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Subtle neuropsychiatric and neurocognitive changes in hereditary gelsolin amyloidosis (AGel amyloidosis)  [PDF]
Mari Kantanen,Sari Kiuru-Enari,Oili Salonen,Markku Kaipainen,Laura Hokkanen
PeerJ , 2015, DOI: 10.7717/peerj.493
Abstract: Hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant form of systemic amyloidosis caused by a c.640G>A or c.640G>T mutation in the gene coding for gelsolin. Principal clinical manifestations include corneal lattice dystrophy, cranial neuropathy and cutis laxa with vascular fragility. Signs of minor CNS involvement have also been observed, possibly related to cerebral amyloid angiopathy (CAA). To investigate further if AGel amyloidosis carries a risk for a specific neuropsychological or psychiatric symptomatology we studied 35 AGel patients and 29 control subjects. Neuropsychological tests showed abnormalities in visuocontructional and -spatial performance in AGel patients, also some indication of problems in processing efficacy was found. At psychiatric evaluation the patient group showed more psychiatric symptomatology, mainly depression. In brain MRI, available in 16 patients and 14 controls, we found microhemorrhages or microcalcifications only in the patient group, although the number of findings was small. Our study shows that AGel amyloidosis can be associated with visuoconstructional problems and depression, but severe neuropsychiatric involvement is not characteristic. The gelsolin mutation may even induce cerebrovascular fragility, but further epidemiological and histopathological as well as longitudinal follow-up studies are needed to clarify gelsolin-related vascular pathology and its clinical consequences.
Medullary thyroid carcinoma: Sporadic, hereditary  [PDF]
Paunovi? Ivan R.,Dikli? Aleksandar ?.,Krgovi? Ksenija Lj.,?ivaljevi? Vladan R.
Acta Chirurgica Iugoslavica , 2003, DOI: 10.2298/aci0303113p
Abstract: Medullary thyroid cancer (MTC) is uncommon thyroid tumor with specific characteristics which undoubtedly divide this tumor from other thyroid malignances. Patients with sporadic or hereditary form of MTC differ in clinical presentation, recurrence of the disease and outcome. The aim of study was to establish surgical characteristics of MTC as well as clinical factors that influence surgical treatment. The study group consisted of 68 patients with MTC managed at the Center for Endocrine Surgery between 1987. and 1999. Retrospective analysis included clinical form of the disease, general data, histological and other tumor characteristics. Mean age of the patients were 47.3 years (female/male ratio: 1.5:1). Mean size of tumor was 80.5 cm3, 72.1% patients had tumor greater than 4 cm. in diameter or extrathyroid spread. The majority of patients were in II and III stadium of the disease. Primary operation (at least total thyroidectomy) was performed in 57 (84%) patients. 2(3%) had postoperatively temporally nerve palsy and 7(10.29%) temporally hypoparathyroidism. The overall survival was 46.8 + 9.9% after 9 years and 63.6 + 7.2% at 5 years. Postoperative calcitonin value is significant predictor of survival /Spearman's coefficient (R=0.7048)/, worse prognosis is in correlation with high postoperative calcitonin values. The treatment of choice is at least total thyroidectomy and central lymph nodes resection if enlarged lymph nodes are found. Precise operative technique lowers the risk of postoperative complications. Complex approach to the patient with MTC includes all available methods in pre and postoperative evaluation as well as surgeon's knowledge and skill.
Guideline of transthyretin-related hereditary amyloidosis for clinicians  [cached]
Ando Yukio,Coelho Teresa,Berk John L,Cruz Márcia Waddington
Orphanet Journal of Rare Diseases , 2013, DOI: 10.1186/1750-1172-8-31
Abstract: Transthyretin amyloidosis is a progressive and eventually fatal disease primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy. Given its phenotypic unpredictability and variability, transthyretin amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. This article aims to help physicians better understand transthyretin amyloidosis—and, specifically, familial amyloidotic polyneuropathy—so they can recognize and manage the disease more easily and discuss it with their patients. We provide guidance on making a definitive diagnosis, explain methods for disease staging and evaluation of disease progression, and discuss symptom mitigation and treatment strategies, including liver transplant and several pharmacotherapies that have shown promise in clinical trials.
Clinico-Pathological Characterization of Hereditary, Familial and Sporadic Prostate Cancer  [PDF]
Diem Nguyen Bentzon, Anne Sofie Lynnerup, Michael Borre
Open Journal of Urology (OJU) , 2012, DOI: 10.4236/oju.2012.22008
Abstract: Aim: To characterize familial prostate cancer including hereditary prostate cancer and assess the disease-free survival following radical prostatectomy. Methods: A self-administered written questionnaire was forwarded to 709 prostatectomized patients from the Aarhus Prostate Cancer Study containing questions about cases of prostate cancer (PC), age at diagnosis, vital status, and age at death for all first-degree relatives. Patients were then divided into groups according to their family history: hereditary prostate cancer (HPC), familial prostate cancer (FPC), and sporadic prostate cancer (SPC) groups. The information from a subset of both FPC (n = 17) and SPC (n = 17) groups were validated in the Danish Cancer Register and the Civil Registration System. Between groups, we described the association of age, prostatespecific antigen (PSA), postoperative Gleason score and T Stage. A Kaplan-Meier curve demonstrated postoperative disease-free survival in each group. Results: The response rate was 81% (574/709). About 21% of the patients were categorized in the FPC group, of which 7% were identified as having HPC. The median follow-up time was 63 months for HPC, 65 months for FPC and 88 months for SPC. Overall, there was no significant difference between groups in clinical features and disease-free survival except that patients with HPC were significantly associated with younger age than sporadic cases (p = 0.02). The proportion of self-reported PC diagnoses confirmed in the cancer register was 27.8%. The index persons with SPC reported no PC in first-degree relatives and none was found the cancer register. Conclusion: Overall, we found no difference in clinical characteristics and survival, following radical prostatectomy except that patients with HPC were younger at diagnosis. These results are in line with previously reported data.
Thymidylate synthase gene (TYMS) polymorphisms in sporadic and hereditary breast cancer
José da Silva Nogueira Junior, Fernando Augusto de Lima Marson, Carmen Sílvia Bertuzzo
BMC Research Notes , 2012, DOI: 10.1186/1756-0500-5-676
Abstract: In this study we included a total of 204 subjects, 70 with BC (33 with SBC, and 37 with HBC) and 134 healthy subjects (controls). The Polymerase Chain Reaction was the method used.Results demonstrated a high frequency of the 3R allele at BC, SBC, and HBC groups. The frequency of genotype 2R/3R was significantly higher in BC group. This work showed association between the 2R/3R variants (OR = 4.14, CI95% = 1.77-9.71) in the development of SBC, and 2R/2R (OR = 0.233, CI95% = 1.63-7.65) and 2R/3R (OR = 3.53, CI95% = 0.06-0.81) for developing HBC. To BC, there was association with the genotype 2R/3R (OR: 3.79, CI95% = 2.03-7.08).Our results show relation to the development of BC in association with the analyzed polymorphisms.Breast cancer (BC) is a genetic disease characterized by an out of control growing breast cells, resulting in cellular proliferation, invasion of surrounding tissues and other organs, with possibility of metastasis [1]. BC is the second leading cancer in the population, it is the most common cancer among women, and the second leading cause of death within them, with approximately 460.000 deaths/year worldwide [1,2].In recent years risk factors for BC have been identified, although the etiology of the disease is still not understood. Risk factors that contribute to the development of BC include age, ethnicity, reproduction, some kind of hormones, lifestyle, bone density, genetic factors [3] and family history [4]. The majority of hereditary breast cancer (HBC) susceptibility can be attributed to germline mutations of to Breast Cancer 1 and Breast Cancer 2 genes (BRCA1 and BRCA2), which are responsible for 30-40% of HBC. Clinically, the basis of HBC is established at an early age, family history, bilateral BC, male BC, ovarian and/or tube cancer, and lower survival when compared to the sporadic form [5].Most of BC are sporadic (SBC), resulting from gene mutations, uncorrected, located in somatic cells, and unrelated to germline mutation. Risk factors
New insights into the clinical evaluation of hereditary transthyretin amyloidosis patients: a single center's experience
Suhr OB, Gustavsson S, Heldestad V, H rnsten R, Lindqvist P, Nordh E, Wiklund U
Degenerative Neurological and Neuromuscular Disease , 2012, DOI: http://dx.doi.org/10.2147/DNND.S24652
Abstract: sights into the clinical evaluation of hereditary transthyretin amyloidosis patients: a single center's experience Review (1208) Total Article Views Authors: Suhr OB, Gustavsson S, Heldestad V, H rnsten R, Lindqvist P, Nordh E, Wiklund U Published Date August 2012 Volume 2012:2 Pages 93 - 106 DOI: http://dx.doi.org/10.2147/DNND.S24652 Received: 04 April 2012 Accepted: 06 June 2012 Published: 30 August 2012 Ole B Suhr,1 Sandra Gustavsson,1 Victoria Heldestad,2 Rolf H rnsten,3 Per Lindqvist,1 Erik Nordh,2 Urban Wiklund4 1Department of Public Health and Clinical Medicine, 2Department of Pharmacology and Clinical Neuroscience, 3Department of Surgical and Perioperative Sciences, Clinical Physiology, Heart Centre, 4Department of Radiation Sciences, Biomedical Engineering, Ume University, Ume , Sweden Abstract: Over the last decade, new medical treatment modalities have emerged based on increased insights into amyloid formation. With the increased possibilities for treatment of amyloidosis caused by transthyretin (TTR) amyloid deposits comes the need for diagnostic procedures for early diagnosis and better tools to follow disease progression. This is of particular importance in clinical trials evaluating the efficacy of new treatments. Until recently, the treatment of TTR amyloidosis (ATTR) was based solely on liver transplantation, a procedure that has halted disease progression in many patients. Liver transplantation has been especially effective in patients under the age of 50 years carrying the TTR V30M mutation, whereas the outcome of the procedure has been variable for others, particularly elderly male patients and those carrying a non-V30M mutation. This review concentrates on new insights derived from our center's experience with liver transplantation, how to implement this experience in evaluation of new treatment modalities for ATTR, and how to facilitate early diagnosis of neuropathy with easily available diagnostic tools. Attention has focused on manifestations of the disease that involve the heart and the peripheral nervous system; change in peripheral nerve function has been the primary endpoint in two controlled clinical trials, one finished and one ongoing. New insights into the amyloid formation process and the lessons learned from liver transplantation give the opportunity to design potentially effective treatment modalities for ATTR. It appears reasonable to suspect that a combination of different treatment modalities may be required to treat the disease, and that different treatment regimes will be designed according to the phenotype of the disease. For the patients and their relatives there is now a solid foundation for optimism, with prospects of several effective medical treatment possibilities within the coming decade.
Survival of hereditary non-polyposis colorectal cancer patients compared with sporadic colorectal cancer patients
Vittoria Stigliano, Daniela Assisi, Maurizio Cosimelli, Raffaele Palmirotta, Diana Giannarelli, Marcella Mottolese, Lupe Mete, Raffaello Mancini, Vincenzo Casale
Journal of Experimental & Clinical Cancer Research , 2008, DOI: 10.1186/1756-9966-27-39
Abstract: We analyzed a cohort of 40 (25 males and 15 females) HNPCC cases with a hospital consecutive series of 573 (312 males and 261 females) sporadic CRC observed during the period 1970–1993. In 15 HNPCC patients we performed mutational analysis for microsatellite instability. Survival rates were calculated by Kaplan-Meier method and compared with log rank test.The median age at diagnosis of the primary CRC was 46.8 years in the HNPCC series versus 61 years in sporadic CRC group. In HNPCC group 85% had a right cancer location, vs. 57% in the sporadic cancer group. In the sporadic cancer group 61.6% were early-stages cancer (Dukes' A and B) vs. 70% in the HNPCC group (p = ns). The crude 5-years cumulative survival after the primary CRC was 94.2% in HNPCC patients vs. 75.3% in sporadic cancer patients (p < 0.0001).Our results show that overall survival of colorectal cancer in patients with HNPCC is better than sporadic CRC patients. The different outcome probably relates to the specific tumorigenesis involving DNA mismatch repair dysfunction.Colorectal cancer is one of the most common neoplasm in humans [1,2]. It's known that a definite fraction, ranging between 1 and 5% of all cases of colorectal tumors, is transmitted from one generation to another in accordance with an autosomal dominant model; this is the case of Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and of Familial Adenomatous Polyposis (FAP) [2].HNPCC is an autosomal dominant disease characterized by early appearance of cancer usually of the right colon, frequent occurrence of multiple lesions (both synchronous and metachronous) and a striking association with tumours of other organs, in particular endometrium, urinary tract, ovary, stomach and small bowel. The Amsterdam criteria, currently used for the diagnosis of HNPCC, were introduced in 1989 to provide a uniform evaluation of familial and personal history. They were revised in 1999 and included various extra-colonic tumours: 1) at least three or more
Clinical management of gastrointestinal amyloidosis  [PDF]
Hajime Isomoto, Yasuhiro Kamo, Chun Chuan Chen, Kazuhiko Nakao
Open Journal of Gastroenterology (OJGas) , 2012, DOI: 10.4236/ojgas.2012.24030
Abstract: Amyloidosis is characterized by extracellular deposition of abnormal protein, consisting of primary, secondary, hemodialysis-related, hereditary, senile and localized type. Primary amyloidosis is associated with monoclonal light chains. Secondary amyloidosis is associated with inflammatory, infectious, and neoplastic diseases. Amyloid deposition in the gastrointestinal tract can manifest the symptoms including diarrhea, steatorrhea, or constipation. For diagnosis, one should obtain an immunofixation of serum or urine as well as biopsy sampling of gastrointestinal mucosa stained specifically. While most gastrointestinal complications are managed symptomatically, treatment depends upon the type of amyloidosis. Causal therapy is reserved for a select few from various subtypes of this disorder.
New insights into the clinical evaluation of hereditary transthyretin amyloidosis patients: a single center's experience  [cached]
Suhr OB,Gustavsson S,Heldestad V,Hörnsten R
Degenerative Neurological and Neuromuscular Disease , 2012,
Abstract: Ole B Suhr,1 Sandra Gustavsson,1 Victoria Heldestad,2 Rolf H rnsten,3 Per Lindqvist,1 Erik Nordh,2 Urban Wiklund41Department of Public Health and Clinical Medicine, 2Department of Pharmacology and Clinical Neuroscience, 3Department of Surgical and Perioperative Sciences, Clinical Physiology, Heart Centre, 4Department of Radiation Sciences, Biomedical Engineering, Ume University, Ume , SwedenAbstract: Over the last decade, new medical treatment modalities have emerged based on increased insights into amyloid formation. With the increased possibilities for treatment of amyloidosis caused by transthyretin (TTR) amyloid deposits comes the need for diagnostic procedures for early diagnosis and better tools to follow disease progression. This is of particular importance in clinical trials evaluating the efficacy of new treatments. Until recently, the treatment of TTR amyloidosis (ATTR) was based solely on liver transplantation, a procedure that has halted disease progression in many patients. Liver transplantation has been especially effective in patients under the age of 50 years carrying the TTR V30M mutation, whereas the outcome of the procedure has been variable for others, particularly elderly male patients and those carrying a non-V30M mutation. This review concentrates on new insights derived from our center's experience with liver transplantation, how to implement this experience in evaluation of new treatment modalities for ATTR, and how to facilitate early diagnosis of neuropathy with easily available diagnostic tools. Attention has focused on manifestations of the disease that involve the heart and the peripheral nervous system; change in peripheral nerve function has been the primary endpoint in two controlled clinical trials, one finished and one ongoing. New insights into the amyloid formation process and the lessons learned from liver transplantation give the opportunity to design potentially effective treatment modalities for ATTR. It appears reasonable to suspect that a combination of different treatment modalities may be required to treat the disease, and that different treatment regimes will be designed according to the phenotype of the disease. For the patients and their relatives there is now a solid foundation for optimism, with prospects of several effective medical treatment possibilities within the coming decade.Keywords: neuropathy, cardiomyopathy, amyloid, diagnostic tools, new treatment modalities
Allele Specific Expression of the Transthyretin Gene in Swedish Patients with Hereditary Transthyretin Amyloidosis (ATTR V30M) Is Similar between the Two Alleles  [PDF]
Nina Norgren, Urban Hellman, Bo G?ran Ericzon, Malin Olsson, Ole B. Suhr
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049981
Abstract: Background Hereditary transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease characterized by extracellular deposits of amyloid fibrils composed of misfolded TTR. The differences in penetrance and age at onset are vast, both between and within populations, with a generally late onset for Swedish carriers. In a recent study the entire TTR gene including the 3′ UTR in Swedish, French and Japanese ATTR patients was sequenced. The study disclosed a SNP in the V30M TTR 3′ UTR of the Swedish ATTR population that was not present in either the French or the Japanese populations (rs62093482-C>T). This SNP could create a new binding site for miRNA, which would increase degradation of the mutated TTR’s mRNA thus decrease variant TTR formation and thereby delay the onset of the disease. The aim of the present study was to disclose differences in allele specific TTR expression among Swedish V30M patients, and to see if selected miRNA had any effect upon the expression. Methodology/Principal Findings Allele-specific expression was measured on nine liver biopsies from Swedish ATTR patients using SNaPshot Multiplex assay. Luciferase activity was measured on cell lines transfected with constructs containing the TTR 3′ UTR. Allele-specific expression measured on liver biopsies from Swedish ATTR patients showed no difference in expression between the two alleles. Neither was there any difference in expression between cell lines co-transfected with two constructs with or without the TTR 3′ UTR SNP regardless of added miRNA. Conclusions/Significance The SNP found in the 3′ UTR of the TTR gene has no effect on degrading the variant allele’s expression and thus has no impact on the diminished penetrance of the trait in the Swedish population. However, the 3′ UTR SNP is unique for patients descending from the Swedish founder, and this SNP could be utilized to identify ATTR patients of Swedish descent.
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