic mutation (TTR Ser 6), TTR Asn 90, found previously in the normal Portuguese and German populations, and three other mutations, one of them TTR Ala 60.
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PMID:TTR exon scanning in peripheral neuropathies. 763 83

A transthyretin mutation was discovered in a French family with familial amyloidotic polyneuropathy originally described in 1983. The syndrome is of early onset (approximate age 35 to 40) with carpal tunnel syndrome. Death is from cardiac disease. By direct genomic DNA sequencing an A-->G mutation was found in the position corresponding to the first base of transthyretin codon 49. The predicted alanine for threonine substitution in the transthyretin protein was proven by amino acid sequencing of transthyretin isolated from the plasma of an affected subject. Since the DNA mutation does not result in the creation or abolition of a restriction endonuclease recognition site, a new DNA analysis technique was used in which site directed mutagenesis is used to create an RFLP when the introduced mutation is in proximity to the natural mutation. Using a 27 nucleotide mutagenesis primer in the PCR reaction, a new Bg1I site was created on amplification of the variant allele. Using this test, termed PCR-IMRA, four affected members of the family were shown to have the mutation.
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PMID:A transthyretin variant (alanine 49) associated with familial amyloidotic polyneuropathy in a French family. 809 1

We report the characteristics of one patient and two asymptomatic carriers from a Japanese family with familial amyloidotic polyneuropathy (FAP). The clinical features were somatic sensory and motor neuropathy with well-preserved autonomic function and late onset with slow insidious progression. These symptoms and signs are different from those of type 1 FAP. There were massive amyloid deposits with transthyretin (TTR) in the myocardium and the sural nerve. DNA sequencing of the TTR gene and amino acid sequence analysis of serum TTR revealed a new mutation in which Gly97 was substituted for Ala. We suggest that patients with somatic sensory and motor neuropathy of unknown origin without apparent autonomic dysfunction should be further studied for TTR mutation.
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PMID:Familial amyloidotic polyneuropathy with late-onset and well-preserved autonomic function: a Japanese kindred with novel mutant transthyretin (Ala97 to Gly). 813 16

Serum transthyretin (TTR) is a protein of liver origin that under normal conditions transports approximately 20% T4. Missense mutations of the TTR gene produce familial amyloidotic polyneuropathy and rarely, euthyroid hyperthyroxinemia (EHT). Of the 3 TTR variants so far identified with increased affinity for T4, Ser6, Thr109, and Met119, only TTR-Thr109 has high enough affinity for T4 to produce consistent hyperthyroxinemia in the heterozygous individuals. Because the mutation GCC-->ACC in codon 109 results in the loss of one Bso FI site in exon 4 of the TTR gene, the use of this enzyme was suggested to screen for TR-Thr109 in subjects with EHT. We investigated a family with dominantly inherited EHT, in which two of eight affected members received ablative thyroid treatment for presumed thyrotoxicosis, and one was misdiagnosed as having resistance to thyroid hormone. All affected individuals had serum reverse T3 concentrations above normal and average T4 50% above the mean of unaffected relatives. Total T3 and TSH levels were within the normal range. Although loss of the Bso FI site in one allele of the two TTR suggested the presence of Thr109, gene sequencing revealed a different mutation in the same codon (GCC-->GTC) producing TTR-Val109. T4-binding to TTR-Val109 was compared to that of the normal TTR-Ala109 and the formerly identified variant TTR-Thr109. Association constants were 1.3, 9.5, and 13.6 X 10(7) M-1 for TTR-Ala109, Val109, and Thr109, respectively. Thus, for equally expressed mutant and normal allele and 20% of serum T4 bound to TTR, the calculated mean serum T4 concentration of heterozygotes for TTR-Val109 should be 50% above the normal mean; the observed value being 55%. These results are in agreement with the observations based on the crystallographic structure of TTR-Thr109 indicating that the extra atoms in Val as in Thr, which are absent in the Ala of the wild type TTR, widen the ligand binding site.
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PMID:A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone--a clinical research center study. 878 93

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

A 59-year old male of German origin noticed exercise-independent cardiac arrhythmia two years before admission. An alanine 47 transthyretin variant of Familial Amyloid Polyneuropathy with hypertrophic cardiomyopathy, peripheral sensory-motor polyneuropathy, I, degree AV heart block was diagnosed. To diminish production and deposition of mutant transthyretin and to prevent disease progression orthotopic liver transplantation was performed. Prior to transplant the patient complained of inappetence. Postoperatively, he received a chemically defined enteral nutrition regime that was discontinued after 30 months until return of appetite and weight gain indicated marked improvement. However, a duodenal biopsy still demonstrated amyloid deposits 24 months after transplantation. Echocardiographic findings remained unchanged. Neurologic examination showed an improvement of sensory-motor polyneuropathy with regression of electromyographic changes. Only traces of variant transthyretin were detectable in plasma samples taken 12 months after the operation. During the 3 year follow-up, no additional symptoms have occurred and progression of amyloidosis was prevented. Currently, orthotopic liver transplantation is the only specific treatment to prevent progression of familial amyloid polyneuropathy.
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PMID:[Liver transplantation in familial amyloid polyneuropathy. Case report and review of the literature]. 933 4

Mutations of the transthyretin (TTR) gene are associated with familial amyloidotic polyneuropathy (FAP). Two new mutations were detected in French patients with TTR amyloidosis. The first patient was a 72 year old man who presented with severe and rapidly evolving sensory motor polyneuropathy of the 4 limbs, a bilateral carpal tunnel syndrome and a restrictive cardiomyopathy. His father died after a clinical history suggestive in retrospect of TTR amyloidosis. The second patient was a 75 year old man who presented with axonal sensory neuropathy of the 4 limbs and a bilateral carpal tunnel syndrome. In both cases immunohistochemistry performed on a nerve biopsy reveled TTR positive amyloid. Direct genomic sequencing of the full TTR gene coding region indicated two heterozygous transversions encoding Ser for Ala 91 substitution in the third exon of the gene in patient 1 and Ser for Tyr 116 substitution in the fourth exon of the gene in patient 2. The mutations were confirmed by digesting PCR products with restriction enzymes and were not found in a control population of 100 unrelated individuals. The Ser 116 substitution was also detected in the daughter and the 70 year old sister of the proband. However the absence of symptomatology suggestive of TTR amyloidosis may be related to the late onset of the disease. The clinical immunohistochemical and molecular studies in both patients are highly suggestive of an association between the Ser 91 and Ser 116 TTR variants with amyloidosis.
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PMID:New transthyretin variants SER 91 and SER 116 associated with familial amyloidotic polyneuropathy. Mutations in brief no. 151. Online. 1062 35

We describe two Italian first cousins with familial amyloidotic polyneuropathy associated with transthyretin variant consisting of the substitution of alanine for glycine at codon 47 (TTR Ala-47), from a family with a history of cardiac failure. The 40-year-old patient presented with autonomic dysfunction and the 44-year-old cousin with congestive heart failure. Both developed sensorimotor and autonomic polyneuropathy. Since a similar clinical picture has been described in another Italian family, the cardiac involvement must be regarded as a salient and early feature of the TTR Ala-47 mutation.
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PMID:An Italian family with Ala-47 transthyretin mutation associated with cardiomyopathy and polyneuropathy. 1067 64

Cardiac failure in transthyretin (TTR) amyloidosis patients has been shown to be caused by different mutations in the TTR gene. In the present case, a 73-year-old man from Northern Sweden was evaluated for heart failure. Amyloid deposits were found in subcutaneous fat and in intestinal biopsies. The presence of a variant form of TTR was detected in the plasma by electrospray ionisation mass spectrometry (ESI-MS). The mutation was located by single-strand conformation polymorphism (SSCP) analysis of the TTR gene where a band shift was seen in exon 2. Direct sequencing of exon 2 revealed a single base-pair substitution (G1724T). This transversion results in an amino acid substitution at codon 45, alanine to serine (ATTR Ala45Ser). Mass spectrometry analysis excluded that the variant is a polymorphism, since no similar shift in molecular weight has been present in more than 200 control samples. Congo red and immunostaining of duodenum biopsy specimens confirmed the presence of systemic ATTR amyloidosis, and clinical examination, including echocardiography, found evidence of a restrictive cardiomyopathy. He had 10 years previously been operated for a bilateral carpal tunnel syndrome, but otherwise no symptoms were present that could be attributed to his systemic amyloidosis. No axonal polyneuropathy was noted at nerve conduction studies. This novel mutation is the second amyloidogenic TTR mutation found in the Swedish population.
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PMID:Heart failure caused by a novel amyloidogenic mutation of the transthyretin gene: ATTR Ala45Ser. 1084 18

Familial amyloidotic polyneuropathy type I (FAP I) is a hereditary systemic amyloidosis usually involving the peripheral nervous system. In this paper we report our experience regarding the survival and the evolution of the sensory motor syndrome of the extremities and autonomic dysfunction in four siblings with the Ala-71 variant who were treated by liver transplantation (LT). The four siblings are alive 2-5 years after LT. After the operation, the seriated determinations of TTR-Ala-71 variant showed a constant decrease in serum levels in all cases. Our results support the proposal that LT should be indicated especially in forms with early clinical onset (3rd and 4th decades) and rapid progress to stop the neurological deterioration of the patients.
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PMID:Long-term results of liver transplantation in four siblings from the same family with familial amyloidotic polyneuropathy type I TTR Ala-71. 1111 90


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