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1.
Dr Gösta Holmgren Urban Hellman Jenni Jonasson Hans-eric Lundgren Per Westermark Ole B. Suhr 《Amyloid》2013,20(3):189-192
Familial amyloidotic polyneuropathy (FAP) designates TTR mutations where the phenotype is dominated by a peripheral sensory-motor polyneuropathy. The most common mutation is ATTR Val30Met. FAP in association with ATTR Phe33Leu has been described previously in two American families, one of Polish–Lithuanian descent and the other of Polish–American. In this study, we report the phenotype of the ATTR Phe33Leu in a Swedish family. The proband is a 48 year-old patient from northern Sweden, whose father died with symptoms suggestive of FAP. Characteristic clinical features included polyneuropathy, carpal tunnel syndrome and asymptomatic, but echocardiographic examination diagnosed cardiomyopathy. The family history supports an early intervention with orthotopic liver transplantation in patients with FAP associated with the TTR Phe33Leu, and the patient was submitted for liver transplantation. 相似文献
2.
N Tachibana T Tokuda K Yoshida T Taketomi M Nakazato Y F Li Y Masuda S Ikeda 《Amyloid》1999,6(4):282-288
A matrix-assisted laser desorption ionization/time-of-flight (MALDI/TOF) mass spectrometry (MS) system was used to detect variant transthyretin (TTR) in immunoprecipitated serum TTR molecules obtained from 6 patients with familial amyloid polyneuropathy (FAP) who were already proven not to have ATTR Val30Met. This simple and quick method showed six different patterns of mass spectra of TTR-related immunoprecipitates from these patients, and in each patient the clearly identified characteristic doublet-shaped ion peaks consisted of normal and variant TTR apart from each other peak with a mass difference between them. DNA sequencing confirmed that the patterns of variant TTR corresponded respectively to ATTR Val30Leu, ATTR Phe33Val, ATTR Asp38Ala, ATTR Ser50Arg, ATTR Ala97Gly and ATTR Ala97Ser. ATTR Asp38Ala and ATTR Ala97Ser are previously unknown variants of TTR leading to the development of FAP. ATTR Phe33Val was found in a Chinese FAP patient and ATTR Ala97Ser in a Taiwanese. Serum analysis using immunoprecipitation and MALDI/TOF MS system can provide useful information when investigating FAP patients with diverse types of variant TTR. 相似文献
3.
《Amyloid》2013,20(4):282-288
A matrix-assisted laser desorption ionization/time-of flight (MALDI/TOF) mass spectrometry (MS) system was used io detect variant transthyretin (TTR) in immunoprecipitated serum TTR molecules obtained from 6 patients with familial amyloid polyneuropathy (FAP) who were already proven not to have ATTR Val 30Met. This simple and quick method showed six different patterns of mass spectra of TTR-related immunoprecipitates from these patients, and in each patient the clearly identified characteristic doublet-shaped ion peaks consisted of normal and variant TTR apart from each other peak with a mass difference between them. DNA sequencing confirmed that the patterns of variant TTR corresponded respectively to ATTR Val30Leu, ATTR Phe33Val, ATTR Asp38Ala, ATTR Ser50Arg, ATTR Ala97Gly and ATTR Ala97Ser. ATTR Asp38Ala and ATTR Ala97Ser are previously unknown variants of TTR leading to the development of FAP. ATTR Phe33Val was found in a Chinese FAP patient and ATTR Ala97Ser in a Taiwanese. Serum analysis using immunoprecipitation and MALDI/TOF MS system can provide useful information when investigating FAP patients with diverse types of variant TTR. 相似文献
4.
《Amyloid》2013,20(4):208-214
The number of amyloidogenic transthyretin (TTR) mutations described in the literature is more than 100. However, for several mutations, the phenotype has been described in a few individuals only; thus, the knowledge of the clinical course and the outcome after therapeutical interventions such as liver transplantation is limited.We describe the phenotype associated with five rare amyloidogenic TTR mutations that lately were discovered in Sweden: ATTR Val30Leu, Ala45Ser, Leu55Gln, Gly57Arg and Tyr69His of which ATTR Gly57Arg is previously unknown. The symptoms at onset differed, but cardiomyopathy and peripheral neuropathy were observed in all except the ATTR Tyr69His mutation. Likewise, carpal tunnel syndrome was found or had been present in all cases except the case with the ATTR Val30Leu mutation. The phenotype of the ATTR Tyr69His mutation was characterised by oculo-meningeal symptoms with seizures and a steadily progressing dementia, symptoms rarely found in ATTR amyloidosis, but similar to those previously described for this mutation, where all cases appear to originate from one Swedish family.Two patients with the ATTR Leu55Gln and Ala45Ser mutations have been subjected to liver transplantation, but echocardiographic examination has revealed an increasing cardiomyopathy after transplantation in both cases, the ATTR Leu55Gln patient succumbed 2 years after transplantation from progressive disease. 相似文献
5.
Acceleration of amyloid deposition by administration of amyloid fibrils and transmissibility of disease have been reported in several types of amyloidoses. Families with a variant transthyretin (TTR V30M)-associated familial amyloidotic polyneuropathy (FAP) exhibit genetic anticipation, with TTR V30M-amyloid depositing at an earlier age in successive generations. The molecular bases of anticipation in FAP have remained to be determined. We asked if administration of TTR-amyloid fibrils (ATTR) extracted from the heart of an FAP TTR V30M patient would accelerate ATTR deposition in transgenic mice expressing the human mutant ttr gene responsible for FAP TTR V30M and indeed the administration did accelerate deposition of apolipoprotein A-II- amyloid fibrils (AApoAII), and not ATTR. Our experiments present, for the first time, evidence that the degree of inducibility of ATTR is low relative to AApoAII and we suggest that administration of ATTR may not explain the genetic anticipation which occurs in FAP. 相似文献
6.
Lan Wei Hiroo Kawano Xiaoying Fu Dan Cui Sadahiro Ito Ken-ichi Yamamura Tokuhiro Ishihara Takahiko Tokuda Keiichi Higuchi Shuichiro Maeda 《Amyloid》2004,11(2):113-120
Acceleration of amyloid deposition by administration of amyloid fibrils and transmissibility of disease have been reported in several types of amyloidoses. Families with a variant transthyretin (TTR V30M)-associated familial amyloidotic polyneuropathy (FAP) exhibit genetic anticipation, with TTR V30M-amyloid depositing at an earlier age in successive generations. The molecular bases of anticipation in FAP have remained to be determined. We asked if administration of TTR-amyloid fibrils (ATTR) extracted from the heart of an FAP TTR V30M patient would accelerate ATTR deposition in transgenic mice expressing the human mutant ttr gene responsible for FAP TTR V30M and indeed the administration did accelerate deposition of apolipoprotein A-II-amyloid fibrils (AApoAII), and not A TTR. Our experiments present, for the first time, evidence that the degree of inducibility of ATTR is low relative to AApoAII and we suggest that administration of ATTR may not explain the genetic anticipation which occurs in FAP. 相似文献
7.
Katsuki Haraoka Yukio Ando Eiko Ando Xuguo Sun Masaaki Nakamura Hisayasu Terazaki Shogo Misumi Yutaka Tanoue Takahiro Tajiri Shozo Shoji Takashi Ishizaki Hiroaki Okabe Hidenobu Tanihara 《Amyloid》2002,9(4):247-251
To determine the origin of transthyretin (TTR) in the aqueous humor of patients with familial amyloidotic polyneuropathy (FAP), we measured TTR levels and analyzed the TTR forms in the aqueous humor of three FAP patients (one patient; liver transplanted, and two patients; non-transplanted). The total TTR levels were almost the same as reported previously in non-transplanted patients and slightly increased in a transplanted patient. Analyses with mass spectrometry in the two non-transplanted FAP ATTR V30M patients revealed that both wild type and variant TTR forms were detected in their aqueous humor samples. Moreover, variant TTR forms could be detected in the aqueous humor of the transplanted patient while the liver produced no variant TTR. These results suggest that variant TTR in aqueous humor may be derived from retina where TTR was produced. In conclusion, TTR metabolism may occur in its own ocular cycle and variant TTR produced by the retina may play an important role in amyloid formation in the ocular tissues of FAP patients. 相似文献
8.
Elizabeth B Haagsma Philip N Hawkins Merrill D Benson Helen J Lachmann Alison Bybee Bouke P Hazenberg 《Amyloid》2004,11(1):44-49
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder associated with more than 80 different transthyretin (TTR) mutations. The clinical features of FAP are broad and variable, but knowledge of the pattern and natural history of disease associated with particular mutations nevertheless offers the best guidance for management of individual patients, including the role and timming of treatment by orthotopic liver transplantation. FAP in association with TTR Gly47Glu has been described previously in an Italian kindred, and we report here its phenotype in 7 additional patients from Dutch, British, and American (Finnish) families. Characteristic clinical features included amyloid cardiomyopathy and autonomic failure but, unusually, moderate to severe renal failure was present in more than half of the cases. Only four patients were deemed to be sufficiently fit to undergo orthotopic liver transplantation, and clinical deterioration was generally rapid. These observations support early intervention with orthotopic liver transplantation in patients with FAP associated with TTR Gly47Glu. 相似文献
9.
Katrin Hinderhofer Christian Obermaier Ute Hegenbart Stefan Schönland Marc Seidler Iris Sommer-Ort 《Amyloid》2019,26(2):85-93
The plasma protein transthyretin (TTR) can aggregate into insoluble amyloid fibrils causing systemic amyloidosis (ATTR amyloidosis) in patients carrying a variant TTR protein. If new variants arise, it is crucial to clarify whether they are disease-associated or benign. In this study, we further functionally characterize three new and unclassified TTR variants (Thr40Asn, Phe64Val and the described but not functionally assessed variant Leu12Val), using a simplified, fast isoelectric focusing (IEF) approach. After validating the system with known TTR variants, we assessed the sera of five patients carrying these new TTR variants in a heterozygous state. All three variants showed aberrant banding patterns that were similar to those of other well-characterized TTR variants, including the common Val30Met variant that causes ATTR amyloidosis. In addition to a clear band corresponding to monomeric wild-type TTR, we observed an additional variant band at the cathodal side of the IEF gel. These results indicate conformational instability of the new Thr40Asn, Phe64Val and Leu12Val variants. Together with the clinical and immunohistological data of these patients and affected family members, as well as the absence of these variants in human genetic mutation databases, our results strongly hint that these variants are amyloidogenic and therefore probably disease-associated. These findings have implications for patient therapy and for genetic counselling of family members. 相似文献
10.
M Munar-Qués L Salva-Ladaria P Mulet-Perera M Solé F R López-Andreu M J Saraiva 《Amyloid》2000,7(4):266-269
Vitreous amyloidosis has been reported in patients with familial amyloidotic polyneuropathy (FAP) who are carriers of different mutant transthyretins (TTR). The mutant TTR constitutes the majority of the amyloid vitreous fibrils in heterozygous Val30Met patients. Due to the ocular synthesis of TTR, it is possible that the retina constitutes the source of vitreous amyloid fibrils, if so, orthotopic liver transplantation (OLT) performed to remove the mutant TTR from circulation might not be effective in treating/avoiding vitreous amyloid. We present vitreous amyloidosis in a FAP patient from Maiorca with ATTR Val30Met who underwent OLT at age 38. Progressive impairment of visual acuity (VA) appeared bilaterally 2 years after OLT due to vitreous opacities consistent with amyloid; successful bilateral vitrectomy was performed. Amyloid was demonstrated in the vitrectomy material by Congo red staining, immunohistochemistry and Western blotting analyses were positive with an antibody for human TTR. Mass spectrometry of TTR revealed the presence of the mutant in approximately 20% of the TTR. Future structural studies on vitreous material with different proportions of normal/versus mutant TTR might shed some light on TTR fibrillogenesis. These results show that vitreous deposition of TTR amyloidfibrils occurs after OLT, suggesting that ongoing intraocular synthesis of mutant TTR might contribute to this process. We also present the progression after OLT of vitreous amyloidosis previously diagnosed in three patients with TTR Val71Ala. 相似文献
11.
《Amyloid》2013,20(2):53-62
Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP and is now prevalent in areas other than those seen within conventional endemic foci. We investigated 15 patients with FAP ATTR Val30Met without a family history of FAP who were referred for sural nerve biopsy. Initial symptoms included somatic neuropathy in all patients, while sensory dissociation and autonomic symptoms were apparent only in two and seven patients, respectively. Nonspecific neuropathic features and slight abnormalities in cerebrospinal fluid protein levels and in electrophysiological indices related to nerve conduction led clinicians to initially suspect chronic inflammatory demyelinating polyneuropathy (CIDP) in some patients. Small-fiber predominant loss was observed in a minority of patients. In terms of cardiac involvement, findings suggestive of subclinical cardiomyopathy due to amyloid deposition, such as cardiomegaly on chest X-ray, thickening of the interventricular septum, and granular sparkling echo on echocardiography, were seen alone or in combination in 11 of 14 examined patients. In conclusion, clinicians should consider the possibility of FAP ATTR Val30Met in patients presenting with neuropathy of undetermined etiology to avoid misdiagnosis. Detecting subclinical cardiac involvement may help to diagnose late-onset FAP ATTR Val30Met in those without a family history of the disease. 相似文献
12.
《Amyloid》2013,20(4):266-267
Vitreous amyloidosis has been reported inpatients with familial amyloidotic polyneuropathy (FAP) who are carriers of different mutant transthyretins (TTR). The mutant TTR constitutes the majority of the amyloid vitreous fibrils in heterozygous Val 30 Met patients. Due to the ocular synthesis of TTR, it is possible that the retina constitutes the source of vitreous amyloid fibrils; if so, orthotopic liver transplantation (OLT) performed to remove the mutant TTR from circulation might not be effective in treating/avoiding vitreous amyloid. We present vitreous amyloidosis in a FAP patient from Majorca with ATTR Val30Met who underwent OLT at age 38. Progressive impairment of visual acuity (VA) appeared bilaterally 2 years after OLT due to vitreous opacities consistent with amyloid; successful bilateral vitrectomy was performed. Amyloid was demonstrated in the vitrectomy material by Congo red staining; immunohistochemistry and Western blotting analyses were positive with an antibody for human TTR. Mass spectrometry of TTR revealed the presence of the mutant in approximately 20% of the TTR. Future structural studies on vitreous material with differ ent proportions of normal/versus mutant TTR might shed some light on TTR fibrillogenesis. These results show that vitreous deposition of TTR amyloid fibrils occurs after OLT, suggesting that ongoing intraocular synthesis of mutant TTR might contribute to this process. We also present the progression after OLT of vitreous amyloidosis previously diagnosed in three patients with TTR Val71 Ala. 相似文献
13.
Elizabeth B Haagsma Philip N Hawkins Merrill D Benson Helen J Lachmann Alison Bybee Bouke PC Hazenberg 《Amyloid》2013,20(1):44-49
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder associated with more than 80 different transthyretin (TTR) mutations. The clinical features of FAP are broad and variable, but knowledge of the pattern and natural history of disease associated with particular mutations nevertheless offers the best guidance for management of individual patients, including the role and timing of treatment by orthotopic liver transplantation. FAP in association with TTR Gly47Glu has been described previously in an Italian kindred, and we report here its phenotype in 7 additional patients from Dutch, British, and American (Finnish) families. Characteristic clinical features included amyloid cardiomyopathy and autonomic failure but, unusually, moderate to severe renal failure was present in more than half of the cases. Only four patients were deemed to be sufficiently fit to undergo orthotopic liver transplantation, and clinical deterioration was generally rapid. These observations support early intervention with orthotopic liver transplantation in patients with FAP associated with TTR Gly47Glu. 相似文献
14.
Mitsuharu Ueda Yukio Ando Katsuki Haraoka Shoichi Katsuragi Yasuhiro Terasaki Mineharu Sugimoto Xuguo Sun Makoto Uchino 《Amyloid》2006,13(1):24-30
Although aging is closely related with the onset of senile systemic amyloidosis (SSA) caused by wild-type transthyretin (TTR), the effect of aging on amyloid formation has remained unclear in familial amyloidotic polyneuropathy (FAP), caused by variant- and wild-type TTR. The aim of this study was to elucidate the effects of aging and/or other factors in FAP on amyloid formation in the lung, one of the most important target organs of amyloid deposition in SSA. Pulmonary amyloid distribution was determined using 19 autopsied lung samples from patients with FAP amyloidogenic TTR (ATTR) V30M, the most common type of FAP. Amyloid deposition was observed around the walls of the bronchi/ bronchioles, the pulmonary arteries, and the pulmonary veins, while no amyloid deposits could be found around the lymphatics. In addition, amyloid deposition in the alveolar regions was a characteristic finding in aged patients with FAP ATTR V30M (average ages of the patients with amyloid positive vs. negative: 50.55 +/- 8.75 vs. 39.75 +/- 4.17 years old, p < 0.005), similar to the finding in one SSA patient. These results suggest that aging could play an important role in the progression of pulmonary amyloid formation in FAP ATTR V30M. 相似文献
15.
Mitsuharu Ueda Katsuki Haraoka Shoichi Katsuragi Yasuhiro Terasaki Mineharu Sugimoto 《Amyloid》2013,20(1):24-30
Although aging is closely related with the onset of senile systemic amyloidosis (SSA) caused by wild-type transthyretin (TTR), the effect of aging on amyloid formation has remained unclear in familial amyloidotic polyneuropathy (FAP), caused by variant- and wild-type TTR. The aim of this study was to elucidate the effects of aging and/or other factors in FAP on amyloid formation in the lung, one of the most important target organs of amyloid deposition in SSA. Pulmonary amyloid distribution was determined using 19 autopsied lung samples from patients with FAP amyloidogenic TTR (ATTR) V30M, the most common type of FAP. Amyloid deposition was observed around the walls of the bronchi/ bronchioles, the pulmonary arteries, and the pulmonary veins, while no amyloid deposits could be found around the lymphatics. In addition, amyloid deposition in the alveolar regions was a characteristic finding in aged patients with FAP ATTR V30M (average ages of the patients with amyloid positive vs. negative: 50.55 ± 8.75 vs. 39.75 ± 4.17 years old, p < 0.005), similar to the finding in one SSA patient. These results suggest that aging could play an important role in the progression of pulmonary amyloid formation in FAP ATTR V30M. 相似文献
16.
Dr. Miguel Munar-Qués Jacinto Martínez-Nadal José Juan Torres-Rovira Manel Solé José María Zabay-Becerril Juana María Mulet-Ferrer 《Amyloid》2013,20(4):272-274
We report the case of a female patient with familial amyloid polyneuropathy (FAP) who demonstrated TTR amyloid deposition in the inferior nasal conchal vessels.To our knowledge this location has not been described previously in FAP; in addition, it was detected in a patient who had undergone successful liver transplantation (LTX) 4 years earlier.The amyloid deposition was found incidentally during examination of a right nasal obstruction caused by a nonspecific inflammatory polyp. Small focal deposits of amyloid TTR were observed on deep thick walled vessels, contrasting with the massive deposition reported in neoformed vessels in amyloidomas. This amyloid was clearly deposited between the onset of FAP and LTX and had probably decreased since the graft.If amyloid deposition is frequent in inferior nasal concha in FAP, this location could be a suitable biopsy site. 相似文献
17.
AbstractSome TTR mutants target the central nervous system (CNS). Familial amyloid polyneuropathy (FAP) with leptomeningeal involvement has been described in 9% of transthyretin (TTR) mutations and in valine for methionine at position 30 (V30M) patients. These individuals present dementia, ataxia, brain hemorrhages and focal neurological episodes (FNEs). FNEs occurred also in V30M FAP patients with longer disease duration, who have undergone liver transplant to remove the source of plasma mutant TTR as a form of treatment. It is thus to expect that as better treatments for FAP emerge and prolong survival, meningeal-vascular CNS deposition will increase and need special therapies. Recently, we detected TTR meningeal-vascular deposition in a V30M TTR transgenic mouse model, opening new avenues of research to investigate selective treatments of this condition. Since pre-clinical studies with TTR siRNA therapeutics were shown to promote clearance of TTR non-fibrillar deposits in several organs and tissues, we investigated its effect on TTR meningeal-vascular deposition. We show that systemically administered TTR siRNA promoted TTR clearance in the extracellular matrix of meninges and brain blood vessels. Surprisingly, despite the striking decline of blood TTR, cerebrospinal fluid TTR levels were unaffected. Though this is reassuring because siRNA will not interfere with the neuroprotective role of TTR in the CNS, it raises new questions on therapeutical approaches for CNS ATTR. 相似文献
18.
Victor H. Jimenez-Zepeda Nizar J. Bahlis Janet Gilbertson Nigel Rendell Riccardo Porcari Helen J. Lachmann 《Amyloid》2015,22(1):26-30
Hereditary transthyretin (ATTR) amyloidosis is caused by inheritance of an abnormal TTR gene in an autosomal dominant fashion. In its native state, TTR is a homotetramer consisting of four identical polypeptides. Mutations in the TTR gene contribute to destabilization and dissociation of the TTR tetramer, enabling abnormally folded monomers to self-assemble as amyloid fibrils. Currently, over 120 TTR variants have been described, with varying geographic distributions, degrees of amyloidogenicity and organ involvement. We report here a large Irish family with familial amyloid polyneuropathy (FAP), consisting of multiple affected generations, caused by a novel TTR mutation; p.H110D (H90D). The demonstration, by immunohistochemistry and laser micro dissection–mass spectrometry (LMD/MS) that the amyloid fibrils were composed of TTR, in conjunction with a typical FAP phenotype, indicates that the novel TTR mutation was the cause of amyloidosis. We used a molecular visualization tool PyMOL to analyze the effect of the p.H110D (H90D) replacement on the stability of the TTR molecule. Our data suggest that the loss of two hydrogen bonds and the presence of an additional negative charge in the core of a cluster of acidic residues significantly perturb the tetramer stability and likely contribute to the pathogenic role of this variant. 相似文献
19.