A Novel Rat Model of Hereditary Hemochromatosis Due to a Mutation in Transferrin Receptor 2

PubMed Central

Bartnikas, Thomas B; Wildt, Sheryl J; Wineinger, Amy E; Schmitz-Abe, Klaus; Markianos, Kyriacos; Cooper, Dale M; Fleming, Mark D

2013-01-01

Sporadic iron overload in rats has been reported, but whether it is due to genetic or environmental causes is unknown. In the current study, phenotypic analysis of Hsd:HHCL Wistar rats revealed a low incidence of histologically detected liver iron overload. Here we characterized the pathophysiology of the iron overload and showed that the phenotype is heritable and due to a mutation in a single gene. We identified a single male rat among the 132 screened animals that exhibited predominantly periportal, hepatocellular iron accumulation. This rat expressed low RNA levels of the iron regulatory hormone hepcidin and low protein levels of transferrin receptor 2 (Tfr2), a membrane protein essential for hepcidin expression in humans and mice and mutated in forms of hereditary hemochromatosis. Sequencing of Tfr2 in the iron-overloaded rat revealed a novel Ala679Gly polymorphism in a highly conserved residue. Quantitative trait locus mapping indicated that this polymorphism correlated strongly with serum iron and transferrin saturations in male rats. Expression of the Gly679 variant in tissue culture cell lines revealed decreased steady-state levels of Tfr2. Characterization of iron metabolism in the progeny of polymorphic rats suggested that homozygosity for the Ala679Gly allele leads to a hemochromatosis phenotype. However, we currently cannot exclude the possibility that a polymorphism or mutation in the noncoding region of Tfr2 contributes to the iron-overload phenotype. Hsd:HHCL rats are the first genetic rat model of hereditary hemochromatosis and may prove useful for understanding the molecular mechanisms underlying the regulation of iron metabolism. PMID:23582421

Identification of novel mutations in HFE, HFE2, TfR2, and SLC40A1 genes in Chinese patients affected by hereditary hemochromatosis.

PubMed

Wang, Yongwei; Du, Yali; Liu, Gang; Guo, Shanshan; Hou, Bo; Jiang, Xianyong; Han, Bing; Chang, Yanzhong; Nie, Guangjun

2017-04-01

Hereditary hemochromatosis (HH) is a group of inherited iron-overload disorders associated with pathogenic defects in the genes encoding hemochromatosis (HFE), hemojuvelin (HJV/HFE2), hepcidin (HAMP), transferrin receptor 2 (TfR2), and ferroportin (FPN1/SLC40A1) proteins, and the clinical features are well described. However, there have been only a few detailed reports of HH in Chinese populations. Thus, there is insufficient patient information for population-based analyses in Chinese populations or comparative studies among different ethical groups. In the current work, we describe eight Chinese cases of hereditary hemochromatosis. Gene sequencing results revealed eight mutations (five novel mutations) in HFE, HFE2, TfR2, and SLC40A1 genes in these Chinese HH patients. In addition, we used Polymorphism Phenotyping v2 (Polyphen), Sorting Intolerant From Tolerant (SIFT), and a sequence alignment program to predict the molecular consequences of missense mutations.

Frequency of the S65C mutation in the hemochromatosis gene in Brazil.

PubMed

Oliveira, V C; Caxito, F A; Gomes, K B; Castro, A M; Pardini, V C; Ferreira, A C S

2009-07-14

Development of hereditary hemochromatosis is associated with the C282Y, H63D or S65C mutations in the hemochromatosis gene. Though there is extensive knowledge about the former two, there is little information on the mechanism of action and the allelic frequency of the S65C mutation. We examined the prevalence of the S65C mutation of the hemochromatosis gene in Brazilians with clinical suspicion of hereditary hemochromatosis. Genotyping for this mutation was carried out in 633 individuals with clinical suspicion of hereditary hemochromatosis, using the polymerase chain reaction, followed by enzymatic digestion. The sample comprised 77.1% men and 22.9% women, giving a ratio of approximately 3:1; the mean age was 48.8 +/- 13.8 years. More than half (57.3%) of the individuals in the sample were 41 to 60 years old. The frequency of heterozygotes for this mutation was 0.016; no homozygous mutant patients were found. This is the first analysis of the S65C mutation in individuals suspected of having hereditary hemochromatosis in Brazil.

Ductular reaction in hereditary hemochromatosis: the link between hepatocyte senescence and fibrosis progression.

PubMed

Wood, Marnie J; Gadd, Victoria L; Powell, Lawrie W; Ramm, Grant A; Clouston, Andrew D

2014-03-01

The development of portal fibrosis following the iron loading of hepatocytes is the first stage of fibrogenesis in hereditary hemochromatosis. In other chronic liver diseases it has been shown that a ductular reaction (DR) appears early, correlates with fibrosis progression, and is a consequence of activation of an alternative pathway of hepatocyte replication. This study was designed to investigate the presence of the DR in hemochromatosis and describe its associations. Liver biopsies from 63 C282Y homozygous patients were assessed for hepatic iron concentration (HIC) and graded for iron loading, fibrosis stage, steatosis, and inflammation. Immunostaining allowed quantification of the DR, hepatocyte senescence and proliferation, and analysis incorporated clinical data. Hepatocyte senescence was positively correlated with HIC, serum ferritin, and oxidative stress. A DR was demonstrated and occurred prior to histological fibrosis. HIC, age, hepatocyte senescence and proliferation, portal inflammation, and excessive alcohol consumption all had significant associations with the extent of the DR. In multivariate analysis, iron loading, hepatocyte replicative arrest, and portal inflammation remained independently and significantly associated with the DR. Of factors associated with fibrosis progression, the DR (odds ratio [OR] 10.86 P<0.0001) and the presence of portal inflammation (OR 4.31, P=0.028) remained significant after adjustment for cofactors. The extent of the DR regressed following therapeutic venesection. Iron loading of hepatocytes leads to impaired replication, stimulating the development of the DR in hemochromatosis and this correlates strongly with hepatic fibrosis. Portal inflammation occurs in hemochromatosis and is independently associated with the DR and fibrosis, and thus its role in this disease should be evaluated further. © 2014 by the American Association for the Study of Liver Diseases.

R2*-relaxometry of the pancreas in patients with human hemochromatosis protein associated hereditary hemochromatosis.

PubMed

Henninger, B; Rauch, S; Zoller, H; Plaikner, M; Jaschke, W; Kremser, C

2017-04-01

To evaluate pancreatic iron in patients with human hemochromatosis protein associated hereditary hemochromatosis (HHC) using R2* relaxometry. 81 patients (58 male, 23 female; median age 49.5, range 10-81 years) with HHC were retrospectively studied. All underwent 1.5T magnetic resonance imaging (MRI) of the abdomen. A fat-saturated multi-gradient echo sequence with 12 echoes (TR=200ms; TE-initial 0.99ms; Delta-TE 1.41ms; 12 echoes; flip-angle: 20°) was used for the R2* quantification of the liver and the pancreas. Parameter maps were analyzed using regions of interest (3 in the liver and 2 in the pancreas) and R2* values were correlated. 59/81 patients had a liver R2*≥70 1/s of which 10/59 patients had a pancreas R2*≥50 1/s. No patient presented with a liver R2*<70 1/s and pancreas R2*≥50 1/s. All patients with pancreas R2* values≥50 1/s had liver R2* values≥70 1/s. ROC analysis resulted in a threshold of 209.4 1/s for liver R2* values to identify HFE positive patients with pancreas R2* values≥50 1/s with a median specificity of 78.87% and a median sensitivity of 90%. In patients with HHC R2* relaxometry of the pancreas should be performed when liver iron overload is present and can be omitted in cases with no sign of hepatic iron. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis.

PubMed

Duarte, Tiago L; Caldas, Carolina; Santos, Ana G; Silva-Gomes, Sandro; Santos-Gonçalves, Andreia; Martins, Maria João; Porto, Graça; Lopes, José Manuel

2017-04-01

In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe -/- mice (an established model of human HFE-hemochromatosis). Wild-type, Nrf2 -/- , Hfe -/- and double knockout (Hfe/Nrf2 -/- ) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12-18 (middle-aged) or 24 months (old) for evaluation of liver pathology. Despite the parenchymal iron accumulation, Hfe -/- mice presented no liver injury. The combination of iron overload (Hfe -/- ) and defective antioxidant defences (Nrf2 -/- ) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal-protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner. The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe -/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Preliminary investigation of bottlenose dolphins (Tursiops truncatus) for hfe gene-related hemochromatosis.

PubMed

Phillips, Brianne E; Venn-Watson, Stephanie; Archer, Linda L; Nollens, Hendrik H; Wellehan, James F X

2014-10-01

Hemochromatosis (iron storage disease) has been reported in diverse mammals including bottlenose dolphins (Tursiops truncatus). The primary cause of excessive iron storage in humans is hereditary hemochromatosis. Most human hereditary hemochromatosis cases (up to 90%) are caused by a point mutation in the hfe gene, resulting in a C282Y substitution leading to iron accumulation. To evaluate the possibility of a hereditary hemochromatosis-like genetic predisposition in dolphins, we sequenced the bottlenose dolphin hfe gene, using reverse transcriptase-PCR and hfe primers designed from the dolphin genome, from liver of affected and healthy control dolphins. Sample size included two case animals and five control animals. Although isotype diversity was evident, no coding differences were identified in the hfe gene between any of the animals examined. Because our sample size was small, we cannot exclude the possibility that hemochromatosis in dolphins is due to a coding mutation in the hfe gene. Other potential causes of hemochromatosis, including mutations in different genes, diet, primary liver disease, and insulin resistance, should be evaluated.

Hereditary hemochromatosis: awareness and genetic testing acceptability in Western Romania.

PubMed

Neghina, Adriana Maria; Anghel, Andrei

2010-12-01

a public health strategy to promote early diagnosis of hemochromatosis gene (HFE)-related hemochromatosis (HFE-HH) largely depends on people's acceptance of available screening tests. The present study aimed at evaluating patient awareness of HFE-HH and their acceptance of DNA testing in western Romania. a total of 221 participants were randomly recruited from the ambulatory unit of the Emergency County Hospital in Timisoara, Romania. They received brief information on HFE-HH and were assessed for the signs and symptoms of hemochromatosis. HFE genotyping was offered to all of them. Only two cases (0.9%) had previous knowledge of HFE-HH. Twenty-one cases (9.5%) underwent genetic testing. Characteristics associated with test acceptance were age <45 years, male gender, and educational attainment. Acceptance was associated with a desire to know if they had HFE-HH (85.7%). The most prevalent refusal reason was a desire for more information (41%). larger educational programs are required to increase people's awareness about HFE-HH in western Romania. Nevertheless, within health care settings, the importance of disease detection and patient's educational background appear to be essential for achieving high rates of participation in the genetic test.

Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-yr Phase 2 study.

PubMed

Cançado, Rodolfo; Melo, Murilo R; de Moraes Bastos, Roberto; Santos, Paulo C J L; Guerra-Shinohara, Elivira M; Chiattone, Carlos; Ballas, Samir K

2015-12-01

This open-label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 ± 5 mg/kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12-month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

High prevalence of fibromyalgia in patients with HFE-related hereditary hemochromatosis.

PubMed

Mohammad, Ausaf; Carey, John J; Storan, Eoin; Scarry, Margaret; Coughlan, Robert J; Lee, John M

2013-07-01

Subjects with HFE-related hereditary hemochromatosis (HH) may present with arthralgias, fatigue, and stiffness, yet little is known on the presence of fibromyalgia syndrome (FMS) in these subjects. We determined the prevalence of FMS in a cohort of subjects with HH and evaluated its relationship to subject demographics, disease status, and quality of life. In a cross-sectional study we collected data on 395 consecutive subjects diagnosed with HH who were attending a tertiary referral Hepatology outpatient clinic at Galway University Hospital, Ireland (between October 2009 and June 2010). Subjects underwent a standard assessment including history, clinical examination, and functional assessments for pain and disability. Univariate logistic regression was applied to determine risk factors independently associated with prevalent FMS in these subjects. Three hundred ninety-five subjects met the inclusion criteria. Mean age was 43 years (range, 21 to 59 y) and 260 (66%) were males. One hundred seventy (43%) of the subjects were diagnosed with FMS. Among those with fibromyalgia fatigue and ≥ 11 tender points were present in all of the subjects, widespread pain in 150 (88%), depression in 70 (41%), and arthralgia/joint stiffness in 70 (41%). In subjects with FMS 33% reported some functional impairment (HAQ-DI>0), with 10% reporting moderate-severe functional impairment (HAQ-DI ≥ 1.5). This study reveals a high prevalence of FMS (43%) among subjects with HFE-related hemochromatosis. Prospective studies are needed to better understand the risk factors for FMS in such patients.

Health check-ups and family screening allow detection of hereditary hemochromatosis with less advanced liver fibrosis and survival comparable with the general population.

PubMed

Aleman, Soo; Endalib, Sanam; Stål, Per; Lööf, Lars; Lindgren, Stefan; Sandberg-Gertzén, Hanna; Almer, Sven; Olsson, Sigvard; Danielsson, Ake; Wallerstedt, Sven; Hultcrantz, Rolf

2011-09-01

The information concerning the morbidity and mortality of hereditary hemochromatosis is based primarily on clinical cohorts of symptomatic patients. The major aim of this study was to analyze the long-term prognosis for Swedish patients with this condition, with respect to both clinical features and survival, in relation to the route by which the disease was detected. 373 patients with hemochromatosis detected through routine health check-ups (n = 153), family screening (n = 44), symptoms of arthralgia (n = 23), investigation of other diseases/symptoms (n = 108) or signs of liver disease (n = 45) were monitored for a mean period of 11.9 ± 5.8 years. The degree of liver fibrosis and survival were analyzed. Overall survival among these patients was not significantly different from that of a matched normal population. The patients diagnosed through health check-ups and family screening were detected at an earlier age and had the highest rate of survival. Liver biopsy at the time of diagnosis revealed cirrhosis in 9% of those detected through the health check-ups and 5% in the case of family screening, compared with 13% for the group with arthralgia, 17% for other diseases/symptoms and 42% for liver disease. Health check-ups and family screening allow detection of hereditary hemochromatosis at an earlier age and with less advanced liver fibrosis, although a few of these patients have already developed cirrhosis. Our study indicates that iron indices should be included in health check-ups, and if abnormal, should lead to further investigation.

Clinical penetrance in hereditary hemochromatosis: estimates of the cumulative incidence of severe liver disease among HFE C282Y homozygotes.

PubMed

Grosse, Scott D; Gurrin, Lyle C; Bertalli, Nadine A; Allen, Katrina J

2018-04-01

Iron overload (hemochromatosis) can cause serious, symptomatic disease that is preventable if detected early and managed appropriately. The leading cause of hemochromatosis in populations of predominantly European ancestry is homozygosity of the C282Y variant in the HFE gene. Screening of adults for iron overload or associated genotypes is controversial, largely because of a belief that severe phenotypes are uncommon, although cascade testing of first-degree relatives of patients is widely endorsed. We contend that severe liver disease (cirrhosis or hepatocellular cancer) is not at all uncommon among older males with hereditary hemochromatosis. Our review of the published data from a variety of empirical sources indicates that roughly 1 in 10 male HFE C282Y homozygotes is likely to develop severe liver disease during his lifetime unless iron overload is detected early and treated. New evidence from a randomized controlled trial of treatment allows for evidence-based management of presymptomatic patients. Although population screening for HFE C282Y homozygosity faces multiple barriers, a potentially effective strategy for increasing the early detection and prevention of clinical iron overload and severe disease is to include HFE C282Y homozygosity in lists of medically actionable gene variants when reporting the results of genome or exome sequencing.

Clinical cofactors and hepatic fibrosis in hereditary hemochromatosis: the role of diabetes mellitus.

PubMed

Wood, Marnie J; Powell, Lawrie W; Dixon, Jeannette L; Ramm, Grant A

2012-09-01

The risk of hepatic fibrosis and cirrhosis in hereditary hemochromatosis relates to the degree of iron loading, but iron alone does not explain the variability in disease penetrance. This study sought to identify clinical cofactors that increase the risk of progressive liver disease. We identified 291 patients from our database who were homozygous for the C282Y mutation in HFE and had undergone a liver biopsy with quantification of hepatic iron concentration (HIC) and fibrosis staging. Data were collected from a retrospective chart review, including age, gender, alcohol consumption, medical therapy, smoking history, metabolic risk factors, mobilizable iron, and laboratory results. Male gender, excess alcohol consumption, HIC, and the presence of diabetes were independently associated with increasing fibrosis stage in multivariate analysis. Of these, the presence of diabetes showed the strongest association (odds ratio, 7.32; P = 0.03). The presence of steatosis was associated with higher fibrosis scores, but this was of borderline statistical significance. Risk factors for hepatic steatosis were male gender, impaired glucose tolerance, and increased body mass index. The presence of diabetes was associated with more severe hepatic fibrosis independent of iron loading, male gender, and alcohol consumption. The mechanism for this association is unknown and deserves further evaluation; however, it is possible that diabetes produces an additional hepatic oxidative injury from hyperglycemia. Thus, management of such cofactors in patients with hemochromatosis is important to reduce the risk of liver injury and fibrosis. Copyright © 2012 American Association for the Study of Liver Diseases.

Effects of strain and age on hepatic gene expression profiles in murine models of HFE-associated hereditary hemochromatosis.

PubMed

Lee, Seung-Min; Loguinov, Alexandre; Fleming, Robert E; Vulpe, Christopher D

2015-01-01

Hereditary hemochromatosis is an iron overload disorder most commonly caused by a defect in the HFE gene. While the genetic defect is highly prevalent, the majority of individuals do not develop clinically significant iron overload, suggesting the importance of genetic modifiers. Murine hfe knockout models have demonstrated that strain background has a strong effect on the severity of iron loading. We noted that hepatic iron loading in hfe-/- mice occurs primarily over the first postnatal weeks (loading phase) followed by a timeframe of relatively static iron concentrations (plateau phase). We thus evaluated the effects of background strain and of age on hepatic gene expression in Hfe knockout mice (hfe-/-). Hepatic gene expression profiles were examined using cDNA microarrays in 4- and 8-week-old hfe-/- and wild-type mice on two different genetic backgrounds, C57BL/6J (C57) and AKR/J (AKR). Genes differentially regulated in all hfe-/- mice groups, compared with wild-type mice, including those involved in cell survival, stress and damage responses and lipid metabolism. AKR strain-specific changes in lipid metabolism genes and C57 strain-specific changes in cell adhesion and extracellular matrix protein genes were detected in hfe-/- mice. Mouse strain and age are each significantly associated with hepatic gene expression profiles in hfe-/- mice. These affects may underlie or reflect differences in iron loading in these mice.

Incidence of cardiac arrhythmias in asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity.

PubMed

Shizukuda, Yukitaka; Tripodi, Dorothy J; Zalos, Gloria; Bolan, Charles D; Yau, Yu-Ying; Leitman, Susan F; Waclawiw, Myron A; Rosing, Douglas R

2012-03-15

It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In the present study, we examined the incidence of cardiac arrhythmia in cardiac asymptomatic subjects with HH (New York Heart Association functional class I) and compared it to that in age- and gender-matched normal volunteers. The 42 subjects with HH and the 19 normal control subjects were recruited through the National Heart, Lung, and Blood Institute-sponsored "Heart Study of Hemochromatosis." They completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The subjects with HH were classified as newly diagnosed (group A) and chronically treated (group B) subjects. All subjects with HH had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be greater in the combined HH groups than in the controls. Supraventricular ectopy was more frequently noted in group B compared to in the controls (ectopy rate per hour 11.1 ± 29.9 vs 1.5 ± 3.5, p < 0.05, using the Kruskal-Wallis test). No examples of heart block, other than first-degree atrioventricular node block, were seen in any of the subjects. The incidence of cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in the group A subjects. No life-threatening arrhythmias were observed in our subjects with HH. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic subjects with HH. A larger clinical study is warranted to further clarify our observation. Published by Elsevier Inc.

Hemochromatosis

MedlinePlus

Hemochromatosis is a disease in which too much iron builds up in your body. Your body needs iron but too much of it ... types of hemochromatosis. Primary hemochromatosis is an inherited disease. Secondary hemochromatosis is usually the result of something ...

Acquired Hemochromatosis with Pronounced Pigment Deposition of the Upper Eyelids

PubMed Central

Morrison, Brian; Hu, Shasa

2013-01-01

Hemochromatosis may be classified into two groups: primary (hereditary) or secondary (acquired). The acquired type most commonly occurs after massive intake of iron supplements or blood transfusions and is also known as transfusional iron overload. In the past, hemochromatosis was usually recognized at an advanced stage by the classic triad of hyperpigmentation, diabetes mellitus (“bronze diabetes”), and hepatic cirrhosis. Cutaneous hyperpigmentation is present in 70 percent of patients due to two different mechanisms: (1) hemosiderin deposition resulting in diffuse, slate-gray darkening and (2) increased production of melanin in the epidermis. A 47-year-old woman who receives regular transfusions due to low iron and chronic, unresolving anemia and who subsequently developed pronounced hyperpigmentation of the upper eyelids is described. The presentation, diagnosis, pathogenesis, and treatment options of hyperpigmentation due to secondary hemochromatosis are discussed. PMID:24155994

Effect of C282Y genotype on self-reported musculoskeletal complications in hereditary hemochromatosis.

PubMed

Camacho, António; Funck-Brentano, Thomas; Simão, Márcio; Cancela, Leonor; Ottaviani, Sébastien; Cohen-Solal, Martine; Richette, Pascal

2015-01-01

Arthropathy that mimics osteoarthritis (OA) and osteoporosis (OP) is considered a complication of hereditary hemochromatosis (HH). We have limited data comparing OA and OP prevalence among HH patients with different hemochromatosis type 1 (HFE) genotypes. We investigated the prevalence of OA and OP in patients with HH by C282Y homozygosity and compound heterozygosity (C282Y/H63D) genotype. A total of 306 patients with HH completed a questionnaire. Clinical and demographic characteristics and presence of OA, OP and related complications were compared by genotype, adjusting for age, sex, body mass index (BMI), current smoking and menopausal status. In total, 266 of the 306 patients (87%) were homozygous for C282Y, and 40 (13%) were compound heterozygous. The 2 groups did not differ by median age [60 (interquartile range [IQR] 53 to 68) vs. 61 (55 to 67) years, P=0.8], sex (female: 48.8% vs. 37.5%, P=0.18) or current smoking habits (12.4% vs. 10%, P=0.3). As compared with compound heterozygous patients, C282Y homozygous patients had higher median serum ferritin concentration at diagnosis [1090 (IQR 610 to 2210) vs. 603 (362 to 950) µg/L, P<0.001], higher median transferrin saturation [80% (IQR 66 to 91%) vs. 63% (55 to 72%), P<0.001]) and lower median BMI [24.8 (22.1 to 26.9) vs. 26.2 (23.5 to 30.3) kg/m2, P<0.003]. The overall prevalence of self-reported OA was significantly higher with C282Y homozygosity than compound heterozygosity (53.4% vs. 32.5%; adjusted odds ratio [aOR] 2.4 [95% confidence interval 1.2-5.0]), as was self-reported OP (25.6% vs. 7.5%; aOR 3.5 [1.1-12.1]). Patients with C282Y homozygosity may be at increased risk of musculoskeletal complications of HH.

Effect of C282Y Genotype on Self-Reported Musculoskeletal Complications in Hereditary Hemochromatosis

PubMed Central

Simão, Márcio; Cancela, Leonor; Ottaviani, Sébastien; Cohen-Solal, Martine; Richette, Pascal

2015-01-01

Objective Arthropathy that mimics osteoarthritis (OA) and osteoporosis (OP) is considered a complication of hereditary hemochromatosis (HH). We have limited data comparing OA and OP prevalence among HH patients with different hemochromatosis type 1 (HFE) genotypes. We investigated the prevalence of OA and OP in patients with HH by C282Y homozygosity and compound heterozygosity (C282Y/H63D) genotype. Methods A total of 306 patients with HH completed a questionnaire. Clinical and demographic characteristics and presence of OA, OP and related complications were compared by genotype, adjusting for age, sex, body mass index (BMI), current smoking and menopausal status. Results In total, 266 of the 306 patients (87%) were homozygous for C282Y, and 40 (13%) were compound heterozygous. The 2 groups did not differ by median age [60 (interquartile range [IQR] 53 to 68) vs. 61 (55 to 67) years, P=0.8], sex (female: 48.8% vs. 37.5%, P=0.18) or current smoking habits (12.4% vs. 10%, P=0.3). As compared with compound heterozygous patients, C282Y homozygous patients had higher median serum ferritin concentration at diagnosis [1090 (IQR 610 to 2210) vs. 603 (362 to 950) µg/L, P<0.001], higher median transferrin saturation [80% (IQR 66 to 91%) vs. 63% (55 to 72%), P<0.001]) and lower median BMI [24.8 (22.1 to 26.9) vs. 26.2 (23.5 to 30.3) kg/m2, P<0.003]. The overall prevalence of self-reported OA was significantly higher with C282Y homozygosity than compound heterozygosity (53.4% vs. 32.5%; adjusted odds ratio [aOR] 2.4 [95% confidence interval 1.2–5.0]), as was self-reported OP (25.6% vs. 7.5%; aOR 3.5 [1.1–12.1]). Conclusion Patients with C282Y homozygosity may be at increased risk of musculoskeletal complications of HH. PMID:25822977

Iranian hereditary hemochromatosis patients: baseline characteristics, laboratory data and gene mutations.

PubMed

Zamani, Farhad; Bagheri, Zohreh; Bayat, Maryam; Fereshtehnejad, Seyed-Mohammad; Basi, Ali; Najmabadi, Hossein; Ajdarkosh, Hossein

2012-10-01

Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder in white people, characterized by highly abnormal uptake of iron from the gastrointestinal tracts. Recently, mutation studies have focused to detect the genes responsible for HH. In this cross-sectional study, 12 HH patients were recruited, who were referred to Firoozgar Hospital, Tehran, Iran. In addition to the clinical assessments, a complete laboratory evaluation, imaging modalities, histopathologic assessment, atomic absorption spectrophotometry and gene mutation study were performed. The genetic study for HFE gene mutation was examined for all of the patients since 2006, while non-HFE mutation was conducted since December 2010 (only for 1 of them). Twelve patients were evaluated consisting of 11 men and 1 woman, with the mean age of 39.58±12.68 yr. The average of atomic iron loads was 13.25±4.83-fold higher than normal standards. Four patients had heterozygotic mutation of H63D (33.3%). There was no significant difference in either the iron load of liver (P=0.927) and heart (P=0.164) or serum concentration of ferritin (P=0.907) and TIBC (P=0.937) between the HFE-mutant and without HFE mutation HH cases. In contrast to other studies, C282Y mutation was not detected in any of our Iranian HH patients. Heterozygotic mutations of H63D (HFE) and TFR2 (non-HFE) genes were found to be more common in these patients. Similar to previous reports, these mutations were not found to be significantly associated with severity of presentation in HH patients.

Invariant Natural Killer T Cells are Reduced in Hereditary Hemochromatosis Patients.

PubMed

Maia, M L; Pereira, C S; Melo, G; Pinheiro, I; Exley, M A; Porto, G; Macedo, M F

2015-01-01

Invariant natural killer T (iNKT) cells are CD1d restricted-T cells that react to lipid antigens. iNKT cells were shown to be important in infection, autoimmunity and tumor surveillance. Alterations in the number and function of these cells were described in several pathological conditions including autoimmune and/or liver diseases. CD1d is critical for antigen presentation to iNKT cells, and its expression is increased in liver diseases. The liver is the major organ affected in Hereditary Hemochromatosis (HH), an autosomal recessive disorder caused by excessive iron absorption. Herein, we describe the study of iNKT cells of HH patients. Twenty-eight HH patients and 24 control subjects from Santo António Hospital, Porto, were included in this study. Patient's iron biochemical parameters (serum transferrin saturation and ferritin levels) and the liver function marker alanine transaminase (ALT) were determined at the time of study. Peripheral blood iNKT cells were analyzed by flow cytometry using an anti-CD3 antibody and the CD1d tetramer loaded with PBS57. We found a decrease in the percentage and number of circulating iNKT cells from HH patients when compared with control population independently of age. iNKT cell defects were more pronounced in untreated patients, relating with serum ferritin and transferrin saturation levels. No correlation was found with ALT, a marker of active liver dysfunction. Altogether, our results demonstrate that HH patients have reduced numbers of iNKT cells and that these are influenced by iron overload.

EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).

PubMed

Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

2016-04-01

Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines.

Acquired hemochromatosis with pronounced pigment deposition of the upper eyelids.

PubMed

Chacon, Anna H; Morrison, Brian; Hu, Shasa

2013-10-01

primary (hereditary) or secondary (acquired). The acquired type most commonly occurs after massive intake of iron supplements or blood transfusions and is also known as transfusional iron overload. In the past, hemochromatosis was usually recognized at an advanced stage by the classic triad of hyperpigmentation, diabetes mellitus ("bronze diabetes"), and hepatic cirrhosis. Cutaneous hyperpigmentation is present in 70 percent of patients due to two different mechanisms: (1) hemosiderin deposition resulting in diffuse, slate-gray darkening and (2) increased production of melanin in the epidermis. A 47-year-old woman who receives regular transfusions due to low iron and chronic, unresolving anemia and who subsequently developed pronounced hyperpigmentation of the upper eyelids is described. The presentation, diagnosis, pathogenesis, and treatment options of hyperpigmentation due to secondary hemochromatosis are discussed.

The cost-effectiveness of screening for hereditary hemochromatosis in Germany: a remodeling study.

PubMed

Rogowski, Wolf H

2009-01-01

Genetic tests for hereditary hemochromatosis (HH) are currently included in the German ambulatory care reimbursement scheme but only for symptomatic individuals and the offspring of HH patients. This study synthesizes the most current evidence to examine whether screening in the broader population is cost-effective and to identify the best choice of initial and follow-up screening tests. A probabilistic decision-analytic model was constructed to calculate cost per life year gained (LYG) for HH screening among male Caucasians aged 30. Three strategies were considered in both the general population and male offspring of HH patients: phenotypic (transferrin saturation, TS), genotypic (C282Y mutation), and sequential (genotype if TS is elevated) screening. The incremental cost-effectiveness of sequential screening among male offspring, sequential population-wide screening, and genotypic screening is 41000, 124000, and 161000 Eero/LYG, respectively. All other strategies were subject to simple or extended dominance. The results are subject to high uncertainty. The most influential parameters in the deterministic one-way sensitivity analysis are discounting of life years gained and the adherence of patients to preventive phlebotomy. The current German policy of only screening at-risk individuals is consistent with health economic decision making based on typically accepted thresholds. However, conducting the DNA test after the first elevated TS result is more cost-effective than waiting for a second TS result as recommended by the German guidelines. Further empirical work regarding adherence to long-term prevention recommendations and explicit and well-justified guidance for the choice of discount rates in German economic evaluation are needed.

EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH)

PubMed Central

Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

2016-01-01

Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines. PMID:26153218

Does oxidative stress modulate left ventricular diastolic function in asymptomatic subjects with hereditary hemochromatosis?

PubMed

Shizukuda, Yukitaka; Bolan, Charles D; Tripodi, Dorothy J; Sachdev, Vandana; Nguyen, Tammy T; Botello, Gilberto; Yau, Yu-Ying; Sidenko, Stanislav; Inez, Ernst; Ali, Mir I; Waclawiw, Myron A; Leitman, Susan F; Rosing, Douglas R

2009-11-01

Little is known about the early mechanisms mediating left ventricular (LV) diastolic dysfunction in patients with hereditary hemochromatosis (HH). However, the increased oxidative stress related to iron overload may be involved in this process, and strain rate (SR), a sensitive echocardiography-derived measure of diastolic function, may detect such changes. we evaluated the relationship between left ventricular diastolic function measured with tissue Doppler SR and oxidative stress in asymptomatic HH subjects and control normal subjects. Ninety-four consecutive visits of 43 HH subjects, age 30-74 (50 +/- 10, mean +/- SD), and 37 consecutive visits of 21 normal volunteers, age 30-63 (48 +/- 8), were evaluated over a 3-year period. SR was obtained from the basal septum in apical four-chamber views. All patients had confirmed C282Y homozygosity, a documented history of iron overload, and were New York Heart Association functional class I. Normal volunteers lacked HFE gene mutations causing HH. In the HH subjects, the SR demonstrated moderate but significant correlations with biomarkers of oxidative stress; however, no correlations were noted in normal subjects. The biomarkers of iron overload per se did not show significant correlations with the SR. Although our study was limited by the relatively small subject number, these results suggest that a possible role of oxidative stress to affect LV diastolic function in asymptomatic HH subjects and SR imaging may be a sensitive measure to detect that effect.

[Effectiveness of therapeutic erythrocytapheresis to achieve iron depletion in hereditary type 1 hemochromatosis: report of 30 cases].

PubMed

Poullin, P; Lefèvre, P A

2011-12-01

Weekly phlebotomy schedule is commonly recommended to achieve iron depletion in hereditary hemochromatosis (HH). However, in patients with severe iron overload, more than 2 years may be required, leading to fatigue and lack of compliance. For more than 10 years, we have used erythrocytapheresis (EA) as an alternative treatment. To assess the number of EA to achieve iron depletion and the duration of the iron depletion therapy as well of the tolerance, we retrospectively analysed the data of newly diagnosed hemochromatosis patients, homozygote for the C282Y mutation, followed in our department between 2001 and 2007. EA were performed using a discontinuous or a continuous flow cell separators. The protocol consisted in a bimonthly EA until normalisation of the serum ferritin, with the aim of reducing the patient's hematocrit between 32-35% at the end of each session. Then we performed monthly EA until complete desaturation, defined as serum ferritin concentration below 50 μg/L and transferrin saturation below 40%. Thirty patients were included (23 male, mean age 52 years, range 25-78) and 625 procedures analyzed. The mean volume of removed erythrocytes in each procedure was 416.4 mL (range 150-948), which equals to 374 mg of removed iron. Iron depletion (ferritin < 50 μg/L) was achieved after 11 months with 20 sessions (range 14-78). No serious adverse reactions or citrate toxicity were observed during and after the apheresis procedures. No specific fatigue was reported during the iron depletion therapy. Patient compliance was 100%. Clinical improvement was noted in 12 out of 18 of symptomatic patients. We conclude that HH patients treated with bimonthly EA achieved iron depletion in less than 1 year under good condition of tolerance. These data support the use of EA in patients with a severe iron overload, since it may reduce the number of the procedures as well as the duration of the iron depletion therapy. Copyright © 2011 Elsevier Masson SAS. All rights

Population-based analysis of the frequency of HFE gene polymorphisms: Correlation with the susceptibility to develop hereditary hemochromatosis.

PubMed

Katsarou, Martha-Spyridoula; Latsi, Rosana; Papasavva, Maria; Demertzis, Nikolaos; Kalogridis, Thodoris; Tsatsakis, Aristides M; Spandidos, Demetrios A; Drakoulis, Nikolaos

2016-07-01

Hereditary hemochromatosis (HH) is an autosomal recessive genetic disease, characterized by increased dietary iron absorption. Due to the absence of an effective excretory mechanism, the excess iron in the body may accumulate resulting in toxic effects. The HFE gene also affects the activity of hepcidin, a hormone which acts as a negative regulator of iron metabolism. In this study, we performed a population-based analysis of the distribution of three hemochromatosis-related polymorphisms in the HFE gene (rs1800562, rs1799945 and rs1800730). DNA from 1,446 non‑related individuals of Greek ethnicity was collected and analyzed, either from whole blood or buccal swabs. The frequency distribution of these HFE gene polymorphisms was then determined. The results revealed that in our Greek population cohort (gr) the frequencies of each polymorphism were as follows: rs1800562: GG (wild‑type)=97.0%, GA=1.5%, AA=1.5%; rs1799945: CC (wild‑type)=74.4%, CG=23.4%, GG=2.2%; rs1800730: AA (wild‑type)=98.1%, AT=1.5% and TT=0.4%. No association between the HFE polymorphisms rs1800562, rs1799945 and rs1800730 and gender could be established. As regards the rs1800562 polymorphism, the A allele (mutant) was ~1.8‑fold more frequent in the European population (eur) than in the Greek population [(gr)=2,3%<(eur)=4%]. As for the rs1799945 polymorphism, the G allele (mutant) was 1.2‑fold more frequent in the European population than in the Greek population [(gr)=13,9%<(eur)=17%]. As regards the rs1800730 polymorphism, the T allele (mutant) was ~1.7‑fold more frequent in the European population than in the Greek population [(gr)=1.2%<(eur)=2%]. However, these pathogenic mutations were found more frequently in the Greek population compared to the global population (gl) [rs1800562: (gl)=1%<(gr)=2,3%; rs1799945: (gl)=7%<(gr)=13,9%; rs1800730: (gl)=<1%<(gr)=1.2%]. This suggests that the Greek population may differ genetically from the northern European population

Diabetes in HFE Hemochromatosis

PubMed Central

Acton, Ronald T.

2017-01-01

Diabetes in whites of European descent with hemochromatosis was first attributed to pancreatic siderosis. Later observations revealed that the pathogenesis of diabetes in HFE hemochromatosis is multifactorial and its clinical manifestations are heterogeneous. Increased type 2 diabetes risk in HFE hemochromatosis is associated with one or more factors, including abnormal iron homeostasis and iron overload, decreased insulin secretion, cirrhosis, diabetes in first-degree relatives, increased body mass index, insulin resistance, and metabolic syndrome. In p.C282Y homozygotes, serum ferritin, usually elevated at hemochromatosis diagnosis, largely reflects body iron stores but not diabetes risk. In persons with diabetes type 2 without hemochromatosis diagnoses, serum ferritin levels are higher than those of persons without diabetes, but most values are within the reference range. Phlebotomy therapy to achieve iron depletion does not improve diabetes control in all persons with HFE hemochromatosis. The prevalence of type 2 diabetes diagnosed today in whites of European descent with and without HFE hemochromatosis is similar. Routine iron phenotyping or HFE genotyping of patients with type 2 diabetes is not recommended. Herein, we review diabetes in HFE hemochromatosis and the role of iron in diabetes pathogenesis in whites of European descent with and without HFE hemochromatosis. PMID:28331855

Bloodletting therapy in hemochromatosis: Does it affect trace element homeostasis?

PubMed

Bolann, Bjørn J; Distante, Sonia; Mørkrid, Lars; Ulvik, Rune J

2015-01-01

Hemochromatosis is the most common hereditary disorder in the Nordic population, if left untreated it can result in severe parenchymal iron accumulation. Bloodletting is mainstay treatment. Iron and trace elements partially share cellular uptake and transport mechanisms, and the aim of the present study was to see if bloodletting for hemochromatosis affects trace elements homeostasis. We recruited patients referred for diagnosis and treatment of hemochromatosis, four women and 22 men 23-68 years of age. Thirteen were C282Y homozygote, one was C282Y heterozygote, three were H63D homozygote, seven were compound heterozygote and two had none of the mutations above. Iron and liver function tests were performed; serum levels of trace elements were measured using inductively coupled plasma mass spectrometry. Results before the start of treatment and after normalization of iron parameters were compared. On completion of the bloodlettings the following average serum concentrations increased: Co from 5.6 to 11.5 nmol/L, serum Cu 16.2-17.6 μmol/L, Ni increased from 50.0 to 52.6 nmol/L and Sb from 13.2 to 16.3 nmol/L. Average serum Mn concentration declined from 30.2 to 28.3 nmol/L. All changes were statistically significant (by paired t-test). B, Ba, Cs, Mo, Se, Sr and Zn were not significantly changed. We conclude that bloodlettings in hemochromatosis lead to changes in trace element metabolism, including increased absorption of potentially toxic elements. Copyright © 2014 Elsevier GmbH. All rights reserved.

A national survey of hemochromatosis patients.

PubMed

Mainous, Arch G; Knoll, Michele E; Everett, Charles J; Hulihan, Mary M; Grant, Althea M; Garrison, Cheryl; Koenig, Gerald; Sayers, Cynthia; Allen, Kelsey W

2012-01-01

Hereditary hemochromatosis (HH) is a common genetic disease in the United States, but little is known about the diagnosis from the patient's perspective. The purpose of this study was to characterize the circumstances surrounding the diagnosis of HH and assess treatments and health information needs. We surveyed US adults aged 18 years and older who were diagnosed with HH after 1996. Response rate was 46%, with a total sample size of 979. Respondents were asked about the use of genetic and clinical markers in their diagnosis, current treatments, and health information needs. Results were stratified by age, education, and income status. Total of 90.0% of women and 75.5% of men were genetically tested for HH (P < .01). Approximately half (52.5%) were diagnosed by a gastroenterologist, hematologist, or other specialty physician and half were diagnosed by a primary care provider. Most of the respondents thought their HH had improved with the initial treatment and most patients were still receiving treatment for HH. Patient interest in learning more about specific hemochromatosis topics was generally high. Since the introduction of genetic identification of HH, these tests have been used in the diagnosis of the majority of patients. Primary care physicians may need to be more aware HH and strategies for diagnosis.

Severity of iron overload of proband determines serum ferritin levels in families with HFE-related hemochromatosis: the HEmochromatosis FAmily Study.

PubMed

Jacobs, Esther M G; Hendriks, Jan C M; van Deursen, Cees Th B M; Kreeftenberg, Herman G; de Vries, Richard A; Marx, Joannes J M; Stalenhoef, Anton F H; Verbeek, André L M; Swinkels, Dorine W

2009-01-01

In families of patients with clinically detected hereditary hemochromatosis (HH) early screening has been suggested to prevent morbidity and mortality. Here, we aim to identify determinants for iron overload in first-degree family members of C282Y homozygous probands with clinically detected HH. Data on HFE-genotype, iron parameters, demographics, lifestyle factors and health, were collected from 224 Dutch C282Y homozygous patients with clinically diagnosed HH and 735 of their first-degree family members (FDFM), all participating in the HEmochromatosis FAmily Study (HEFAS). The best predictive multivariable model forecasted 45% of variation of the serum ferritin levels. In this model severity of iron overload in the proband significantly predicted serum ferritin levels in FDFM. Other significant determinants in this model consisted of C282Y homozygosity, compound heterozygosity, age at testing for serum ferritin and supplemental iron intake, whereas a low body mass index showed a protective effect. This study provides a model to assess the risk of development of iron overload for relatives of probands with HH. These results might be instrumental in the development of an optimal strategy for future family screening programs.

Two middle-age-onset hemochromatosis patients with heterozygous mutations in the hemojuvelin gene in a Chinese family.

PubMed

Li, Shufeng; Xue, Jun; Chen, Baojun; Wang, Qiwei; Shi, Minke; Xie, Xiaojing; Zhang, Liang

2014-04-01

Hereditary hemochromatosis is a disorder characterized by enhanced intestinal absorption of dietary iron. Here, we report a heterozygous genotype at two mutation sites in hemojuvelin (HJV) present in two brothers with middle-age-onset hemochromatosis in a Chinese family. To date, only homozygous or compound heterozygous states of HJV gene have been reported as associated with iron overload. However, the patients here were heterozygous for two mutations in one HJV allele in cis: a premature termination mutation (962G>A and 963C>A; C321X) and a mutation in the signal peptide (18G>C; Q6H). Previously unrecognized environmental or other genetic factors may have interacted with the heterozygous genotype in these patients.

Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load.

PubMed

Carroll, G J; Breidahl, W H; Bulsara, M K; Olynyk, J K

2011-01-01

To determine the frequency and character of arthropathy in hereditary hemochromatosis (HH) and to investigate the relationship between this arthropathy, nodal interphalangeal osteoarthritis, and iron load. Participants were recruited from the community by newspaper advertisement and assigned to diagnostic confidence categories for HH (definite/probable or possible/unlikely). Arthropathy was determined by use of a predetermined clinical protocol, radiographs of the hands of all participants, and radiographs of other joints in which clinical criteria were met. An arthropathy considered typical for HH, involving metacarpophalangeal joints 2-5 and bilateral specified large joints, was observed in 10 of 41 patients with definite or probable HH (24%), all of whom were homozygous for the C282Y mutation in the HFE gene, while only 2 of 62 patients with possible/unlikely HH had such an arthropathy (P=0.0024). Arthropathy in definite/probable HH was more common with increasing age and was associated with ferritin concentrations>1,000 μg/liter at the time of diagnosis (odds ratio 14.0 [95% confidence interval 1.30-150.89], P=0.03). A trend toward more episodes requiring phlebotomy was also observed among those with arthropathy, but this was not statistically significant (odds ratio 1.03 [95% confidence interval 0.99-1.06], P=0.097). There was no significant association between arthropathy in definite/probable HH and a history of intensive physical labor (P=0.12). An arthropathy consistent with that commonly attributed to HH was found to occur in 24% of patients with definite/probable HH. The association observed between this arthropathy, homozygosity for C282Y, and serum ferritin concentrations at the time of diagnosis suggests that iron load is likely to be a major determinant of arthropathy in HH and to be more important than occupational factors. Copyright © 2011 by the American College of Rheumatology.

Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice

PubMed Central

Whittlesey, Rebecca L.; Andrews, Nancy C.

2011-01-01

The hereditary hemochromatosis protein HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that inhibits dietary iron absorption and macrophage iron release. HFE mutations are associated with impaired hepatic bone morphogenetic protein (BMP)/SMAD signaling for hepcidin production. TMPRSS6, a transmembrane serine protease mutated in iron-refractory iron deficiency anemia, inhibits hepcidin expression by dampening BMP/SMAD signaling. In the present study, we used genetic approaches in mice to examine the relationship between Hfe and Tmprss6 in the regulation of systemic iron homeostasis. Heterozygous loss of Tmprss6 in Hfe−/− mice reduced systemic iron overload, whereas homozygous loss caused systemic iron deficiency and elevated hepatic expression of hepcidin and other Bmp/Smad target genes. In contrast, neither genetic loss of Hfe nor hepatic Hfe overexpression modulated the hepcidin elevation and systemic iron deficiency of Tmprss6−/− mice. These results indicate that genetic loss of Tmprss6 increases Bmp/Smad signaling in an Hfe-independent manner that can restore Bmp/Smad signaling in Hfe−/− mice. Furthermore, these results suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-associated hereditary hemochromatosis, raising the possibility that pharmacologic inhibition of TMPRSS6 could attenuate iron loading in this disorder. PMID:21355094

Molecular basis of HFE-hemochromatosis

PubMed Central

Vujić, Maja

2014-01-01

Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH). The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-HH as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH-associated pathologies. PMID:24653703

Molecular basis of HFE-hemochromatosis.

PubMed

Vujić, Maja

2014-01-01

Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH). The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-HH as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH-associated pathologies.

Effect of pH on the stability of hemochromatosis factor E: a combined spectroscopic and molecular dynamics simulation-based study.

PubMed

Khan, Parvez; Shandilya, Ashutosh; Jayaram, B; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

2017-05-01

Hereditary hemochromatosis is an iron overburden condition, which is mainly governed by hereditary hemochromatosis factor E (HFE), a member of major histocompatibility complex class I. To understand the effect of pH on the structure and stability of HFE, we have cloned, expressed, and purified the HFE in the bacterial system and performed circular dichroism, fluorescence, and absorbance measurements at a wide pH range (pH 3.0-11.0). We found that HFE remains stable in the pH range 7.5-11.0 and gets completely acid denatured at low pH values. In this work, we also analyzed the contribution of salt bridges to the stability of HFE. We further performed molecular dynamics simulations for 80 ns at different pH values. An excellent agreement was observed between results from biophysical and MD simulation studies. At lower pH, HFE undergoes denaturation and may be driven toward a degradation pathway, such as ubiquitination. Hence, HFE is not available to bind again with transferrin receptor1 to negatively regulate iron homeostasis. Further we postulated that, might be low pH of cancerous cells helps them to meet their high iron requirement.

The myths and realities of hemochromatosis

PubMed Central

Beaton, Melanie D; Adams, Paul C

2007-01-01

Hemochromatosis is a common genetic condition and yet there are still a number of misperceptions surrounding the diagnosis and management of this condition. Hemochromatosis affects both men and women. Typical patients do not have alcoholism or viral hepatitis, and often have normal liver enzymes. Clinical expression is highly variable. Genetic testing is widely available and particularly useful in family studies. Hemochromatosis can be readily diagnosed and treated. The purpose of the present review is to address the medical myths and misconceptions of hemochromatosis. PMID:17299614

Iron overload in a murine model of hereditary hemochromatosis is associated with accelerated progression of osteoarthritis under mechanical stress.

PubMed

Camacho, A; Simão, M; Ea, H-K; Cohen-Solal, M; Richette, P; Branco, J; Cancela, M L

2016-03-01

Hereditary hemochromatosis (HH) is a disease caused by mutations in the Hfe gene characterised by systemic iron overload and associated with an increased prevalence of osteoarthritis (OA) but the role of iron overload in the development of OA is still undefined. To further understand the molecular mechanisms involved we have used a murine model of HH and studied the progression of experimental OA under mechanical stress. OA was surgically induced in the knee joints of 10-week-old C57BL6 (wild-type) mice and Hfe-KO mice. OA progression was assessed using histology, micro CT, gene expression and immunohistochemistry at 8 weeks after surgery. Hfe-KO mice showed a systemic iron overload and an increased iron accumulation in the knee synovial membrane following surgery. The histological OA score was significantly higher in the Hfe-KO mice at 8 weeks after surgery. Micro CT study of the proximal tibia revealed increased subchondral bone volume and increased trabecular thickness. Gene expression and immunohistochemical analysis showed a significant increase in the expression of matrix metallopeptidase 3 (MMP-3) in the joints of Hfe-KO mice compared with control mice at 8 weeks after surgery. HH was associated with an accelerated development of OA in mice. Our findings suggest that synovial iron overload has a definite role in the progression of HH-related OA. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Hemochromatosis

MedlinePlus

... in the body. It is also called iron overload. Causes Hemochromatosis may be a genetic disorder passed ... blood transfusions over time may lead to iron overload. Long-term alcohol use and other health conditions. ...

Hemochromatosis

MedlinePlus

... Fax: 407–333–1284 Email: mail@ americanhs. org Internet: www. americanhs. org American Liver Foundation 39 Broadway, ... or 212–668–1000 Fax: 212–483–8179 Internet: www. liverfoundation. org 7 Hemochromatosis Iron Disorders Institute ...

Hemochromatosis and Vibrio vulnificus wound infections.

PubMed

Barton, James C; Acton, Ronald T

2009-10-01

There are several reports of persons with hemochromatosis and Vibrio vulnificus primary septicemia, but few accounts of persons with hemochromatosis and V. vulnificus wound infection. A 58-year-old white man developed infection of a forearm injury exposed to seawater in the Gulf of Mexico near the Alabama coast. At age 66, he was diagnosed to have hemochromatosis. Transferrin saturation was 89% and serum ferritin was 4761 pmol/L. HFE genotype was C282Y/C282Y. Serum levels of hepatic enzymes, glucose, IgG, IgA, and IgM, and blood levels of T, B, and natural killer cells were normal. We identified previous reports of only 2 similar cases: a woman from Alabama and a man from northern Australia. Mean age of the 3 subjects was 51 years at diagnosis of infection. Each had elevated serum iron measures or iron overload complications; both men were diagnosed to have hemochromatosis after they developed infection. Each of the 3 had recent exposure of a wound on an extremity to seawater, rapid development of a necrotizing soft tissue infection that required debridement and skin grafting, and positive wound or blood cultures. Each subject survived the infection. V. vulnificus wound infection occurs in some persons with hemochromatosis, but the risk of infection may be small. All patients with V. vulnificus infections should be evaluated for hemochromatosis, iron overload, and liver disorders.

Hemochromatosis simulating rheumatoid arthritis: a case report.

PubMed

Barbosa, Fabíola Brasil; Callegari, Amanda; Sarinho, José Célso; Lucena, Juliana; Casagrande, Renielly; de Souza, Branca Dias Batista

2014-01-01

This is a report of a patient who had a previous diagnosis of rheumatoid arthritis, nonerosive, rheumatoid factor negative, that despite the therapeutic approach presented progressive worsening of the articular and general condition. After extensive research, she had a diagnosis of hemochromatosis. Joint symptoms are common manifestations in hemochromatosis. The arthropathy of hemochromatosis may resemble inflammatory arthropathy mimicking RA, particularly in the most common sites as 2nd and 3rd metacarpophalangeal. Radiologically are observed decreased joint space, subchondral sclerosis, cyst formation and chondrocalcinosis. Treatment with disease modifying drugs for rheumatoid arthritis tend to worsen the clinical picture, since the liver is the major site of deposition of iron in hemochromatosis and these medications are known to be hepatotoxic. Phlebotomy treatment for hemochromatosis is apparently ineffective in reversing the articular manifestations, which requires the association with iron chelating drugs. Due to the apparent difficulty in differentiating between the two diseases, a screening profile of iron in patients with rheumatoid arthritis with atypical progression is necessary.

Iron storage disease (hemochromatosis) and hepcidin response to iron load in two species of pteropodid fruit bats relative to the common vampire bat.

PubMed

Stasiak, Iga M; Smith, Dale A; Ganz, Tomas; Crawshaw, Graham J; Hammermueller, Jutta D; Bienzle, Dorothee; Lillie, Brandon N

2018-07-01

Hepcidin is the key regulator of iron homeostasis in the body. Iron storage disease (hemochromatosis) is a frequent cause of liver disease and mortality in captive Egyptian fruit bats (Rousettus aegyptiacus), but reasons underlying this condition are unknown. Hereditary hemochromatosis in humans is due to deficiency of hepcidin or resistance to the action of hepcidin. Here, we investigated the role of hepcidin in iron metabolism in one species of pteropodid bat that is prone to iron storage disease [Egyptian fruit bat (with and without hemochromatosis)], one species of pteropodid bat where iron storage disease is rare [straw-colored fruit bat (Eidolon helvum)], and one species of bat with a natural diet very high in iron, in which iron storage disease is not reported [common vampire bat (Desmodus rotundus)]. Iron challenge via intramuscular injection of iron dextran resulted in significantly increased liver iron content and histologic iron scores in all three species, and increased plasma iron in Egyptian fruit bats and straw-colored fruit bats. Hepcidin mRNA expression increased in response to iron administration in healthy Egyptian fruit bats and common vampire bats, but not in straw-colored fruit bats or Egyptian fruit bats with hemochromatosis. Hepcidin gene expression significantly correlated with liver iron content in Egyptian fruit bats and common vampire bats, and with transferrin saturation and plasma ferritin concentration in Egyptian fruit bats. Induction of hepcidin gene expression in response to iron challenge is absent in straw-colored fruit bats and in Egyptian fruit bats with hemochromatosis and, relative to common vampire bats and healthy humans, is low in Egyptain fruit bats without hemochromatosis. Limited hepcidin response to iron challenge may contribute to the increased susceptibility of Egyptian fruit bats to iron storage disease.

A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation?

PubMed

Lucotte, Gérard; Dieterlen, Florent

2003-01-01

The aim of this new meta-analysis (to the end of 2002) is to compile the Y allele frequencies of the C282Y mutation of hereditary hemochromatosis (HFE gene) for 63 European populations, representing a total of 10,708 unrelated people concerning control samples. A new allele map of C282Y frequencies in Europe was constructed. The highest European frequencies are observed in the Celtic populations in Ireland, in the United Kingdom, and in France, but elevated frequencies are also observed in Scandinavia.

The efficiency of therapeutic erythrocytapheresis compared to phlebotomy: a mathematical tool for predicting response in hereditary hemochromatosis, polycythemia vera, and secondary erythrocytosis.

PubMed

Evers, Dorothea; Kerkhoffs, Jean-Louis; Van Egmond, Liane; Schipperus, Martin R; Wijermans, Pierre W

2014-06-01

Recently, therapeutic erythrocytapheresis (TE) was suggested to be more efficient in depletion of red blood cells (RBC) compared to manual phlebotomy in the treatment of hereditary hemochromatosis (HH), polycythemia vera (PV), and secondary erythrocytosis (SE). The efficiency rate (ER) of TE, that is, the increase in RBC depletion achieved with one TE cycle compared to one phlebotomy procedure, can be calculated based on estimated blood volume (BV), preprocedural hematocrit (Hct(B)), and delta-hematocrit (ΔHct). In a retrospective evaluation of 843 TE procedures (in 45 HH, 33 PV, and 40 SE patients) the mean ER was 1.86 ± 0.62 with the highest rates achieved in HH patients. An ER of 1.5 was not reached in 37.9% of all procedures mainly concerning patients with a BV below 4,500 ml. In 12 newly diagnosed homozygous HH patients, the induction phase duration was medially 38.4 weeks (medially 10.5 procedures). During the maintenance treatment of HH, PV, and SE, the interval between TE procedures was medially 13.4 weeks. This mathematical model can help select the proper treatment modality for the individual patient. Especially for patients with a large BV and high achievable ΔHct, TE appears to be more efficient than manual phlebotomy in RBC depletion thereby potentially reducing the numbers of procedures and expanding the interprocedural time period for HH, PV, and SE. © 2013 Wiley Periodicals, Inc.

Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients*

PubMed Central

Vieira, Fatima Mendonça Jorge; Nakhle, Maria Cristina; Abrantes-Lemos, Clarice Pires; Cançado, Eduardo Luiz Rachid; dos Reis, Vitor Manoel Silva

2013-01-01

BACKGROUND Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil. OBJECTIVES Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors (hepatitis C, HIV, alcoholism and estrogen) and their link with HFE mutations. METHODS An ambispective study of 60 patients with PCT was conducted during the period from 2003 to 2012. Serological tests for hepatitis C and HIV were performed and histories of alcohol abuse and estrogen intake were investigated. HFE mutations were identified with real-time PCR. RESULTS Porphyria cutanea tarda predominated in males and alcohol abuse was the main precipitating factor. Estrogen intake was the sole precipitating factor present in 25% of female patients. Hepatitis C was present in 41.7%. All HIV-positive patients (15.3%) had a history of alcohol abuse. Allele frequency for HFE mutations, i.e., C282Y (p = 0.0001) and H63D (p = 0.0004), were significantly higher in porphyria cutanea tarda patients, compared to control group. HFE mutations had no association with the other precipitating factors. CONCLUSIONS Alcohol abuse, hepatitis C and estrogen intake are prevalent precipitating factors in our porphyria cutanea tarda population; however, hemochromatosis in itself can also contribute to the outbreak of porphyria cutanea tarda, which makes the research for HFE mutations necessary in these patients PMID:24068123

An immunohistochemical study of placental syncytiotrophoblasts in neonatal hemochromatosis.

PubMed

Shimono, Aiko; Imoto, Yuko; Sakamoto, Haruhiko; Chiba, Yoichi; Matsumoto, Koichi; Kawauchi, Machi; Kusaka, Takashi; Tanaka, Hirokazu; Hata, Toshiyuki; Kushida, Yoshio; Ueno, Masaki

2016-12-01

Neonatal hemochromatosis (NH) is a rare neonatal disorder that results in liver cirrhosis with hemosiderin deposition in the liver and other organs, similarly to hereditary hemochromatosis. Excess iron is transferred from the mother to fetus through the placenta in NH. We examined the expression of iron metabolism-related substances in placental syncytiotrophoblasts (STB) by immunostaining to clarify how the transfer of iron through STB increases in NH. Immunostaining was performed using formalin-fixed, paraffin-embedded sections of placentae from three NH cases, four gestational age-matched controls, and, depending on the antibody examined, five to seven full-term controls. The reactivity of immunostaining was assessed by averages of scores assigned by 3 researchers. On the microvillar surface of STB, the reactions of the antibodies against transferrin receptor 1 (TFR1), transferrin, ferritin, hepcidin, ferroportin, divalent metal transporter-1 (DMT1), hephaestin, and HFE were stronger in NH than in controls. In the cytoplasm, the reactions of antibodies against TFR1, transferrin, ferritin, hepcidin, DMT1, hephaestin, HFE, and ZIP 14 were stronger in NH than in gestational age-matched controls. Among these reactions, those of anti-TFR1 antibody on the surface of STB in NH was especially marked. In the placenta of NH, increases in expressions of TFR1, transferrin, and ferritin of which those of TFR1 were especially marked, reflect increased iron influx from the mother to fetus. The hepcidin observed on the surface and in the cytoplasm of STB of NH is suggested to be from the mother, possibly to compensate for the decreased fetal liver-derived hepcidin. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis.

PubMed

Del-Castillo-Rueda, Alejandro; Moreno-Carralero, María-Isabel; Cuadrado-Grande, Nuria; Alvarez-Sala-Walther, Luis-Antonio; Enríquez-de-Salamanca, Rafael; Méndez, Manuel; Morán-Jiménez, María-Josefa

2012-10-15

Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G>A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A (p.A376D) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype. Copyright © 2012. Published by Elsevier B.V.

The hemochromatosis protein HFE 20 years later: An emerging role in antigen presentation and in the immune system

PubMed Central

Chung, Jacqueline W.; Santos, Manuela M.

2017-01-01

Abstract Introduction Since its discovery, the hemochromatosis protein HFE has been primarily defined by its role in iron metabolism and homeostasis, and its involvement in the genetic disease termed hereditary hemochromatosis (HH). While HH patients are typically afflicted by dysregulated iron levels, many are also affected by several immune defects and increased incidence of autoimmune diseases that have thereby implicated HFE in the immune response. Growing evidence has supported an immunological role for HFE with recent studies describing HFE specifically as it relates to MHC I antigen presentation. Methods/Results Here, we present a comprehensive overview of the relationship between iron metabolism, HFE, and the immune system to better understand the origin and cause of immune defects in HH patients. We further describe the role of HFE in MHC I antigen presentation and its potential to impair autoimmune responses in homeostatic conditions, a mechanism which may be exploited by tumors to evade immune surveillance. Conclusion Overall, this increased understanding of the role of HFE in the immune response sets the stage for better treatment and management of HH and other iron‐related diseases, as well as of the immune defects related to this condition. PMID:28474781

Evaluation of a workplace hemochromatosis screening program.

PubMed

Stave, G M; Mignogna, J J; Powell, G S; Hunt, C M

1999-05-01

Hemochromatosis is a common inherited disorder of iron metabolism with significant health consequences for the employed population. Although screening for hemochromatosis has been recommended, workplace screening programs remain uncommon. In the first year of a newly initiated corporate screening program, 1968 employees were tested. The screening algorithm included measurement of serum iron and transferrin and subsequent ferritin levels in those employees with elevated iron/transferrin ratios. Thirteen percent of men and 21% of women had elevated iron/transferrin ratios. Of these, 14 men and 2 women had elevated ferritin levels. Of these 16, three had liver biopsies and all three have hemochromatosis. The cost of the screening program was $27,850. The cost per diagnosis was $9283 and the cost per year of life saved was $928. These costs compare very favorably with other common workplace screening programs. Several barriers to obtaining definitive diagnoses on all patients with a positive screening result were identified; strategies to overcome these barriers would further enhance the cost effectiveness of the program. We conclude that workplace hemochromatosis screening is highly cost effective and should be incorporated into health promotion/disease prevention programs.

Rare HFE variants are the most frequent cause of hemochromatosis in non-c282y homozygous patients with hemochromatosis.

PubMed

Hamdi-Rozé, Houda; Beaumont-Epinette, Marie-Pascale; Ben Ali, Zeineb; Le Lan, Caroline; Loustaud-Ratti, Véronique; Causse, Xavier; Loreal, Olivier; Deugnier, Yves; Brissot, Pierre; Jouanolle, Anne-Marie; Bardou-Jacquet, Edouard

2016-12-01

p.Cys282Tyr (C282Y) homozygosity explains most cases of HFE-related hemochromatosis, but a significant number of patients presenting with typical type I hemochromatosis phenotype remain unexplained. We sought to describe the clinical relevance of rare HFE variants in non-C282Y homozygotes. Patients referred for hemochromatosis to the National Reference Centre for Rare Iron Overload Diseases from 2004 to 2010 were studied. Sequencing was performed for coding region and intronic flanking sequences of HFE, HAMP, HFE2, TFR2, and SLC40A1. Nine private HFE variants were identified in 13 of 206 unrelated patients. Among those, five have not been previously described: p.Leu270Argfs*4, p.Ala271Valfs*25, p.Tyr52*, p.Lys166Asn, and p.Asp141Tyr. Our results show that rare HFE variants are identified more frequently than variants in the other genes associated with iron overload. Rare HFE variants are therefore the most frequent cause of hemochromatosis in non-C282Y homozygote HFE patients. Am. J. Hematol. 91:1202-1205, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Non-Coding Keratin Variants Associate with Liver Fibrosis Progression in Patients with Hemochromatosis

PubMed Central

Lunova, Mariia; Guldiken, Nurdan; Lienau, Tim C.; Stickel, Felix; Omary, M. Bishr

2012-01-01

Background Keratins 8 and 18 (K8/K18) are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with end-stage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis. Methods The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene) mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previously-generated transgenic mice overexpressing K8 G62C were studied for their susceptibility to iron overload. Susceptibility to iron toxicity of primary hepatocytes that express K8 wild-type and G62C was also assessed. Results We identified amino-acid-altering keratin heterozygous variants in 10 of 162 hemochromatosis patients (6.2%) and non-coding heterozygous variants in 6 additional patients (3.7%). Two novel K8 variants (Q169E/R275W) were found. K8 R341H was the most common amino-acid altering variant (4 patients), and exclusively associated with an intronic KRT8 IVS7+10delC deletion. Intronic, but not amino-acid-altering variants associated with the development of liver fibrosis. In mice, or ex vivo, the K8 G62C variant did not affect iron-accumulation in response to iron-rich diet or the extent of iron-induced hepatocellular injury. Conclusion In patients with hemochromatosis, intronic but not exonic K8/K18 variants associate with liver fibrosis development. PMID:22412904

Hyperferritinemia increases the risk of hyperuricemia in HFE-hereditary hemochromatosis.

PubMed

Flais, Jérémy; Bardou-Jacquet, Edouard; Deugnier, Yves; Coiffier, Guillaume; Perdriger, Aleth; Chalès, Gérard; Ropert, Martine; Loréal, Olivier; Guggenbuhl, Pascal

2017-05-01

Hyperuricemia is becoming increasingly frequent in the population, and is known to be sometimes the cause of gout. The impact of uric acid is still not clearly understood, however. The iron metabolism may interact with the uric acid metabolism. The aim of this study was to examine the relationship between the serum uric acid and serum ferritin levels in a cohort of hemochromatosis patients who were homozygous for the HFE p.Cys282Tyr mutation. 738 patients with the HFE gene mutation Cys282Tyr in the homozygous state were included in the study. The variables measured during the initial evaluation were compared in univariate analysis by Student's t test. In multivariate analysis, linear stepwise regression was used. In the group of hyperuricemic patients, ferritinemia was significantly higher than in the group of non-hyperuricemic patients (1576.7±1387.4μg/l vs. 1095.63±1319.24μg/l, P<0.005). With multivariate analysis, only ferritin and BMI independently explained the uricemia (R 2 =0.258) after adjustment for age, glycemia and CRP. The correlation between uricemia and log(ferritin) with partial regression correlation coefficients was 0.307 (P<0.01). The increase in uricemia is associated with the increase in ferritin in a population of patients who were homozygous for the HFE gene mutation p.Cys282Tyr and this independently of factors commonly associated with hyperuricemia. The increase in uric acid associated with hyperferritinemia, could be a response to the visceral toxicity of excess non-transferrin bound iron linked to oxidative stress via the antioxidant properties of uric acid. Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Hereditary Hemochromatosis

MedlinePlus

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Absorption of Manganese and Iron in a Mouse Model of Hemochromatosis

PubMed Central

Kim, Jonghan; Buckett, Peter D.; Wessling-Resnick, Marianne

2013-01-01

Hereditary hemochromatosis, an iron overload disease associated with excessive intestinal iron absorption, is commonly caused by loss of HFE gene function. Both iron and manganese absorption are regulated by iron status, but the relationships between the transport pathways of these metals and how they are affected by HFE-associated hemochromatosis remain poorly understood. Loss of HFE function is known to alter the intestinal expression of DMT1 (divalent metal transporter-1) and Fpn (ferroportin), transporters that have been implicated in absorption of both iron and manganese. Although the influence of HFE deficiency on dietary iron absorption has been characterized, potential effects on manganese metabolism have yet to be explored. To investigate the role of HFE in manganese absorption, we characterized the uptake and distribution of the metal in Hfe −/− knockout mice after intravenous, intragastric, and intranasal administration of 54Mn. These values were compared to intravenous and intragastric administration of 59Fe. Intestinal absorption of 59Fe was increased and clearance of injected 59Fe was also increased in Hfe−/− mice compared to controls. Hfe −/− mice displayed greater intestinal absorption of 54Mn compared to wild-type Hfe+/+ control mice. After intravenous injection, the distribution of 59Fe to heart and liver was greater in Hfe −/− mice but no remarkable differences were observed for 54Mn. Although olfactory absorption of 54Mn into blood was unchanged in Hfe −/− mice, higher levels of intranasally-instilled 54Mn were associated with Hfe−/− brain compared to controls. These results show that manganese transport and metabolism can be modified by HFE deficiency. PMID:23705020

A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis.

PubMed

Phatak, Pradyumna; Brissot, Pierre; Wurster, Mark; Adams, Paul C; Bonkovsky, Herbert L; Gross, John; Malfertheiner, Peter; McLaren, Gordon D; Niederau, Claus; Piperno, Alberto; Powell, Lawrie W; Russo, Mark W; Stoelzel, Ulrich; Stremmel, Wolfgang; Griffel, Louis; Lynch, Nicola; Zhang, Yiyun; Pietrangelo, Antonello

2010-11-01

Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once-daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300-2000 ng/mL, transferrin saturation ≥ 45%, and no known history of cirrhosis were enrolled in this dose-escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty-nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose-dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48-week treatment period; six patients had alanine aminotransferase > 3 × baseline and greater than the upper limit of normal range, and eight patients had serum creatinine > 33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to < 250 ng/mL. Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population.

A Phase 1/2, Dose-Escalation Trial of Deferasirox for the Treatment of Iron Overload in HFE-Related Hereditary Hemochromatosis

PubMed Central

Phatak, Pradyumna; Brissot, Pierre; Wurster, Mark; Adams, Paul C; Bonkovsky, Herbert L; Gross, John; Malfertheiner, Peter; McLaren, Gordon D; Niederau, Claus; Piperno, Alberto; Powell, Lawrie W; Russo, Mark W; Stoelzel, Ulrich; Stremmel, Wolfgang; Griffel, Louis; Lynch, Nicola; Zhang, Yiyun; Pietrangelo, Antonello

2010-01-01

Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once-daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300-2000 ng/mL, transferrin saturation ≥45%, and no known history of cirrhosis were enrolled in this dose-escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty-nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose-dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48-week treatment period; six patients had alanine aminotransferase >3× baseline and greater than the upper limit of normal range, and eight patients had serum creatinine >33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to <250 ng/mL. Conclusion: Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population. (Hepatology

MicroRNA Expression Analysis in Serum of Patients with Congenital Hemochromatosis and Age-Related Macular Degeneration (AMD)

PubMed Central

Szemraj, Maciej; Oszajca, Katarzyna; Szemraj, Janusz; Jurowski, Piotr

2017-01-01

Background Congenital hemochromatosis is a disorder caused by mutations of genes involved in iron metabolism, leading to increased levels of iron concentration in tissues and serum. High concentrations of iron can lead to the development of AMD. The aim of this study was to analyze circulating miRNAs in the serum of congenital hemochromatosis patients with AMD and their correlation with the expression of genes involved in iron metabolism. Material/Methods Peripheral blood monolayer cells and serum were obtained from patients with congenital hemochromatosis, congenital hemochromatosis and AMD, AMD patients without congenital hemochromatosis, and healthy controls. Serum miRNAs expressions were analyzed by RT-PCR (qRT-PCR) using TaqMan MicroRNA probes, and proteins levels were measured by ELSA kits. Gene polymorphisms in TF and TFRC genes were determined using the TaqMan discrimination assay. Results Statistical analysis of the miRNAs expressions selected for further study the miR-31, miR-133a, miR-141, miR-145, miR-149, and miR-182, which are involved in the posttranscriptional expression of iron-related genes: TF, TFRI, DMT1, FTL, and FPN1. It was discovered that the observed changes in the expressions of the miRNAs was correlated with the level of protein in the serum of the analyzed genes. There were no statistically significant differences in the distribution of genotype and allele frequencies in TF and TFRC genes between analyzed groups of patients. Conclusions The differences studied in the miRNA serum profile, in conjunction with the changes in the analyzed protein levels, may be useful in the early detection of congenital hemochromatosis in patients who may develop AMD disease. PMID:28827515

Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening

PubMed Central

McLaren, Gordon D; McLaren, Christine E; Adams, Paul C; Barton, James C; Reboussin, David M; Gordeuk, Victor R; Acton, Ronald T; Harris, Emily L; Speechley, Mark R; Sholinsky, Phyliss; Dawkins, Fitzroy W; Snively, Beverly M; Vogt, Thomas M; Eckfeldt, John H

2008-01-01

BACKGROUND: Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences. OBJECTIVE: To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening. METHODS: Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364). RESULTS: Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects. CONCLUSIONS: Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study. PMID:19018338

Anti-obesity and pro-diabetic effects of hemochromatosis.

PubMed

Abbas, Mousa Al; Abraham, Deveraprabu; Kushner, James P; McClain, Donald A

2014-10-01

Levels of tissue iron contribute to determining diabetes risk, but little is known about the effects of higher iron levels on weight, and on the interaction of weight and iron overload on diabetes risk. Therefore, the effect of iron on body mass index and diabetes in individuals with iron overload from hereditary hemochromatosis (HH), compared to non-HH siblings and historical controls was examined. Chart reviews were performed on a cohort of adults (age ≥40, N = 101) with the common C282Y/C282Y HFE genotype, compared to wild type siblings (N = 32) and comparable NHANES cohorts, with respect to body mass index and diabetes status. Males with HH have lower body mass index (BMI) than control siblings. Females had a trend toward decreased BMI that was not significant, possibly related to decreased degrees of iron overload. In both males and females, increased rates of diabetes were seen, especially in the overweight or obese. High tissue iron levels may be both pro- and anti-diabetic. The prevalence of obesity and diabetes in HH is likely dependent upon the degree of iron overload, caloric intake, and other genetic and environmental factors, contributing to the observed heterogeneity in the frequency of disease-related morbidities in HH. Copyright © 2014 The Obesity Society.

Anti-Obesity and Pro-Diabetic Effects of Hemochromatosis

PubMed Central

Abbas, Mousa Al; Abraham, Deveraprabu; Kushner, James P.; McClain, Donald A.

2014-01-01

Objective Levels of tissue iron contribute to determining diabetes risk, but little is known about the effects of higher iron levels on weight, nor on the interaction of weight and iron overload on diabetes risk. We therefore examined the effect of iron on body mass index and diabetes in individuals with iron overload from hereditary hemochromatosis (HH), compared to non-HH siblings and historical controls. Methods Chart reviews were performed on a cohort of adults (age ≥40, N=101) with the common C282Y/C282Y HFE genotype, compared to wild type siblings (N=32) and comparable NHANES cohorts, with respect to body mass index and diabetes status. Results Males with HH have lower body mass index (BMI) than control siblings. Females had a trend toward decreased BMI that was not significant, possibly related to decreased degrees of iron overload. In both males and females, increased rates of diabetes were seen, especially in the overweight or obese. Conclusions High tissue iron levels may be both pro- and anti-diabetic. The prevalence of obesity and diabetes in HH is likely dependent upon the degree of iron overload, caloric intake, and other genetic and environmental factors, contributing to the observed heterogeneity in the frequency of disease-related morbidities in HH. PMID:25044717

Hemochromatosis detection in a health screening program at an Alabama forest products mill.

PubMed

Barton, James C; Cheatwood, Susan M; Key, Timothy J; Acton, Ronald T

2002-08-01

We analyzed hemochromatosis detection in a 11.5-year multiphasic health screening program at a forest products mill. There were 2199 participants: 2032 Whites (1506 men, 526 women) and 167 African Americans (124 men, 43 women); 85.0% of employees were screened. Iron and transferrin saturation were measured in a serum biochemistry profile on specimens obtained after overnight fasting; ferritin was measured in participants with elevated iron concentrations or transferrin saturation > 48%. Participants with elevated ferritin levels underwent further evaluation. Eight White men were diagnosed to have hemochromatosis (frequency 0.0039 in Whites, 0.0053 in White men). The estimated cost per case detected was $8826. Family members of two participants with hemochromatosis were also diagnosed to have hemochromatosis or iron overload. We conclude that detecting hemochromatosis in a workplace multiphasic health screening program is efficacious and economical.

Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis

PubMed Central

Valenti, Luca; Maggioni, Paolo; Piperno, Alberto; Rametta, Raffaela; Pelucchi, Sara; Mariani, Raffaella; Dongiovanni, Paola; Fracanzani, Anna Ludovica; Fargion, Silvia

2012-01-01

AIM: To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH). METHODS: We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d in males or females) or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology (n = 100) or ultrasound (n = 23). The PNPLA3 rs738409 single nucleotide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay (assay on demand, Applied Biosystems). The association of the PNPLA3 I148M protein variant (p.I148M) with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis. RESULTS: PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine aminotransaminase (ALT) levels. The p.148M variant was also associated with higher aspartate aminotransferase (P = 0.0014) and ALT levels (P = 0.017) at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity (stage) of fibrosis (estimated coefficient 0.56 ± 0.27, P = 0.041). In the overall series of patients, the p.148M variant was associated with cirrhosis in lean (P = 0.049), but not in overweight patients (P = not significant). At logistic regression analysis, cirrhosis was associated with BMI ≥ 25 (OR 1.82, 95% CI: 1.02-3.55), ferritin

A case report of neonatal diabetes due to neonatal hemochromatosis.

PubMed

Cetinkaya, Semra; Kunak, Benal; Kara, Cengiz; Demirçeken, Fulya; Yarali, Neşe; Polat, Emine; Aycan, Zehra

2010-05-01

A 6-week-old girl, the first child of non-consanguineous parents, was admitted to the hospital for evaluation of vomiting. She was small for gestational age (1500 g). On admission, she weighed 1830 g, and appeared dehydrated. The blood glucose was 880 mg/dL. Insulin and C-peptide levels were <1 microIU/ml and 0.1 pmol/L, respectively. Antibodies of diabetes were negative. The serum triglyceride level was markedly elevated (5322 mg/dL). After a few days of insulin therapy, the triglyceride levels dramatically decreased, but cholestasis persisted. A liver biopsy revealed diffuse iron deposition and the diagnosis of neonatal hemochromatosis was established. In neonatal hemochromatosis, diabetes may occur as a result of iron deposition in the pancreas. The coexistence of neonatal diabetes secondary to neonatal hemochromatosis with a fatal course during the infancy period has not been previously reported. In this report, an infant with neonatal diabetes secondary to neonatal hemochromatosis is presented as the first case in the literature involving the coexistence of these two conditions.

Screening for hemochromatosis by measuring ferritin levels: a more effective approach

PubMed Central

Waalen, Jill; Felitti, Vincent J.; Gelbart, Terri

2008-01-01

Because the penetrance of HFE hemochromatosis is low, traditional population screening measuring the transferrin saturation is unlikely to be cost-effective because the majority of subjects detected neither have clinical disease nor are likely to develop it. Three independent studies show that only patients with serum ferritin concentrations more than 1000 μg/L are at risk for cirrhosis, one of the main morbidities of hemochromatosis. Among 29 699 white subjects participating in the Scripps/Kaiser hemochromatosis study, only 59 had serum ferritin levels more than 1000 μg/L; 24 had homozygous mutant or compound heterozygous mutant HFE genotypes. In all but 5 of the other subjects, the causes of elevated ferritin were excessive alcohol intake, cancer, or liver disease. Screening for hemochromatosis with serum ferritin levels will detect the majority of patients who will be clinically affected and may detect other clinically significant disease in patients who do not have hemochromatosis genotypes. Because the ferritin level of the majority of adult homozygotes for HFE mutations does not rise over long periods of time, excluding subjects with serum ferritin levels less than or equal to 1000 μg/L should not result in missed opportunities for early treatment of patients who could benefit. PMID:18025154

Neonatal hemochromatosis. Case series from Bahrain.

PubMed

Isa, Hasan M; Mohamed, Afaf M

2013-12-01

To review clinical presentations, diagnosis, response to treatment, and outcome of infants with neonatal hemochromatosis (NH). This is a retrospective review of all cases admitted to the Pediatric Department at Salmaniya Medical Center, Manama, Bahrain between March 2008 and May 2011. The diagnosis was based on serum iron and ferritin, alpha-fetoprotein levels (AFP), liver and buccal biopsies, and abdominal MRI scan. Ten patients (8 males and 2 females) were diagnosed with NH. Two patients were intrauterine growth restriction (IUGR) and 6 were preterm. The median birth weight was 1.700 grams. The median age at presentation was 16 days, and at diagnosis was 23 days. Two patients had positive consanguinity. Clinical presentations of the infants were hepatosplenomegaly (n=5), ascites (n=3), and hypoglycemia (n=6). All patients had raised ferritin levels, prolonged prothrombin time, and 9 patients had high serum iron and serum AFP. Abdominal MRI showed iron overload in the liver (n=8). Liver biopsies showed evidence of hemochromatosis (n=3). Buccal biopsies stained positive for iron (n=1). Eight patients received antioxidant therapy and survived. Two patients passed away. Neonatal hemochromatosis is a rare liver disease of newborns with a spectrum of clinical severity. Elevated serum ferritin and AFP support the diagnosis after excluding other causes of neonatal liver failure. The use of antioxidant therapy helps to improve the outcome.

A Mouse Model of Cardiomyopathy Induced by Mutations in the Hemochromatosis HFE Gene.

PubMed

Djemai, Haidar; Thomasson, Rémi; Trzaskus, Yvan; Mougenot, Nathalie; Meziani, Amira; Toussaint, Jean-François; Noirez, Philippe; Vitiello, Damien

2017-07-01

The heart is 1 of the organs most affected by hereditary hemochromatosis (HH). The clinical impact of cardiomyopathy in patients with HH requires a particular diagnosis and less invasive treatments. We developed a model of cardiomyopathy in knockout (KO) mice for the high-Fe (HFE) gene and assessed left ventricular (LV) function and structure from 7-20 months. Male wild-type (WT) heterozygous and KO SV129 mice for the HFE gene were used in this study. Twenty-four mice were used to assess LV function and structure by echocardiography at 7, 14, 18, and 20 months. Evaluations of LV function and structure and myocardial fibrosis were performed at 7 and 20 months. The percent decrease of LV thickness-to-radius ratio between 7 and 20 months was higher in KO mice compared with WT mice (-30.2% ± 5.3% vs -10.5% ± 4.9%; P < 0.01). The LV diameters were higher in old mice compared with young mice (+13% at end-diastole; +33% at end-systole; P < 0.001). The LV ejection fraction values were lower in KO mice compared with WT mice between 7 and 20 months. The highest difference was found at 14 months (60.0% ± 7.6% vs 78.1% ± 3.5%; P < 0.001). Myocardial fibrosis was higher in old KO mice compared with old WT mice (+55%; P < 0.001), and myocardial iron deposition was slightly increased in old KO mice compared with old WT mice (1.31% ± 0.33% vs 0.84% ± 0.22%; P = 0.056). The present mouse model has the potential to allow the determination of underlying mechanisms involved in the cardiomyopathy induced by HFE-related hemochromatosis. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Diagnosis of hepatic iron overload: a family study illustrating pitfalls in diagnosing hemochromatosis.

PubMed

Schranz, Melanie; Talasz, Heribert; Graziadei, Ivo; Winder, Thomas; Sergi, Consolato; Bogner, Klaus; Vogel, Wolfgang; Zoller, Heinz

2009-03-01

Recent identification of genetic variants in iron storage disease has changed the classification system and diagnostic algorithms for hemochromatosis. Clinical diagnosis of the disease requires phenotypic evidence of iron overload because the commonly disease-associated HFE genotypes have an incomplete penetrance. Furthermore, approximately 20% of patients with a clinical diagnosis of hemochromatosis have no disease-associated genotype, which underlines the importance of clear phenotypic criteria of hemochromatosis. A diagnosis of hemochromatosis cannot be made even in patients with liver cirrhosis simply on the basis of genetic testing that indicates that iron overload is the cause of the disease and not its consequence. Proper diagnosis requires integration of clinical presentation, family history, and the results of biochemical and histopathologic tests. Here we propose a rational diagnostic algorithm for hepatic iron overload syndromes and illustrate potential pitfalls by presenting a family study in a pedigree with rare HFE variants (H63D and E168Q), in cis on the same chromosome. Although the clinical suspicion of hemochromatosis was confirmed by histology, chemical analysis of liver tissue revealed a normal hepatic iron concentration, which is compatible with the genetic finding of 1 normal and 1 doubly mutated allele. In conclusion, clinical suspicion of hemochromatosis and elevated serum iron parameters should prompt HFE genotyping for C282Y and H63D. Should they be uninformative, further genetic tests should be recommended only if iron overload in liver tissue has been confirmed chemically.

Synchrotron X-ray microscopy and spectroscopy analysis of iron in hemochromatosis liver and intestines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ko, J .Y. Peter; Sham, Tsun-Kong; Chakrabarti, Subrata

2009-12-01

Hemochromatosis is a genetic disorder that causes body to store excess iron in organs such as heart or liver. Distribution of iron, as well as copper, zinc and calcium, and chemical identity of iron in hemochromatosis liver and intestine were investigated by X-ray microprobe experiments, which consist of X-ray microscopy and micro-X-ray absorption fine structure. Our results show that iron concentration in hemochromatosis liver tissue is high, while much less Fe is found in intestinal tissue. Moreover, chemical identity of Fe in hemochromatosis liver can be identified. X-ray microprobe experiments allows for examining elemental distribution at an excellent spatial resolution.more » Moreover, chemical identity of element of interest can be obtained.« less

Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease.

PubMed

Sandhu, Kam; Flintoff, Kaledas; Chatfield, Mark D; Dixon, Jeannette L; Ramm, Louise E; Ramm, Grant A; Powell, Lawrie W; Subramaniam, V Nathan; Wallace, Daniel F

2018-05-09

The clinical progression of HFE-related hereditary hemochromatosis (HH) and its phenotypic variability has been well studied. Less is known about the natural history of non-HFE HH caused by mutations in the HJV , HAMP or TFR2 genes. The purpose of this study was to compare the phenotypic and clinical presentations of hepcidin-deficient forms of HH. A literature review of all published cases of genetically confirmed HJV, HAMP and TFR2 HH was performed. Phenotypic and clinical data from a total of 156 subjects with non-HFE HH was extracted from 53 publications and compared with data from 984 subjects with HFE -p.C282Y homozygous HH from the QIMR Berghofer Hemochromatosis Database. Analyses confirmed that non-HFE forms of HH have an earlier age of onset and a more severe clinical course than HFE HH. HJV and HAMP HH are phenotypically and clinically very similar and have the most severe presentation, with cardiomyopathy and hypogonadism being particularly prevalent findings. TFR2 HH is more intermediate in its age of onset and severity. All clinical outcomes analyzed were more prevalent in the juvenile forms of HH, with the exception of arthritis and arthropathy which were more commonly seen in HFE HH. This is the first comprehensive analysis comparing the different phenotypic and clinical aspects of the genetic forms of HH and the results will be valuable for the differential diagnosis and management of these conditions. Importantly, our analyses indicate that factors other than iron overload may be contributing to joint pathology in subjects with HFE HH. Copyright © 2018 American Society of Hematology.

Bone morphogenetic protein signaling is impaired in an Hfe knockout mouse model of hemochromatosis

PubMed Central

Corradini, Elena; Garuti, Cinzia; Montosi, Giuliana; Ventura, Paolo; Andriopoulos, Billy; Lin, Herbert Y.; Pietrangelo, Antonello; Babitt, Jodie L.

2009-01-01

Background and Aims Mutations in HFE are the most common cause of the iron-overload disorder hereditary hemochromatosis (HH). Levels of the main iron regulatory hormone, hepcidin, are inappropriately low in HH mouse models and patients with HFE mutations, indicating that HFE regulates hepcidin. The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is an important endogenous regulator of hepcidin expression. We investigated whether HFE is involved in BMP6-SMAD regulation of hepcidin expression. Methods The BMP6-SMAD pathway was examined in Hfe knockout (KO) mice and in wild-type (WT) mice as controls. Mice were placed on diets of varying iron content. Hepcidin induction by BMP6 was examined in primary hepatocytes from Hfe KO mice; data were compared with those of WT mice. Results Liver levels of Bmp6 mRNA were higher in Hfe KO mice; these were appropriate for the increased hepatic levels of iron in these mice, compared with WT mice. However, levels of hepatic phosphorylated Smad 1/5/8 protein (an intracellular mediator of Bmp6 signaling) and Id1 mRNA (a target gene of Bmp6) were inappropriately low for the body iron burden and Bmp6 mRNA levels in Hfe KO, compared with WT mice. BMP6 induction of hepcidin expression was reduced in Hfe KO hepatocytes compared with WT hepatocytes. Conclusions HFE is not involved in regulation of BMP6 by iron, but does regulate the downstream signals of BMP6 that are triggered by iron. PMID:19591830

Sample-to-SNP kit: a reliable, easy and fast tool for the detection of HFE p.H63D and p.C282Y variations associated to hereditary hemochromatosis.

PubMed

Nielsen, Peter B; Petersen, Maja S; Ystaas, Viviana; Andersen, Rolf V; Hansen, Karin M; Blaabjerg, Vibeke; Refstrup, Mette

2012-10-01

Classical hereditary hemochromatosis involves the HFE-gene and diagnostic analysis of the DNA variants HFE p.C282Y (c.845G>A; rs1800562) and HFE p.H63D (c.187C>G; rs1799945). The affected protein alters the iron homeostasis resulting in iron overload in various tissues. The aim of this study was to validate the TaqMan-based Sample-to-SNP protocol for the analysis of the HFE-p.C282Y and p.H63D variants with regard to accuracy, usefulness and reproducibility compared to an existing SNP protocol. The Sample-to-SNP protocol uses an approach where the DNA template is made accessible from a cell lysate followed by TaqMan analysis. Besides the HFE-SNPs other eight SNPs were used as well. These SNPs were: Coagulation factor II-gene F2 c.20210G>A, Coagulation factor V-gene F5 p.R506Q (c.1517G>A; rs121917732), Mitochondria SNP: mt7028 G>A, Mitochondria SNP: mt12308 A>G, Proprotein convertase subtilisin/kexin type 9-gene PCSK9 p.R46L (c.137G>T), Plutathione S-transferase pi 1-gene GSTP1 p.I105V (c313A>G; rs1695), LXR g.-171 A>G, ZNF202 g.-118 G>T. In conclusion the Sample-to-SNP kit proved to be an accurate, reliable, robust, easy to use and rapid TaqMan-based SNP detection protocol, which could be quickly implemented in a routine diagnostic or research facility. Copyright © 2012. Published by Elsevier B.V.

Pathophysiological consequences and benefits of HFE mutations: 20 years of research

PubMed Central

Hollerer, Ina; Bachmann, André; Muckenthaler, Martina U.

2017-01-01

Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis, and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers. PMID:28280078

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients

PubMed Central

Pelucchi, Sara; Mariani, Raffaella; Calza, Stefano; Fracanzani, Anna Ludovica; Modignani, Giulia Litta; Bertola, Francesca; Busti, Fabiana; Trombini, Paola; Fraquelli, Mirella; Forni, Gian Luca; Girelli, Domenico; Fargion, Silvia; Specchia, Claudia; Piperno, Alberto

2012-01-01

Background Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors. Design and Methods: In the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. Results We found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. Conclusions While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of

High-Performance Multiplex SNP Analysis of Three Hemochromatosis-Related Mutations With Capillary Array Electrophoresis Microplates

PubMed Central

Medintz, Igor; Wong, Wendy W.; Berti, Lorenzo; Shiow, Lawrence; Tom, Jennifer; Scherer, James; Sensabaugh, George; Mathies, Richard A.

2001-01-01

An assay is described for high-throughput single nucleotide polymorphism (SNP) genotyping on a microfabricated capillary array electrophoresis (CAE) microchip. The assay targets the three common variants at the HFE locus associated with the genetic disease hereditary hemochromatosis (HHC). The assay employs allele-specific PCR (ASPCR) for the C282Y (845g->a), H63D (187c->g), and S65C (193a->t) variants using fluorescently-labeled energy-transfer (ET) allele-specific primers. Using a 96-channel radial CAE microplate, the labeled ASPCR products generated from 96 samples in a reference Caucasian population are simultaneously separated with single-base-pair resolution and genotyped in under 10 min. Detection is accomplished with a laser-excited rotary four-color fluorescence scanner. The allele-specific amplicons are differentiated on the basis of both their size and the color of the label emission. This study is the first demonstration of the combined use of ASPCR with ET primers and microfabricated radial CAE microplates to perform multiplex SNP analyses in a clinically relevant population. PMID:11230165

The infectious disease blood safety risk of Australian hemochromatosis donations.

PubMed

Hoad, Veronica; Bentley, Peter; Bell, Barbara; Pathak, Praveen; Chan, Hiu Tat; Keller, Anthony

2016-12-01

It has been suggested that blood donors with hereditary hemochromatosis may pose an increased infectious disease risk and adversely affect recipient outcomes. This study compares the infectious disease risk of whole blood (WB) donors enrolled as therapeutic (T) donors to voluntary WB donors to evaluate the safety of blood products provided by the T donors. This was a retrospective cohort study of all WB donations at the Australian Red Cross Blood Service who donated between January 1, 2011, and December 31, 2013, comparing a yearly mean of 11,789 T donors with 107,773 total donations and a yearly mean of 468,889 voluntary WB donors with 2,584,705 total donations. We compared postdonation notification of infectious illnesses, bacterial contamination screening results, and positive tests for blood borne viruses in T and WB donors. Rates of transfusion-transmissible infections in donations destined for component manufacture were significantly lower in therapeutic donations compared to voluntary donations (8.4 vs. 21.6 per 100,000 donations). Bacterial contamination (43.0 vs. 45.9 per 100,000 donations) and postdonation illness reporting (136.2 vs. 110.8 per 100,000 donations) were similar in both cohorts. The Australian therapeutic venisection program enables T donors to provide a safe and acceptable source of donated WB that has a low infectious disease risk profile. © 2016 AABB.

Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients.

PubMed

Vieira, Fatima Mendonça Jorge; Nakhle, Maria Cristina; Abrantes-Lemos, Clarice Pires; Cançado, Eduardo Luiz Rachid; Reis, Vitor Manoel Silva dos

2013-01-01

Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil. Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors (hepatitis C, HIV, alcoholism and estrogen) and their link with HFE mutations. An ambispective study of 60 patients with PCT was conducted during the period from 2003 to 2012. Serological tests for hepatitis C and HIV were performed and histories of alcohol abuse and estrogen intake were investigated. HFE mutations were identified with real-time PCR. Porphyria cutanea tarda predominated in males and alcohol abuse was the main precipitating factor. Estrogen intake was the sole precipitating factor present in 25% of female patients. Hepatitis C was present in 41.7%. All HIV-positive patients (15.3%) had a history of alcohol abuse. Allele frequency for HFE mutations, i.e., C282Y (p = 0.0001) and H63D (p = 0.0004), were significantly higher in porphyria cutanea tarda patients, compared to control group. HFE mutations had no association with the other precipitating factors. Alcohol abuse, hepatitis C and estrogen intake are prevalent precipitating factors in our porphyria cutanea tarda population; however, hemochromatosis in itself can also contribute to the outbreak of porphyria cutanea tarda, which makes the research for HFE mutations necessary in these patients.

Hemochromatosis caused by excessive vitamin iron intake.

PubMed Central

Hennigar, G. R.; Greene, W. B.; Walker, E. M.; de Saussure, C.

1979-01-01

Rare cases of hemochromatosis have been reported in patients who underwent prolonged oral iron therapy for hemolytic anemia or prolonged self-treatment with iron pills. A proportionately large segment of the South African Bantu tribe, who ingest large quantities of an alcoholic beverage brewed in iron pots, are found to have the disease. Reports of health fadists developing hemochromatosis due to excessive dietary iron intake, however, are extremely rare. This report presents clinical considerations and pathologic findings in a compulsive health fadist who consumed large numbers of vitamins containing iron. Clinical findings included the development and progression of cirrhosis of the liver, bronzing of the skin, and diabetes mellitus, all consistent with a diagnosis of hemochromatosis. Light microscopy of liver biopsies taken late in the course of the disease revealed a massive buildup of iron in the hepatocytes, less in the Kupffer cells, and sparse deposition in the epithelial cells of the bile duct. Minimal periportal fibrosis was noted. Electron microscopy showed numerous pleomorphic siderosomes with varying degrees of crystallization and ferritin attached at uniform intervals to the membranes of residual bodies. Abundant free ferritin was observed in most cells. The aggregated and membrane-associated ferritin was verified by non-dispersive x-ray analysis. An additional finding, noted only by electron microscopy, was the presence of many fat-storing cells of Ito, which are thought to be involved in the onset of fibrosis. Images Figure 11 Figure 12 Figure 5 Figure 6 Figure 1 Figure 2 Figure 3 Figure 4 Figure 7 Figure 8 Figure 9 Figure 10 PMID:474711

Genetics Home Reference: hereditary spherocytosis

MedlinePlus

... occur anytime from early childhood to adulthood. About half of affected individuals develop hard deposits in the ... of hereditary spherocytosis in people of other ethnic backgrounds is unknown, but it is much less common. ...

Iron overload: what is the role of public health?

PubMed

Hulihan, Mary M; Sayers, Cindy A; Grosse, Scott D; Garrison, Cheryl; Grant, Althea M

2011-12-01

Hereditary hemochromatosis type 1, also known as hereditary hemochromatosis classical (HHC), is an iron overload disorder associated, in most cases, with mutations of the hemochromatosis (HFE) gene. Although suggested algorithms for diagnosing iron overload are available, there are still questions about options for genetic and biochemical screening for hemochromatosis and duration of treatment. This article provides a summary of an expert workgroup meeting convened on September 24-25, 2009, entitled "Iron Overload: What is the Role of Public Health?" The purpose of the meeting was to enable subject matter experts to share their most recent clinical and scientific iron overload information and to facilitate the discussion of future endeavors, with special emphasis on the role of public health in this field. The two main topics were the research priorities of the field, including clinical, genetic, and public health issues, and the concerns about the validity of current screening recommendations for the condition. Published by Elsevier Inc.

Learning about Hereditary Hemochromatosis

MedlinePlus

... New Horizons and Research Patient Management Policy and Ethics Issues Quick Links for Patient Care Education All About ... Genome Exhibition Talking Glossary: English Talking Glossary: Español Issues ... Contacts Media Resources NHGRI-Related News Journal Articles ...

The WT hemochromatosis protein HFE inhibits CD8⁺ T-lymphocyte activation.

PubMed

Reuben, Alexandre; Phénix, Mikaël; Santos, Manuela M; Lapointe, Réjean

2014-06-01

MHC class I (MHC I) antigen presentation is a ubiquitous process by which cells present endogenous proteins to CD8(+) T lymphocytes during immune surveillance and response. Hereditary hemochromatosis protein, HFE, is involved in cellular iron uptake but, while structurally homologous to MHC I, is unable to bind peptides. However, increasing evidence suggests a role for HFE in the immune system. Here, we investigated the impact of HFE on CD8(+) T-lymphocyte activation. Using transient HFE transfection assays in a model of APCs, we show that WT HFE (HFEWT ), but not C282Y-mutated HFE, inhibits secretion of MIP-1β from antigen-specific CD8(+) T lymphocytes. HFEWT expression also resulted in major decreases in CD8(+) T-lymphocyte activation as measured by 4-1BB expression. We further demonstrate that inhibition of CD8(+) T-lymphocyte activation was independent of MHC I surface levels, β2-m competition, HFE interaction with transferrin receptor, antigen origin, or epitope affinity. Finally, we identified the α1-2 domains of HFEWT as being responsible for inhibiting CD8(+) T-lymphocyte activation. Our data imply a new role for HFEWT in altering CD8(+) T-lymphocyte reactivity, which could modulate antigen immunogenicity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis

PubMed Central

Ramos, Emilio; Ruchala, Piotr; Goodnough, Julia B.; Kautz, Léon; Preza, Gloria C.; Nemeth, Elizabeta

2012-01-01

The deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused iron-loading anemias. In a recent study, we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibility of using minihepcidins for the prevention and treatment of iron overload in hepcidin-deficient mice. An optimized minihepcidin (PR65) was developed that had superior potency and duration of action compared with natural hepcidin or other minihepcidins, and favorable cost of synthesis. PR65 was administered by subcutaneous injection daily for 2 weeks to iron-depleted or iron-loaded hepcidin knockout mice. PR65 administration to iron-depleted mice prevented liver iron loading, decreased heart iron levels, and caused the expected iron retention in the spleen and duodenum. At high doses, PR65 treatment also caused anemia because of profound iron restriction. PR65 administration to hepcidin knockout mice with pre-existing iron overload had a more moderate effect and caused partial redistribution of iron from the liver to the spleen. Our study demonstrates that minihepcidins could be beneficial in iron overload disorders either used alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation. PMID:22990014

Prevalence of C282Y, H63D, and S65C mutations in hereditary HFE-hemochromatosis gene in Lithuanian population.

PubMed

Kucinskas, Laimutis; Juzenas, Simonas; Sventoraityte, Jurgita; Cedaviciute, Ruta; Vitkauskiene, Astra; Kalibatas, Vytenis; Kondrackiene, Jurate; Kupcinskas, Limas

2012-04-01

HFE-hemochromatosis is a common autosomal recessive disease caused by HFE gene mutations and characterized as iron overload and failure of different organs. The aim of this study was to determine the prevalence of C282Y (c.845 G>A), H63D (c.187 C>G), and S65C (c.193A>T) alleles of HFE gene in the Lithuanian population. One thousand and eleven healthy blood donors of Lithuanian nationality were examined in four different ethnic Lithuanian regions to determine HFE gene alleles and genotype frequencies. The samples of DNA were analyzed for the presence of restriction fragment length polymorphism and validated by DNA sequencing. Among 1,011 blood donors tested, the frequency of C282Y, H63D, and S65C alleles were 2.6%, 15.9%, and 1.9%, respectively. One third of the tested subjects (n = 336) had at least one of the C282Y or H63D HFE gene mutations. The screening of Lithuanian blood donors has detected 13 (1.3%) subjects with a genotype C282Y/C282Y or C282Y/H63D responsible for the development of HFE-hemochromatosis. The prevalence of C282Y mutation was significantly higher among the inhabitants of Zemaitija (Somogitia) at the Baltic Sea area (5.9%) in comparison to the regions of continental part of Lithuania (2.4% in Dzukija, 2.3% in Aukstaitija, and 2% in Suvalkija, p < 0.05). These data support the hypothesis that the p.C282Y mutation originated from Scandinavia and spread with the Vikings along the Baltic Sea coast. The first epidemiological investigation of HFE gene mutations in ethnic Lithuanians showed that the frequencies of H63D, C282Y, and S65C of HFE gene alleles are similar to the other North-Eastern Europeans, especially in the Baltic region (Estonia, Latvia), Poland, and part of Russia (Moscow region).

Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening.

PubMed

McLaren, Gordon D; McLaren, Christine E; Adams, Paul C; Barton, James C; Reboussin, David M; Gordeuk, Victor R; Acton, Ronald T; Harris, Emily L; Speechley, Mark R; Sholinsky, Phyliss; Dawkins, Fitzroy W; Snively, Beverly M; Vogt, Thomas M; Eckfeldt, John H

2008-11-01

Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences. To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening. Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364). Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects. Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study.

Common founder effects of hereditary hemochromatosis, Wilson´s disease, the long QT syndrome and autosomal recessive deafness caused by two novel mutations in the WHRN and TMC1 genes.

PubMed

Olsson, K Sigvard; Wålinder, Olof; Jansson, Ulf; Wilbe, Maria; Bondeson, Marie-Louise; Stattin, Eva-Lena; Raha-Chowdhury, Ruma; Williams, Roger

2017-01-01

Genealogy and molecular genetic studies of a Swedish river valley population resulted in a large pedigree, showing that the hereditary hemochromatosis (HH) HFE/p. C282Y mutation is inherited with other recessive disorders such as Wilson´s disease (WND), a rare recessive disorder of copper overload. The population also contain individuals with the Swedish long QT syndrome (LQTS1) founder mutation ( KCNQ1 /p.Y111C) which in homozygotes causes the Jervell & Lange Nielsen syndrome (JLNS) and hearing loss (HL).Aims of the study were to test whether the Swedish long QT founder mutation originated in an ancestral HFE family and if carriers had an increased risk for hemochromatosis (HH), a treatable disorder. We also aimed to identify the pathogenic mutation causing the hearing loss disorder segregating in the pedigree. LQTS patients were asked about their ancestry and possible origin in a HH family. They were also offered a predictive testing for the HFE genotype. Church books were screened for families with hearing loss. One HH family had two members with hearing loss, who underwent molecular genetic analysis of the LQTS founder mutation, connexin 26 and thereafter exome sequencing. Another family with hearing loss in repeat generations was also analyzed for connexin 26 and underwent exome sequencing. Of nine LQTS patients studied, four carried a HFE mutation (two p.C282Y, two p.H63D), none was homozygous. Three LQTS patients confirmed origin in a female founder ( b 1694, identical to AJ b 1694, a HFE pedigree member from the Fax river. Her descent of 44 HH families, included also 29 families with hearing loss (HL) suggesting JLNS. Eleven LQTS probands confirmed origin in a second founder couple (b 1614/1605) in which the woman b 1605 was identical to a HFE pedigree member from the Fjällsjö river. In her descent there were not only 64 HH, six WND families, one JLNS, but also 48 hearing loss families. Most hearing loss was non syndromic and caused by founder effects of

Recurrent pregnancy-induced diabetes insipidus in a woman with hemochromatosis.

PubMed

Krysiak, Robert; Kobielusz-Gembala, Iwona; Okopien, Boguslaw

2010-01-01

Diabetes insipidus is a rare disorder in pregnant women, predating pregnancy or appearing for the first time during gestation. In pregnancy it usually affects women with HELLP syndrome or acute fatty liver of pregnancy and results from the reduced hepatic degradation of placental vasopressinase leading to its increased activity. Although infiltrative diseases have been found to cause diabetes insipidus in non-pregnant population, very few studies showed that these disorders may manifest for the first time during gestation. We describe here the case of transient diabetes insipidus in two subsequent pregnancies of a female with hemochromatosis. The first symptoms of this disease appeared for the first time at the beginning of the third trimester of her second pregnancy, and diagnosis was established on the basis of typical clinical presentation, confirmed by a water deprivation test. Diabetes insipidus resulted from the increased activity of vasopressinase, caused by hemochromatosis-induced liver dysfunction, the presence of which was confirmed between the pregnancies by liver biopsy and identification of the HFE gene mutation. Subsequent desferrioxamine treatment resulted in a less severe clinical course of diabetes insipidus in the last patient's pregnancy. In both pregnancies, the patient was successfully treated with oral desmopressin, which is resistant to degradation by placental vasopressinase. Although unrecognized pituitary disorders may pose a serious health problem to the mother and fetus, hemochromatosis-induced diabetes insipidus, as the case of our patient demonstrates, if effectively diagnosed and treated, cannot be regarded as a contraindication for pregnancy.

Structural basis of urea-induced unfolding: Unraveling the folding pathway of hemochromatosis factor E.

PubMed

Khan, Parvez; Prakash, Amresh; Haque, Md Anzarul; Islam, Asimul; Hassan, Md Imtaiyaz; Ahmad, Faizan

2016-10-01

Hereditary hemochromatosis factor E (HFE) is a type 1 transmembrane protein, and acts as a negative regulator of iron-uptake. The equilibrium unfolding and conformational stability of the HFE protein was examined in the presence of urea. The folding and unfolding transitions were monitored with the help of circular dichroism (CD), intrinsic fluorescence and absorption spectroscopy. Analysis of transition curves revealed that the folding of HFE is not a two-state process. However, it involved stable intermediates. Transition curves (plot of fluorescence (F346) and CD signal at 222nm (θ222) versus [Urea], the molar urea concentration) revealed a biphasic transition with midpoint (Cm) values at 2.88M and 4.95M urea. Whereas, absorption analysis shows one two-state transition centered at 2.96M. To estimate the protein stability, denaturation curves were analyzed for Gibbs free energy change in the absence of urea (ΔGD(0)) associated with the equilibrium of denaturation exist between native state↔denatured state. The intermediate state was further characterized by hydrophobic probe, 1-anilinonaphthalene-8-sulfonic acid (ANS-binding). For seeing the effect of urea on the structure and dynamics of HFE, molecular dynamics simulation for 60ns was also performed. A clear correspondence was established between the in vitro and in silico studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Hereditary Diffuse Gastric Cancer

MedlinePlus

... Hereditary Diffuse Gastric Cancer Request Permissions Hereditary Diffuse Gastric Cancer Approved by the Cancer.Net Editorial Board , 10/2017 What is hereditary diffuse gastric cancer? Hereditary diffuse gastric cancer (HDGC) is a rare ...

Genetics Home Reference: hereditary hemochromatosis

MedlinePlus

... of sex hormones is evident. Females usually begin menstruation in a normal manner, but menses stop after ... in an autosomal recessive pattern , which means both copies of the gene in each cell have mutations. ...

Preserving the national blood supply.

PubMed

Brittenham, G M; Klein, H G; Kushner, J P; Ajioka, R S

2001-01-01

This paper examines the current state of the blood supply in the US and focuses on the potential for augmenting blood availability by attention to the iron status of donors. Increasing demands are being made upon the national blood supply as rates of blood donation are declining, in part because of the loss of blood donors as a result of enhanced screening and testing procedures. Iron-related means of expanding the blood supply include the use of blood from individuals undergoing therapeutic phlebotomy for hereditary hemochromatosis and enhancing the retention and commitment of women of childbearing age as donors by using iron supplementation to prevent iron deficiency. In Section I, Dr. Klein discuss the circumstances responsible for a decline in the population of eligible donors, including public attitudes toward donation, factors influencing the retention of donors by blood centers, and the effects of increased screening and testing to maintain the safety of the blood supply. In Section II, Drs. Kushner and Ajioka focus on the consequences of the decision by the US Food and Drug Administration (FDA) to develop recommendations to permit blood centers to collect blood from patients with hereditary hemochromatosis and to distribute this blood obtained without disease labeling if all other screening and testing procedures are passed. After summarizing the pathophysiology of hereditary hemochromatosis, the use by blood centers of blood obtained from heterozygotes and homozygotes for hereditary hemochromatosis is considered. In Section III, Dr. Brittenham reviews the use of low dose, short-term carbonyl iron supplementation for women donors of childbearing age. Replacing the iron lost at donation can help prevent iron deficiency in women of childbearing age and, by decreasing deferral, enhance the retention and commitment of women who give blood regularly. He emphasizes the use by blood centers of iron-related means to enhance recruitment and retention of blood donors.

A diagnostic approach to hemochromatosis

PubMed Central

Tavill, Anthony S; Adams, Paul C

2006-01-01

In the present clinical review, a diagnostic approach to hemochromatosis is discussed from the perspective of two clinicians with extensive experience in this area. The introduction of genetic testing and large-scale population screening studies have broadened our understanding of the clinical expression of disease and the utility of biochemical iron tests for the detection of disease and for the assessment of disease severity. Liver biopsy has become more of a prognostic test than a diagnostic test. The authors offer a stepwise, diagnostic algorithm based on current evidence-based data, that they regard as most cost-effective. An early diagnosis can lead to phlebotomy therapy to prevent the development of cirrhosis. PMID:16955151

Iron Storage Disease: Facts, Fiction and Progress

PubMed Central

Beutler, Ernest

2007-01-01

There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25 amino acid peptide hepcidin is upregulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves. PMID:17540589

Hereditary Pheochromocytoma.

PubMed

Santos, Pedro; Pimenta, Tiago; Taveira-Gomes, Antonio

2014-08-01

Pheochromocytomas (PHEO) and paragangliomas (PGL) are rare neuroendocrine tumors with an estimated occurrence of 2 to 5 patients per million per year and an incidence of about 1 per 100 000 in the general population. These tumors may arise sporadically or be associated to various syndromes, namely multiple endocrine neoplasia type 2, neurofibromatosis type 1, Von Hippel-Lindau syndrome, and hereditary paraganglioma-pheochromocytoma syndromes. This article aims to review the current epidemiology, pathogenesis, clinical presentation, and genetic aspects of syndromes associated with hereditary PHEO/PGL. The literature research, conducted at PubMed database, included review articles, published from February 2009 to February 2014, written in English or Portuguese, using as query: "Hereditary AND Pheochromocytoma." These tumors can be part of a myriad hereditary conditions that are not yet fully understood. Nevertheless, important systemic symptoms and even fatal outcomes can occur. Knowledge of these hereditary conditions can ensure a more efficient detection, treatment, and even prevention of these neuroectodermal tumors, thus new tests and studies should be conducted. © The Author(s) 2014.

Sclerosing bone dysplasias: genetic, clinical and radiology update of hereditary and non-hereditary disorders

PubMed Central

Boulet, Cedric; Madani, Hardi; Lenchik, Leon; Vanhoenacker, Filip; Amalnath, Deepak S; de Mey, Johan

2016-01-01

There is a wide variety of hereditary and non-hereditary bone dysplasias, many with unique radiographic findings. Hereditary bony dysplasias include osteopoikilosis, osteopathia striata, osteopetrosis, progressive diaphyseal dysplasia, hereditary multiple diaphyseal sclerosis and pyknodysostosis. Non-hereditary dysplasias include melorheostosis, intramedullary osteosclerosis and overlap syndromes. Although many of these dysplasias are uncommon, radiologists should be familiar with their genetic, clinical and imaging findings to allow for differentiation from acquired causes of bony sclerosis. We present an overview of hereditary and non-hereditary bony dysplasias with focus on the pathogenesis, clinical and radiographic findings of each disorder. PMID:26898950

HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis.

PubMed

Allen, Katrina J; Bertalli, Nadine A; Osborne, Nicholas J; Constantine, Clare C; Delatycki, Martin B; Nisselle, Amy E; Nicoll, Amanda J; Gertig, Dorota M; McLaren, Christine E; Giles, Graham G; Hopper, John L; Anderson, Gregory J; Olynyk, John K; Powell, Lawrie W; Gurrin, Lyle C

2010-09-01

Hemochromatosis gene (HFE)-associated hereditary hemochromatosis (HH) is a genetic predisposition to iron overload and subsequent signs and symptoms of disease that potentially affects approximately 80,000 persons in Australia and almost 1 million persons in the United States. Most clinical cases are homozygous for the Cys282Tyr (C282Y) mutation in the HFE gene, with serum ferritin (SF) concentration >1000 microg/L as the strongest predictor of cirrhosis. The optimal treatment regimen for those with SF concentrations above the normal range but <1000 microg/L is unknown. We assessed HFE mutations in a prospective cohort of 31,192 participants of northern European descent, aged 40-69 years. An HFE-stratified random sample of 1438 participants including all C282Y homozygotes with iron studies 12 years apart were examined by physicians blinded to participants' HFE genotype. All previously undiagnosed C282Y homozygotes (35 male, 67 female) and all HFE wild-types (131 male, 160 female) with baseline and follow-up SF concentrations <1000 microg/L were assessed for HH-associated signs and symptoms including abnormal second/third metacarpophalangeal joints (MCP2/3), raised liver enzymes, hepatomegaly, and self-reported liver disease, fatigue, diabetes mellitus, and use of arthritis medication. The prevalence of HH-associated signs and symptoms was similar for C282Y homozygotes and HFE wild-types for both normal and moderately elevated SF concentrations. The maximum prevalence difference between HFE genotype groups with moderately elevated SF was 11% (MCP2/3, 95% confidence interval = -6%, 29%; P = 0.22) and for normal SF was 6% (arthritis medicine use, 95% confidence interval = -3%, 16%; P = 0.11). Previously undiagnosed C282Y homozygotes with SF concentrations that remain below 1000 microg/L are at low risk of developing HH-associated signs and symptoms at an age when disease would be expected to have developed. These observations have implications for the management of C

Ferritin light chain gene mutations in two Brazilian families with hereditary hyperferritinemia-cataract syndrome

PubMed Central

Petroni, Roberta Cardoso; da Rosa, Susana Elaine Alves; de Carvalho, Flavia Pereira; Santana, Rúbia Anita Ferraz; Hyppolito, Joyce Esteves; Nascimento, Claudia Mac Donald Bley; Hamerschlak, Nelson; Campregher, Paulo Vidal

2017-01-01

ABSTRACT Hereditary hyperferritinemia-cataract syndrome is an autosomal dominant genetic disorder associated with mutations in the 5’UTR region of the ferritin light chain gene. These mutations cause the ferritin levels to increase even in the absence of iron overload. Patients also develop bilateral cataract early due to accumulation of ferritin in the lens, and many are misdiagnosed as having hemochromatosis and thus not properly treated. The first cases were described in 1995 and several mutations have already been identified. However, this syndrome is still a poorly understood. We report two cases of unrelated Brazilian families with clinical suspicion of the syndrome, which were treated in our department. For the definitive diagnosis, the affected patients, their parents and siblings were submitted to Sanger sequencing of the 5’UTR region for detection of the ferritin light gene mutation. Single nucleotide polymorphism-like mutations were found in the affected patients, previously described. The test assisted in making the accurate diagnosis of the disease, and its description is important so that the test can be incorporated into clinical practice. PMID:28746593

Cardiac iron deposition in idiopathic hemochromatosis: histologic and analytic assessment of 14 hearts from autopsy.

PubMed

Olson, L J; Edwards, W D; McCall, J T; Ilstrup, D M; Gersh, B J

1987-12-01

In each heart taken from autopsies of 14 men with idiopathic hemochromatosis, the conduction system, atria and 10 sites in the ventricles were histologically graded for stainable iron. Stainable iron was exclusively sarcoplasmic; none was observed in the interstitium. The histologic grade for the same anatomic site varied among hearts and among different anatomic sites in the same heart. Ten hearts had stainable iron in all ventricular sites; one of the three hearts from patients who had undergone therapeutic phlebotomy had no iron at any site. Seven hearts had iron in the atria but at a lesser grade than that found in the ventricles; six hearts had mild focal iron deposition in the atrioventricular conduction system. None of the 14 hearts had stainable iron in the sinus node. Elemental iron was quantitated by atomic absorption spectroscopy in ventricular specimens contiguous to those studied histologically and also in age-matched control hearts. Elemental iron content was markedly increased in hearts with idiopathic hemochromatosis compared with control hearts (p less than 0.01). The quantity of elemental iron varied greatly, similar to stainable iron, but was highest subepicardially. Among the hearts from the 11 patients without prior phlebotomy, three had no stainable iron in the right ventricular septal subendocardium, suggesting that sampling error may be a problem in the evaluation of hemochromatosis by endomyocardial biopsy. The sarcoplasmic location of the iron indicates that cardiac involvement in idiopathic hemochromatosis represents a storage disease and not an infiltrative process; this finding is consistent with the normal ventricular wall thicknesses observed.

Presence of hemochromatosis-associated mutations in Hispanic patients with iron overload.

PubMed

Nieves-Santiago, Paul; Cancel, Dilany; Canales, Dialma; Toro, Doris H

2011-09-01

To determine the characteristics of the Puerto Rico Veteran population with iron overload in terms of demographic features, clinical manifestations, and the presence of hereditary hemochromatosis (HH) mutations, and to compare such characteristics in patients with and without HH mutations. A retrospective study was conducted in patients with iron overload (transferrin saturation > or = 45%) who were tested for HH mutations from January 2003 to June 2007. Data collected included age, gender, body mass index, hemoglobin level, platelet count, ferritin level, transferrin saturation, ceruloplasmin, alfa-1 antitrypsin, anti-nuclear antibodies, aspartate aminotransferase, alanine aminotransferase, alfa-fetoprotein, viral hepatitis profile, imaging studies, and comorbid conditions. Patients were grouped according to the results of the commercially available HH DNA mutation analysis as homozygote, heterozygote, compound heterozygote, or negative. 94 patients were studied. Most patients were male (90/94); the mean age was 60 years. Of the study group, 36% (34/94) was found positive for HH mutations. The most common mutation was H63D, which was found in 85% (29/34) of patients; 4 homozygotes and 25 heterozygotes. C282Y mutation was identified in only 12% (4/34) of patients, of which one was homozygote. A compound heterozygote (C282Y/ H63D) was also identified. After analyzing the data for confounding factors, 6 of 29 heterozygotes had no other risk factors for liver disease other than the H63D mutation. The predominance of H63D mutations in our population deserves further investigation since it considerably differs from other studied populations with iron overload in which C282Y is the most common mutation.

Differences in hepatic phenotype between hemochromatosis patients with HFE C282Y homozygosity and other HFE genotypes.

PubMed

Cheng, Raymond; Barton, James C; Morrison, Elizabeth D; Phatak, Pradyumna D; Krawitt, Edward L; Gordon, Stuart C; Kowdley, Kris V

2009-07-01

There are limited data comparing hepatic phenotype among hemochromatosis patients with different HFE genotypes. The goal of this study was to compare hepatic histopathologic features and hepatic iron concentration (HIC) among patients with phenotypic hemochromatosis and different HFE genotypes. We studied 182 US patients with phenotypic hemochromatosis. Degree of hepatic fibrosis, pattern of iron deposition, presence of steatosis or necroinflammation, and HIC were compared among different HFE genotypes. C282Y/H63D compound heterozygotes and patients with HFE genotypes other than C282Y/C282Y were more likely to have stainable Kupffer cell iron (31.1% vs. 9.5%; P=0.02), portal or lobular inflammation (28.9% vs. 15.6%; P=0.03), and steatosis (33.3% vs. 10.2%; P<0.01) on liver biopsy than C282Y homozygotes. Mean log10 HIC (P<0.05) and log10 ferritin (P<0.05) were higher among C282Y homozygotes than in patients with other HFE genotypes. In a logistic regression analysis using age, sex, HFE genotype, log10 ferritin, and log10 HIC as independent variables, log10 serum ferritin (P=0.0008), male sex (P=0.0086), and log10 HIC (P=0.047), but not HFE genotype (P=0.0554) were independently associated with presence or absence of advanced hepatic fibrosis. C282Y/H63D compound heterozygotes and other non-C282Y homozygotes which express the hepatic hemochromatosis phenotype frequently have evidence of steatosis or chronic hepatitis and lower body iron stores than C282Y homozygotes. These data suggest that presence of concomitant liver disease may explain expression of the hemochromatosis phenotype among non-C282Y homozygotes. Increased age, HIC, and ferritin are associated with advanced hepatic fibrosis, regardless of HFE genotype.

Erythrocytic Pyruvate Kinase Mutations Causing Hemolytic Anemia, Osteosclerosis, and Secondary Hemochromatosis in Dogs

PubMed Central

Gultekin, G. Inal; Raj, K.; Foureman, P.; Lehman, S.; Manhart, K.; Abdulmalik, O.; Giger, U.

2013-01-01

Background Erythrocytic pyruvate kinase (PK) deficiency, first documented in Basenjis, is the most common inherited erythroenzymopathy in dogs. Objectives To report 3 new breed-specific PK-LR gene mutations and a retrospective survey of PK mutations in a small and selected group of Beagles and West Highland White Terriers (WHWT). Animals Labrador Retrievers (2 siblings, 5 unrelated), Pugs (2 siblings, 1 unrelated), Beagles (39 anemic, 29 other), WHWTs (22 anemic, 226 nonanemic), Cairn Terrier (n = 1). Methods Exons of the PK-LR gene were sequenced from genomic DNA of young dogs (<2 years) with persistent highly regenerative hemolytic anemia. Results A nonsense mutation (c.799C>T) resulting in a premature stop codon was identified in anemic Labrador Retriever siblings that had osteosclerosis, high serum ferritin concentrations, and severe hepatic secondary hemochromatosis. Anemic Pug and Beagle revealed 2 different missense mutations (c.848T>C, c.994G>A, respectively) resulting in intolerable amino acid changes to protein structure and enzyme function. Breed-specific mutation tests were developed. Among the biased group of 248 WHWTs, 9% and 35% were homozygous (affected) and heterozygous, respectively, for the previously described mutation (mutant allele frequency 0.26). A PK-deficient Cairn Terrier had the same insertion mutation as the affected WHWTs. Of the selected group of 68 Beagles, 35% were PK-deficient and 3% were carriers (0.37). Conclusions and Clinical Importance Erythrocytic PK deficiency is caused by different mutations in different dog breeds and causes chronic severe hemolytic anemia, hemosiderosis, and secondary hemochromatosis because of chronic hemolysis and, an as yet unexplained osteosclerosis. The newly developed breed-specific mutation assays simplify the diagnosis of PK deficiency. PMID:22805166

Model of reticuloendothelial iron metabolism in humans: Abnormal behavior in idiopathic hemochromatosis and in inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fillet, G.; Beguin, Y.; Baldelli, L.

1989-08-01

Iron transport in the reticuloendothelial (RE) system plays a central role in iron metabolism, but its regulation has not been characterized physiologically in vivo in humans. In particular, why serum iron is elevated and RE cells are much less iron-loaded than parenchymal cells in idiopathic hemochromatosis is not known. The processing of erythrocyte iron by the RE system was studied after intravenous (IV) injection of 59Fe heat-damaged RBCs (HDRBCs) and 55Fe transferrin in normal subjects and in patients with iron deficiency, idiopathic hemochromatosis, inflammation, marrow aplasia, or hyperplastic erythropoiesis. Early release of 59Fe by the RE system was calculated frommore » the plasma iron turnover and the 59Fe plasma reappearance curve. Late release was calculated from the ratio of 59Fe/55Fe RBC utilization in 2 weeks. The partitioning of iron between the early (release from heme catabolism) and late (release from RE stores) phases depended on the size of RE iron stores, as illustrated by the inverse relationship observed between early release and plasma ferritin (P less than .001). There was a strong correlation between early release and the rate of change of serum iron levels during the first three hours in normal subjects (r = .85, P less than .001). Inflammation produced a blockade of the early release phase, whereas in idiopathic hemochromatosis early release was considerably increased as compared with subjects with similar iron stores. Based on these results, we describe a model of RE iron metabolism in humans. We conclude that the RE system appears to determine the diurnal fluctuations in serum iron levels through variations in the immediate output of heme iron. In idiopathic hemochromatosis, a defect of the RE cell in withholding iron freed from hemoglobin could be responsible for the high serum iron levels and low RE iron stores.« less

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data.

PubMed

Wallace, Daniel F; Subramaniam, V Nathan

2016-06-01

The prevalence of HFE-related hereditary hemochromatosis (HH) among European populations has been well studied. There are no prevalence data for atypical forms of HH caused by mutations in HFE2, HAMP, TFR2, or SLC40A1. The purpose of this study was to estimate the population prevalence of these non-HFE forms of HH. A list of HH pathogenic variants in publically available next-generation sequence (NGS) databases was compiled and allele frequencies were determined. Of 161 variants previously associated with HH, 43 were represented among the NGS data sets; an additional 40 unreported functional variants also were identified. The predicted prevalence of HFE HH and the p.Cys282Tyr mutation closely matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2-, and HAMP-related forms are predicted to be rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. Significantly, SLC40A1 variants that have been previously associated with autosomal-dominant ferroportin disease were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans. We have, for the first time, estimated the population prevalence of non-HFE HH. This methodology could be applied to estimate the population prevalence of a wide variety of genetic disorders.Genet Med 18 6, 618-626.

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients.

PubMed

Pelucchi, Sara; Mariani, Raffaella; Calza, Stefano; Fracanzani, Anna Ludovica; Modignani, Giulia Litta; Bertola, Francesca; Busti, Fabiana; Trombini, Paola; Fraquelli, Mirella; Forni, Gian Luca; Girelli, Domenico; Fargion, Silvia; Specchia, Claudia; Piperno, Alberto

2012-12-01

Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors. In the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. We found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-hereditary hemochromatosis, with emphasis on

[Hereditary hypophosphatemia in adults].

PubMed

Vélayoudom-Céphise, F-L; Vantyghem, M-C; Wémeau, J-L

2005-12-17

Hereditary hypophosphatemic rickets groups together X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) and hereditary hypophosphatemic rickets with hypercalciuria (HHRH, autosomal recessive). Clinical and biological characteristics and treatment depend on specific etiology. Mutations causing hereditary hypophosphatemic rickets involve PHEX located on Xp11.22 for XLH and FGF-23 located on 12p13 for ADHR. The gene involved in HHRH remains unknown: candidates may encode proteins that modulate phosphate transporter expression or activity. Others forms of rickets must be ruled out: acquired hypophosphatemia due to oncogenic osteomalacia, X-linked recessive hypophosphatemic rickets or Dent's disease, and hereditary 1, 25-dihydroxyvitamin D-resistant rickets with a defect either in the 1-alpha-hydroxylase gene (pseudo-vitamin D deficiency rickets, PDDR) or in the vitamin D receptor (hereditary vitamin D-resistant rickets, HVDRR).

Lymphocyte gene expression signatures from patients and mouse models of hereditary hemochromatosis reveal a function of HFE as a negative regulator of CD8+ T-lymphocyte activation and differentiation in vivo.

PubMed

Costa, Mónica; Cruz, Eugénia; Oliveira, Susana; Benes, Vladimir; Ivacevic, Tomi; Silva, Maria João; Vieira, Inês; Dias, Francisco; Fonseca, Sónia; Gonçalves, Marta; Lima, Margarida; Leitão, Catarina; Muckenthaler, Martina U; Pinto, Jorge; Porto, Graça

2015-01-01

Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe-/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe-/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe-/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes in HH.

Lymphocyte Gene Expression Signatures from Patients and Mouse Models of Hereditary Hemochromatosis Reveal a Function of HFE as a Negative Regulator of CD8+ T-Lymphocyte Activation and Differentiation In Vivo

PubMed Central

Costa, Mónica; Cruz, Eugénia; Oliveira, Susana; Benes, Vladimir; Ivacevic, Tomi; Silva, Maria João; Vieira, Inês; Dias, Francisco; Fonseca, Sónia; Gonçalves, Marta; Lima, Margarida; Leitão, Catarina; Muckenthaler, Martina U.; Pinto, Jorge; Porto, Graça

2015-01-01

Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe -/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe -/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe -/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes in HH. PMID

The Southern French registry of genetic hemochromatosis: a tool for determining clinical prevalence of the disorder and genotype penetrance

PubMed Central

Aguilar-Martinez, Patricia; Bismuth, Michael; Blanc, François; Blanc, Pierre; Cunat, Severine; Dereure, Olivier; Dujols, Pierre; Giansily-Blaizot, Muriel; Jorgensen, Christian; Konate, Amadou; Larrey, Dominique; Le Quellec, Alain; Mura, Thibault; Raingeard, Isabelle; Ramos, Jeanne; Renard, Eric; Rousseau, Florence; Schved, Jean-François; Picot, Marie-Christine

2010-01-01

Background Despite great progress in understanding the mechanisms underlying genetic hemochromatosis, data on the prevalence and the penetrance of the disorder are conflicting. Design and Methods A registry of patients with genetic hemochromatosis was established in the South of France and a regional health network was developed to allow the inclusion of all the diagnosed patients. C282Y homozygous patients classified in stages 2 (biological iron overload), 3 and 4 (clinical manifestations of iron overload, stage 4 being the more severe) according to the classification of the French National Authority for Health were included in the registry over a 6-year period. Results A total of 352 symptomatic C282Y homozygotes were identified, resulting in a total prevalence of 1.83 per 10,000 (95% CI: 1.63 to 2.02) in subjects over 20 years and 2.40 per 10,000 (95% CI, 2.15 to 2.65) among subjects of European descent. Among Europeans, the total calculated penetrance was 15.8% in stage 2 or higher, 12.1% in stage 3 or 4 and 2.9% in stage 4. The penetrance was slightly higher in males (18.7%) than in females (13.2%). It was 19.9% for individuals over 40 years of age (24.1% and 16.3% in males and females, respectively) with a maximum of 31% in subjects between 50 and 54 years old. Among 249 patients with complete records, 24% were in stage 2, the majority (58%) were in stage 3, and 18% in stage 4. There was a higher proportion of males, and excessive alcohol intake was more prevalent in stage 4 than in stages 2 and 3 combined. Conclusions A French Mediterranean regional hemochromatosis registry with strict inclusion criteria is a useful tool for characterizing the history of this disease, particularly for the most severely affected patients, as defined by the disease severity classification. The total prevalence of symptomatic C282Y homozygotes in the region was found to be low. However, clinical penetrance (stages 3 and 4) was not negligible. PMID:20145272

Effect of Native American ancestry on iron-related phenotypes of Alabama hemochromatosis probands with HFE C282Y homozygosity

PubMed Central

Barton, James C; Barton, Ellen H; Acton, Ronald T

2006-01-01

Background In age-matched cohorts of screening study participants recruited from primary care clinics, mean serum transferrin saturation values were significantly lower and mean serum ferritin concentrations were significantly higher in Native Americans than in whites. Twenty-eight percent of 80 Alabama white hemochromatosis probands with HFE C282Y homozygosity previously reported having Native American ancestry, but the possible effect of this ancestry on hemochromatosis phenotypes was unknown. Methods We compiled observations in these 80 probands and used univariate and multivariate methods to analyze associations of age, sex, Native American ancestry (as a dichotomous variable), report of ethanol consumption (as a dichotomous variable), percentage transferrin saturation and loge serum ferritin concentration at diagnosis, quantities of iron removed by phlebotomy to achieve iron depletion, and quantities of excess iron removed by phlebotomy. Results In a univariate analysis in which probands were grouped by sex, there were no significant differences in reports of ethanol consumption, transferrin saturation, loge serum ferritin concentration, quantities of iron removed to achieve iron depletion, and quantities of excess iron removed by phlebotomy in probands who reported Native American ancestry than in those who did not. In multivariate analyses, transferrin saturation (as a dependent variable) was not significantly associated with any of the available variables, including reports of Native American ancestry and ethanol consumption. The independent variable quantities of excess iron removed by phlebotomy was significantly associated with loge serum ferritin used as a dependent variable (p < 0.0001), but not with reports of Native American ancestry or reports of ethanol consumption. Loge serum ferritin was the only independent variable significantly associated with quantities of excess iron removed by phlebotomy used as a dependent variable (p < 0.0001) (p < 0

Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yaouanq, J.; Perichon, M.; Treut, A.L.

1994-02-01

The hemochromatosis gene (HFE) maps to 6p21.3 and is less than 1 cM from the HLA class I gene; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. The authors therefore embarked upon a linkage-disequilibrium analysis of HFE and normalmore » chromosomes for the Brittany population. In this report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. 69 refs., 1 fig., 5

Usefulness of Magnetic Resonance Imaging for the Diagnosis of Hemochromatosis with Severe Hepatic Steatosis in Nonalcoholic Fatty Liver Disease.

PubMed

Nozaki, Yuichi; Sato, Noriko; Tajima, Tsuyoshi; Hasuo, Kanehiro; Kojima, Yasushi; Umemoto, Kumiko; Mishima, Saori; Mikami, Shintaro; Nakayama, Tomohiro; Igari, Toru; Akiyama, Junichi; Imamura, Masatoshi; Masaki, Naohiko; Yanase, Mikio

2016-01-01

The ratio of the number of patients with non-alcoholic steatohepatitis (NASH) to the total number of patients with liver dysfunction has increased in many countries around the world. Liver dysfunction is also caused by multiple blood transfusions in patients with leukemia and other hematological diseases, with liver dysfunction often accompanied by secondary hemochromatosis. This study describes a 25-year-old man with secondary hemochromatosis combined with NASH. Magnetic resonance imaging was useful for visualizing the distributions of both iron and fat in the liver of this patient in order to make a differential diagnosis and to evaluate the effect of treatment.

[Using value of information analysis in decision making about applied research. The case of genetic screening for hemochromatosis in Germany].

PubMed

Rogowski, W H; Grosse, S D; Meyer, E; John, J; Palmer, S

2012-05-01

Public decision makers face demands to invest in applied research in order to accelerate the adoption of new genetic tests. However, such an investment is profitable only if the results gained from further investigations have a significant impact on health care practice. An upper limit for the value of additional information aimed at improving the basis for reimbursement decisions is given by the expected value of perfect information (EVPI). This study illustrates the significance of the concept of EVPI on the basis of a probabilistic cost-effectiveness model of screening for hereditary hemochromatosis among German men. In the present example, population-based screening can barely be recommended at threshold values of 50,000 or 100,000 Euro per life year gained and also the value of additional research which might cause this decision to be overturned is small: At the mentioned threshold values, the EVPI in the German public health care system was ca. 500,000 and 2,200,000 Euro, respectively. An analysis of EVPI by individual parameters or groups of parameters shows that additional research about adherence to preventive phlebotomy could potentially provide the highest benefit. The potential value of further research also depends on methodological assumptions regarding the decision maker's time horizon as well as on scenarios with an impact on the number of affected patients and the cost-effectiveness of screening.

76 FR 12122 - Disease, Disability, and Injury Prevention and Control Special Emphasis Panel (SEP): The...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-04

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention Disease, Disability, and Injury Prevention and Control Special Emphasis Panel (SEP): The Association of Genetic Biomarkers and Hereditary Hemochromatosis, DD11-008, Initial Review Correction: This notice was published in...

HLA-A and -B alleles and haplotypes in hemochromatosis probands with HFE C282Y homozygosity in central Alabama.

PubMed

Barton, James C; Acton, Ronald T

2002-10-07

We wanted to quantify HLA-A and -B allele and haplotype frequencies in Alabama hemochromatosis probands with HFE C282Y homozygosity and controls, and to compare results to those in other populations. Alleles were detected using DNA-based typing (probands) and microlymphocytotoxicity (controls). Alleles were determined in 139 probands (1,321 controls) and haplotypes in 118 probands (605 controls). In probands, A*03 positivity was 0.7482 (0.2739 controls; p = or < 0.0001; odds ratio (OR) 7.9); positivity for B*07, B*14, and B*56 was also increased. In probands, haplotypes A*03-B*07 and A*03-B*14 were more frequent (p < 0.0001, respectively; OR = 12.3 and 11.1, respectively). The haplotypes A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*35, A*03-B*44, A*03-B*47, and A*03-B*57 were also significantly more frequent in probands. 37.3% of probands were HLA-haploidentical with other proband(s). A*03 and A*03-B*07 frequencies are increased in Alabama probands, as in other hemochromatosis cohorts. Increased absolute frequencies of A*03-B*35 have been reported only in the present Alabama probands and in hemochromatosis patients in Italy. Increased absolute frequencies of A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*44, A*03-B*47, and A*03-B*57 in hemochromatosis cohorts have not been reported previously.

Advances in Hereditary Colorectal and Pancreatic Cancer

PubMed Central

Underhill, Meghan L.; Germansky, Katharine A.; Yurgelun, Matthew B.

2017-01-01

Purpose Innovations in genetic medicine have lead to improvements in the early detection, prevention, and treatment of cancer for patients with inherited risks of gastrointestinal cancer, particularly hereditary colorectal cancer and hereditary pancreatic cancer. Methods This review provides an update on recent data and key advances that have improved the identification, understanding, and management of patients with hereditary colorectal cancer and hereditary pancreatic cancer. Findings This review details recent and emerging data that highlight the developing landscape of genetics in hereditary colorectal and pancreatic cancer risk. A summary is provided of the current state-of-the-art practices for identifying, evaluating, and managing patients with suspected hereditary colorectal cancer and pancreatic cancer risk. The impact of next-generation sequencing technologies in the clinical diagnosis of hereditary gastrointestinal cancer and also in discovery efforts of novel genes linked to familial cancer risk are discussed. Emerging targeted therapies that may play a particularly important role in the treatment of patients with hereditary forms of colorectal cancer and pancreatic cancer are also reviewed. Current approaches for pancreatic cancer screening and the psychosocial impact of such procedures are also detailed. Implications Given the availability of novel diagnostic, risk-reducing, and therapeutic strategies that exist for patients with hereditary risk for colorectal or pancreatic cancer, it is imperative that clinicians be vigilant about evaluating patients for hereditary cancer syndromes. Continuing to advance genetics research in hereditary gastrointestinal cancers will allow for more progress to be made in personalized medicine and prevention. PMID:27045993

HLA haplotype map of river valley populations with hemochromatosis traced through five centuries in Central Sweden.

PubMed

Olsson, K Sigvard; Ritter, Bernd; Hansson, Norbeth; Chowdhury, Ruma R

2008-07-01

The hemochromatosis mutation, C282Y of the HFE gene, seems to have originated from a single event which once occurred in a person living in the north west of Europe carrying human leukocyte antigen (HLA)-A3-B7. In descendants of this ancestor also other haplotypes appear probably caused by local recombinations and founder effects. The background of these associations is unknown. Isolated river valley populations may be fruitful for the mapping of genetic disorders such as hemochromatosis. In this study, we try to test this hypothesis in a study from central Sweden where the haplotyope A1-B8 was common. HLA haplotypes and HFE mutations were studied in hemochromatosis patients with present or past parental origin in a sparsely populated (1/km(2)) rural district (n = 8366 in the year of 2005), in central Sweden. Pedigrees were constructed from the Swedish church book registry. Extended haplotypes were studied to evaluate origin of recombinations. There were 87 original probands, 36 females and 51 males identified during 30 yr, of whom 86% carried C282Y/C282Y and 14% C282Y/H63D. Of 32 different HLA haplotypes A1-B8 was the most common (34%), followed by A3-B7 (16%), both in strong linkage disequilibrium with controls, (P < 0.001). Twenty-nine different families with A1-B8 had a common founder origin 15 generations ago in small bottleneck populations of the late 16th century. A second A1-B8 founder born 1655 was of Norwegian origin. Most of the A3 carriers (n = 26) had a common founder origin 16 generations ago in an even smaller nearby river valley. A fourth founder family carrying HLA-A2 seems to have originated from a recombination along the descendant lines from the A3 ancestor supported by extended haplotype studies. A1-haplotypes with alleles at the B locus different from B8 had a similar recombination origin as HLA-A2 alleles and a common founder origin 11 generations ago. The intergenerational time interval averaged 35.5 +/- 7.9 yr in men and 31.9 +/- 5.9 in

Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin.

PubMed

Latour, Chloé; Besson-Fournier, Céline; Meynard, Delphine; Silvestri, Laura; Gourbeyre, Ophélie; Aguilar-Martinez, Patricia; Schmidt, Paul J; Fleming, Mark D; Roth, Marie-Paule; Coppin, Hélène

2016-01-01

Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up-regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and β2-microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6-deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6-deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6-deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys. These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice. © 2015 by the American Association for the Study of Liver Diseases.

Diabetes in first-degree family members: a predictor of type 2 diabetes in 159 nonscreening Alabama hemochromatosis probands with HFE C282Y homozygosity.

PubMed

Barton, James C; Barton, J Clayborn; Acton, Ronald T

2014-01-01

OBJECTIVE We sought to identify predictors of diabetes diagnosed before hemochromatosis. RESEARCH DESIGN AND METHODS We studied these 16 variables in 159 nonscreening hemochromatosis probands with HFE C282Y homozygosity: age; sex; BMI; diabetes reports in first-degree family members (dichotomous); heavy ethanol consumption; cigarette smoking; elevated serum alanine aminotransferase/aspartate aminotransferase levels; nonalcoholic fatty liver; chronic viral hepatitis; cirrhosis; hand arthropathy; iron removed by phlebotomy; and positivity for HLA-A*01, B*08; A*03, B*07; and A*03, B*14 haplotypes. We performed univariable and multivariable analyses. RESULTS Twenty-three probands (14.5%) had diabetes; 19 were men. Each of the 23 probands had type 2 diabetes. Mean BMI was greater in probands with diabetes (31.7 ± 8.5 [SD] kg/m(2) vs. 27.6 ± 5.1 kg/m(2); P = 0.032). Reports of any first-degree family member with diabetes were more prevalent in probands with than in probands without diabetes (69.6 vs. 17.6%; P < 0.0001). In probands with diabetes, the odds ratio (OR) of maternal diabetes was 6.7 (95% CI 2.3-19.7; P = 0.0005) and of sibling diabetes was 11.7 (3.0-45.5; P = 0.0004). In a logistic regression model, predictors of diabetes at hemochromatosis diagnosis in 159 probands were diabetes reports in family members (OR 8.5 [95% CI 2.9-24.8]; P < 0.0001) and BMI (1.1 [1.0-1.2]; P = 0.049). This model explained 26.0% of total deviance contributing to diabetes. CONCLUSIONS In nonscreening hemochromatosis probands with HFE C282Y homozygosity, a heritable factor(s) increases the risk of diabetes diagnosed before hemochromatosis.

Harlequin color change after abdominal paracentesis in a newborn with neonatal hemochromatosis.

PubMed

Cizmeci, Mehmet N; Alagoz, Demet; Avsar, Mehmet I; Alis, Gulten; Tutanc, Murat

2014-01-01

Harlequin color change is a distinctive cutaneous phenomenon presenting as a well-demarcated color change, with half of the body displaying erythema and the other half pallor. Only a few cases have been reported, possibly because of under-recognition. Recognition of this benign, self-limited condition may enable physicians to avoid unnecessary interventions. Herein we describe a neonate with nonimmune hydrops fetalis due to neonatal hemochromatosis who developed Harlequin color change after abdominal paracentesis. © 2014 Wiley Periodicals, Inc.

Hereditary Angioedema: Not An Allergy

PubMed Central

Bhivgade, Sanjay; Melkote, Shubha; Ghate, Smita; Jerajani, H R

2012-01-01

Hereditary angioedema is a genetic disorder due to a deficiency or malfunction of C1 esterase inhibitor. We herein describe a case of 25-year-old male who presented with swelling over face since one day. There was history of similar episodes since two years with gradual subsidence of swelling without any treatment. Investigations revealed grossly reduced complement C4 and C1 esterase inhibitor level. Patient was diagnosed to have hereditary angioedema type 1 and started on stanozolol 2 mg three times a day with no recurrence in one year of follow-up. Hereditary angioedema resembles angioedema of an allergic reaction. However, the cause is different. PMID:23248378

HFE Gene Mutations and Iron Status in 100 Healthy Polish Children.

PubMed

Kaczorowska-Hac, Barbara; Luszczyk, Marcin; Antosiewicz, Jedrzej; Ziolkowski, Wieslaw; Adamkiewicz-Drozynska, Elzbieta; Mysliwiec, Malgorzata; Milosz, Ewa; Kaczor, Jan J

2017-07-01

Iron participates in oxygen transport, energetic, metabolic, and immunologic processes. There are 2 main causes of iron overload: hereditary hemochromatosis which is a primary cause, is a metabolic disorder caused by mutations of genes that control iron metabolism and secondary hemochromatosis caused by multitransfusions, chronic hemolysis, and intake of iron rich food. The most common type of hereditary hemochromatosis is caused by HFE gene mutation. In this study, we analyzed iron metabolism in 100 healthy Polish children in relation to their HFE gene status. The wild-type HFE gene was predominant being observed in 60 children (60%). Twenty-five children (25%), presented with heterozygotic H63D mutation, and 15 children (15%), presented with other mutations (heterozygotic C282Y and S65C mutation, compound heterozygotes C282Y/S65C, C282Y/H63D, H63D homozygote). The mean concentration of iron, the level of ferritin, and transferrin saturation were statistically higher in the group of HFE variants compared with the wild-type group. H63D carriers presented with higher mean concentration of iron, ferritin levels, and transferrin saturation compared with the wild-type group. Male HFE carriers presented with higher iron concentration, transferrin saturation, and ferritin levels than females. This preliminary investigation demonstrates allelic impact on potential disease progression from childhood.

Adenine alleviates iron overload by cAMP/PKA mediated hepatic hepcidin in mice.

PubMed

Zhang, Yingqi; Wang, Xudong; Wu, Qian; Wang, Hao; Zhao, Lu; Wang, Xinhui; Mu, Mingdao; Xie, Enjun; He, Xuyan; Shao, Dandan; Shang, Yanna; Lai, Yongrong; Ginzburg, Yelena; Min, Junxia; Wang, Fudi

2018-03-30

Hemochromatosis is prevalent and often associated with high rates of morbidity and mortality worldwide. The safe alternative iron-reducing approaches are urgently needed in order to better control iron overload. Our unbiased vitamin screen for modulators of hepcidin, a master iron regulatory hormone, identifies adenine (vitamin B4) as a potent hepcidin agonist. Adenine significantly induced hepcidin mRNA level and promoter activity activation in human cell lines, possibly through BMP/SMAD pathway. Further studies in mice validated the effect of adenine on hepcidin upregulation. Consistently, adenine dietary supplement in mice led to an increase of hepatic hepcidin expression compared with normal diet-fed mice via BMP/SMAD pathway. Notably, adenine-rich diet significantly ameliorated iron overload accompanied by the enhanced hepcidin expression in both high iron-fed mice and in Hfe -/- mice, a murine model of hereditary hemochromatosis. To further validate this finding, we selected pharmacological inhibitors against BMP (LDN193189). We found LDN193189 strongly blocked the hepcidin induction by adenine. Moreover, we uncovered an essential role of cAMP/PKA-dependent axis in triggering adenine-induced hepcidin expression in primary hepatocytes by using 8 br cAMP, a cAMP analog, and H89, a potent inhibitor for PKA signaling. These findings suggest a potential therapeutic role of adenine for hereditary hemochromatosis. © 2018 Wiley Periodicals, Inc.

Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis.

PubMed

Bittencourt, Paulo Lisboa; Marin, Maria Lúcia Carnevale; Couto, Cláudia Alves; Cançado, Eduardo Luiz Rachid; Carrilho, Flair José; Goldberg, Anna Carla

2009-01-01

Approximately one-half of Brazilian patients with hereditary hemochromatosis (HH) are neither homozygous for the C282Y mutation nor compound heterozygous for the H63D and C282Y mutations that are associated with HH in Caucasians. Other mutations have been described in the HFE gene as well as in genes involved in iron metabolism, such as transferrin receptor 2 (TfR2) and ferroportin 1 (SCL40A1). To evaluate the role of HFE, TfR2 and SCL40A1 mutations in Brazilian subjects with HH. Nineteen male subjects (median age 42 [range: 20-72] years) with HH were evaluated using the Haemochromatosis StripAssay A. This assay is capable of detecting twelve HFE mutations, which are V53M, V59M, H63D, H63H, S65C, Q127H, P160delC, E168Q, E168X, W169X, C282Y and Q283, four TfR2 mutations, which are E60X, M172K, Y250X, AVAQ594-597del, and two SCL40A1 mutations, which are N144H and V162del. In our cohort, nine (47%) patients were homozygous for the C282Y mutation, two (11%) were heterozygous for the H63D mutation, and one each (5%) was either heterozygous for C282Y or compound heterozygous for C282Y and H63D. No other mutations in the HFE, TfR2 or SCL40A1 genes were observed in the studied patients. One-third of Brazilian subjects with the classical phenotype of HH do not carry HFE or other mutations that are currently associated with the disease in Caucasians. This observation suggests a role for other yet unknown mutations in the aforementioned genes or in other genes involved in iron homeostasis in the pathogenesis of HH in Brazil.

Epidemiology of hereditary ocular disorders.

PubMed

Rosenberg, Thomas

2003-01-01

Molecular genetic evidence has contributed significantly to the understanding of the fundamental molecular biology of the eye in health and disease, but it has also exposed the inadequacy of our traditional clinically based classification of hereditary eye disorders by unravelling significant genetic non-allelic heterogeneity in many eye disorders. Furthermore, our understanding of the epidemiology of hereditary ocular disorders has gained considerably by the establishment of mutation spectra in a rapidly growing number of monogenic eye disorders. In this overview, special emphasis has been put on the growing impact of genetic eye diseases in visual impairment, genetic heterogeneity, and the role of founder mutations for the skewed appearance of certain hereditary ocular disorders in some populations.

Hemochromatosis and Iron Overload Screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.

PubMed

McLaren, Christine E; Barton, James C; Adams, Paul C; Harris, Emily L; Acton, Ronald T; Press, Nancy; Reboussin, David M; McLaren, Gordon D; Sholinsky, Phyliss; Walker, Ann P; Gordeuk, Victor R; Leiendecker-Foster, Catherine; Dawkins, Fitzroy W; Eckfeldt, John H; Mellen, Beverly G; Speechley, Mark; Thomson, Elizabeth

2003-02-01

The HEIRS Study will evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multiethnic, primary care-based sample of 100,000 adults over a 5-year period. Participants are recruited from 5 Field Centers. Laboratory testing and data management and analysis are performed in a Central Laboratory and Coordinating Center, respectively. Participants undergo testing for serum iron measures and common mutations of the hemochromatosis gene ( ) on chromosome 6p and answer questions on demographics, health, and genetic testing attitudes. Participants with elevated values of transferrin saturation and serum ferritin and/or C282Y homozygosity are invited to undergo a comprehensive clinical examination (CCE), as are frequency-matched control subjects. These examinations provide data on personal and family medical history, lifestyle characteristics, physical examination, genetic counseling, and assessment of ethical, legal, and social implications. Primary and secondary causes of iron overload will be distinguished by clinical criteria. Iron overload will be confirmed by quantification of iron stores. Recruiting family members of cases will permit DNA analysis for additional genetic factors that affect iron overload. Of the first 50,520 screened, 51% are white, 24% are African American, 11% are Asian, 11% are Hispanic, and 3% are of other, mixed, or unidentified race; 63% are female and 37% are male. Information from the HEIRS Study will inform policy regarding the feasibility, optimal approach, and potential individual and public health benefits and risks of primary care-based screening for iron overload and hemochromatosis.

[Hereditary gastric and pancreatic cancer predisposition syndromes].

PubMed

Leoz, María Liz; Sánchez, Ariadna; Carballal, Sabela; Ruano, Lucía; Ocaña, Teresa; Pellisé, María; Castells, Antoni; Balaguer, Francesc; Moreira, Leticia

2016-01-01

The most common hereditary gastrointestinal cancers are colorectal, mainly hereditary nonpolyposis colorectal cancer (Lynch syndrome) and familial adenomatous polyposis. Other extracolonic neoplasms, including the gastric and pancreatic adenocarcinomas, are less well known and studied because they account for a relatively small percentage of hereditary gastrointestinal cancers. Nonetheless, they merit special attention because of the high associated morbidity and mortality rates. We review the hereditary and familial syndromes associated with gastric and pancreatic cancers with a view to improving knowledge and understanding of these diseases, in order to heighten diagnostic suspicion and thus implement appropriate diagnostic strategies, screening, surveillance and treatment. Copyright © 2016 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.

[Hereditary angioedema: a therapeutic revolution].

PubMed

Bouillet, L

2012-03-01

Hereditary angioedema is a rare disease, often diagnosed with delay because of a heterogeneous clinical presentation. Before diagnosis, patients frequently present subcutaneous edema or abdominal pains during many years. Laryngeal edema can be life-threatening. Hereditary angioedema may impair the quality of life of the patients and their social and professional life. It is important that the physicians recognize and treat the disease as soon as possible after the first attacks. Since the past five years, new drugs developed for hereditary angioedema have changed dramatically the outcome of this disorder. The objective of this review is to detail the new therapeutic guidelines. Copyright © 2012 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Hereditary medullary thyroid carcinoma: the management dilemma.

PubMed

Zhou, Ping; Liu, Jian; Cheng, Shao-Wen; Wang, Bing; Yang, Rong; Peng, Ling

2012-06-01

Hereditary medullary thyroid carcinoma (hereditary MTC) is a rare malignancy, accounting for 25-30% of all MTC. It occurs as part of multiple endocrine neoplasia type 2 (MEN 2). Autosomal dominant gain-of-function mutations in the RET proto-oncogene is the cause of the disease, in which the common mutations are codons 609, 611, 618, 620, 630, 634 and 918. In recent years, the spectrum of RET gene mutations has changed. The classical mutations reduced, whereas the less aggressive mutations increased. Hereditary MTC is a time-dependent disease. Stages of the disorder at diagnosis can significantly influence survival rates. Based on the genotype-phenotype, RET mutations have been classified into four risk levels by American Thyroid Association (ATA) at 2009. The classification system guides the hereditary MTC management, including risk assessment, biochemical screenings and surgical intervention. Though the application of genetic testing and codon-specific phenotypes in hereditary MTC diagnosis is effective with high accuracy, there are some difficulties in implementing RET gene testing as a routine for MTC diagnosis. And most of carriers with RET mutations did not undergo thyroidectomy at the age recommended by the ATA guidelines. The aim of the study is to review the hereditary MTC and discuss the management dilemma.

Genetics Home Reference: hereditary hemorrhagic telangiectasia

MedlinePlus

... Central OMIM: JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic ... 10.1097/GIM.0b013e3182136d32. Review. Citation on PubMed McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead ...

Genetics Home Reference: distal hereditary motor neuropathy, type II

MedlinePlus

... hereditary motor neuropathy, type II Distal hereditary motor neuropathy, type II Printable PDF Open All Close All ... the expand/collapse boxes. Description Distal hereditary motor neuropathy, type II is a progressive disorder that affects ...

A Method for the Construction of Hereditary Constitutive Equations of Laminates Bases on a Hereditary Constitutive Equation for a Layer

NASA Astrophysics Data System (ADS)

Dumansky, Alexander M.; Tairova, Lyudmila P.

2008-09-01

A method for the construction of hereditary constitutive equation is proposed for the laminate on the basis of hereditary constitutive equations of a layer. The method is developed from the assumption that in the directions of axes of orthotropy the layer follows elastic behavior, and obeys hereditary constitutive equations under shear. The constitutive equations of the laminate are constructed on the basis of classical laminate theory and algebra of resolvent operators. Effective matrix algorithm and relationships of operator algebra are used to derive visco-elastic stiffness and compliance of the laminate. The example of construction of hereditary constitutive equations of cross-ply carbon fiber-reinforced plastic is presented.

Clinical guideline seom: hereditary colorectal cancer.

PubMed

Guillén-Ponce, C; Serrano, R; Sánchez-Heras, A B; Teulé, A; Chirivella, I; Martín, T; Martínez, E; Morales, R; Robles, L

2015-12-01

Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer; these mutations are estimated to account for only 5-6 % of colorectal cancer (CRC) cases overall. Up to 25-30 % of patients have a family history of CRC that suggests a hereditary component, common exposures among family members, or a combination of both. Cancers in people with a hereditary predisposition typically occur at an earlier age than in sporadic cases. A predisposition to CRC may include a predisposition to other cancers, such as endometrial cancer. We describe genetics, current diagnosis and management of CRC hereditary syndromes pointing to a multidisciplinary approach to achieve the best results in patients and family outcomes.

Morbidity and mortality in first-degree relatives of C282Y homozygous probands with clinically detected haemochromatosis compared with the general population: the HEmochromatosis FAmily Study (HEFAS).

PubMed

Jacobs, E M G; Hendriks, J C M; Marx, J J M; van Deursen, C Th B M; Kreeftenberg, H G; de Vries, R A; Stalenhoef, A F H; Verbeek, A L M; Swinkels, D W

2007-12-01

Family screening has been suggested as a sophisticated model for the early detection of HFE-related hereditary haemochromatosis (HH). However, until now, controlled studies on the morbidity and mortality in families with HH are lacking. Data on iron parameters, morbidity and mortality were collected from 224 dutch C282Y-homozygous probands with clinically overt HH and 735 of their first-degree family members, all participating in the HEmochromatosis fAmily study (HEfAs). These data were compared with results obtained from an age- and gender-matched normal population. HEfAs and controls filled in similar questionnaires on demographics, lifestyle factors, health, morbidity and mortality. A significantly higher proportion of the HEfAs first-degree family members reported to be diagnosed with haemochromatosis-related diseases: 45.7 vs 19.4% of the matched normal population (McNemar p<0.001). Mortality among siblings, children and parents in the HEFAS population was similar to that in the relatives of matched control. In this study we show that, morbidity among first-degree family members of C282Y-homozygous probands previously diagnosed with clinically proven HH is higher than that in an age- and gender-matched normal population. Further studies are needed to definitely connect these increase morbidity figures to increase prevalenc of the C282Y mutated HFE-gene and elevated serum iron indices.

Thyroid-stimulating hormone and free thyroxine levels in persons with HFE C282Y homozygosity, a common hemochromatosis genotype: the HEIRS study.

PubMed

Barton, James C; Leiendecker-Foster, Catherine; Reboussin, David M; Adams, Paul C; Acton, Ronald T; Eckfeldt, John H

2008-08-01

Relationships of thyroid and iron measures in large cohorts are unreported. We evaluated thyroid-stimulating hormone (TSH) and free thyroxine (T4) in white participants of the primary care-based Hemochromatosis and Iron Overload Screening (HEIRS) Study. We measured serum TSH and free T4 in 176 HFE C282Y homozygotes without previous hemochromatosis diagnoses and in 312 controls without HFE C282Y or H63D who had normal serum iron measures and were matched to C282Y homozygotes for Field Center, age group, and initial screening date. We defined hypothyroidism as having TSH >5.00 mIU/L and free T4 <0.70 ng/dL, and hyperthyroidism as having TSH <0.400 mIU/L and free T4 >1.85 ng/dL. Multivariate analyses were performed using age, sex, Field Center, log(10) serum ferritin (SF), HFE genotype, log(10) TSH, and log(10) free T4. Prevalences of hypothyroidism in C282Y homozygotes and controls were 1.7% and 1.3%, respectively, and of hyperthyroidism 0% and 1.0%, respectively. Corresponding prevalences did not differ significantly. Correlations of log(10) SF with log(10) free T4 were positive (p = 0.2368, C282Y homozygotes; p = 0.0492, controls). Independent predictors of log(10) free T4 were log(10) TSH (negative association) and age (positive association); positive predictors of log(10) SF were age, male sex, and C282Y homozygosity. Proportions of C282Y homozygotes and controls who took medications to supplement or suppress thyroid function did not differ significantly. Prevalences of hypothyroidism and hyperthyroidism are similar in C282Y homozygotes without previous hemochromatosis diagnoses and controls. In controls, there is a significant positive association of SF with free T4. We conclude that there is no rationale for routine measurement of TSH or free T4 levels in hemochromatosis or iron overload screening programs.

Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene.

PubMed

Altès, Albert; Bach, Vanessa; Ruiz, Angels; Esteve, Anna; Felez, Jordi; Remacha, Angel F; Sardà, M Pilar; Baiget, Montserrat

2009-10-01

Most hereditary hemochromatosis (HH) patients are homozygous for the C282Y mutation of the HFE gene. Nevertheless, penetrance of the disease is very variable. In some patients, penetrance can be mediated by concomitant mutations in other iron master genes. We evaluated the clinical impact of hepcidin (HAMP) and hemojuvelin mutations in a cohort of 100 Spanish patients homozygous for the C282Y mutation of the HFE gene. HAMP and hemojuvelin mutations were evaluated in all patients by bidirectional direct cycle sequencing. Phenotype-genotype interactions were evaluated. A heterozygous mutation of the HAMP gene (G71D) was found in only one out of 100 cases. Following, we performed a study of several members of that family, and we observed several members had a digenic inheritance of the C282Y mutation of the HFE gene and the G71D mutation of the HAMP gene. This mutation in the HAMP gene did not modify the phenotype of the individuals who were homozygous for the C282Y mutation. One other patient presented a new polymorphism in the hemojuvelin gene, without consequences in iron load or clinical course of the disease. In conclusion, HAMP and hemojuvelin mutations are rare among Spanish HH patients, and their impact in this population is not significant.

Morphological clues to the appropriate recognition of hereditary renal neoplasms.

PubMed

Moch, Holger; Ohashi, Riuko; Gandhi, Jatin S; Amin, Mahul B

2018-05-01

An important emerging role of the surgical pathologist besides the traditional tasks of establishment of the diagnosis and documentation of prognostic and predictive factors, is to recognize the possibility of a hereditary condition in cases where the histology is suggestive for a familial cancer syndrome. In recent years, the knowledge regarding all of the above roles, including the role of recognition of familial cancer, has particularly expanded in renal neoplasms with the close scrutiny to morphology, molecular correlates and clinical features of the different sub-types of renal cell carcinoma. Awareness of these clinically distinctive sub-types and their associated histologic clues will prompt the pathologist for further immunohistochemical or molecular work up, to look for clinical information to support the suspected diagnosis of familial cancer, to alert managing physician/s to look for stigmata of history of familial cancer, which will permit triaging patients and their families for appropriate genetic counseling. This review provides a comprehensive review of the known sub-types of renal cell carcinoma that have a predilection to occur in the setting of hereditary disease; examples include renal cancers occurring in the background of von Hippel Lindau disease, hereditary leiomyomatosis and renal cell carcinoma syndrome, tuberous sclerosis, Birt Hogg Dube syndrome and succinate dehydrogenase deficiency. Herein we focus on diagnostic clues for renal tumors occurring in a non-pediatric setting that should prompt their correct recognition and reiterate the importance of the correct diagnosis. Copyright © 2018 Elsevier Inc. All rights reserved.

Hereditary Gastrointestinal Cancer Syndromes

PubMed Central

Lynch, Jane F.; Shaw, Trudy G.

2011-01-01

ABSTRACT The rapid growth of molecular genetics and its attendant germline mutation discoveries has enabled identification of persons who are at an inordinately high cancer risk and, therefore, ideal candidates for prevention. However, one must fully appreciate the extensive genotypic and phenotypic heterogeneity that exists in hereditary cancer. Once the causative germline mutation has been identified in a patient, high-risk members of the family can be similarly tested and identified and provided highly targeted surveillance and management opportunities. DNA testing can change the individual's presumed risk status and affect decision making by patients and their physicians regarding surveillance and management. Our purpose is to describe familial/hereditary cancers of the gastrointestinal tract, including familial Barrett's esophagus, hereditary diffuse gastric cancer, gastrointestinal stromal tumors, familial adenomatous polyposis and desmoid tumors, Lynch syndrome, small bowel cancer, and familial pancreatic cancer. We use our discussion of Lynch syndrome as a model for diagnostic and clinical translation strategies for all hereditary gastrointestinal tract cancers, which clearly can then be extended to cancer of all anatomic sites. Highly pertinent questions from the patient's perspective include the following: What kind of counseling will be provided to a patient with a Lynch syndrome mutation, and should that counseling be mandatory? Does the proband have the responsibility to inform relatives about the familial mutation, even if the relatives do not want to know whether they carry it? Is the patient is responsible for notifying family members that a parent or sibling has Lynch syndrome? Can notification be forced and, if so, under what circumstances? These questions point out the need for criteria regarding which family members to inform and how to inform them. PMID:22368732

Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

PubMed

Giavina-Bianchi, Pedro; França, Alfeu T; Grumach, Anete S; Motta, Abílio A; Fernandes, Fátima R; Campos, Regis A; Valle, Solange O; Rosário, Nelson A; Sole, Dirceu

2011-01-01

Hereditary angioedema is an autosomal dominant disease characterized by edema attacks with multiple organ involvement. It is caused by a quantitative or functional deficiency of the C1 inhibitor, which is a member of the serine protease inhibitor family. Hereditary angioedema is unknown to many health professionals and is therefore an underdiagnosed disease. The causes of death from hereditary angioedema include laryngeal edema with asphyxia. The estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40%. In addition to edema of the glottis, hereditary angioedema often results in edema of the gastrointestinal tract, which can be incapacitating. Patients with hereditary angioedema may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, thus mimicking acute surgical abdomen. It is estimated that patients with hereditary angioedema experience some degree of disability 20-100 days per year. The Experts in Clinical Immunology and Allergy of the "Associação Brasileira de Alergia e Imunopatologia -ASBAI" developed these guidelines for the diagnosis, therapy, and management of hereditary angioedema.

Leigh-like encephalopathy complicating Leber's hereditary optic neuropathy.

PubMed

Funalot, Benoît; Reynier, Pascal; Vighetto, Alain; Ranoux, Danièle; Bonnefont, Jean-Paul; Godinot, Catherine; Malthièry, Yves; Mas, Jean-Louis

2002-09-01

Leber's hereditary optic neuropathy is a mitochondrial disease caused by point mutations in mitochondrial DNA. It usually presents as severe bilateral visual loss in young adults. We report on a neurological disorder resembling Leigh syndrome, which complicated Leber's hereditary optic neuropathy in three unrelated male patients harboring mitochondrial DNA mutations at nucleotide positions 3460, 14459, and 14484, respectively. This Leigh-like encephalopathy appears to be associated with a much more severe outcome than isolated Leber's hereditary optic neuropathy.

The establishment and utility of Sweha-Reg: a Swedish population-based registry to understand hereditary angioedema

PubMed Central

Mallbris, Lotus; Nordenfelt, Patrik; Björkander, Janne; Lindfors, Anders; Werner, Sonja; Wahlgren, Carl-Fredrik

2007-01-01

Background The importance of acquiring comprehensive epidemiological and clinical data on hereditary angioedema has increasingly caught the attention of physicians and scientists around the world. The development of networks and creation of comprehensive policies to improve care of people suffering from rare diseases, such as hereditary angioedema, is a stated top priority of the European Union. Hereditary angioedema is a rare disease, that it may be life-threatening. Although the exact prevalence is unknown, current estimates suggest that it is 1/10,000–1/150,000 individuals. The low prevalence requires combined efforts to gain accurate epidemiological data on the disease and so give us tools to reduce morbidity and mortality, and improve quality of life of sufferers. Methods Sweha-Reg is a population-based registry of hereditary angioedema in Sweden with the objectives of providing epidemiological data, and so creates a framework for the study of this disease. The registry contains individual-based data on diagnoses, treatments and outcomes. Conclusion The present manuscript seeks to raise awareness of the existence of Sweha-Reg to stimulate the international collaboration of registries. A synthesis of data from similar registries across several countries is required to approach an inclusive course understanding of HAE. PMID:18053127

Hereditary Gingival Fibromatosis

ERIC Educational Resources Information Center

Nevin, N. C.

1971-01-01

Case studies of two siblings suffering from a gum disorder in which enlargement of the gingival mucosa is caused by a fibrosis. The disorder in the two children was felt to be an hereditary recessive trait. (CD)

[Clinicopathological characteristics of hereditary ovarian cancer syndrome].

PubMed

Zhong, Yan; Sheng, Xiu-gui; Ma, Zhi-fang; Ma, Yue-bing; Liu, Nai-fu; Chen, Yue-ting; Gao, Rong; Wang, Ying-ying; Sun, Li

2009-09-01

To explore the clinicopathological characteristics of hereditary ovarian cancer syndrome (HOCS). From Jan. 2000 to Jan. 2007, among 580 cases of primary ovarian cancer, 42 cases (hereditary group), who had a positive family history of ovarian cancer and met the diagnostic criteria of HOCS, were analyzed retrospectively. One hundred cases without a family history of ovarian cancer were enrolled randomizely as control group (sporadic group). The incidence of HOCS was 7.2% (42/580). Forty-two cases associated tumors affected at least 2 successive generations in 31 families and affected 1 generation in 8 families. Eighty-seven percent (27/31) was from maternal lineage, while 13% (4/31) from paternal lineage. Earlier age of onset was significantly difference between two groups [(49 +/- 10) years vs. (55 +/- 10) years, P < 0.05]. There were 90% belong to serous adenocarcinoma in the hereditary group, while 84% in the sporadic group. There was statistical difference in the proportion of mucinous adenocarcinoma (0 vs. 11%, P < 0.05). The most common clinical manifestations were abdominal distention and anorexia (64% vs. 70%, P > 0.05), International Federational of Gynecology Obstetrics (FIGO) stage III (62% vs. 63%, P > 0.05) between two groups. Fourteen cases (33%,14/42) were previously untreated in the hereditary group, while 40 cases (40%, 40/100) in the sporadic group. There were 15 cases (36%, 15/42) underwent secondary surgery and 15 cases (36%, 15/42) underwent third surgery or more in hereditary group, while 50 cases (50%,50/100) and 27 cases (27%, 27/100) in the sporadic group. The mean number of chemotherapy cycles received in two groups was 13.3 and 11.8 (P > 0.05). The 3-year and 5-year survival rate in hereditary group were 73.6% and 54.9% respectively, compared with 47.4% and 21.2% (P < 0.05) in sporadic group. Hereditary ovarian cancer mostly from maternal lineage are featuring in early age of onset, serous adenocarcinoma, advanced stage (stage III), and

Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study in 150 patients grouped according to molecular and clinical characteristics

PubMed Central

Bianchi, Paola; Fermo, Elisa; Vercellati, Cristina; Marcello, Anna P.; Porretti, Laura; Cortelezzi, Agostino; Barcellini, Wilma; Zanella, Alberto

2012-01-01

Background The laboratory diagnosis of hereditary spherocytosis commonly relies on NaCl-based or glycerol-based red cell osmotic fragility tests; more recently, an assay directly targeting the hereditary spherocytosis molecular defect (eosin-5′-maleimide-binding test) has been proposed. None of the available tests identifies all cases of hereditary spherocytosis. Design and Methods We compared the performances of the eosin-5′-maleimide-binding test, NaCl-osmotic fragility studies on fresh and incubated blood, the glycerol lysis test, the acidified glycerol lysis test, and the Pink test on a series of 150 patients with hereditary spherocytosis grouped according to clinical phenotype and the defective protein, with the final aim of finding the combination of tests associated with the highest diagnostic power, even in the mildest cases of hereditary spherocytosis. Results The eosin-5′-maleimide-binding test had a sensitivity of 93% and a specificity of 98% for detecting hereditary spherocytosis: the sensitivity was independent of the type and amount of molecular defect and of the clinical phenotype. The acidified glycerol lysis test and Pink test showed comparable sensitivity (95% and 91%). The sensitivity of NaCl osmotic fragility tests, commonly considered the gold standard for the diagnosis of hereditary spherocytosis, was 68% on fresh blood and 81% on incubated blood, and further decreased in compensated cases (53% and 64%, respectively). The combination of the eosin-5′-maleimide-binding test and acidified glycerol lysis test enabled all patients with hereditary spherocytosis to be identified. The eosin-5′-maleimide-binding test showed the greatest disease specificity. Conclusions Each type of test fails to diagnose some cases of hereditary spherocytosis. The association of an eosin-5′-maleimide-binding test and an acidified glycerol lysis test enabled identification of all patients with hereditary spherocytosis in this series and, therefore

Erythrocytapheresis compared with whole blood phlebotomy for the treatment of hereditary haemochromatosis

PubMed Central

Sundic, Tatjana; Hervig, Tor; Hannisdal, Signe; Assmus, Jörg; Ulvik, Rune J.; Olaussen, Richard W.; Berentsen, Sigbjørn

2014-01-01

Background Hereditary haemochromatosis may result in severe organ damage which can be prevented by therapy. We studied the possible advantages and disadvantages of erythrocytapheresis as compared with phlebotomy in patients with hereditary haemochromatosis. Materials and methods In a prospective, randomised, open-label study, patients with hereditary haemochromatosis were randomised to bi-weekly apheresis or weekly whole blood phlebotomy. Primary end-points were decrease in ferritin levels and transferrin saturation. Secondary endpoints were decrease in haemoglobin levels, discomfort during the therapeutic procedure, costs and technicians’ working time. Results Sixty-two patients were included. Thirty patients were randomised to apheresis and 32 to whole blood phlebotomy. Initially, ferritin levels declined more rapidly in the apheresis group, and the difference became statistically highly significant at 11 weeks; however, time to normalisation of ferritin level was equal in the two groups. We observed no significant differences in decline of transferrin saturation, haemoglobin levels or discomfort. The mean cumulative technician time consumption until the ferritin level reached 50 μg/L was longer in the apheresis group, but the difference was not statistically significant. The cumulative costs for materials until achievement of the desired ferritin levels were three-fold higher in the apheresis group. Conclusion Treatment of hereditary haemochromatosis with erythrocytapheresis instead of whole blood phlebotomy results in a more rapid initial decline in ferritin levels and a reduced number of procedures per patient, but not in earlier achievement of target ferritin level. The frequency of discomfort was equally low with the two methods. The costs and, probably, technician time consumption were higher in the apheresis group. PMID:24333062

HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.

PubMed

Gurrin, Lyle C; Bertalli, Nadine A; Dalton, Gregory W; Osborne, Nicholas J; Constantine, Clare C; McLaren, Christine E; English, Dallas R; Gertig, Dorota M; Delatycki, Martin B; Nicoll, Amanda J; Southey, Melissa C; Hopper, John L; Giles, Graham G; Anderson, Gregory J; Olynyk, John K; Powell, Lawrie W; Allen, Katrina J

2009-07-01

The risk of hemochromatosis-related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population-based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis-related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE-genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, completed questionnaires and gave blood. Clinical examinations were blinded to HFE genotype. A total of 180 (84 males) clinically examined C282Y/H63D participants were compared with 330 (149 males) controls with neither HFE mutation; 132 (65 males) and 270 (122 males), respectively, had serum iron measures at both timepoints. Mean serum ferritin (SF) and transferrin saturation (TS) were significantly greater for male and female compound heterozygotes than for wild-types at baseline and follow-up (all P < 0.02) except for females who were premenopausal at baseline, where SF was similar in both genotype groups. For subjects with serum measures from both baseline and follow-up, mean SF and TS levels did not change significantly for men or for postmenopausal women, but for premenopausal women SF levels increased from 43 to 109 microg/L for compound heterozygotes and from 35 to 64 microg/L for wild-types (both P < 0.001). Male and female compound heterozygotes had a similar prevalence of hemochromatosis-related morbidity to wild-types. One of 82 males and zero of 95 females had documented iron overload-related disease. For male compound heterozygotes, mean iron indices do not change during middle age but for female compound heterozygotes menopause results in increased mean SF. Although compound heterozygotes might maintain elevated iron indices during middle age, documented iron overload-related disease is rare.

Allelic variants of hereditary prions: The bimodularity principle.

PubMed

Tikhodeyev, Oleg N; Tarasov, Oleg V; Bondarev, Stanislav A

2017-01-02

Modern biology requires modern genetic concepts equally valid for all discovered mechanisms of inheritance, either "canonical" (mediated by DNA sequences) or epigenetic. Applying basic genetic terms such as "gene" and "allele" to protein hereditary factors is one of the necessary steps toward these concepts. The basic idea that different variants of the same prion protein can be considered as alleles has been previously proposed by Chernoff and Tuite. In this paper, the notion of prion allele is further developed. We propose the idea that any prion allele is a bimodular hereditary system that depends on a certain DNA sequence (DNA determinant) and a certain epigenetic mark (epigenetic determinant). Alteration of any of these 2 determinants may lead to establishment of a new prion allele. The bimodularity principle is valid not only for hereditary prions; it seems to be universal for any epigenetic hereditary factor.

Allelic variants of hereditary prions: The bimodularity principle

PubMed Central

Tikhodeyev, Oleg N.; Tarasov, Oleg V.; Bondarev, Stanislav A.

2017-01-01

ABSTRACT Modern biology requires modern genetic concepts equally valid for all discovered mechanisms of inheritance, either “canonical” (mediated by DNA sequences) or epigenetic. Applying basic genetic terms such as “gene” and “allele” to protein hereditary factors is one of the necessary steps toward these concepts. The basic idea that different variants of the same prion protein can be considered as alleles has been previously proposed by Chernoff and Tuite. In this paper, the notion of prion allele is further developed. We propose the idea that any prion allele is a bimodular hereditary system that depends on a certain DNA sequence (DNA determinant) and a certain epigenetic mark (epigenetic determinant). Alteration of any of these 2 determinants may lead to establishment of a new prion allele. The bimodularity principle is valid not only for hereditary prions; it seems to be universal for any epigenetic hereditary factor. PMID:28281926

Hereditary Hearing Loss.

ERIC Educational Resources Information Center

Tran, LenhAnh P.; Grundfast, Kenneth M.

1997-01-01

This article discusses inheritance patterns in hearing loss, epidemiology, clues to genetic causes, locating genes that cause hereditary disorders, genes related to hearing loss disorders in individuals with Usher syndrome, Waardenburg syndrome, Treacher-Collins syndrome, Branchio-oto-renal and Pendred syndromes, and the significance of finding…

Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

PubMed

Agudo, Antonio; Bonet, Catalina; Sala, Núria; Muñoz, Xavier; Aranda, Núria; Fonseca-Nunes, Ana; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie Christine; Vineis, Paolo; Panico, Salvatore; Palli, Domenico; Tumino, Rosario; Grioni, Sara; Quirós, J Ramón; Molina, Esther; Navarro, Carmen; Barricarte, Aurelio; Chamosa, Saioa; Allen, Naomi E; Khaw, Kay-Tee; Bueno-de-Mesquita, H Bas; Siersema, Peter D; Numans, Mattijs E; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Kaaks, Rudof; Canzian, Federico; Boeing, Heiner; Meidtner, Karina; Johansson, Mattias; Sund, Malin; Manjer, Jonas; Overvad, Kim; Tjonneland, Anne; Lund, Eiliv; Weiderpass, Elisabete; Jenab, Mazda; Fedirko, Veronika; Offerhaus, G Johan A; Riboli, Elio; González, Carlos A; Jakszyn, Paula

2013-06-01

Hereditary hemochromatosis (HH) is a strong risk factor for hepatocellular cancer, and mutations in the HFE gene associated with HH and iron overload may be related to other tumors, but no studies have been reported for gastric cancer (GC). A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 365 incident gastric adenocarcinoma and 1284 controls matched by center, sex, age and date of blood collection. Genotype analysis was performed for two functional polymorphisms (C282Y/rs1800562 and H63D/rs1799945) and seven tagSNPs of the HFE genomic region. Association with all gastric adenocarcinoma, and according to anatomical localization and histological subtype, was assessed by means of the odds ratio (OR) and 95% confidence interval (CI) estimated by unconditional logistic regression adjusted for the matching variables. We observed a significant association for H63D with OR (per rare allele) of 1.32 (CI = 1.03-1.69). In subgroup analyses, the association was stronger for non-cardia anatomical subsite (OR = 1.60, CI = 1.16-2.21) and intestinal histological subtype (OR = 1.82, CI = 1.27-2.62). Among intestinal cases, two tagSNPs (rs1572982 and rs6918586) also showed a significant association that disappeared after adjustment for H63D. No association with tumors located in the cardia or with diffuse subtype was found for any of the nine SNPs analyzed. Our results suggest that H63D variant in HFE gene seems to be associated with GC risk of the non-cardia region and intestinal type, possibly due to its association with iron overload although a role for other mechanisms cannot be entirely ruled out.

Genetics Home Reference: hereditary myopathy with early respiratory failure

MedlinePlus

... Home Health Conditions HMERF Hereditary myopathy with early respiratory failure Printable PDF Open All Close All Enable ... expand/collapse boxes. Description Hereditary myopathy with early respiratory failure ( HMERF ) is an inherited muscle disease that ...

Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis.

PubMed

de Tayrac, Marie; Roth, Marie-Paule; Jouanolle, Anne-Marie; Coppin, Hélène; le Gac, Gérald; Piperno, Alberto; Férec, Claude; Pelucchi, Sara; Scotet, Virginie; Bardou-Jacquet, Edouard; Ropert, Martine; Bouvet, Régis; Génin, Emmanuelle; Mosser, Jean; Deugnier, Yves

2015-03-01

Hereditary hemochromatosis (HH) is the most common form of genetic iron loading disease. It is mainly related to the homozygous C282Y/C282Y mutation in the HFE gene that is, however, a necessary but not a sufficient condition to develop clinical and even biochemical HH. This suggests that modifier genes are likely involved in the expressivity of the disease. Our aim was to identify such modifier genes. We performed a genome-wide association study (GWAS) using DNA collected from 474 unrelated C282Y homozygotes. Associations were examined for both quantitative iron burden indices and clinical outcomes with 534,213 single nucleotide polymorphisms (SNP) genotypes, with replication analyses in an independent sample of 748 C282Y homozygotes from four different European centres. One SNP met genome-wide statistical significance for association with transferrin concentration (rs3811647, GWAS p value of 7×10(-9) and replication p value of 5×10(-13)). This SNP, located within intron 11 of the TF gene, had a pleiotropic effect on serum iron (GWAS p value of 4.9×10(-6) and replication p value of 3.2×10(-6)). Both serum transferrin and iron levels were associated with serum ferritin levels, amount of iron removed and global clinical stage (p<0.01). Serum iron levels were also associated with fibrosis stage (p<0.0001). This GWAS, the largest one performed so far in unselected HFE-associated HH (HFE-HH) patients, identified the rs3811647 polymorphism in the TF gene as the only SNP significantly associated with iron metabolism through serum transferrin and iron levels. Because these two outcomes were clearly associated with the biochemical and clinical expression of the disease, an indirect link between the rs3811647 polymorphism and the phenotypic presentation of HFE-HH is likely. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Type I hereditary punctate keratoderma.

PubMed

Asadi, Arash K

2003-10-01

A 75-year-old man with a history of prostatic carcinoma and atypical fibroxanthoma reports a long-standing history of 1-2 mm depressed, hyperkeratotic papules on the palms. His mother suffered a similar condition. Histologically, the papules demonstrated hyperkeratosis, without columns of parakeratosis. A diagnosis of type I hereditary punctate keratoderma (Buschke-Fisher-Brauer disease) was made. This condition, which is classified as one of the three hereditary forms of punctate palmoplantar keratoderma, is an autosomal-dominant condition with variable penetrance. It is characterized clinically by multiple, tiny, punctate keratoses of the palms and soles. Affected individuals appear to be at increased risk of developing malignant conditions.

Hereditary angioedema: a bradykinin-mediated swelling disorder.

PubMed

Björkqvist, Jenny; Sala-Cunill, Anna; Renné, Thomas

2013-03-01

Edema is tissue swelling and is a common symptom in a variety of diseases. Edema form due to accumulation of fluids, either through reduced drainage or increased vascular permeability. There are multiple vascular signalling pathways that regulate vessel permeability. An important mediator that increases vascular leak is the peptide hormone bradykinin, which is the principal agent in the swelling disorder hereditary angioedema. The disease is autosomal dominant inherited and presents clinically with recurrent episodes of acute swelling that can be life-threatening involving the skin, the oropharyngeal, laryngeal, and gastrointestinal mucosa. Three different types of hereditary angiodema exist in patients. The review summarises current knowledge on the pathophysiology of hereditary angiodema and focuses on recent experimental and pharmacological findings that have led to a better understanding and new treatments for the disease.

[Paediatric retinal detachment and hereditary vitreoretinal disorders].

PubMed

Meier, P

2013-09-01

The number of retinal detachments in children is very low in comparison to the number in adults. One predisposing factor for development of paediatric retinal detachment is suffering from hereditary vitreoretinal degeneration (e.g., Stickler syndrome, Wagner syndrome, Kniest dysplasia, familial exudative vitreoretinopathy, congenital X-linked retinoschisis, Knobloch syndrome, incontinentia pigmenti, Norrie disease). Hereditary vitreoretinopathies are characterised by an abnormal-appearing vitreous gel with associated retinal changes. In most of these eyes further ocular abnormalities can be diagnosed. A group of hereditary disorders is associated with characteristic systemic abnormalities. Allied conditions should be considered in the clinical diagnosis. Vitreoretinopathies are the most common cause of inherited retinal detachment. In most eyes primary vitrectomy is necessary, and disease-specific surgical treatment is discussed. Georg Thieme Verlag KG Stuttgart · New York.

Genetics Home Reference: hereditary leiomyomatosis and renal cell cancer

MedlinePlus

... Home Health Conditions HLRCC Hereditary leiomyomatosis and renal cell cancer Printable PDF Open All Close All Enable Javascript ... expand/collapse boxes. Description Hereditary leiomyomatosis and renal cell cancer ( HLRCC ) is a disorder in which affected individuals ...

Intention to Obtain Genetic Testing for Melanoma among Individuals at Low to Moderate Risk for Hereditary Melanoma

ERIC Educational Resources Information Center

Vadaparampil, Susan T.; Azzarello, Lora; Pickard, Jennifer; Jacobsen, Paul B.

2007-01-01

Background: Melanoma is a serious skin cancer that has been on the rise in the United States. Some genetic component is apparent. Purpose: The purpose of this study was to identify demographic, clinical, attitudinal, and health belief factors associated with intention to obtain genetic testing for hereditary melanoma among unaffected first-degree…

Is Pancreatic Cancer Hereditary?

MedlinePlus

... Trials Database Supporting Research Raising Awareness Our Blog Patient Education Pancreas News Basics of Pancreatic Cancer FAQs The ... Detection- Goggins Lab Sol Goldman Center Discussion Board Patient Education / Basics of Pancreatic Cancer Is pancreatic cancer hereditary? ...

The Southern French registry of genetic hemochromatosis: a tool for determining clinical prevalence of the disorder and genotype penetrance.

PubMed

Aguilar-Martinez, Patricia; Bismuth, Michael; Blanc, François; Blanc, Pierre; Cunat, Severine; Dereure, Olivier; Dujols, Pierre; Giansily-Blaizot, Muriel; Jorgensen, Christian; Konate, Amadou; Larrey, Dominique; Le Quellec, Alain; Mura, Thibault; Raingeard, Isabelle; Ramos, Jeanne; Renard, Eric; Rousseau, Florence; Schved, Jean-François; Picot, Marie-Christine

2010-04-01

Despite great progress in understanding the mechanisms underlying genetic hemochromatosis, data on the prevalence and the penetrance of the disorder are conflicting. A registry of patients with genetic hemochromatosis was established in the South of France and a regional health network was developed to allow the inclusion of all the diagnosed patients. C282Y homozygous patients classified in stages 2 (biological iron overload), 3 and 4 (clinical manifestations of iron overload, stage 4 being the more severe) according to the classification of the French National Authority for Health were included in the registry over a 6-year period. A total of 352 symptomatic C282Y homozygotes were identified, resulting in a total prevalence of 1.83 per 10,000 (95% CI: 1.63 to 2.02) in subjects over 20 years and 2.40 per 10,000 (95% CI, 2.15 to 2.65) among subjects of European descent. Among Europeans, the total calculated penetrance was 15.8% in stage 2 or higher, 12.1% in stage 3 or 4 and 2.9% in stage 4. The penetrance was slightly higher in males (18.7%) than in females (13.2%). It was 19.9% for individuals over 40 years of age (24.1% and 16.3% in males and females, respectively) with a maximum of 31% in subjects between 50 and 54 years old. Among 249 patients with complete records, 24% were in stage 2, the majority (58%) were in stage 3, and 18% in stage 4. There was a higher proportion of males, and excessive alcohol intake was more prevalent in stage 4 than in stages 2 and 3 combined. A French Mediterranean regional hemochromatosis registry with strict inclusion criteria is a useful tool for characterizing the history of this disease, particularly for the most severely affected patients, as defined by the disease severity classification. The total prevalence of symptomatic C282Y homozygotes in the region was found to be low. However, clinical penetrance (stages 3 and 4) was not negligible.

Hereditary and non-hereditary microangiopathies in the young. An up-date.

PubMed

Ringelstein, E Bernd; Kleffner, Ilka; Dittrich, Ralf; Kuhlenbäumer, Gregor; Ritter, Martin A

2010-12-15

In recent years, a considerable number of new sporadic or hereditary small artery diseases of the brain have been detected which preferably occur in younger age, below 45 years. Cerebral microangiopathies constitute an appreciable portion of all strokes. In middle aged patients, hereditary cerebral small vessel diseases have to be separated from sporadic degenerative cerebral microangiopathy which is mainly due to a high vascular risk load. Features of the following disorders and details how to differentiate them, are reviewed here, namely CADASIL, MELAS, AD-RVLC, HEMID, CARASIL, PADMAL, FABRY, COL4A1-related cerebral small vessel diseases and a Portuguese type of autosomal dominant cerebral small vessel disease (SVDB). The symptomatic overlap of the cerebral microangiopathies include also other distinctive non-hereditary diseases like posterior (reversible) encephalopathy and Susac's syndrome which are also described. Some of the microangiopathies described here are not only seen in the young but also in the elderly. The precise diagnosis has direct therapeutic implications in several of these entities. Cerebral microangiopathies cause recurring strokes and diffuse white matter lesions leading to a broad spectrum of gait disturbances and in most of these disorders cognitive impairment or even vascular dementia in the long term. Often, they also involve the eye, the inner ear or the kidney. Several typical imaging findings from illustrative cases are presented. The order in which these diseases are presented here is not dictated by an inner logic principle, because a genetically or pathophysiologically based classification system of all these entities does not exist yet. Some entities are well established and not unusual, whereas others have only been described in a few cases in total. Copyright © 2010 Elsevier B.V. All rights reserved.

Serum ferritin is a biomarker for liver mortality in the Hemochromatosis and Iron Overload Screening Study.

PubMed

Adams, Paul C; Barton, James C; Guo, Helen; Alter, David; Speechley, Mark

2015-01-01

We identified no reports of long-term follow-up of participants in hemochromatosis screening programs. We evaluated causes of death and survival in non-C282Y homozygous Canadian participants in the primary care-based hemochromatosis and iron overload screening (HEIRS) study. Initial screening (IS) included transferrin saturation (TS), serum ferritin (SF), HFE genotyping (C282Y, H63D), and health questionnaire responses. By definition, participants without C282Y or H63D had HFE wt/wt. We linked 20,306 Canadian participants to the Ontario Death Registry for dates and causes of death 9 y after IS. We computed Cox proportional hazards to identify factors with increased death risks and Kaplan-Meier curves to estimate survival of non-C282Y homozygous participants with SF ≤ 1,000 μg/L and > 1,000 μg/dL. There were 19,052 evaluable participants (IS mean age 49 y; 60% women; 93 C282Y homozygotes). There were 988 deaths. Significantly increased hazard ratios for all-cause mortality were positively associated with TS, SF, men, and C282Y homozygosity, and liver disease, diabetes, and heart failure reports. Non-C282Y homozygous participants with SF > 1,000 μg/L had lower survival than those with SF ≤ 1,000 μg/L (p < 0.0001). Nine years after initial screening, non-C282Y homozygous participants and SF > 1,000 μg/L was associated with decreased survival.

Hfe Deficiency Impairs Pulmonary Neutrophil Recruitment in Response to Inflammation

PubMed Central

Benesova, Karolina; Vujić Spasić, Maja; Schaefer, Sebastian M.; Stolte, Jens; Baehr-Ivacevic, Tomi; Waldow, Katharina; Zhou, Zhe; Klingmueller, Ursula; Benes, Vladimir; Mall, Marcus A.; Muckenthaler, Martina U.

2012-01-01

Regulation of iron homeostasis and the inflammatory response are tightly linked to protect the host from infection. Here we investigate how imbalanced systemic iron homeostasis in a murine disease model of hereditary hemochromatosis (Hfe−/− mice) affects the inflammatory responses of the lung. We induced acute pulmonary inflammation in Hfe−/− and wild-type mice by intratracheal instillation of 20 µg of lipopolysaccharide (LPS) and analyzed local and systemic inflammatory responses and iron-related parameters. We show that in Hfe−/− mice neutrophil recruitment to the bronchoalveolar space is attenuated compared to wild-type mice although circulating neutrophil numbers in the bloodstream were elevated to similar levels in Hfe−/− and wild-type mice. The underlying molecular mechanisms are likely multifactorial and include elevated systemic iron levels, alveolar macrophage iron deficiency and/or hitherto unexplored functions of Hfe in resident pulmonary cell types. As a consequence, pulmonary cytokine expression is out of balance and neutrophils fail to be recruited efficiently to the bronchoalveolar compartment, a process required to protect the host from infections. In conclusion, our findings suggest a novel role for Hfe and/or imbalanced iron homeostasis in the regulation of the inflammatory response in the lung and hereditary hemochromatosis. PMID:22745741

Population screening for genetic disorders in the 21st century: evidence, economics, and ethics.

PubMed

Grosse, S D; Rogowski, W H; Ross, L F; Cornel, M C; Dondorp, W J; Khoury, M J

2010-01-01

Proposals for population screening for genetic diseases require careful scrutiny by decision makers because of the potential for harms and the need to demonstrate benefits commensurate with the opportunity cost of resources expended. We review current evidence-based processes used in the United States, the United Kingdom, and the Netherlands to assess genetic screening programs, including newborn screening programs, carrier screening, and organized cascade testing of relatives of patients with genetic syndromes. In particular, we address critical evidentiary, economic, and ethical issues that arise in the appraisal of screening tests offered to the population. Specific case studies include newborn screening for congenital adrenal hyperplasia and cystic fibrosis and adult screening for hereditary hemochromatosis. Organizations and countries often reach different conclusions about the suitability of screening tests for implementation on a population basis. Deciding when and how to introduce pilot screening programs is challenging. In certain cases, e.g., hereditary hemochromatosis, a consensus does not support general screening although cascade screening may be cost-effective. Genetic screening policies have often been determined by technological capability, advocacy, and medical opinion rather than through a rigorous evidence-based review process. Decision making should take into account principles of ethics and opportunity costs. Copyright 2009 S. Karger AG, Basel.

Mutations in the hereditary haemochromatosis gene HFE in professional endurance athletes

PubMed Central

Chicharro, J; Hoyos, J; Gomez-Gallego, F; Villa, J; Bandres, F; Celaya, P; Jimenez, F; Alonso, J; Cordova, A; Lucia, A

2004-01-01

Background: Hereditary haemochromatosis, a disease that affects iron metabolism, progresses with a greater or lesser tendency to induce iron overload, possibly leading to severe organ dysfunction. Most elite endurance athletes take iron supplements during their active sporting life, which could aggravate this condition. Objective: To determine the prevalence and discuss potential clinical implications of mutations of HFE (the gene responsible for hereditary haemochromatosis) in endurance athletes. Methods: Basal concentrations of iron, ferritin, and transferrin and transferrin saturation were determined in the period before competition in 65 highly trained athletes. Possible mutations in the HFE gene were evaluated in each subject by extracting genomic DNA from peripheral blood. The restriction enzymes SnaBI and BclI were used to detect the mutations 845G→A (C282Y) and 187C→G (H63D). Results: Our findings indicate a high prevalence of HFE gene mutations in this population (49.2%) compared with sedentary controls (33.5%). No association was detected in the athletes between mutations and blood iron markers. Conclusions: The findings support the need to assess regularly iron stores in elite endurance athletes. PMID:15273174

Gastric tumours in hereditary cancer syndromes: clinical features, molecular biology and strategies for prevention.

PubMed

Sereno, María; Aguayo, Cristina; Guillén Ponce, Carmen; Gómez-Raposo, César; Zambrana, Francisco; Gómez-López, Miriam; Casado, Enrique

2011-09-01

Gastric cancer is the major cause of cancer-related deaths worldwide. The majority of them are classified as sporadic, whereas the remaining 10% exhibit familial clustering. Hereditary diffuse gastric cancer (HDGC) syndrome is the most important condition that leads to hereditary gastric cancer. However, other hereditary cancer syndromes, such as hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, Peutz-Jeghers syndrome, Li-Fraumeni syndrome and hereditary breast and ovarian cancer, entail a higher risk compared to the general population for developing this kind of neoplasia. In this review, we describe briefly the most important aspects related to clinical features, molecular biology and strategies for prevention in hereditary gastric associated to different cancer syndromes.

Open-heart surgery using a centrifugal pump: a case of hereditary spherocytosis.

PubMed

Matsuzaki, Yuichi; Tomioka, Hideyuki; Saso, Masaki; Azuma, Takashi; Saito, Satoshi; Aomi, Shigeyuki; Yamazaki, Kenji

2016-08-26

Hereditary spherocytosis is a genetic, frequently familial hemolytic blood disease characterized by varying degrees of hemolytic anemia, splenomegaly, and jaundice. There are few reports on adult open-heart surgery for patients with hereditary spherocytosis. We report a rare case of an adult open-heart surgery associated with hereditary spherocytosis. A 63-year-old man was admitted for congestive heart failure due to bicuspid aortic valve, aortic valve regurgitation, and sinus of subaortic aneurysm. The family history, the microscopic findings of the blood smear, and the characteristic osmotic fragility confirmed the diagnosis of hereditary spherocytosis. Furthermore, splenectomy had not been undertaken preoperatively. The patient underwent a successful operation by means of a centrifugal pump. Haptoglobin was used during the cardiopulmonary bypass, and a biological valve was selected to prevent hemolysis. No significant hemolysis occurred intraoperatively or postoperatively. There are no previous reports of patients with hereditary spherocytosis, and bicuspid aortic valve. We have successfully performed an adult open-heart surgery using a centrifugal pump in an adult patient suffering from hereditary spherocytosis and bicuspid aortic valve.

Label-free detection of DNA hybridization using carbon nanotube network field-effect transistors

NASA Astrophysics Data System (ADS)

Star, Alexander; Tu, Eugene; Niemann, Joseph; Gabriel, Jean-Christophe P.; Joiner, C. Steve; Valcke, Christian

2006-01-01

We report carbon nanotube network field-effect transistors (NTNFETs) that function as selective detectors of DNA immobilization and hybridization. NTNFETs with immobilized synthetic oligonucleotides have been shown to specifically recognize target DNA sequences, including H63D single-nucleotide polymorphism (SNP) discrimination in the HFE gene, responsible for hereditary hemochromatosis. The electronic responses of NTNFETs upon single-stranded DNA immobilization and subsequent DNA hybridization events were confirmed by using fluorescence-labeled oligonucleotides and then were further explored for label-free DNA detection at picomolar to micromolar concentrations. We have also observed a strong effect of DNA counterions on the electronic response, thus suggesting a charge-based mechanism of DNA detection using NTNFET devices. Implementation of label-free electronic detection assays using NTNFETs constitutes an important step toward low-cost, low-complexity, highly sensitive and accurate molecular diagnostics. hemochromatosis | SNP | biosensor

[Organization of medico-genetic counseling for hereditary hearing impairment].

PubMed

Markova, T G

2009-01-01

High frequency of hereditary pathologies resulting in congenital and prelingual auditory inefficiency necessitates organization of readily available medico-genetic counseling services based at specialized centres and an integrated dispensary system for the observation of families at risk of hereditary hearing impairment and identification of high-risk groups among the general population. Correct clinical diagnosis provides a basis for the strategy of molecular-genetic examination of a given patient and members of his (her) family. Results of the examination can be used for family planning and the choice of measures for the prevention of recurrent cases. The objective of the present work was to draw up the main lines of cooperative activities of deafness specialists and geneticists, propose indications for medico-genetic counseling, and distinguish groups at high risk of development of hereditary hearing impairment among the affected subjects and in the general population. It is shown that the efficiency of measures for the prevention of hereditary hearing loss is directly related to the availability of medico-genetic aid and the degree of involvement of risk groups in the examination.

Hereditary breast cancer: from molecular pathology to tailored therapies.

PubMed

Tan, D S P; Marchiò, C; Reis-Filho, J S

2008-10-01

Hereditary breast cancer accounts for up to 5-10% of all breast carcinomas. Recent studies have demonstrated that mutations in two high-penetrance genes, namely BRCA1 and BRCA2, are responsible for about 16% of the familial risk of breast cancer. Even though subsequent studies have failed to find another high-penetrance breast cancer susceptibility gene, several genes that confer a moderate to low risk of breast cancer development have been identified; moreover, hereditary breast cancer can be part of multiple cancer syndromes. In this review we will focus on the hereditary breast carcinomas caused by mutations in BRCA1, BRCA2, Fanconi anaemia (FANC) genes, CHK2 and ATM tumour suppressor genes. We describe the hallmark histological features of these carcinomas compared with non-hereditary breast cancers and show how an accurate histopathological diagnosis may help improve the identification of patients to be screened for mutations. Finally, novel therapeutic approaches to treat patients with BRCA1 and BRCA2 germ line mutations, including cross-linking agents and PARP inhibitors, are discussed.

Eighty percent of French sport winners in Olympic, World and Europeans competitions have mutations in the hemochromatosis HFE gene.

PubMed

Hermine, Olivier; Dine, Gérard; Genty, Vincent; Marquet, Laurie-Anne; Fumagalli, Gabriela; Tafflet, Muriel; Guillem, Flavia; Van Lierde, Françoise; Rousseaux-Blanchi, Marie-Philippe; Palierne, Christian; Lapostolle, Jean-Claude; Cervetti, Jean-Pierre; Frey, Alain; Jouven, Xavier; Noirez, Philippe; Toussaint, Jean-François

2015-12-01

The HFE gene encodes a protein involved in iron homeostasis; individuals with mutations in both alleles develop hemochromatosis. 27% of the French population is heterozygous for mutations in this gene. We found that 80% of the French athletes who won international competitions in rowing, Nordic skiing and judo display mutations in one allele of HFE, thus demonstrating the existence of a favourable phenotype linked to this heterozygosity. Copyright © 2015. Published by Elsevier B.V.

Red blood cell vesiculation in hereditary hemolytic anemia

PubMed Central

Alaarg, Amr; Schiffelers, Raymond M.; van Solinge, Wouter W.; van Wijk, Richard

2013-01-01

Hereditary hemolytic anemia encompasses a heterogeneous group of anemias characterized by decreased red blood cell survival because of inherited membrane, enzyme, or hemoglobin disorders. Affected red blood cells are more fragile, less deformable, and more susceptible to shear stress and oxidative damage, and show increased vesiculation. Red blood cells, as essentially all cells, constitutively release phospholipid extracellular vesicles in vivo and in vitro in a process known as vesiculation. These extracellular vesicles comprise a heterogeneous group of vesicles of different sizes and intracellular origins. They are described in literature as exosomes if they originate from multi-vesicular bodies, or as microvesicles when formed by a one-step budding process directly from the plasma membrane. Extracellular vesicles contain a multitude of bioactive molecules that are implicated in intercellular communication and in different biological and pathophysiological processes. Mature red blood cells release in principle only microvesicles. In hereditary hemolytic anemias, the underlying molecular defect affects and determines red blood cell vesiculation, resulting in shedding microvesicles of different compositions and concentrations. Despite extensive research into red blood cell biochemistry and physiology, little is known about red cell deformability and vesiculation in hereditary hemolytic anemias, and the associated pathophysiological role is incompletely assessed. In this review, we discuss recent progress in understanding extracellular vesicles biology, with focus on red blood cell vesiculation. Also, we review recent scientific findings on the molecular defects of hereditary hemolytic anemias, and their correlation with red blood cell deformability and vesiculation. Integrating bio-analytical findings on abnormalities of red blood cells and their microvesicles will be critical for a better understanding of the pathophysiology of hereditary hemolytic anemias. PMID

Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS Study initial screening

PubMed Central

Barton, James C.; Acton, Ronald T.; Leiendecker-Foster, Catherine; Lovato, Laura; Adams, Paul C.; Eckfeldt, John H.; McLaren, Christine E.; Reiss, Jacob A.; McLaren, Gordon D.; Reboussin, David M.; Gordeuk, Victor R.; Speechley, Mark R.; Press, Richard D.; Dawkins, Fitzroy W.

2013-01-01

There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25–29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL. Fifty-one participants reported previous H/IO; 23 (45%) reported medical conditions associated with H/IO. Prevalences of reports of arthritis, diabetes, liver disease or liver cancer, heart failure, fertility problems or impotence, and blood relatives with H/IO were significantly greater in participants with previous H/IO reports than in those without. Only 7.8% of the 51 participants with previous H/IO reports had elevated TS; 13.7% had elevated SF. Only one participant had C282Y homozygosity. Three participants aged 25–29 years were heterozygous for potentially deleterious mutations in HFE2, TFR2, and HAMP promoter, respectively. Prevalences of self-reported conditions, screening iron phenotypes, and C282Y homozygosity were similar in 1,165 participants aged 30 years or greater who reported previous H/IO. We conclude that persons who report previous H/IO diagnoses in screening programs are unlikely to have H/IO phenotypes or genotypes. Previous H/IO reports in some participants could be explained by treatment that induced iron depletion before initial screening, misdiagnosis, or participant misunderstanding of their physician or the initial screening questionnaire. PMID:17726683

Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives.

PubMed

Barton, James C; Barton, J Clayborn

2015-01-01

We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes A (∗) 01, B (∗) 08; A (∗) 02, B (∗) 44; A (∗) 03, B (∗) 07; A (∗) 03, B (∗) 14; and A (∗) 29, B (∗) 44. There were 138 men (58.7%). Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto's thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.

Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives

PubMed Central

Barton, James C.; Barton, J. Clayborn

2015-01-01

We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes A∗01, B∗08; A∗02, B∗44; A∗03, B∗07; A∗03, B∗14; and A∗29, B∗44. There were 138 men (58.7%). Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto's thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH. PMID:26504855

Pes cavus and hereditary neuropathies: when a relationship should be suspected.

PubMed

Piazza, S; Ricci, G; Caldarazzo Ienco, E; Carlesi, C; Volpi, L; Siciliano, G; Mancuso, M

2010-12-01

The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the first signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or confirm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a "spy sign," discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases.

Hereditary chronic pancreatitis: implications for surgical treatment and follow-up.

PubMed

Cowles, R A; Eckhauser, F E; Knol, J A

2001-02-01

Hereditary pancreatitis is an uncommon cause of chronic pancreatitis in Western society. It should be suspected when chronic pancreatitis presents in young adults. The diagnosis is made when chronic pancreatitis is present in several members of the same family who are determined not to have other risk factors for chronic pancreatitis. Molecular research focusing on mutations in the trypsinogen gene has uncovered the genetic defects associated with hereditary pancreatitis, and this knowledge has suggested the possible pathophysiologic mechanism of this disease. Because patients with hereditary pancreatitis develop their disease early in life they are very likely to require treatment for complications. As in patients with chronic pancreatitis of other etiologies those with hereditary pancreatitis should be treated medically for acute exacerbations. When complications occur or when the disease causes intractable pain surgery is recommended. Surgical therapy is tailored to the patient's pancreatic anatomy based on endoscopic retrograde cholangiopancreatography or CT scan. The two patients described in this report underwent successful longitudinal pancreaticojejunostomy (Puestow procedure) with good results. Finally it has been shown that patients with hereditary pancreatitis are at increased risk for developing pancreatic adenocarcinoma. Although not widely used pancreatic cancer screening programs have been suggested for surveillance of these patients.

Genetics of hereditary disorders of magnesium homeostasis.

PubMed

Schlingmann, Karl P; Konrad, Martin; Seyberth, Hannsjörg W

2004-01-01

Magnesium plays an essential role in many biochemical and physiological processes. Homeostasis of magnesium is tightly regulated and depends on the balance between intestinal absorption and renal excretion. During the last decades, various hereditary disorders of magnesium handling have been clinically characterized and genetic studies in affected individuals have led to the identification of some molecular components of cellular magnesium transport. In addition to these hereditary forms of magnesium deficiency, recent studies have revealed a high prevalence of latent hypomagnesemia in the general population. This finding is of special interest in view of the association between hypomagnesemia and common chronic diseases such as diabetes, coronary heart disease, hypertension, and asthma. However, valuable methods for the diagnosis of body and tissue magnesium deficiency are still lacking. This review focuses on clinical and genetic aspects of hereditary disorders of magnesium homeostasis. We will review primary defects of epithelial magnesium transport, disorders associated with defects in Ca(2+)/ Mg(2+) sensing, as well as diseases characterized by renal salt wasting and hypokalemic alkalosis, with special emphasis on disturbed magnesium homeostasis.

[Consensus on clinical diagnosis, treatment and pedigree management of hereditary colorectal cancer in China].

PubMed

2018-01-23

Hereditary colorectal cancer can be divded into two categories based on the presence or absence of polyps. The first category is characterized by the development of polyposis, which includes familial adenomatous polyposis (FAP); The second category is nonpolyposis colorectal cancer, which is represented by Lynch syndrome. "Consensus on clinical diagnosis, treatment and pedigree management of hereditary colorectal cancer in China" developed by the Genetics Group of the Committee of Colorectal Cancer, Chinese Anti-cancer Association, is composed of three sections, including hereditary nonpolyposis syndrome, polyposis syndrome as well as genetic evaluation of hereditary colorectal cancer. The consensus aims to provide recommendations on management of the respective hereditary syndromes in terms of definition, clinical and pathological features, diagnostic standards, treatment, and follow-ups. In addition to describing diagnostic and treatment strategies, prophylactic treatment as well as genetic screening and pedigree monitoring is highly recommended. Through the establishment of this expert consensus, we hope to promote better understanding of hereditary colorectal cancer for clinicians and encourage standardized treatment through multidisciplinery approaches, eventually improving clinical treatment and pedigree management of hereditary colorectal cancer in China.

Mutator gene and hereditary non-polyposis colorectal cancer

DOEpatents

de la Chapelle, Albert [Helsingfors, FI; Vogelstein, Bert [Baltimore, MD; Kinzler, Kenneth W [Baltimore, MD

2008-02-05

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

Hereditary myopathies with early respiratory insufficiency in adults.

PubMed

Naddaf, Elie; Milone, Margherita

2017-11-01

Hereditary myopathies with early respiratory insufficiency as a predominant feature of the clinical phenotype are uncommon and underestimated in adults. We reviewed the clinical and laboratory data of patients with hereditary myopathies who demonstrated early respiratory insufficiency before the need for ambulatory assistance. Only patients with disease-causing mutations or a specific histopathological diagnosis were included. Patients with cardiomyopathy were excluded. We identified 22 patients; half had isolated respiratory symptoms at onset. The diagnosis of the myopathy was often delayed, resulting in delayed ventilatory support. The most common myopathies were adult-onset Pompe disease, myofibrillar myopathy, multi-minicore disease, and myotonic dystrophy type 1. Single cases of laminopathy, MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike events), centronuclear myopathy, and cytoplasmic body myopathy were identified. We highlighted the most common hereditary myopathies associated with early respiratory insufficiency as the predominant clinical feature, and underscored the importance of a timely diagnosis for patient care. Muscle Nerve 56: 881-886, 2017. © 2017 Wiley Periodicals, Inc.

Iron oxides in human spleen.

PubMed

Kopáni, Martin; Miglierini, Marcel; Lančok, Adriana; Dekan, Július; Čaplovicová, Mária; Jakubovský, Ján; Boča, Roman; Mrazova, Hedviga

2015-10-01

Iron is an essential element for fundamental cell functions and a catalyst for chemical reactions. Three samples extracted from the human spleen were investigated by scanning (SEM) and transmission electron microscopy (TEM), Mössbauer spectrometry (MS), and SQUID magnetometry. The sample with diagnosis of hemosiderosis (H) differs from that referring to hereditary spherocytosis and the reference sample. SEM reveals iron-rich micrometer-sized aggregate of various structures-tiny fibrils in hereditary spherocytosis sample and no fibrils in hemochromatosis. Hematite and magnetite particles from 2 to 6 μm in TEM with diffraction in all samples were shown. The SQUID magnetometry shows different amount of diamagnetic, paramagnetic and ferrimagnetic structures in the tissues. The MS results indicate contribution of ferromagnetically split sextets for all investigated samples. Their occurrence indicates that at least part of the sample is magnetically ordered below the critical temperature. The iron accumulation process is different in hereditary spherocytosis and hemosiderosis. This fact may be the reason of different iron crystallization.

Potential nonresponse bias in a clinical examination after initial screening using iron phenotyping and HFE genotyping in the hemochromatosis and iron overload screening study.

PubMed

Speechley, Mark; Barton, James C; Passmore, Leah; Harrison, Helen; Reboussin, David M; Harris, Emily L; Rivers, Charles A; Fadojutimi-Akinsiku, Margaret; Wenzel, Lari; Diaz, Sharmin

2009-12-01

Little is known about the factors affecting participation in clinical assessments after HEmochromatosis and IRon Overload Screening. Initial screening of 101,168 primary care patients in the HEmochromatosis and IRon Overload Screening study was performed using serum iron measures and hemochromatosis gene (HFE) genotyping. Using iron phenotypes and HFE genotypes, we identified 2256 cases and 1232 controls eligible to participate in a clinical examination. To assess the potential for nonresponse bias, we compared the sociodemographic, health status, and attitudinal characteristics of participants and nonparticipants using adjusted odds ratios (ORs) and 95% confidence interval (CI). Overall participation was 74% in cases and 52% in controls; in both groups, participation was highest at a health maintenance organization and lowest among those under 45 years of age (cases: OR = 0.68; 95% CI 0.53, 0.87; controls: OR = 0.59; 95% CI 0.44, 0.78). In controls only, participation was also lower among those over 65 years of age than the reference group aged 46-64 (OR = 0.64; 95% CI 0.47, 0.88). Among cases, participation was higher in HFE C282Y homozygotes (OR = 3.98; 95% CI 2.60, 6.09), H63D homozygotes (OR = 2.79; 95% CI 1.23, 6.32), and C282Y/H63D compound heterozygotes (OR = 1.82; 95% CI 1.03, 3.22) than in other genotypes, and lower among non-Caucasians and those who preferred a non-English language than in Caucasians and those who preferred English (p < 0.0001). Subjects with greatest risk to have iron overload (C282Y homozygotes; cases > or =45 years; Caucasians) were more likely to participate in a postscreening clinical examination than other subjects. We detected no evidence of strong selection bias.

A Novel Approach to Improving Utilization of Laboratory Testing.

PubMed

Zhou, Yaolin; Procop, Gary W; Riley, Jacquelyn D

2018-02-01

- The incorporation of best practice guidelines into one's institution is a challenging goal of utilization management, and the successful adoption of such guidelines depends on institutional context. Laboratorians who have access to key clinical data are well positioned to understand existing local practices and promote more appropriate laboratory testing. - To apply a novel approach to utilization management by reviewing international clinical guidelines and current institutional practices to create a reliable mechanism to improve detection and reduce unnecessary tests in our patient population. - We targeted a frequently ordered genetic test for HFE-related hereditary hemochromatosis, a disorder of low penetrance. After reviewing international practice guidelines, we evaluated 918 HFE tests and found that all patients with new diagnoses had transferrin saturation levels that were significantly higher than those of patients with nonrisk genotypes (72% versus 42%; P < .001). - Our "one-button" order that restricts HFE genetic tests to patients with transferrin saturation greater than 45% is consistent with published practice guidelines and detected 100% of new patients with HFE-related hereditary hemochromatosis. - Our proposed algorithm differs from previously published approaches in that it incorporates both clinical practice guidelines and local physician practices, yet requires no additional hands-on effort from pathologists or clinicians. This novel approach to utilization management embraces the role of pathologists as leaders in promoting high-quality patient care in local health care systems.

Advances and challenges in hereditary cancer pharmacogenetics.

PubMed

Cascorbi, Ingolf; Werk, Anneke Nina

2017-01-01

Cancer pharmacogenetics usually considers tumor-specific targets. However, hereditary genetic variants may interfere with the pharmacokinetics of antimetabolites and other anti-cancer drugs, which may lead to severe adverse events. Areas covered: Here, the impact of hereditary genes considered in drug labels such as thiopurine S-methyltransferase (TPMT), UDP-glucuronosyltransferase 1A1 (UTG1A1) and dihydropyrimidine dehydrogenase (DPYD) are discussed with respect to guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Moreover, the association between genetic variants of drug transporters with the clinical outcome is comprehensively discussed. Expert opinion: Precision therapy in the field of oncology is developing tremendously. There are a number of somatic tumor genetic markers that are indicative for treatment with anti-cancer drugs. By contrast, for some hereditary variants, recommendations have been developed. Although we have vast knowledge on the association between drug transporter variants and clinical outcome, the overall data is inconsistent and the predictability of the related phenotype is low. Further developments in research may lead to the discovery of rare, but functionally relevant single nucleotide polymorphisms and a better understanding of multiple genomic, epigenomic as well as phenotypic factors, contributing to drug response in malignancies.

[The research advances and applications of genome editing in hereditary eye diseases].

PubMed

Cai, S W; Zhang, Y; Hou, M Z; Liu, Y; Li, X R

2017-05-11

Genome editing is a cutting-edge technology that generates DNA double strand breaks at the specific genomic DNA sequence through nuclease recognition and cleavage, and then achieves insertion, replacement, or deletion of the target gene via endogenous DNA repair mechanisms, such as non-homologous end joining, homology directed repair, and homologous recombination. So far, more than 600 human hereditary eye diseases and systemic hereditary diseases with ocular phenotypes have been found. However, most of these diseases are of incompletely elucidated pathogenesis and without effective therapies. Genome editing technology can precisely target and alter the genomes of animals, establish animal models of the hereditary diseases, and elucidate the relationship between the target gene and the disease phenotype, thereby providing a powerful approach to studying the pathogenic mechanisms underlying the hereditary eye diseases. In addition, correction of gene mutations by the genome editing brings a new hope to gene therapy for the hereditary eye diseases. This review introduces the molecular characteristics of 4 major enzymes used in the genome editing, including homing endonucleases, zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9), and summarizes the current applications of this technology in investigating the pathogenic mechanisms underlying the hereditary eye diseases. (Chin J Ophthalmol, 2017, 53: 386-371 ) .

[Asymptomatic classical hereditary xanthinuria type 1].

PubMed

Yakubov, Renata; Nir, Vered; Kassem, Eiass; Klein-Kremer, Adi

2012-06-01

We report on a girl who was diagnosed with classical hereditary xanthinuria due to an incidental finding of extremely low Levels of uric acid in the blood. The girl is compLetely asymptomatic. Hereditary xanthinuria is a rare autosomal recessive disease that usually causes early urolithiasis but may cause rheumatoid arthritis-like disease and even be associated with defects in the formation of bone, hair and teeth. In Israel it has mostly been described in patients of Bedouin origin. Throughout the world, only about 150 cases have been described; about two thirds of these patients were asymptomatic. Since the clinical presentation and age of symptom appearance are diverse, the case raises questions as to the required follow-up of these patients and as to whether a low oxalate diet should be initiated.

Analysis of Genetic Mutations in a Cohort of Hereditary Optic Neuropathy in Shanghai, China.

PubMed

Gan, Dekang; Li, Mengwei; Wu, Jihong; Sun, Xinghuai; Tian, Guohong

2017-01-01

To evaluate the clinical classification and characteristics of hereditary optic neuropathy patients in a single center in China. Retrospective case study. Patients diagnosed with hereditary optic neuropathy between January 2014 and December 2015 in the neuro-ophthalmology division in Shanghai Eye and ENT Hospital of Fudan University were recruited. Clinical features as well as visual field, brain/orbital MRI, and spectrum domain optical coherence tomography (SD-OCT) were analyzed. Eighty-two patients diagnosed by gene test were evaluated, including 66 males and 16 females. The mean age of the patients was 19.4 years (range, 5-46 years). A total of 158 eyes were analyzed, including 6 unilateral, 61 bilateral, and 15 sequential. The median duration of the disease was 0.5 year (range, 0.1-20 years). Genetic test identified 68 patients with Leber hereditary optic neuropathy, 9 with dominant optic neuropathy, and 2 with a Wolfram gene mutation. There was also one case of hereditary spastic paraplegia, spinocerebellar ataxia, and polymicrogyria with optic nerve atrophy, respectively. Leber hereditary optic neuropathy is the most common detected type of hereditary optic neuropathy in Shanghai, China. The detection of other autosomal mutations in hereditary optic neuropathy is limited by the currently available technique.

Successful management of neonatal hemochromatosis by exchange transfusion and immunoglobulin: a case report.

PubMed

Babor, F; Hadzik, B; Stannigel, H; Mayatepek, E; Hoehn, T

2013-01-01

Neonatal hemochromatosis (NH) is a rare and severe liver disease of mainly intra-uterine onset, characterized by neonatal liver failure, hepatic and extrahepatic iron accumulation. This leads to an altered iron metabolism with resulting siderosis. The disease represents the most common cause of liver failure in neonates and is also the most common indication for neonatal liver transplantation. We present a case of a newborn diagnosed with NH and life threatening liver failure. Initial treatment consisted of chelation therapy and antioxidants, but lack of laboratory and clinical improvement led to an exchange transfusion followed by the singular substitution of intravenous immunoglobulin (IVIG). Both, exchange transfusion and IVIG were tolerated well and led to an improvement of the general condition of the patient and recovery of liver synthetic function. The subsequent favorable course of the disease is described in this case report.

Profound Morphological Changes in the Erythrocytes and Fibrin Networks of Patients with Hemochromatosis or with Hyperferritinemia, and Their Normalization by Iron Chelators and Other Agents

PubMed Central

Pretorius, Etheresia; Bester, Janette; Vermeulen, Natasha; Lipinski, Boguslaw; Gericke, George S.; Kell, Douglas B.

2014-01-01

It is well-known that individuals with increased iron levels are more prone to thrombotic diseases, mainly due to the presence of unliganded iron, and thereby the increased production of hydroxyl radicals. It is also known that erythrocytes (RBCs) may play an important role during thrombotic events. Therefore the purpose of the current study was to assess whether RBCs had an altered morphology in individuals with hereditary hemochromatosis (HH), as well as some who displayed hyperferritinemia (HF). Using scanning electron microscopy, we also assessed means by which the RBC and fibrin morphology might be normalized. An important objective was to test the hypothesis that the altered RBC morphology was due to the presence of excess unliganded iron by removing it through chelation. Very striking differences were observed, in that the erythrocytes from HH and HF individuals were distorted and had a much greater axial ratio compared to that accompanying the discoid appearance seen in the normal samples. The response to thrombin, and the appearance of a platelet-rich plasma smear, were also markedly different. These differences could largely be reversed by the iron chelator desferal and to some degree by the iron chelator clioquinol, or by the free radical trapping agents salicylate or selenite (that may themselves also be iron chelators). These findings are consistent with the view that the aberrant morphology of the HH and HF erythrocytes is caused, at least in part, by unliganded (‘free’) iron, whether derived directly via raised ferritin levels or otherwise, and that lowering it or affecting the consequences of its action may be of therapeutic benefit. The findings also bear on the question of the extent to which accepting blood donations from HH individuals may be desirable or otherwise. PMID:24416376

Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network

PubMed Central

Gallego, Carlos J.; Burt, Amber; Sundaresan, Agnes S.; Ye, Zi; Shaw, Christopher; Crosslin, David R.; Crane, Paul K.; Fullerton, S. Malia; Hansen, Kris; Carrell, David; Kuivaniemi, Helena; Derr, Kimberly; de Andrade, Mariza; McCarty, Catherine A.; Kitchner, Terrie E.; Ragon, Brittany K.; Stallings, Sarah C.; Papa, Gabriella; Bochenek, Joseph; Smith, Maureen E.; Aufox, Sharon A.; Pacheco, Jennifer A.; Patel, Vaibhav; Friesema, Elisha M.; Erwin, Angelika Ludtke; Gottesman, Omri; Gerhard, Glenn S.; Ritchie, Marylyn; Motulsky, Arno G.; Kullo, Iftikhar J.; Larson, Eric B.; Tromp, Gerard; Brilliant, Murray H.; Bottinger, Erwin; Denny, Joshua C.; Roden, Dan M.; Williams, Marc S.; Jarvik, Gail P.

2015-01-01

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data. PMID:26365338

Rodent models of congenital and hereditary cataract in man.

PubMed

Tripathi, B J; Tripathi, R C; Borisuth, N S; Dhaliwal, R; Dhaliwal, D

1991-01-01

Because the organogenesis and physiology of the lens are essentially similar in various mammals, an understanding of the etiology and pathogenesis of the formation of cataract in an animal model will enhance our knowledge of cataractogenesis in man. In this review, we summarize the background, etiology, and pathogenesis of cataracts that occur in rodents. The main advantages of using rodent mutants include the well-researched genetics of the animals and the comparative ease of breeding of large litters. Numerous rodent models of congenital and hereditary cataracts have been studied extensively. In mice, the models include the Cts strain, Fraser mouse, lens opacity gene (Lop) strain, Lop-2 and Lop-3 strains, Philly mouse, Nakano mouse, Nop strain, Deer mouse, Emory mouse, Swiss Webster strain, Balb/c-nct/nct mouse, and SAM-R/3 strain. The rat models include BUdR, ICR, Sprague-Dawley, and Wistar rats, the spontaneously hypertensive rat (SHR), the John Rapp inbred strain of Dahl salt-sensitive rat, as well as WBN/Kob, Royal College of Surgeons (RCS), and Brown-Norway rats. Other proposed models for the study of hereditary cataract include the degu and the guinea pig. Because of the ease of making clinical observations in vivo and the subsequent availability of the intact lens for laboratory analyses at different stages of cataract formation, these animals provide excellent models for clinicopathologic correlations, for monitoring of the natural history of the aging process and of metabolic defects, as well as for investigations on the effect of cataract-modulating agents and drugs, including the prospect of gene therapy.

Genetics Home Reference: hereditary antithrombin deficiency

MedlinePlus

... at higher than average risk for developing abnormal blood clots, particularly a type of clot that occurs in ... in the lungs. In hereditary antithrombin deficiency , abnormal blood clots usually form only in veins, although they may ...

Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE hemochromatosis.

PubMed

Bardou-Jacquet, Edouard; Morcet, Jeff; Manet, Ghislain; Lainé, Fabrice; Perrin, Michèle; Jouanolle, Anne-Marie; Guyader, Dominique; Moirand, Romain; Viel, Jean-François; Deugnier, Yves

2015-03-01

Mortality studies in patients with hemochromatosis give conflicting results especially with respect to extrahepatic causes of death. Our objective was to assess mortality and causes of death in a cohort of patients homozygous for the C282Y mutation in the HFE gene, diagnosed since the availability of HFE testing. We studied 1085 C282Y homozygotes, consecutively diagnosed from 1996 to 2009, and treated according to current recommendations. Mortality and causes of death were obtained from death certificates and compared to those of the general population. Standardized mortality ratios (SMRs) were used to assess specific causes of death and the Cox model was used to identify prognostic factors for death. Patients were followed for 8.3±3.9 years. Overall the SMR was the same as in the general population (0.94 CI: 0.71-1.22). Patients with serum ferritin⩾2000 μg/L had increased liver-related deaths (SMR: 23.9 CI: 13.9-38.2), especially due to hepatic cancer (SMR: 49.1 CI: 24.5-87.9). Patients with serum ferritin between normal and 1000 μg/L had a lower mortality than the general population (SMR: 0.27 CI: 0.1-0.5), due to a decreased mortality, related to reduced cardiovascular events and extrahepatic cancers in the absence of increased liver-related mortality. Age, diabetes, alcohol consumption, and hepatic fibrosis were independent prognostic factors of death. In treated HFE hemochromatosis, only patients with serum ferritin higher than 2000 μg/L have an increased mortality, mainly related to liver diseases. Those with mild iron burden have a decreased overall mortality in relation to reduced cardiovascular and extrahepatic cancer-related events. These results support a beneficial effect of early and sustained management of patients with iron excess, even when mild. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis

PubMed Central

Ramos, Pedro; Guy, Ella; Chen, Nan; Proenca, Catia C.; Gardenghi, Sara; Casu, Carla; Follenzi, Antonia; Van Rooijen, Nico; Grady, Robert W.; de Sousa, Maria

2011-01-01

In hereditary hemochromatosis, mutations in HFE lead to iron overload through abnormally low levels of hepcidin. In addition, HFE potentially modulates cellular iron uptake by interacting with transferrin receptor, a crucial protein during erythropoiesis. However, the role of HFE in this process was never explored. We hypothesize that HFE modulates erythropoiesis by affecting dietary iron absorption and erythroid iron intake. To investigate this, we used Hfe-KO mice in conditions of altered dietary iron and erythropoiesis. We show that Hfe-KO mice can overcome phlebotomy-induced anemia more rapidly than wild-type mice (even when iron loaded). Second, we evaluated mice combining the hemochromatosis and β-thalassemia phenotypes. Our results suggest that lack of Hfe is advantageous in conditions of increased erythropoietic activity because of augmented iron mobilization driven by deficient hepcidin response. Lastly, we demonstrate that Hfe is expressed in erythroid cells and impairs iron uptake, whereas its absence exclusively from the hematopoietic compartment is sufficient to accelerate recovery from phlebotomy. In summary, we demonstrate that Hfe influences erythropoiesis by 2 distinct mechanisms: limiting hepcidin expression under conditions of simultaneous iron overload and stress erythropoiesis, and impairing transferrin-bound iron uptake by erythroid cells. Moreover, our results provide novel suggestions to improve the treatment of hemochromatosis. PMID:21059897

Hereditary pituitary hyperplasia with infantile gigantism.

PubMed

Gläsker, Sven; Vortmeyer, Alexander O; Lafferty, Antony R A; Hofman, Paul L; Li, Jie; Weil, Robert J; Zhuang, Zhengping; Oldfield, Edward H

2011-12-01

We report hereditary pituitary hyperplasia. The objective of the study was to describe the results of the clinical and laboratory analysis of this rare instance of hereditary pituitary hyperplasia. The study is a retrospective analysis of three cases from one family. The study was conducted at the National Institutes of Health, a tertiary referral center. A mother and both her sons had very early-onset gigantism associated with high levels of serum GH and prolactin. The condition was treated by total hypophysectomy. We performed clinical, pathological, and molecular evaluations, including evaluation basal and provocative endocrine testing, neuroradiological assessment, and assessment of the pituitary tissue by microscopic evaluation, immunohistochemistry, and electron microscopy. All three family members had very early onset of gigantism associated with abnormally high serum levels of GH and prolactin. Serum GHRH levels were not elevated in either of the boys. The clinical, radiographic, surgical, and histological findings indicated mammosomatotroph hyperplasia. The pituitary gland of both boys revealed diffuse mammosomatotroph hyperplasia of the entire pituitary gland without evidence of adenoma. Prolactin and GH were secreted by the same cells within the same secretory granules. Western blot and immunohistochemistry demonstrated expression of GHRH in clusters of cells distributed throughout the hyperplastic pituitary of both boys. This hereditary condition seems to be a result of embryonic pituitary maldevelopment with retention and expansion of the mammosomatotrophs. The findings suggest that it is caused by paracrine or autocrine pituitary GHRH secretion during pituitary development.

Genetic Testing for Hereditary Colorectal Cancer

MedlinePlus

... Submit Button Past Emails March 22nd is National Lynch Syndrome Awareness Day! Language: English (US) Español (Spanish) Recommend ... sure to tell your family members. What is Lynch Syndrome? Lynch syndrome is a hereditary cancer syndrome, meaning ...

Review of approaches to the recording of background lesions in toxicologic pathology studies in rats.

PubMed

McInnes, E F; Scudamore, C L

2014-08-17

Pathological evaluation of lesions caused directly by xenobiotic treatment must always take into account the recognition of background (incidental) findings. Background lesions can be congenital or hereditary, histological variations, changes related to trauma or normal aging and physiologic or hormonal changes. This review focuses on the importance and correct approach to recording of background changes and includes discussion on sources of variability in background changes, the correct use of terminology, the concept of thresholds, historical control data, diagnostic drift, blind reading of slides, scoring and artifacts. The review is illustrated with background lesions in Sprague Dawley and Wistar rats. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The metabolomic signature of Leber's hereditary optic neuropathy reveals endoplasmic reticulum stress.

PubMed

Chao de la Barca, Juan Manuel; Simard, Gilles; Amati-Bonneau, Patrizia; Safiedeen, Zainab; Prunier-Mirebeau, Delphine; Chupin, Stéphanie; Gadras, Cédric; Tessier, Lydie; Gueguen, Naïg; Chevrollier, Arnaud; Desquiret-Dumas, Valérie; Ferré, Marc; Bris, Céline; Kouassi Nzoughet, Judith; Bocca, Cinzia; Leruez, Stéphanie; Verny, Christophe; Miléa, Dan; Bonneau, Dominique; Lenaers, Guy; Martinez, M Carmen; Procaccio, Vincent; Reynier, Pascal

2016-11-01

Leber's hereditary optic neuropathy (MIM#535000), the commonest mitochondrial DNA-related disease, is caused by mutations affecting mitochondrial complex I. The clinical expression of the disorder, usually occurring in young adults, is typically characterized by subacute, usually sequential, bilateral visual loss, resulting from the degeneration of retinal ganglion cells. As the precise action of mitochondrial DNA mutations on the overall cell metabolism in Leber's hereditary optic neuropathy is unknown, we investigated the metabolomic profile of the disease. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites in fibroblasts from 16 patients with Leber's hereditary optic neuropathy and eight healthy control subjects. Latent variable-based statistical methods were used to identify discriminating metabolites. One hundred and twenty-four of the metabolites were considered to be accurately quantified. A supervised orthogonal partial least squares discriminant analysis model separating patients with Leber's hereditary optic neuropathy from control subjects showed good predictive capability (Q 2cumulated = 0.57). Thirty-eight metabolites appeared to be the most significant variables, defining a Leber's hereditary optic neuropathy metabolic signature that revealed decreased concentrations of all proteinogenic amino acids, spermidine, putrescine, isovaleryl-carnitine, propionyl-carnitine and five sphingomyelin species, together with increased concentrations of 10 phosphatidylcholine species. This signature was not reproduced by the inhibition of complex I with rotenone or piericidin A in control fibroblasts. The importance of sphingomyelins and phosphatidylcholines in the Leber's hereditary optic neuropathy signature, together with the decreased amino acid pool, suggested an involvement of the endoplasmic reticulum. This was confirmed by the significantly increased phosphorylation of PERK and eIF2α, as well as

Clinical and Laboratory Associations with Persistent Hyperferritinemia in 373 Black Hemochromatosis and Iron Overload Screening Study Participants.

PubMed

Barton, James C; Barton, J Clayborn; Adams, Paul C

2017-01-01

373 black participants had elevated screening and post-screening serum ferritin (SF) (> 300 μg/L men; > 200 μg/L women). We retrospectively studied SF and post-screening age; sex; body mass index; transferrin saturation (TS); ALT; AST; GGT; elevated C-reactive protein; ß-thalassemia; neutrophils; lymphocytes; monocytes; platelets; metacarpophalangeal joint hypertrophy; hepatomegaly; splenomegaly; diabetes; HFE H63D positivity; iron/alcohol intakes; and blood/erythrocyte transfusion units. Liver disease was defined as elevated ALT or AST. We computed correlations of SF and TS with: age; body mass index; ALT; AST; GGT; C-reactive protein; blood cell counts; and iron/alcohol. We compared participants with SF > 1,000 and ≤ 1,000 μg/L and performed regressions on SF. There were 237 men (63.5%). Mean age was 55 ± 13 (SD) y. 143 participants had liver disease (62 hepatitis B or C). There were significant correlations of SF: TS, ALT, AST, GGT, and monocytes (positive); and SF and TS with platelets (negative). 22 participants with SF > 1,000 μg/L had significantly higher median TS, ALT, and AST, and prevalences of anemia and transfusion > 10 units; and lower median platelets. Regression on SF revealed significant associations: TS; male sex; age; GGT; transfusion units (positive); and splenomegaly (negative) (p < 0.0001, 0.0016, 0.0281, 0.0025, 0.0001, and 0.0096, respectively). Five men with SF > 1,000 μg/L and elevated TS had presumed primary iron overload (hemochromatosis). Four participants had transfusion iron overload. Persistent hyperferritinemia in 373 black adults was associated with male sex, age, TS, GGT, and transfusion. 2.4% had primary iron overload (hemochromatosis) or transfusion iron overload.

[Leber hereditary optic neuropathy].

PubMed

Mazunin, I O; Volodko, N V

2018-01-01

Leber hereditary optic neuropathy is characterized by bilateral, painless loss of vision in children and young adults (generally up to 25 years old). Since its first description in 1871, the understanding of its etiology and pathogenesis has improved considerably. The article considers Leber neuropathy from the points of view of ophthalmology, neurology and molecular genetics, and presents data on experimental treatment methods, one of which is undergoing clinical trial.

Hereditary Hemorrhagic Telangiectasia Management.

PubMed

Peterson, Jeffrey

2017-01-01

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that can lead to frequent and severe sequelae. Although the condition has no cure, many of its physical symptoms can be managed to improve the quality of life and lower the risk of life-threatening complications. This article discusses HHT presentation, genetic screening, diagnosis, and management. The management of HHT can involve interventional radiology techniques, particularly for patients with pulmonary arteriovenous malformations.

Genetics Home Reference: hereditary neuralgic amyotrophy

MedlinePlus

... tissues. This change in the functioning of septin proteins seems to particularly affect the brachial plexus, but the reason for this ... SH, Andermann E, Bird TD, Chance PF. SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy. ...

Hepcidin expression does not rescue the iron-poor phenotype of Kupffer cells in Hfe-null mice after liver transplantation.

PubMed

Garuti, Cinzia; Tian, Yinghua; Montosi, Giuliana; Sabelli, Manuela; Corradini, Elena; Graf, Rolf; Ventura, Paolo; Vegetti, Alberto; Clavien, Pierre-Alain; Pietrangelo, Antonello

2010-07-01

Hemochromatosis is a common hereditary disease caused by mutations in HFE and characterized by increased absorption of iron in the intestine. However, the intestine does not appear to be the site of mutant HFE activity in the disease; we investigated the role of the liver-the source of the iron regulatory hormone hepcidin-in pathogenesis in mice. We exchanged livers between Hfe wild-type (+/+) and Hfe null (-/-) mice by orthotopic liver transplantation (OLT) and assessed histopathology, serum and tissue iron parameters, and hepatic hepcidin messenger RNA expression. At 6-8 months after OLT, Hfe(-/-) mice that received Hfe(-/-) livers maintained the hemochromatosis phenotype: iron accumulation in hepatocytes but not Kupffer cells (KC), increased transferrin levels, and low levels of iron in the spleen. Hfe(+/+) mice that received Hfe(-/-) livers had increased levels of iron in serum and liver and low levels of iron in spleen. However, they did not develop the iron-poor KCs that characterize hemochromatosis: KCs appeared iron rich, although hepatic hepcidin expression was low. Transplantation of Hfe(+/+) livers into Hfe(-/-) mice prevented hepatic iron accumulation but did not return spleen and plasma levels of iron to normal; KCs still appeared to be iron poor, despite normal hepcidin expression. In Hfe(-/-) mice, transplantation of livers from Hfe(+/+) mice reversed the iron-loading phenotype associated with hemochromatosis (regardless of Hfe expression in intestine). However, KCs still had low levels of iron that were not affected by hepatic hepcidin expression. These findings indicate an independent, iron-modifying effect of HFE in KCs. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

[Hereditary haemochromatosis].

PubMed

Bismuth, Michael; Aguilar-Martinez, Patricia; Michel, Henri

2003-11-08

EPIDEMIOLOGY ADN PHYSIOPATHOLOGY: Hereditary haemochromatosis is the most common genetic disease in France. Its frequency is on average 1 out of 300 French individuals. It is due to excessive dietary iron absorption, leading to accumulation of iron in the body. Mutations of the HFE1 gene are responsible for the majority of the case of haemochromatosis. FROM A CLINICAL POINT OF VIEW: The first clinical manifestations (weakness, sexual dysfunction, arthralgia, cardiac symptoms, dyspnoea on effort) can occur after the age of 30 years in men and 35 years in women (protected for longer by menstruation, pregnancy and delivery). In the absence of diagnosis, severe complications can develop during the 5th decade: nervous breakdown, arthropathy, heart failure, diabetes mellitus, cirrhosis with risk of progression towards carcinoma, responsible for handicaps and premature death. DIAGNOSTIC ELEMENTS: The diagnosis is evoked in the case of an increase in transferrine saturation (>45%), associated or not with excessive ferritin plasma levels. It is confirmed by the genetic test, showing homozygotes for the C282Y mutation or compound heterozygotes for the C282Y and H63D mutations on the HFE1 gene. RMI quantifies hepatic iron loading and generally avoids the need for a liver biopsy. The differential diagnosis must exclude secondary iron overload due to chronic transfusions in congenital or acquired blood diseases, a polymetabolic syndrome, chronic viral or alcoholic hepatic diseases and porphyria cutanea tarda. EFFICIENT TREATMENT: Today, haemochromatosis is still treated by phlebotomy. This consists in withdrawing 400 to 500ml of blood every week at the initial depletion stage and subsequently a maintenance therapy in order to maintain ferritin levels below 50 ng/ml. Paradoxically and through ignorance, hereditary haemochromatosis remains a serious disease, although its diagnosis is easy and the treatment simple and effective.

Hereditary rickets. How genetic alterations explain the biochemical and clinical phenotypes.

PubMed

Papadopoulou, Anna; Gole, Evaggelia; Nicolaidou, Polyxeni

2013-12-01

The reemergence of vitamin D deficiency in the industrialized countries resurrects the "threat" of nutritional rickets, especially among pediatric populations, a fact that may lead to underdiagnosis of hereditary rickets. Today, hereditary rickets may be subdivided into two main groups according to their biochemical profile: the one associated with defects in vitamin D synthesis and action and the second associated with abnormal phosphorus metabolism. The classification of the patients in a particular group of hereditary rickets is determinative of the treatment to follow. This review, through the recent advances on vitamin D and P metabolism, discusses the molecular and biochemical defects associated to each group of inherited rickets, as well as the clinical phenotypes and the recommended therapeutic approaches.

Characterization of the hepcidin gene in eight species of bats.

PubMed

Stasiak, Iga M; Smith, Dale A; Crawshaw, Graham J; Hammermueller, Jutta D; Bienzle, Dorothee; Lillie, Brandon N

2014-02-01

Hemochromatosis, or iron storage disease, has been associated with significant liver disease and mortality in captive Egyptian fruit bats (Rousettus aegyptiacus). The physiologic basis for this susceptibility has not been established. In humans, a deficiency or resistance to the iron regulatory hormone, hepcidin has been implicated in the development of hereditary hemochromatosis. In the present study, we compared the coding sequence of the hepcidin gene in eight species of bats representing three distinct taxonomic families with diverse life histories and dietary preferences. Bat hepcidin mRNA encoded a 23 amino acid signal peptide, a 34 or 35 amino acid pro-region, and a 25 amino acid mature peptide, similar to other mammalian species. Differences in the sequence of the portion of the hepcidin gene that encodes the mature peptide that might account for the increased susceptibility of the Egyptian fruit bat to iron storage disease were not identified. Variability in gene sequence corresponded to the taxonomic relationship amongst species. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synovial osteochondromatosis in hereditary arthro-ophthalmopathy (Wagner-Stickler syndrome).

PubMed

Tins, Bernhard; Cassar-Pullicino, Victor

2003-05-01

A case of bilateral synovial osteochondromatosis in a patient with hereditary arthro-ophthalmopathy is presented. The osteochondral lesions were largely calcified in one joint and largely chondromatous in the other. Typical features of hereditary arthro-ophthalmopathy are reviewed and it is hypothesised that the abnormal collagen in this syndrome is responsible for the development of synovial osteochondromatosis. Synovial manifestations of skeletal dysplasias have to our knowledge not been described previously but we suggest that synovial osteochondromatosis can be the manifestation of an underlying skeletal dysplasia.

A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy.

PubMed

Tsai, Pei-Chien; Soong, Bing-Wen; Mademan, Inès; Huang, Yen-Hua; Liu, Chia-Rung; Hsiao, Cheng-Tsung; Wu, Hung-Ta; Liu, Tze-Tze; Liu, Yo-Tsen; Tseng, Yen-Ting; Lin, Kon-Ping; Yang, Ueng-Cheng; Chung, Ki Wha; Choi, Byung-Ok; Nicholson, Garth A; Kennerson, Marina L; Chan, Chih-Chiang; De Jonghe, Peter; Cheng, Tzu-Hao; Liao, Yi-Chu; Züchner, Stephan; Baets, Jonathan; Lee, Yi-Chung

2017-05-01

Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A > G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that co-segregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS. © The Author (2017). Published by Oxford University Press on behalf of

Previously undiagnosed hereditary spherocytosis in a patient with jaundice and pyelonephritis: a case report.

PubMed

Tateno, Yuki; Suzuki, Ryoji; Kitamura, Yukihiro

2016-12-01

Hereditary spherocytosis is autosomal dominant inherited extravascular hemolytic disorder and is the commonest cause of inherited hemolysis in northern Europe and the United States. The classical clinical features of hereditary spherocytosis are anemia, jaundice, and splenomegaly. However, all of these classical features are not always revealed in the case of mild hemolysis or when hemolysis is well compensated. Patients with hereditary spherocytosis may remain undiagnosed for years if their hemolysis is mild. A 42-year-old Asian woman presented to our clinic with a sudden onset of high fever with shaking chills and jaundice, suggesting septicemia; however, following detailed investigation, the patient was diagnosed with pyelonephritis and accelerated hemolysis of hereditary spherocytosis due to infection. It is important to note that transient anemia or jaundice can sometimes be the only initial presenting symptoms in cases of undiagnosed latent hereditary spherocytosis. This case also highlights the fact that physicians should consider concomitant hemolytic disease in patients in whom jaundice and infections that rarely cause jaundice coexist.

[Leber's hereditary optic neuropathy].

PubMed

Hilo, Wasseem; Jabaly-Habib, Haneen; Modi, Naftali; Briscoe, Daniel

2013-08-01

Lebers hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by subacute severe visual loss in both eyes, which usually manifests in young adulthood. The disease has maternal inheritance due to mitochondrial DNA mutation. The final diagnosis is genetic. There is still no proven treatment, but there is significant progress in developments on the genetics of the disease to reach gene therapy. In this article we review the latest literature relevant to this disease.

Hereditary Pituitary Hyperplasia with Infantile Gigantism

PubMed Central

Gläsker, Sven; Vortmeyer, Alexander O.; Lafferty, Antony R. A.; Hofman, Paul L.; Li, Jie; Weil, Robert J.; Zhuang, Zhengping

2011-01-01

Context: We report hereditary pituitary hyperplasia. Objective: The objective of the study was to describe the results of the clinical and laboratory analysis of this rare instance of hereditary pituitary hyperplasia. Design: The study is a retrospective analysis of three cases from one family. Setting: The study was conducted at the National Institutes of Health, a tertiary referral center. Patients: A mother and both her sons had very early-onset gigantism associated with high levels of serum GH and prolactin. Interventions: The condition was treated by total hypophysectomy. Main Outcome Measure(s): We performed clinical, pathological, and molecular evaluations, including evaluation basal and provocative endocrine testing, neuroradiological assessment, and assessment of the pituitary tissue by microscopic evaluation, immunohistochemistry, and electron microscopy. Results: All three family members had very early onset of gigantism associated with abnormally high serum levels of GH and prolactin. Serum GHRH levels were not elevated in either of the boys. The clinical, radiographic, surgical, and histological findings indicated mammosomatotroph hyperplasia. The pituitary gland of both boys revealed diffuse mammosomatotroph hyperplasia of the entire pituitary gland without evidence of adenoma. Prolactin and GH were secreted by the same cells within the same secretory granules. Western blot and immunohistochemistry demonstrated expression of GHRH in clusters of cells distributed throughout the hyperplastic pituitary of both boys. Conclusions: This hereditary condition seems to be a result of embryonic pituitary maldevelopment with retention and expansion of the mammosomatotrophs. The findings suggest that it is caused by paracrine or autocrine pituitary GHRH secretion during pituitary development. PMID:21976722

Pituitary function in patients with hereditary haemochromatosis.

PubMed

Uitz, P M; Hartleb, S; Schaefer, S; Al-Fakhri, N; Kann, P H

2013-01-01

Haemochromatosis may impair the function of endocrine organs, amongst others the pituitary gland. It was the aim of this study to determine pituitary function in adult patients with genetically defined hereditary haemochromatosis in a prospective diagnostic study using a standardised stimulation test. Therefore, 22 patients (7 females, 15 males; age at diagnosis of haemochromatosis 48.1 ± 7.9 years; age at study inclusion 50.7 ± 7.7 years) with genetically defined hereditary haemochromatosis were investigated by a combined pituitary stimulation test (CRH, GHRH/arginine, GnRH, TRH). In 11 patients (50% of the study population; 2 females, 9 males), pituitary insufficiencies were detected [isolated corticotrophic insufficiency (peak cortisol < 181.25 μg/l/500 nmol/l) n=10 (2 females, 8 males); combined corticotrophic and borderline gonadotrophic insufficiency (basal testosterone 2.4-3.0 μg/l without basal LH-elevation) in 1 male]. Somatotrophic pituitary insufficiencies were not found. IFG-1 concentrations below -2 standard deviations in 7 patients (32%) may be attributed to impaired hepatic IGF-1 synthesis. Hypopituitarism, particularly corticotrophic insufficiency, seems to be prevalent in a considerable number of middle-aged patients with hereditary haemochromatosis. Despite normal somatotrophic function, low IGF-1 serum concentrations may be found in a subgroup of haemochromatosis patients. © Georg Thieme Verlag KG Stuttgart · New York.

Identification of Patients at Risk for Hereditary Colorectal Cancer

PubMed Central

Mishra, Nitin; Hall, Jason

2012-01-01

Diagnosis of hereditary colorectal cancer syndromes requires clinical suspicion and knowledge of such syndromes. Lynch syndrome is the most common cause of hereditary colorectal cancer. Other less common causes include familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome, and others. There have been a growing number of clinical and molecular tools used to screen and test at risk individuals. Screening tools include diagnostic clinical criteria, family history, genetic prediction models, and tumor testing. Patients who are high risk based on screening should be referred for genetic testing. PMID:23730221

Hereditary Gigantism-the biblical giant Goliath and his brothers

PubMed Central

Donnelly, Deirdre E; Morrison, Patrick J

2014-01-01

The biblical giant Goliath has an identifiable family tree suggestive of autosomal dominant inheritance. We suggest that he had a hereditary pituitary disorder possibly due to the AIP gene, causing early onset and familial acromegaly or gigantism. We comment on the evidence within the scriptures for his other relatives including a relative with six digits and speculate on possible causes of the six digits. Recognition of a hereditary pituitary disorder in the biblical Goliath and his family sheds additional information on his and other family members’ battles with David and his relatives. PMID:25075136

Hereditary Gigantism-the biblical giant Goliath and his brothers.

PubMed

Donnelly, Deirdre E; Morrison, Patrick J

2014-05-01

The biblical giant Goliath has an identifiable family tree suggestive of autosomal dominant inheritance. We suggest that he had a hereditary pituitary disorder possibly due to the AIP gene, causing early onset and familial acromegaly or gigantism. We comment on the evidence within the scriptures for his other relatives including a relative with six digits and speculate on possible causes of the six digits. Recognition of a hereditary pituitary disorder in the biblical Goliath and his family sheds additional information on his and other family members' battles with David and his relatives.

Hereditary pediatric cataract on the Arabian Peninsula

PubMed Central

Khan, Arif O.

2011-01-01

Hereditary pediatric cataract on the Arabian Peninsula does not follow the same epidemiological patterns as described for Western populations. This article describes selected genetic causes for inherited pediatric cataract in the region. PMID:23960971

Genetics 101 --The Hereditary Material of Life

MedlinePlus

... of this page please turn Javascript on. Feature: Genetics 101 Genetics 101 — The Hereditary Material of Life Past Issues / Summer 2013 Table of Contents Genetics is the study of heredity, the process in ...

Topological Structures and Membrane Nanostructures of Erythrocytes after Splenectomy in Hereditary Spherocytosis Patients via Atomic Force Microscopy.

PubMed

Li, Ying; Lu, Liyuan; Li, Juan

2016-09-01

Hereditary spherocytosis is an inherited red blood cell membrane disorder resulting from mutations of genes encoding erythrocyte membrane and cytoskeletal proteins. Few equipments can observe the structural characteristics of hereditary spherocytosis directly expect for atomic force microscopy In our study, we proved atomic force microscopy is a powerful and sensitive instrument to describe the characteristics of hereditary spherocytosis. Erythrocytes from hereditary spherocytosis patients were small spheroidal, lacking a well-organized lattice on the cell membrane, with smaller cell surface particles and had reduced valley to peak distance and average cell membrane roughness vs. those from healthy individuals. These observations indicated defects in the certain cell membrane structural proteins such as α- and β-spectrin, ankyrin, etc. Until now, splenectomy is still the most effective treatment for symptoms relief for hereditary spherocytosis. In this study, we further solved the mysteries of membrane nanostructure changes of erythrocytes before and after splenectomy in hereditary spherocytosis by atomic force microscopy. After splenectomy, the cells were larger, but still spheroidal-shaped. The membrane ultrastructure was disorganized and characterized by a reduced surface particle size and lower than normal Ra values. These observations indicated that although splenectomy can effectively relieve the symptoms of hereditary spherocytosis, it has little effect on correction of cytoskeletal membrane defects of hereditary spherocytosis. We concluded that atomic force microscopy is a powerful tool to investigate the pathophysiological mechanisms of hereditary spherocytosis and to monitor treatment efficacy in clinical practices. To the best of our knowledge, this is the first report to study hereditary spherocytosis with atomic force microscopy and offers important mechanistic insight into the underlying role of splenectomy.

Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload

PubMed Central

Preza, Gloria C.; Ruchala, Piotr; Pinon, Rogelio; Ramos, Emilio; Qiao, Bo; Peralta, Michael A.; Sharma, Shantanu; Waring, Alan; Ganz, Tomas; Nemeth, Elizabeta

2011-01-01

Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although transgenic hepcidin replacement in mouse models of these diseases prevents iron overload or decreases its potential toxicity, natural hepcidin is prohibitively expensive for human application and has unfavorable pharmacologic properties. Here, we report the rational design of hepcidin agonists based on the mutagenesis of hepcidin and the hepcidin-binding region of ferroportin and computer modeling of their docking. We identified specific hydrophobic/aromatic residues required for hepcidin-ferroportin binding and obtained evidence in vitro that a thiol-disulfide interaction between ferroportin C326 and the hepcidin disulfide cage may stabilize binding. Guided by this model, we showed that 7–9 N-terminal amino acids of hepcidin, including a single thiol cysteine, comprised the minimal structure that retained hepcidin activity, as shown by the induction of ferroportin degradation in reporter cells. Further modifications to increase resistance to proteolysis and oral bioavailability yielded minihepcidins that, after parenteral or oral administration to mice, lowered serum iron levels comparably to those after parenteral native hepcidin. Moreover, liver iron concentrations were lower in mice chronically treated with minihepcidins than those in mice treated with solvent alone. Minihepcidins may be useful for the treatment of iron overload disorders. PMID:22045566

Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload.

PubMed

Preza, Gloria C; Ruchala, Piotr; Pinon, Rogelio; Ramos, Emilio; Qiao, Bo; Peralta, Michael A; Sharma, Shantanu; Waring, Alan; Ganz, Tomas; Nemeth, Elizabeta

2011-12-01

Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although transgenic hepcidin replacement in mouse models of these diseases prevents iron overload or decreases its potential toxicity, natural hepcidin is prohibitively expensive for human application and has unfavorable pharmacologic properties. Here, we report the rational design of hepcidin agonists based on the mutagenesis of hepcidin and the hepcidin-binding region of ferroportin and computer modeling of their docking. We identified specific hydrophobic/aromatic residues required for hepcidin-ferroportin binding and obtained evidence in vitro that a thiol-disulfide interaction between ferroportin C326 and the hepcidin disulfide cage may stabilize binding. Guided by this model, we showed that 7–9 N-terminal amino acids of hepcidin, including a single thiol cysteine, comprised the minimal structure that retained hepcidin activity, as shown by the induction of ferroportin degradation in reporter cells. Further modifications to increase resistance to proteolysis and oral bioavailability yielded minihepcidins that, after parenteral or oral administration to mice, lowered serum iron levels comparably to those after parenteral native hepcidin. Moreover, liver iron concentrations were lower in mice chronically treated with minihepcidins than those in mice treated with solvent alone. Minihepcidins may be useful for the treatment of iron overload disorders.

[The progress and prospect of application of genetic testing technology-based gene detection technology in the diagnosis and treatment of hereditary cancer].

PubMed

He, J X; Jiang, Y F

2017-08-06

Hereditary cancer is caused by specific pathogenic gene mutations. Early detection and early intervention are the most effective ways to prevent and control hereditary cancer. High-throughput sequencing based genetic testing technology (NGS) breaks through the restrictions of pedigree analysis, provide a convenient and efficient method to detect and diagnose hereditary cancer. Here, we introduce the mechanism of hereditary cancer, summarize, discuss and prospect the application of NGS and other genetic tests in the diagnosis of hereditary retinoblastoma, hereditary breast and ovarian cancer syndrome, hereditary colorectal cancer and other complex and rare hereditary tumors.

Risk prediction for early-onset gastric carcinoma: a case-control study of polygenic gastric cancer in Han Chinese with hereditary background.

PubMed

Yuan, Jiajia; Li, Yanyan; Tian, Tiantian; Li, Na; Zhu, Yan; Zou, Jianling; Gao, Jing; Shen, Lin

2016-06-07

Recent genomewide studies have identified several germline variations associated with gastric cancer. The aim of the present study was to identify, in a Chinese Han population, the individual and combined effects of those single nucleotide polymorphisms (SNPs) that increase the risk of early-onset gastric cancer. We conducted a case-control study comprising 116 patients with gastric cancer as well as 102 sex- and age-matched controls and confirmed that the SNPs MUC1 (mucin 1) rs9841504 and ZBTB20 (zinc finger and BTB domain containing 20) rs4072037 were associated with an increased gastric cancer risk. Of the 116 patients diagnosed with cancer, 65 had at least 1 direct lineal relative with carcinoma of the digestive system or breast/ovarian cancer. These 65 had another 4 SNPs associated with gastric cancer susceptibility: PSCA (prostate stem cell antigen) rs2294008, PLCE1 (phospholipase C epsilon 1) rs2274223, PTGER4/PRKAA1 (prostaglandin E receptor 4/ protein kinase AMP-activated catalytic subunit alpha 1) rs13361707, and TYMS (thymidylate synthetase) rs2790. However, each of these low-penetrance susceptibility polymorphisms alone is not considered influential enough to predict the absolute risk of early-onset gastric cancer. Thus we decided to study different combinations of polygenes as they affected for our population. Those subjects with both the risk alleles MUC1 rs9841504 and ZBTB20 rs4072037 had a greater than 3-fold increased risk of gastric cancer. Also those with a hereditary background including the risk alleles PLCE1 rs2274223 and PTGER4/PRKAA1 rs13361707 were 3 times more susceptible to cardia cancer than those without. These findings show that the study of combined polymorphisms, instead of single low-penetrance variations in susceptibility, may lead to a high-risk classification for a specific population.

Risk prediction for early-onset gastric carcinoma: a case-control study of polygenic gastric cancer in Han Chinese with hereditary background

PubMed Central

Yuan, Jiajia; Li, Yanyan; Tian, Tiantian; Li, Na; Zhu, Yan; Zou, Jianling; Gao, Jing; Shen, Lin

2016-01-01

Recent genomewide studies have identified several germline variations associated with gastric cancer. The aim of the present study was to identify, in a Chinese Han population, the individual and combined effects of those single nucleotide polymorphisms (SNPs) that increase the risk of early-onset gastric cancer. We conducted a case-control study comprising 116 patients with gastric cancer as well as 102 sex- and age-matched controls and confirmed that the SNPs MUC1 (mucin 1) rs9841504 and ZBTB20 (zinc finger and BTB domain containing 20) rs4072037 were associated with an increased gastric cancer risk. Of the 116 patients diagnosed with cancer, 65 had at least 1 direct lineal relative with carcinoma of the digestive system or breast/ovarian cancer. These 65 had another 4 SNPs associated with gastric cancer susceptibility: PSCA (prostate stem cell antigen) rs2294008, PLCE1 (phospholipase C epsilon 1) rs2274223, PTGER4/PRKAA1 (prostaglandin E receptor 4/protein kinase AMP-activated catalytic subunit alpha 1) rs13361707, and TYMS (thymidylate synthetase) rs2790. However, each of these low-penetrance susceptibility polymorphisms alone is not considered influential enough to predict the absolute risk of early-onset gastric cancer. Thus we decided to study different combinations of polygenes as they affected for our population. Those subjects with both the risk alleles MUC1 rs9841504 and ZBTB20 rs4072037 had a greater than 3-fold increased risk of gastric cancer. Also those with a hereditary background including the risk alleles PLCE1 rs2274223 and PTGER4/PRKAA1 rs13361707 were 3 times more susceptible to cardia cancer than those without. These findings show that the study of combined polymorphisms, instead of single low-penetrance variations in susceptibility, may lead to a high-risk classification for a specific population. PMID:27127881

Hereditary inclusion-body myopathies.

PubMed

Broccolini, Aldobrando; Mirabella, Massimiliano

2015-04-01

The term hereditary inclusion-body myopathies (HIBMs) defines a group of rare muscle disorders with autosomal recessive or dominant inheritance and presence of muscle fibers with rimmed vacuoles and collection of cytoplasmic or nuclear 15-21 nm diameter tubulofilaments as revealed by muscle biopsy. The most common form of HIBM is due to mutations of the GNE gene that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. This results in abnormal sialylation of glycoproteins that possibly leads to muscle fiber degeneration. Mutations of the valosin containing protein are instead responsible for hereditary inclusion-body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD), with these three phenotypic features having a variable penetrance. IBMPFD probably represents a disorder of abnormal cellular trafficking of proteins and maturation of the autophagosome. HIBM with congenital joint contractures and external ophthalmoplegia is due to mutations of the Myosin Heavy Chain IIa gene that exerts a pathogenic effect through interference with filament assembly or functional defects in ATPase activity. This review illustrates the clinical and pathologic characteristics of HIBMs and the main clues available to date concerning the possible pathogenic mechanisms and therapeutic perspectives of these disorders. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

Dysphonia and vocal fold telangiectasia in hereditary hemorrhagic telangiectasia.

PubMed

Chang, Joseph; Yung, Katherine C

2014-11-01

This case report is the first documentation of dysphonia and vocal fold telangiectasia as a complication of hereditary hemorrhagic telangiectasia (HHT). Case report of a 40-year-old man with HHT presenting with 2 years of worsening hoarseness. Hoarseness corresponded with a period of anticoagulation. Endoscopy revealed vocal fold scarring, vocal fold telangiectasias, and plica ventricular is suggestive of previous submucosal vocal fold hemorrhage and subsequent counterproductive compensation with ventricular phonation. Hereditary hemorrhagic telangiectasia may present as dysphonia with vocal fold telangiectasias and place patients at risk of vocal fold hemorrhage. © The Author(s) 2014.

Genetics Home Reference: hereditary cerebral amyloid angiopathy

MedlinePlus

... uncommon in individuals with the Iowa type. This type is characterized by memory loss, problems with vocabulary and the production of speech, personality changes, and involuntary muscle twitches (myoclonus). Two types of hereditary cerebral amyloid angiopathy , known as familial ...

Network for Early Onset Cystic Kidney Diseases-A Comprehensive Multidisciplinary Approach to Hereditary Cystic Kidney Diseases in Childhood.

PubMed

König, Jens Christian; Titieni, Andrea; Konrad, Martin

2018-01-01

Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome, and hepatocyte nuclear factor-1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype-phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases. To tackle these challenges comprehensive scientific approaches are urgently needed that match the ongoing "revolution" in genetics and molecular biology with an improved efficacy of clinical data collection. Network for early onset cystic kidney diseases (NEOCYST) is a multidisciplinary, multicenter collaborative combining a detailed collection of clinical data with translational scientific approaches addressing the genetic, molecular, and functional background of hereditary cystic kidney diseases. Consisting of seven work packages, including an international registry as well as a biobank, NEOCYST is not only dedicated to current scientific questions, but also provides a platform for longitudinal clinical surveillance and provides precious sources for high-quality research projects and future clinical trials. Funded by the German Federal Government, the NEOCYST collaborative started in February 2016. Here, we would like to introduce the rationale, design, and objectives of the network followed by a short overview on the current state of progress.

Hereditary chronic pancreatitis

PubMed Central

Rosendahl, Jonas; Bödeker, Hans; Mössner, Joachim; Teich, Niels

2007-01-01

Hereditary chronic pancreatitis (HCP) is a very rare form of early onset chronic pancreatitis. With the exception of the young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. As well, diagnostic criteria and treatment of HCP resemble that of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, most patients have a mild disease. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2), the serine protease inhibitor, Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) have been found to be associated with chronic pancreatitis (idiopathic and hereditary) as well. Genetic testing should only be performed in carefully selected patients by direct DNA sequencing and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications, such as pseudocysts, bile duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. Pancreatic cancer risk is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer. PMID:17204147

Genetics Home Reference: Leber hereditary optic neuropathy

MedlinePlus

... What is the prognosis of a genetic condition? Genetic and Rare Diseases Information Center Frequency The prevalence of LHON in ... Nerve Disorders Health Topic: Vision Impairment and Blindness Genetic and Rare Diseases Information Center (1 link) Leber hereditary optic neuropathy ...

Proton Pump Inhibitors Decrease Phlebotomy Need in HFE Hemochromatosis: Double-Blind Randomized Placebo-Controlled Trial.

PubMed

Vanclooster, Annick; van Deursen, Cees; Jaspers, Reggy; Cassiman, David; Koek, Ger

2017-09-01

Phlebotomy constitutes the established treatment for HFE-related hemochromatosis. Retrospective studies have suggested proton pump inhibitors (PPIs) reduce the need for phlebotomy in this population. We conducted a randomized controlled trial to prove this. Thirty p.C282Y homozygous patients were randomly allocated to PPI (pantoprazole 40 mg/day) or placebo for 12 months. Phlebotomies were performed when serum ferritin was > 100 μg/L. Phlebotomy need turned out to be significantly lower in patients taking PPI (P = .0052). PPI treatment significantly reduces the need for phlebotomies in p.C282Y homozygous patients. In view of the known long-term safety profile of PPI, they can be a valuable addition to standard therapy. Clinicaltrials.gov: NCT01524757. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Development and validation of a simple questionnaire for the identification of hereditary breast cancer in primary care

PubMed Central

2009-01-01

Background Breast cancer is a significant public health problem worldwide and the development of tools to identify individuals at-risk for hereditary breast cancer syndromes, where specific interventions can be proposed to reduce risk, has become increasingly relevant. A previous study in Southern Brazil has shown that a family history suggestive of these syndromes may be prevalent at the primary care level. Development of a simple and sensitive instrument, easily applicable in primary care units, would be particularly helpful in underserved communities in which identification and referral of high-risk individuals is difficult. Methods A simple 7-question instrument about family history of breast, ovarian and colorectal cancer, FHS-7, was developed to screen for individuals with an increased risk for hereditary breast cancer syndromes. FHS-7 was applied to 9218 women during routine visits to primary care units in Southern Brazil. Two consecutive samples of 885 women and 910 women who answered positively to at least one question and negatively to all questions were included, respectively. The sensitivity, specificity and positive and negative predictive values were determined. Results Of the 885 women reporting a positive family history, 211 (23.8%; CI95%: 21.5–26.2) had a pedigree suggestive of a hereditary breast and/or breast and colorectal cancer syndrome. Using as cut point one positive answer, the sensitivity and specificity of the instrument were 87.6% and 56.4%, respectively. Concordance between answers in two different applications was given by a intra-class correlation (ICC) of 0.84 for at least one positive answer. Temporal stability of the instrument was adequate (ICC = 0.65). Conclusion A simple instrument for the identification of the most common hereditary breast cancer syndrome phenotypes, showing good specificity and temporal stability was developed and could be used as a screening tool in primary care to refer at-risk individuals for genetic

Genetics Home Reference: hereditary diffuse gastric cancer

MedlinePlus

... Pennell E, MacMillan A, Fernandez B, Keller G, Lynch H, Shah SP, Guilford P, Gallinger S, Corso G, Roviello F, Caldas C, Oliveira C, Pharoah PD, Huntsman DG. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. 2015 Apr; ...

Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma

PubMed Central

Hedayati, Mehdi; Zarif Yeganeh, Marjan; Sheikhol Eslami, Sara; Rezghi Barez, Shekoofe; Hoghooghi Rad, Laleh; Azizi, Fereidoun

2011-01-01

Medullary thyroid carcinoma occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of RET proto-oncogene in MTC development have been well demonstrated. To investigate the spectrum of predominant RET germline mutations in exons 10, 11, and 16 in hereditary MTC in Iranian population, 217 participants were included. Genomic DNAs were extracted from the leukocytes using the standard Salting Out/Proteinase K method. Mutation detection was performed through PCR-RFLP and DNA sequencing. In 217 participants, 43 missense mutations were identified in exons 10 (6%), 11 (13%), and 16 (0.9%). Moreover, a novel germline mutation was detected in exon 11 (S686N). Also four different polymorphisms were found in intron 16 in eight patients. The obtained data showed the frequency profile of RET mutations in Iranian individuals with MTC (19.8%). The most frequent mutation in our population was C634G whereas in most population it was C634R. Altogether, these results underline the importance of the genetic background of family members of any patient with MTC. PMID:21765987

The Molecular Basis of Hereditary Enamel Defects in Humans

PubMed Central

Carrion, I.A.; Morris, C.

2015-01-01

The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue include cell differentiation; production of a unique extracellular matrix; processing of the extracellular matrix; altering of cell function during different stages of enamel formation; cell movement and attachment; regulation of ion and protein movement; and regulation of hydration, pH, and other conditions of the microenvironment, to name just a few. Not surprising, there is a plethora of hereditary conditions with an enamel phenotype. The objective of this review was to identify the hereditary conditions listed on Online Mendelian Inheritance in Man (OMIM) that have an associated enamel phenotype and whether a causative gene has been identified. The OMIM database was searched with the terms amelogenesis, enamel, dental, and tooth, and all results were screened by 2 individuals to determine if an enamel phenotype was identified. Gene and gene product function was reviewed on OMIM and from publications identified in PubMed. The search strategy revealed 91 conditions listed in OMIM as having an enamel phenotype, and of those, 71 have a known molecular etiology or linked genetic loci. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, and transmembrane proteins. The most common enamel phenotype was a deficient amount of enamel, or enamel hypoplasia, with hypomineralization defects being reported less frequently. Knowing these molecular defects allows an initial cataloging of molecular pathways that lead to hereditary enamel defects in humans. This knowledge provides insight into the diverse molecular pathways involved in enamel formation and can be useful when searching for the genetic etiology of hereditary conditions that involve enamel. PMID:25389004

The molecular basis of hereditary enamel defects in humans.

PubMed

Wright, J T; Carrion, I A; Morris, C

2015-01-01

The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue include cell differentiation; production of a unique extracellular matrix; processing of the extracellular matrix; altering of cell function during different stages of enamel formation; cell movement and attachment; regulation of ion and protein movement; and regulation of hydration, pH, and other conditions of the microenvironment, to name just a few. Not surprising, there is a plethora of hereditary conditions with an enamel phenotype. The objective of this review was to identify the hereditary conditions listed on Online Mendelian Inheritance in Man (OMIM) that have an associated enamel phenotype and whether a causative gene has been identified. The OMIM database was searched with the terms amelogenesis, enamel, dental, and tooth, and all results were screened by 2 individuals to determine if an enamel phenotype was identified. Gene and gene product function was reviewed on OMIM and from publications identified in PubMed. The search strategy revealed 91 conditions listed in OMIM as having an enamel phenotype, and of those, 71 have a known molecular etiology or linked genetic loci. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, and transmembrane proteins. The most common enamel phenotype was a deficient amount of enamel, or enamel hypoplasia, with hypomineralization defects being reported less frequently. Knowing these molecular defects allows an initial cataloging of molecular pathways that lead to hereditary enamel defects in humans. This knowledge provides insight into the diverse molecular pathways involved in enamel formation and can be useful when searching for the genetic etiology of hereditary conditions that involve enamel. © International & American Associations for

Psychological distress in women at risk for hereditary breast cancer: the role of family communication and perceived social support.

PubMed

den Heijer, Mariska; Seynaeve, Caroline; Vanheusden, Kathleen; Duivenvoorden, Hugo J; Bartels, Carina C M; Menke-Pluymers, Marian B E; Tibben, Aad

2011-12-01

Hereditary breast cancer has a profound impact on individual family members and on their mutual communication and interactions. The way at-risk women cope with the threat of hereditary breast cancer may depend on the quality of family communication about hereditary breast cancer and on the perceived social support from family and friends. To examine the associations of family communication and social support with long-term psychological distress in a group of women at risk for hereditary breast cancer, who opted either for regular breast surveillance or prophylactic surgery. The study cohort consisted of 222 women at risk for hereditary breast cancer, who previously participated in a study on the psychological consequences of either regular breast cancer surveillance or prophylactic surgery. General and breast cancer specific distress, hereditary cancer-related family communication, perceived social support, and demographics were assessed. Using structural equation modelling, we found that open communication about hereditary cancer within the family was associated with less general and breast cancer specific distress. In addition, perceived support from family and friends was indirectly associated with less general and breast cancer-specific distress through open communication within the family. These findings indicate that family communication and perceived social support from friends and family are of paramount importance in the long-term adaptation to being at risk for hereditary breast cancer. Attention for these issues needs to be incorporated in the care of women at risk for hereditary breast cancer. Copyright © 2010 John Wiley & Sons, Ltd.

Difference equation state approximations for nonlinear hereditary control problems

NASA Technical Reports Server (NTRS)

Rosen, I. G.

1982-01-01

Discrete approximation schemes for the solution of nonlinear hereditary control problems are constructed. The methods involve approximation by a sequence of optimal control problems in which the original infinite dimensional state equation has been approximated by a finite dimensional discrete difference equation. Convergence of the state approximations is argued using linear semigroup theory and is then used to demonstrate that solutions to the approximating optimal control problems in some sense approximate solutions to the original control problem. Two schemes, one based upon piecewise constant approximation, and the other involving spline functions are discussed. Numerical results are presented, analyzed and used to compare the schemes to other available approximation methods for the solution of hereditary control problems.

Hereditary properdin deficiency in three families of Tunisian Jews.

PubMed

Schlesinger, M; Mashal, U; Levy, J; Fishelson, Z

1993-09-01

Hereditary properdin deficiency is a rare genetic disorder of the complement system. Three propositi and six additional family members with properdin deficiency have been found following analysis of the hemolytic activity of the classical (CH50) and the alternative (AP50) complement pathways in the sera of 101 survivors of meningococcal infections and 59 survivors of severe pneumococcal and Haemophilus influenza infections. All the properdin-deficient individuals had undetectable levels of properdin by radial immunodiffusion and by Western blotting. They belonged to three non-related families of Tunisian Jews who came from different parts of Tunisia. Two patients had a meningococcal infection at 15 and 16 years of age, respectively, and one had Haemophilus influenza meningitis at 1.5 years of age. In contrast to the fulminant and fatal course of meningococcal infection which was previously described in some properdin-deficient patients, our patients had a relatively mild disease. Properdin deficiency may not be as rare as previously thought. Analysis of AP50, in addition to CH50, in sera of patients who had meningococcal infection, will probably disclose many more cases of hereditary properdin deficiency. In addition, our findings indicate that, as in other complement abnormalities, hereditary properdin deficiency may also be associated with the ethnic origin of the patient.

Therapeutic management of neonatal hemochromatosis: report of four cases and literature review.

PubMed

Annagür, Ali; Altunhan, Hüseyin; Yüksekkaya, Hasan Ali; Örs, Rahmi

2011-10-01

Neonatal hemochromatosis (NH) is a rare disease of iron metabolism that starts at intrauterine period causing liver failure and extrahepatic siderozis. The etiology of NH has not been understood exactly, yet it is accepted that a maternofetal alloimmune disorder that leads to liver failure in fetus causes the illness. The prognosis of NH is generally bad and death is inevitable if left untreated. The efficiency of chelation-antioxidant coctail used in medical treatment is between 10% and 20% and these patients frequently need liver transplantation. In our study, we presented four newborn cases diagnosed as NH and treated medically. Of the four patients, one died of pulmonary hemorrhage and another died of multiorgan failure in the first week of hospitalization. The other two patients' clinical status and laboratory parameters recovered with medical treatment. However, since liver transplantation was not carried out, one of these patients died at the age of two and a half months and the other at eighth month due to sepsis. In this study, we would like to emphasize the importance of early liver transplantation in patients recovered with medical treatment.

Singapore Cancer Network (SCAN) Guidelines for Referral for Genetic Evaluation of Common Hereditary Cancer Syndromes.

PubMed

2015-10-01

The SCAN cancer genetics workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for referral for genetic evaluation of common hereditary cancer syndromes. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. To formulate referral guidelines for the 3 most commonly encountered hereditary cancer syndromes to guide healthcare providers in Singapore who care for cancer patients and/or their family members, 7, 5, and 3 sets of international guidelines respectively for hereditary breast and ovarian cancer (HBOC) syndrome, Lynch syndrome (LS), and familial adenomatous polyposis (FAP) were evaluated. For each syndrome, the most applicable one was selected, with modifications made such that they would be appropriate to the local context. These adapted guidelines form the SCAN Guidelines 2015 for referral for genetic evaluation of common hereditary cancer syndromes.

Network for Early Onset Cystic Kidney Diseases—A Comprehensive Multidisciplinary Approach to Hereditary Cystic Kidney Diseases in Childhood

PubMed Central

König, Jens Christian; Titieni, Andrea; Konrad, Martin; Bergmann, C.

2018-01-01

Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet–Biedl syndrome, and hepatocyte nuclear factor-1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype–phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases. To tackle these challenges comprehensive scientific approaches are urgently needed that match the ongoing “revolution” in genetics and molecular biology with an improved efficacy of clinical data collection. Network for early onset cystic kidney diseases (NEOCYST) is a multidisciplinary, multicenter collaborative combining a detailed collection of clinical data with translational scientific approaches addressing the genetic, molecular, and functional background of hereditary cystic kidney diseases. Consisting of seven work packages, including an international registry as well as a biobank, NEOCYST is not only dedicated to current scientific questions, but also provides a platform for longitudinal clinical surveillance and provides precious sources for high-quality research projects and future clinical trials. Funded by the German Federal Government, the NEOCYST collaborative started in February 2016. Here, we would like to introduce the rationale, design, and objectives of the network followed by a short overview on the current state of progress. PMID:29497606

Hemojuvelin regulates the innate immune response to peritoneal bacterial infection in mice.

PubMed

Wu, Qian; Shen, Yuanyuan; Tao, Yunlong; Wei, Jiayu; Wang, Hao; An, Peng; Zhang, Zhuzhen; Gao, Hong; Zhou, Tianhua; Wang, Fudi; Min, Junxia

2017-01-01

Hereditary hemochromatosis and iron imbalance are associated with susceptibility to bacterial infection; however, the underlying mechanisms are poorly understood. Here, we performed in vivo bacterial infection screening using several mouse models of hemochromatosis, including Hfe ( Hfe -/- ), hemojuvelin ( Hjv -/- ), and macrophage-specific ferroportin-1 ( Fpn1 fl/fl ; LysM-Cre + ) knockout mice. We found that Hjv -/- mice, but not Hfe -/- or Fpn1 fl/fl ; LysM-Cre + mice, are highly susceptible to peritoneal infection by both Gram-negative and Gram-positive bacteria. Interestingly, phagocytic cells in the peritoneum of Hjv -/- mice have reduced bacterial clearance, IFN-γ secretion, and nitric oxide production; in contrast, both cell migration and phagocytosis are normal. Expressing Hjv in RAW264.7 cells increased the level of phosphorylated Stat1 and nitric oxide production. Moreover, macrophage-specific Hjv knockout mice are susceptible to bacterial infection. Finally, we found that Hjv facilitates the secretion of IFN-γ via the IL-12/Jak2/Stat4 signaling pathway. Together, these findings reveal a novel protective role of Hjv in the early stages of antimicrobial defense.

Ventricular assist device implantation in a young patient with non-compaction cardiomyopathy and hereditary spherocytosis.

PubMed

Huenges, Katharina; Panholzer, Bernd; Cremer, Jochen; Haneya, Assad

2018-04-01

A case of a 15-year-old female patient with acute heart failure due to non-compaction cardiomyopathy and hereditary anaemia (hereditary spherocytic elliptocytosis) requiring ventricular assist device implantation as a bridge to transplantation is presented. The possible effects of mechanical stress on erythrocytes potentially induced by mechanical circulatory support remains unclear, but it may lead to haemolytic crisis in patients suffering from hereditary anaemia. In our case, ventricular assist device therapy was feasible, and haematological complications did not occur within 6 weeks of bridging our patient to heart transplantation.

Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome.

PubMed Central

Nielsen, J E; Jensen, L N; Krabbe, K

1995-01-01

Hereditary haemochromatosis is characterised by excessive parenchymal iron deposition, particularly in the liver. Usually hereditary haemochromatosis is not associated with neurological symptoms and iron deposition in the brain has not previously been described as a pathological phenomenon. A patient is reported with hereditary haemochromatosis and a syndrome of dementia, dysarthria, a slowly progressive gait disturbance, imbalance, muscle weakness, rigidity, bradykinesia, tremor, ataxia, and dyssynergia. The findings on MRI of a large signal decrease in the basal ganglia, consistent with excessive iron accumulation, indicate a causal relation to the symptoms. Although the neurological symptoms did not improve in our patient, hereditary haemochromatosis should be considered in the differential diagnosis of parkinsonian syndromes, because complications of iron induced organ injury may be prevented by phlebotomy. Images PMID:7673967

Genetic and Dietary Iron Overload Differentially Affect the Course of Salmonella Typhimurium Infection

PubMed Central

Nairz, Manfred; Schroll, Andrea; Haschka, David; Dichtl, Stefanie; Tymoszuk, Piotr; Demetz, Egon; Moser, Patrizia; Haas, Hubertus; Fang, Ferric C.; Theurl, Igor; Weiss, Günter

2017-01-01

Genetic and dietary forms of iron overload have distinctive clinical and pathophysiological features. HFE-associated hereditary hemochromatosis is characterized by overwhelming intestinal iron absorption, parenchymal iron deposition, and macrophage iron depletion. In contrast, excessive dietary iron intake results in iron deposition in macrophages. However, the functional consequences of genetic and dietary iron overload for the control of microbes are incompletely understood. Using Hfe+/+ and Hfe−/− mice in combination with oral iron overload in a model of Salmonella enterica serovar Typhimurium infection, we found animals of either genotype to induce hepcidin antimicrobial peptide expression and hypoferremia following systemic infection in an Hfe-independent manner. As predicted, Hfe−/− mice, a model of hereditary hemochromatosis, displayed reduced spleen iron content, which translated into improved control of Salmonella replication. Salmonella adapted to the iron-poor microenvironment in the spleens of Hfe−/− mice by inducing the expression of its siderophore iron-uptake machinery. Dietary iron loading resulted in higher bacterial numbers in both WT and Hfe−/− mice, although Hfe deficiency still resulted in better pathogen control and improved survival. This suggests that Hfe deficiency may exert protective effects in addition to the control of iron availability for intracellular bacteria. Our data show that a dynamic adaptation of iron metabolism in both immune cells and microbes shapes the host-pathogen interaction in the setting of systemic Salmonella infection. Moreover, Hfe-associated iron overload and dietary iron excess result in different outcomes in infection, indicating that tissue and cellular iron distribution determines the susceptibility to infection with specific pathogens. PMID:28443246

Molecular biology of hereditary diabetes insipidus.

PubMed

Fujiwara, T Mary; Bichet, Daniel G

2005-10-01

The identification, characterization, and mutational analysis of three different genes-the arginine vasopressin gene (AVP), the arginine vasopressin receptor 2 gene (AVPR2), and the vasopressin-sensitive water channel gene (aquaporin 2 [AQP2])-provide the basis for understanding of three different hereditary forms of "pure" diabetes insipidus: Neurohypophyseal diabetes insipidus, X-linked nephrogenic diabetes insipidus (NDI), and non-X-linked NDI, respectively. It is clinically useful to distinguish two types of hereditary NDI: A "pure" type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients who have congenital NDI and bear mutations in the AVPR2 or AQP2 genes have a "pure" NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride, and calcium. Patients who bear inactivating mutations in genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA and CLCNKB in combination, or BSND) that encode the membrane proteins of the thick ascending limb of the loop of Henle have a complex polyuro-polydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium. These advances provide diagnostic and clinical tools for physicians who care for these patients.

Newly designed 11-gene panel reveals first case of hereditary amyloidosis captured by massive parallel sequencing.

PubMed

Chyra Kufova, Zuzana; Sevcikova, Tereza; Januska, Jaroslav; Vojta, Petr; Boday, Arpad; Vanickova, Pavla; Filipova, Jana; Growkova, Katerina; Jelinek, Tomas; Hajduch, Marian; Hajek, Roman

2018-02-17

Amyloidosis is caused by deposition of abnormal protein fibrils, leading to damage of organ function. Hereditary amyloidosis represents a monogenic disease caused by germline mutations in 11 amyloidogenic precursor protein genes. One of the important but non-specific symptoms of amyloidosis is hypertrophic cardiomyopathy. Diagnostics of hereditary amyloidosis is complicated and the real cause can remain overlooked. We aimed to design hereditary amyloidosis gene panel and to introduce new next-generation sequencing (NGS) approach to investigate hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance. Design of target enrichment DNA library preparation using Haloplex Custom Kit containing 11 amyloidogenic genes was followed by MiSeq Illumina sequencing and bioinformatics identification of germline variants using tool VarScan in a cohort of 40 patients. We present design of NGS panel for 11 genes ( TTR , FGA , APOA1 , APOA2 , LYZ , GSN , CST3 , PRNP , APP , B2M , ITM2B ) connected to various forms of amyloidosis. We detected one mutation, which is responsible for hereditary amyloidosis. Some other single nucleotide variants are so far undescribed or rare variants or represent common polymorphisms in European population. We report one positive case of hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance and set up first panel for NGS in hereditary amyloidosis. This work may facilitate successful implementation of the NGS method by other researchers or clinicians and may improve the diagnostic process after validation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

An Investigation of Similarities in Parent-Child Test Scores for Evidence of Hereditary Components.

ERIC Educational Resources Information Center

Stafford, Richard E.

This study on psychological traits examines three hypotheses: (1) there is a similarity between parents and their children unexplained by a similarity between the parents, (2) this similarity may be explained by hereditary components, and (3) these hereditary components are of the discrete or segregated type of inheritance. There were 104 families…

Heterogeneity of Hereditary Hearing Loss in Iran: a Comprehensive Review

PubMed Central

Beheshtian, Maryam; Babanejad, Mojgan; Azaiez, Hela; Bazazzadegan, Niloofar; Kolbe, Diana; Sloan-Heggen, Christina; Arzhangi, Sanaz; Booth, Kevin; Mohseni, Marzieh; Frees, Kathy; Hossein Azizi, Mohammad; Daneshi, Ahmad; Farhadi, Mohammad; Kahrizi, Kimia; Smith, Richard JH; Najmabadi, Hossein

2017-01-01

A significant contribution to the causes of hereditary hearing impairment comes from genetic factors. More than 120 genes and 160 loci have been identified to be involved in hearing impairment. Given that consanguine populations are more vulnerable to most inherited diseases, such as hereditary hearing loss (HHL), the genetic picture of HHL among the Iranian population, which consists of at least eight ethnic subgroups with a high rate of intermarriage, is expected to be highly heterogeneous. Using an electronic literature review through various databases such as PubMed, MEDLINE, and Scopus, we review the current picture of HHL in Iran. In this review, we present more than 39 deafness genes reported to cause non-syndromic HHL in Iran, of which the most prevalent causative genes include GJB2, SLC26A4, MYO15A, and MYO7A. In addition, we highlight some of the more common genetic causes of syndromic HHL in Iran. These results are of importance for further investigation and elucidation of the molecular basis of HHL in Iran and also for developing a national diagnostic tool tailored to the Iranian context enabling early and efficient diagnosis of hereditary hearing impairment. PMID:27743438

Difference equation state approximations for nonlinear hereditary control problems

NASA Technical Reports Server (NTRS)

Rosen, I. G.

1984-01-01

Discrete approximation schemes for the solution of nonlinear hereditary control problems are constructed. The methods involve approximation by a sequence of optimal control problems in which the original infinite dimensional state equation has been approximated by a finite dimensional discrete difference equation. Convergence of the state approximations is argued using linear semigroup theory and is then used to demonstrate that solutions to the approximating optimal control problems in some sense approximate solutions to the original control problem. Two schemes, one based upon piecewise constant approximation, and the other involving spline functions are discussed. Numerical results are presented, analyzed and used to compare the schemes to other available approximation methods for the solution of hereditary control problems. Previously announced in STAR as N83-33589

Management of acute attacks of hereditary angioedema: potential role of icatibant

PubMed Central

Longhurst, Hilary J

2010-01-01

Icatibant (Firazyr®) is a novel subcutaneous treatment recently licensed in the European Union for acute hereditary angioedema. Hereditary angioedema, resulting from inherited partial C1 inhibitor deficiency, is a disabling condition characterized by intermittent episodes of bradykinin-mediated angioedema. Icatibant blocks bradykinin B2 receptors, attenutating the episode. Randomized double-blind, placebo-controlled trials of icatibant, showed significant superiority over oral tranexamic acid in 74 European patients and a trend to improvement in a similar US trial comparing icatibant with placebo in 55 patients. Outcomes for several endpoints did not reach significance in the US trial, perhaps because of low participant numbers and confounding factors: a further trial is planned. Open label studies have shown benefit in multiple treatments for attacks at all sites. Approximately 10% of patients require a second dose for re-emergent symptoms, usually 10 to 27 hours after the initial treatment. Its subcutaneous route of administration, good tolerability and novel mode of action make icatibant a promising addition to the limited repertoire of treatments for hereditary angioedema. PMID:20859548

Management of acute attacks of hereditary angioedema: potential role of icatibant.

PubMed

Longhurst, Hilary J

2010-09-07

Icatibant (Firazyr(®)) is a novel subcutaneous treatment recently licensed in the European Union for acute hereditary angioedema. Hereditary angioedema, resulting from inherited partial C1 inhibitor deficiency, is a disabling condition characterized by intermittent episodes of bradykinin-mediated angioedema. Icatibant blocks bradykinin B2 receptors, attenutating the episode. Randomized double-blind, placebo-controlled trials of icatibant, showed significant superiority over oral tranexamic acid in 74 European patients and a trend to improvement in a similar US trial comparing icatibant with placebo in 55 patients. Outcomes for several endpoints did not reach significance in the US trial, perhaps because of low participant numbers and confounding factors: a further trial is planned. Open label studies have shown benefit in multiple treatments for attacks at all sites. Approximately 10% of patients require a second dose for re-emergent symptoms, usually 10 to 27 hours after the initial treatment. Its subcutaneous route of administration, good tolerability and novel mode of action make icatibant a promising addition to the limited repertoire of treatments for hereditary angioedema.

Determining the Parameters of Fractional Exponential Hereditary Kernels for Nonlinear Viscoelastic Materials

NASA Astrophysics Data System (ADS)

Golub, V. P.; Pavlyuk, Ya. V.; Fernati, P. V.

2013-03-01

The parameters of fractional-exponential hereditary kernels for nonlinear viscoelastic materials are determined. Methods for determining the parameters used in the third-order theory of viscoelasticity and in nonlinear theories based on the similarity of primary creep curves and the similarity of isochronous creep curves are analyzed. The parameters of fractional-exponential hereditary kernels are determined and tested against experimental data for microplastic, TC-8/3-250 glass-reinforced plastics, SVAM glass-reinforced plastics. The results (tables and plots) are analyzed

Red cell 2,3-diphosphoglycerate levels in children with hereditary haemolytic anaemias.

PubMed

Haidas, S; Zannos-Mariolea, L; Matsaniotis, N

1975-12-01

The role of red cell 2,3-diphosphoglycerate (2,3-DPG) in increasing the availability of haemoglobin oxygen in neonatal jaundice and hereditary haemolytic anaemias was investigated. Measurements of 2,3-DPG were carried out on 58 normal children and six normal adults, 18 full-term newborns with neonatal jaundice and 57 cases (51 children and six adults) with hereditary haemolytic anaemias. In normal children and adults, with a mean haemoglobin of 12.69 g/dl, mean 2,3-DPG was 14.90 mumol/g Hb. In jaundiced newborns with a mean haemoglobin of 16.04 g/dl mean 2,3-DPG levels were 14.51 mumol/g Hb, i.e. normal. 2,3-DPG levels were increased in patients with beta-thalassaemia major, alpha-thalassaemia, sickle-cell disease, favism, hereditary spherocytosis and in heterozygotes for beta-thalassaemia with increased haemoglobin F. In heterozygotes for beta-thalassaemia with increased haemoglobin A2 only and in sickle cell trait 2,3-DPG levels were normal.

Hereditary angioneurotic edema treated by partial uvulectomy.

PubMed

Waeckerle, J F; Smith, H A; McNabney, W K

1976-06-01

Hereditary angioneurotic edema (HANE) is a rare familial disease of C1 esterase inhibitor deficiency that produces recurring attacks of acute, circumscribed, noninflammatory edema. The technique of partial uvulectomy to treat HANE can reduce the mortality from this condition due to asphyxiation. Three cases in which partial uvulectomy was the successful mode of treatment are described.

[Treatment of hereditary angioedema].

PubMed

Qian, X

1990-06-01

Hereditary angioedema is a rare familial disease caused by the defect of complement C1esterase inhibitor (C1-INH). It is characterized by recurrent acute edema of the extremities, the face, the respiratory tract and the gastrointestinal tract. Acute laryngeal edema usually produces laryngeal obstruction. Two cases have been treated since 1986, one of them had been admitted for forty-five times because of recurrent acute laryngeal edema. Investigations showed two families with a high incidence of this disease. Laboratory examination showed a remarkable decrease of C1-INH and C4. Tracheotomy is indicated in patients with laryngeal edema. Great success was achieved in two patients treated with danazol.

Bevacizumab as a treatment for hereditary hemorrhagic telangiectasia in children: a case report

PubMed Central

Ospina, Fabio E; Echeverri, Alex; Posso-Osorio, Iván; Jaimes, Lina; Gutierrez, Jaiber

2017-01-01

Abstract Case description: Five-year-old female patient with hereditary hemorrhagic telangiectasia. Clinical Findings: Deterioration of cardiopulmonary function with higher oxygen requirements secondary to pulmonary arteriovenous shunts, epistaxis. Treatment and Outcome: The patient was treated with the monoclonal antibody bevacizumab, which inhibits the vascular endothelial growth factor, with good clinical outcome. Clinical Relevance: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations in different organs, making its clinical presentations varied. Systemic therapeutic options for a generalized disease are limited. The monoclonal antibody bevacizumab, seems to be a good option in this disorder. Although reported as successful in adult population, its use in pediatric population has not yet been reported. Here we report the use of bevacizumab in a 5-year-old female patient with hereditary hemorrhagic telangiectasia, showing clinical benefits and good outcome. PMID:29021642

Increased Retinal Expression of the Pro-Angiogenic Receptor GPR91 via BMP6 in a Mouse Model of Juvenile Hemochromatosis.

PubMed

Arjunan, Pachiappan; Gnanaprakasam, Jaya P; Ananth, Sudha; Romej, Michelle A; Rajalakshmi, Veeranan-Karmegam; Prasad, Puttur D; Martin, Pamela M; Gurusamy, Mariappan; Thangaraju, Muthusamy; Bhutia, Yangzom D; Ganapathy, Vadivel

2016-04-01

Hemochromatosis, an iron-overload disease, occurs as adult and juvenile types. Mutations in hemojuvelin (HJV), an iron-regulatory protein and a bone morphogenetic protein (BMP) coreceptor, underlie most of the juvenile type. Hjv(-/-) mice accumulate excess iron in retina and exhibit aberrant vascularization and angiomas. A succinate receptor, GPR91, is pro-angiogenic in retina. We hypothesized that Hjv(-/-) retinas have increased BMP signaling and increased GPR91 expression as the basis of angiomas. Expression of GPR91 was examined by qPCR, immunofluorescence, and Western blot in wild-type and Hjv(-/-) mouse retinas and pRPE cells. Influence of excess iron and BMP6 on GPR91 expression was investigated in ARPE-19 cells, and wild-type and Hjv(-/-) pRPE cells. Succinate was used to activate GPR91 and determine the effects of GPR91 signaling on VEGF expression. Signaling of BMP6 was studied by the expression of Smad1/5/8 and pSmad4, and the BMP-target gene Id1. The interaction of pSmad4 with GPR91 promoter was studied by ChIP. Expression of GPR91 was higher in Hjv(-/-) retinas and RPE than in wild-type counterparts. Unexpectedly, BMP signaling was increased, not decreased, in Hjv(-/-) retinas and RPE. Bone morphogenetic protein 6 induced GPR91 in RPE, suggesting that increased BMP signaling in Hjv(-/-) retinas was likely responsible for GPR91 upregulation. Exposure of RPE to excess iron and succinate as well as BMP6 and succinate increased VEGF expression. Bone morphogenetic protein 6 promoted the interaction of pSmad4 with GPR91 promoter in RPE. G-protein-coupled receptor 91 is a BMP6 target and Hjv deletion enhances BMP signaling in retina, thus underscoring a role for excess iron and hemochromatosis in abnormal retinal vascularization.

Dysfunctional elimination syndrome in three generations of one family: might it be hereditary?

PubMed

Yucel, Selcuk; Ates, Mutlu; Erdogru, Tibet; Baykara, Mehmet

2004-12-01

Dysfunctional elimination syndrome is a diagnosis gaining popularity in pediatric urologic published studies. However, its etiopathogenesis is still unclear. We report a family with 5 cases (3 urodynamically proven) of dysfunctional elimination syndrome in three generations. On the basis of the findings in this family, we revisit the hypothesis that the etiopathogenesis of dysfunctional elimination syndrome might be hereditary. We believe our observations might support the concept of the hereditary transmission of dysfunctional elimination syndrome.

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape.

PubMed

Castellanos, Elisabeth; Gel, Bernat; Rosas, Inma; Tornero, Eva; Santín, Sheila; Pluvinet, Raquel; Velasco, Juan; Sumoy, Lauro; Del Valle, Jesús; Perucho, Manuel; Blanco, Ignacio; Navarro, Matilde; Brunet, Joan; Pineda, Marta; Feliubadaló, Lidia; Capellá, Gabi; Lázaro, Conxi; Serra, Eduard

2017-01-04

We wanted to implement an NGS strategy to globally analyze hereditary cancer with diagnostic quality while retaining the same degree of understanding and control we had in pre-NGS strategies. To do this, we developed the I2HCP panel, a custom bait library covering 122 hereditary cancer genes. We improved bait design, tested different NGS platforms and created a clinically driven custom data analysis pipeline. The I2HCP panel was developed using a training set of hereditary colorectal cancer, hereditary breast and ovarian cancer and neurofibromatosis patients and reached an accuracy, analytical sensitivity and specificity greater than 99%, which was maintained in a validation set. I2HCP changed our diagnostic approach, involving clinicians and a genetic diagnostics team from panel design to reporting. The new strategy improved diagnostic sensitivity, solved uncertain clinical diagnoses and identified mutations in new genes. We assessed the genetic variation in the complete set of hereditary cancer genes, revealing a complex variation landscape that coexists with the disease-causing mutation. We developed, validated and implemented a custom NGS-based strategy for hereditary cancer diagnostics that improved our previous workflows. Additionally, the existence of a rich genetic variation in hereditary cancer genes favors the use of this panel to investigate their role in cancer risk.

Increased risk of death from iron overload among 422 treated probands with HFE hemochromatosis and serum levels of ferritin greater than 1000 μg/L at diagnosis.

PubMed

Barton, James C; Barton, J Clayborn; Acton, Ronald T; So, Jeffrey; Chan, Susanne; Adams, Paul C

2012-04-01

We investigated the risk of death from iron overload among treated hemochromatosis probands who were homozygous for HFE C282Y and had serum levels of ferritin greater than 1000 μg/L at diagnosis. We compared serum levels of ferritin at diagnosis and other conditions with the rate of iron overload-associated death using data from 2 cohorts of probands with hemochromatosis who were homozygous for HFE C282Y (an Alabama cohort, n = 294, 63.9% men and an Ontario cohort, n = 128, 68.8% men). We defined iron overload-associated causes of death as cirrhosis (including hepatic failure and primary liver cancer) caused by iron deposition and cardiomyopathy caused by myocardial siderosis. All probands received phlebotomy and other appropriate therapy. The mean survival times after diagnosis were 13.2 ± 7.3 y and 12.5 ± 8.3 y in Alabama and Ontario probands, respectively. Serum levels of ferritin greater than 1000 μg/L at diagnosis were observed in 30.1% and 47.7% of Alabama and Ontario probands, respectively. In logistic regressions of serum ferritin greater than 1000 μg/L, there were significant positive associations with male sex and cirrhosis in Alabama probands and with age, male sex, increased levels of alanine and aspartate aminotransferases, and cirrhosis in Ontario probands. Of probands with serum levels of ferritin greater than 1000 μg/L at diagnosis, 17.9% of those from Alabama and 14.8% of those from Ontario died of iron overload. Among probands with serum levels of ferritin greater than 1000 μg/L, the relative risk of iron overload-associated death was 5.4 for the Alabama group (95% confidence interval [CI], 2.2-13.1; P = .0002) and 4.9 for the Ontario group (95% CI, 1.1-22.0; P = .0359). In hemochromatosis probands homozygous for HFE C282Y, serum levels of ferritin greater than 1000 μg/L at diagnosis were positively associated with male sex and cirrhosis. Even with treatment, the relative risk of death from iron overload was 5-fold greater in probands with

Stuttering priapism associated with hereditary spherocytosis.

PubMed

Prabhakaran, Karti; Jacobs, Bruce L; Smaldone, Marc C; Franks, Michael E

2007-10-01

Stuttering priapism is a clinical phenomenon that occurs commonly in certain patient populations, including sickle cell anemia and other hematologic dyscrasias. Although the mechanism is still not completely understood, treatment is focused on prevention of recurrence in the outpatient setting, and immediate detumescence and minimizing corporal fibrosis in the acute setting. We present a case of stuttering priapism in a 44 year-old male with hereditary spherocytosis and discuss the pathophysiology and clinical management of this entity.

The Application of Next-Generation Sequencing for Mutation Detection in Autosomal-Dominant Hereditary Hearing Impairment.

PubMed

Gürtler, Nicolas; Röthlisberger, Benno; Ludin, Katja; Schlegel, Christoph; Lalwani, Anil K

2017-07-01

Identification of the causative mutation using next-generation sequencing in autosomal-dominant hereditary hearing impairment, as mutation analysis in hereditary hearing impairment by classic genetic methods, is hindered by the high heterogeneity of the disease. Two Swiss families with autosomal-dominant hereditary hearing impairment. Amplified DNA libraries for next-generation sequencing were constructed from extracted genomic DNA, derived from peripheral blood, and enriched by a custom-made sequence capture library. Validated, pooled libraries were sequenced on an Illumina MiSeq instrument, 300 cycles and paired-end sequencing. Technical data analysis was performed with SeqMonk, variant analysis with GeneTalk or VariantStudio. The detection of mutations in genes related to hearing loss by next-generation sequencing was subsequently confirmed using specific polymerase-chain-reaction and Sanger sequencing. Mutation detection in hearing-loss-related genes. The first family harbored the mutation c.5383+5delGTGA in the TECTA-gene. In the second family, a novel mutation c.2614-2625delCATGGCGCCGTG in the WFS1-gene and a second mutation TCOF1-c.1028G>A were identified. Next-generation sequencing successfully identified the causative mutation in families with autosomal-dominant hereditary hearing impairment. The results helped to clarify the pathogenic role of a known mutation and led to the detection of a novel one. NGS represents a feasible approach with great potential future in the diagnostics of hereditary hearing impairment, even in smaller labs.

Hereditary diffuse gastric cancer: how to look for and how to manage it.

PubMed

Polom, Karol; Marrelli, Daniele; D'Ignazio, Alessia; Roviello, Franco

2018-06-04

With a current molecular revolution, hereditary gastric cancer represents a small group of patients that require a special multidisciplinary treatment. Surgeons being a member of the multidisciplinary teams are an important part of the diagnosis, treatment and follow-up of these patients. The prophylactic nature of the gastrectomy with all different problems associated with this procedure need to be widely discussed with patients. We present a review of how to look for and how to manage a hereditary diffuse-type gastric cancer.

The Effect of the Hemochromatosis (HFE) Genotype on Lead Load and Iron Metabolism among Lead Smelter Workers

PubMed Central

Fan, Guangqin; Du, Guihua; Li, Huijun; Lin, Fen; Sun, Ziyong; Yang, Wei; Feng, Chang; Zhu, Gaochun; Li, Yanshu; Chen, Ying; Jiao, Huan; Zhou, Fankun

2014-01-01

Background Both an excess of toxic lead (Pb) and an essential iron disorder have been implicated in many diseases and public health problems. Iron metabolism genes, such as the hemochromatosis (HFE) gene, have been reported to be modifiers for lead absorption and storage. However, the HFE gene studies among the Asian population with occupationally high lead exposure are lacking. Objectives To explore the modifying effects of the HFE genotype (wild-type, H63D variant and C282Y variant) on the Pb load and iron metabolism among Asian Pb-workers with high occupational exposure. Methods Seven hundred and seventy-one employees from a lead smelter manufacturing company were tested to determine their Pb intoxication parameters, iron metabolic indexes and identify the HFE genotype. Descriptive and multivariate analyses were conducted. Results Forty-five H63D variant carriers and no C282Y variant carrier were found among the 771 subjects. Compared with subjects with the wild-type genotype, H63D variant carriers had higher blood lead levels, even after controlling for factors such as age, sex, marriage, education, smoking and lead exposure levels. Multivariate analyses also showed that the H63D genotype modifies the associations between the blood lead levels and the body iron burden/transferrin. Conclusions No C282Y variant was found in this Asian population. The H63D genotype modified the association between the lead and iron metabolism such that increased blood lead is associated with a higher body iron content or a lower transferrin in the H63D variant. It is indicated that H63D variant carriers may be a potentially highly vulnerable sub-population if they are exposed to high lead levels occupationally. PMID:24988074

Hypogonadism in a patient with mild hereditary haemochromatosis.

PubMed

Wlazlo, N; Peters, W; Bravenboer, B

2012-09-01

Hypogonadism is a potential complication of haemochromatosis, usually seen in patients with severe iron overload and liver cirrhosis. We describe the diagnostic workup of a patient with an early stage of hereditary haemochromatosis, presenting with only mildly elevated liver enzymes and central hypogonadism in the absence of cirrhosis or diabetes, but with concurrent sarcoidosis.

De novo REEP2 missense mutation in pure hereditary spastic paraplegia.

PubMed

Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig

2017-05-01

Alterations in proteins that regulate endoplasmic reticulum morphology are common causes of hereditary spastic paraplegia (SPG1-78, plus others). Mutations in the REEP1 gene that encodes an endoplasmic reticulum-shaping protein are well-known causes of SPG31, a common autosomal dominant spastic paraplegia. A closely-related gene, REEP2, is mutated in SPG72, with both autosomal and recessive inheritances. Here, we report a patient with a pure hereditary spastic paraplegia due to a de novo missense mutation (c.119T > G, p.Met40Arg) in REEP2 at a highly-conserved residue very close to another known pathogenic missense change. This represents only the second autosomal dominant SPG72 missense mutation reported.

Whole-exome sequencing for diagnosis of hereditary ichthyosis.

PubMed

Sitek, J C; Kulseth, M A; Rypdal, K B; Skodje, T; Sheng, Y; Retterstøl, L

2018-02-14

Hereditary ichthyosis constitutes a diverse group of cornification disorders. Identification of the molecular cause facilitates optimal patient care. We wanted to estimate the diagnostic yield of applying whole-exome sequencing (WES) in the routine genetic workup of inherited ichthyosis. During a 3-year-period, all ichthyosis patients, except X-linked and mild vulgar ichthyosis, consecutively admitted to a university hospital clinic were offered WES with subsequent analysis of ichthyosis-related genes as a first-line genetic investigation. Clinical and molecular data have been collected retrospectively. Genetic variants causative for the ichthyosis were identified in 27 of 34 investigated patients (79.4%). In all, 31 causative mutations across 13 genes were disclosed, including 12 novel variants. TGM1 was the most frequently mutated gene, accounting for 43.7% of patients suffering from autosomal recessive congenital ichthyosis (ARCI). Whole-exome sequencing appears an effective tool in disclosing the molecular cause of patients with hereditary ichthyosis seen in clinical practice and should be considered a first-tier genetic test in these patients. © 2018 European Academy of Dermatology and Venereology.

Regulation of HFE expression by Poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter

PubMed Central

Rodova, Marianna; Rudolph, Angela; Chipps, Elizabeth; Islam, M. Rafiq

2013-01-01

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron overload among Caucasians of northern European descent. Over 85% of all cases with HH are due to mutations in the hemochromatosis protein (HFE) involved in iron metabolism. Although the importance in iron homeostasis is well recognized, the mechanism of sensing and regulating iron absorption by HFE, especially in the absence of iron response element in its gene, is not fully understood. In this report, we have identified an inverted repeat sequence (ATGGTcttACCTA) within 1700 bp (−1675/+35) of the HFE promoter capable to form cruciform structure that binds PARP1 and strongly represses HFE promoter. Knockdown of PARP1 increases HFE mRNA and protein. Similarly, hemin or FeCl3 treatments resulted in increase in HFE expression by reducing nuclear PARP1 pool via its apoptosis induced cleavage, leading to upregulation of the iron regulatory hormone hepcidin mRNA. Thus, PARP1 binding to the inverted repeat sequence on the HFE promoter may serve as a novel iron sensing mechanism as increased iron level can trigger PARP1 cleavage and relief of HFE transcriptional repression. PMID:24184271

Regulation of HFE expression by poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter.

PubMed

Pelham, Christopher; Jimenez, Tamara; Rodova, Marianna; Rudolph, Angela; Chipps, Elizabeth; Islam, M Rafiq

2013-12-01

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron overload among Caucasians of northern European descent. Over 85% of all cases with HH are due to mutations in the hemochromatosis protein (HFE) involved in iron metabolism. Although the importance in iron homeostasis is well recognized, the mechanism of sensing and regulating iron absorption by HFE, especially in the absence of iron response element in its gene, is not fully understood. In this report, we have identified an inverted repeat sequence (ATGGTcttACCTA) within 1700bp (-1675/+35) of the HFE promoter capable to form cruciform structure that binds PARP1 and strongly represses HFE promoter. Knockdown of PARP1 increases HFE mRNA and protein. Similarly, hemin or FeCl3 treatments resulted in increase in HFE expression by reducing nuclear PARP1 pool via its apoptosis induced cleavage, leading to upregulation of the iron regulatory hormone hepcidin mRNA. Thus, PARP1 binding to the inverted repeat sequence on the HFE promoter may serve as a novel iron sensing mechanism as increased iron level can trigger PARP1 cleavage and relief of HFE transcriptional repression. © 2013.

Iron overload cardiomyopathy: from diagnosis to management.

PubMed

Díez-López, Carles; Comín-Colet, Josep; González-Costello, José

2018-05-01

Iron overload cardiomyopathy (IOC) is an important predictor of prognosis in a significant number of patients with hereditary hemochromatosis and hematologic diseases. Its prevalence is increasing because of improved treatment strategies, which significantly improve life expectancy. We will review diagnosis, treatment, and recent findings in the field. The development of preclinical translational disease models during the last years have helped our understanding of specific disease pathophysiological pathways that might eventually change the outcomes of these patients. IOC is an overlooked disease because of the progressive silent disease pattern and the lack of physicians' expertise. It mainly affects patients with hemochromatosis and hematologic diseases and its prevalence is expected to increase with the improvement in life expectancy of hematologic disorders. Early diagnosis of IOC in patients at risk by means of biochemical parameters and cardiac imaging can lead to early treatment and improved prognosis. The mainstay of treatment of IOC is conventional heart failure treatment, combined with phlebotomies or iron chelation in the context of anemia. The development of preclinical models has provided a comprehensive look into specific pathophysiological pathways with potential treatment strategies that must be sustained by future randomized trials.

Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia

DOE Office of Scientific and Technical Information (OSTI.GOV)

De Vries, D.D.; Oost, B.A. van; Went, L.N.

1996-04-01

A rare form of Leber hereditary optic neuropathy (LHON) that is associated with hereditary spastic dystonia has been studied in a large Dutch family. Neuropathy and ophthalmological lesions were present together in some family members, whereas only one type of abnormality was found in others. mtDNA mutations previously reported in LHON were not present. Sequence analysis of the protein-coding mitochondrial genes revealed two previously unreported mtDNA mutations. A heteroplasmic A{yields}G transition at nucleotide position 11696 in the ND4 gene resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T{yields}A transitionmore » at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed a severe complex I deficiency, providing a link between these unique mtDNA mutations and this rare, complex phenotype including Leber optic neuropathy. 80 refs., 2 figs., 3 tabs.« less

Combined pulmonary involvement in hereditary lysozyme amyloidosis with associated pulmonary sarcoidosis: a case report.

PubMed

McCarthy, Cormac; Deegan, Alexander P; Garvey, John F; McDonnell, Timothy J

2013-12-17

Sarcoidosis is a multisystem inflammatory disorder of unknown cause which can affect any organ system. Autosomal dominant lysozyme amyloidosis is a very rare form of hereditary amyloidosis. The Arg64 variant is extraordinarily rare with each family showing a particular pattern of organ involvement, however while Sicca syndrome, gastrointestinal involvement and renal failure are common, lymph node involvement is very rare. In this case report we describe the first reported case of sarcoidosis in association with hereditary lysozyme amyloidosis.

Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox.

PubMed

Lescano, Manuel A; Tavares, Letícia C; Santos, Paulo C J L

2017-10-16

Juvenile hemochromatosis (JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage, hypogonadotropic hypogonadism, cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation (g.47G>A), treated with phlebotomies and deferasirox. She presented symptoms such as weakness, skin hyperpigmentation, joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin (SF): 5696 ng/mL, transferrin saturation (TS): 85%]. After sessions of phlebotomies (450 mL every 15 d), the patient presented partial symptomatic improvements and biochemical parameters (SF: 1000 ng/mL, Hb: 11 g/dL). One year later, deferasirox (15 mg/kg per day) was introduced to the treatment, and the patient showed total symptomatic improvement, with significant clearing of the skin, SF: 169 ng/mL, and TS: 50%. Furthermore, after the combined deferasirox-phlebotomy therapy, magnetic resonance imaging measurements revealed normalized level for liver iron (30 μmol/g; reference value < 36 μmol/g). In conclusion, combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.

Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox

PubMed Central

Lescano, Manuel A; Tavares, Letícia C; Santos, Paulo C J L

2017-01-01

Juvenile hemochromatosis (JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage, hypogonadotropic hypogonadism, cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation (g.47G>A), treated with phlebotomies and deferasirox. She presented symptoms such as weakness, skin hyperpigmentation, joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin (SF): 5696 ng/mL, transferrin saturation (TS): 85%]. After sessions of phlebotomies (450 mL every 15 d), the patient presented partial symptomatic improvements and biochemical parameters (SF: 1000 ng/mL, Hb: 11 g/dL). One year later, deferasirox (15 mg/kg per day) was introduced to the treatment, and the patient showed total symptomatic improvement, with significant clearing of the skin, SF: 169 ng/mL, and TS: 50%. Furthermore, after the combined deferasirox-phlebotomy therapy, magnetic resonance imaging measurements revealed normalized level for liver iron (30 μmol/g; reference value < 36 μmol/g). In conclusion, combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms. PMID:29085829

The impact of H63D HFE gene carriage on hemoglobin and iron status in children.

PubMed

Barbara, Kaczorowska-Hac; Marcin, Luszczyk; Jedrzej, Antosiewicz; Wieslaw, Ziolkowski; Elzbieta, Adamkiewicz-Drozynska; Malgorzata, Mysliwiec; Ewa, Milosz; Jacek, Kaczor Jan

2016-12-01

The molecular mechanism that regulates iron homeostasis is based on a network of signals, which reflect on the iron requirements of the body. Hereditary hemochromatosis is a heterogenic metabolic syndrome which is due to unchecked transfer of iron into the bloodstream and its toxic effects on parenchymatous organs. It is caused by the mutation of genes that encode proteins that help hepcidin to monitor serum iron. These proteins include the human hemochromatosis protein -HFE, transferrin-receptor 2, hemojuvelin in rare instances, and ferroportin. HFE-related hemochromatosis is the most frequent form of the disease. Interestingly, the low penetrance of polymorphic HFE genes results in rare clinical presentation of the disease, predominantly in middle-aged males. Taking into account the wide dispersion of HFE mutation in our population and also its unknown role in heterozygotes, we analyzed the impact of H63D HFE carriage in the developmental age, with respect to gender, on the iron status and hemoglobin concentration of carriers in comparison to those of wild-type HFE gene (12.7 ± 3.07 years, 42 boys and 41 girls). H63D carriers presented higher blood iron, transferrin saturation, and ferritin concentration than wild-type probands (p < 0.05.) Interestingly, male H63D carriers showed higher hemoglobin concentration than the unburdened children. Moreover, in the H63D carrier group, a positive correlation between iron and hemoglobin was noted. In conclusion, this study demonstrates that changes in iron metabolism occur at a young age in HFE heterozygotes.

Hereditary arrhythmias and cardiomyopathies: decision-making about genetic testing.

PubMed

Louis, Clauden; Calamaro, Emily; Vinocur, Jeffrey M

2018-01-01

The modern field of clinical genetics has advanced beyond the traditional teachings familiar to most practicing cardiologists. Increased understanding of the roles of genetic testing may improve uptake and appropriateness of use. Clinical genetics has become integral to the management of patients with hereditary arrhythmia and cardiomyopathy diagnoses. Depending on the condition, genetic testing may be useful for diagnosis, prognosis, treatment, family screening, and reproductive planning. However, genetic testing is a powerful tool with potential for underuse, overuse, and misuse. In the absence of a substantial body of literature on how these guidelines are applied in clinical practice, we use a case-based approach to highlight key lessons and pitfalls. Importantly, in many scenarios genetic testing has become the standard of care supported by numerous class I recommendations; genetic counselors can improve accessibility to and appropriate use and application of testing. Optimal management of hereditary arrhythmias and cardiomyopathies incorporates genetic testing, applied as per consensus guidelines, with involvement of a multidisciplinary team.

The potential of disease management for neuromuscular hereditary disorders.

PubMed

Chouinard, Maud-Christine; Gagnon, Cynthia; Laberge, Luc; Tremblay, Carmen; Côté, Charlotte; Leclerc, Nadine; Mathieu, Jean

2009-01-01

Neuromuscular hereditary disorders require long-term multidisciplinary rehabilitation management. Although the need for coordinated healthcare management has long been recognized, most neuromuscular disorders are still lacking clinical guidelines about their long-term management and structured evaluation plan with associated services. One of the most prevalent adult-onset neuromuscular disorders, myotonic dystrophy type 1, generally presents several comorbidities and a variable clinical picture, making management a constant challenge. This article presents a healthcare follow-up plan and proposes a nursing case management within a disease management program as an innovative and promising approach. This disease management program and model consists of eight components including population identification processes, evidence-based practice guidelines, collaborative practice, patient self-management education, and process outcomes evaluation (Disease Management Association of America, 2004). It is believed to have the potential to significantly improve healthcare management for neuromuscular hereditary disorders and will prove useful to nurses delivering and organizing services for this population.

Comparative analysis of human tissue interactomes reveals factors leading to tissue-specific manifestation of hereditary diseases.

PubMed

Barshir, Ruth; Shwartz, Omer; Smoly, Ilan Y; Yeger-Lotem, Esti

2014-06-01

An open question in human genetics is what underlies the tissue-specific manifestation of hereditary diseases, which are caused by genomic aberrations that are present in cells across the human body. Here we analyzed this phenomenon for over 300 hereditary diseases by using comparative network analysis. We created an extensive resource of protein expression and interactions in 16 main human tissues, by integrating recent data of gene and protein expression across tissues with data of protein-protein interactions (PPIs). The resulting tissue interaction networks (interactomes) shared a large fraction of their proteins and PPIs, and only a small fraction of them were tissue-specific. Applying this resource to hereditary diseases, we first show that most of the disease-causing genes are widely expressed across tissues, yet, enigmatically, cause disease phenotypes in few tissues only. Upon testing for factors that could lead to tissue-specific vulnerability, we find that disease-causing genes tend to have elevated transcript levels and increased number of tissue-specific PPIs in their disease tissues compared to unaffected tissues. We demonstrate through several examples that these tissue-specific PPIs can highlight disease mechanisms, and thus, owing to their small number, provide a powerful filter for interrogating disease etiologies. As two thirds of the hereditary diseases are associated with these factors, comparative tissue analysis offers a meaningful and efficient framework for enhancing the understanding of the molecular basis of hereditary diseases.

Recommendations regarding splenectomy in hereditary hemolytic anemias

PubMed Central

Iolascon, Achille; Andolfo, Immacolata; Barcellini, Wilma; Corcione, Francesco; Garçon, Loïc; De Franceschi, Lucia; Pignata, Claudio; Graziadei, Giovanna; Pospisilova, Dagmar; Rees, David C.; de Montalembert, Mariane; Rivella, Stefano; Gambale, Antonella; Russo, Roberta; Ribeiro, Leticia; Vives-Corrons, Jules; Martinez, Patricia Aguilar; Kattamis, Antonis; Gulbis, Beatrice; Cappellini, Maria Domenica; Roberts, Irene; Tamary, Hannah

2017-01-01

Hereditary hemolytic anemias are a group of disorders with a variety of causes, including red cell membrane defects, red blood cell enzyme disorders, congenital dyserythropoietic anemias, thalassemia syndromes and hemoglobinopathies. As damaged red blood cells passing through the red pulp of the spleen are removed by splenic macrophages, splenectomy is one possible therapeutic approach to the management of severely affected patients. However, except for hereditary spherocytosis for which the effectiveness of splenectomy has been well documented, the efficacy of splenectomy in other anemias within this group has yet to be determined and there are concerns regarding short- and long-term infectious and thrombotic complications. In light of the priorities identified by the European Hematology Association Roadmap we generated specific recommendations for each disorder, except thalassemia syndromes for which there are other, recent guidelines. Our recommendations are intended to enable clinicians to achieve better informed decisions on disease management by splenectomy, on the type of splenectomy and the possible consequences. As no randomized clinical trials, case control or cohort studies regarding splenectomy in these disorders were found in the literature, recommendations for each disease were based on expert opinion and were subsequently critically revised and modified by the Splenectomy in Rare Anemias Study Group, which includes hematologists caring for both adults and children. PMID:28550188

Hepatitis C infection in patients with hereditary bleeding disorders: epidemiology, natural history, and management.

PubMed

Papadopoulos, Nikolaos; Argiana, Vasiliki; Deutsch, Melanie

2018-01-01

Hereditary bleeding disorders include a group of diseases with abnormalities of coagulation. Prior to 1990, infection with hepatitis C virus (HCV) was mainly transmitted via pooled plasma products as a treatment for hereditary bleeding disorders. Anti-HCV positivity in these patients may be as high as >70% in some areas, while some of them have also been coinfected with human immunodeficiency virus. Since about 20% of HCV-infected patients clear the infection naturally, chronic HCV infection represents a significant health problem in this group of patients. Mortality due to chronic HCV infection is estimated to be >10 times higher in patients with hemophilia than in the general population, and is mainly due to liver cirrhosis and hepatocellular carcinoma. The antiviral treatment of HCV in patients with hereditary bleeding disorders is not different from that of any other infected patients. Nevertheless, many patients with hereditary bleeding disorders have declined (Peg)interferon-based treatment because of side effects. In recent years, multiple orally administrated direct-acting antivirals (DAAs) have been approved for HCV treatment. Unfortunately, there is not much experience from treating these patients with DAA regimens, as major studies and real-life data did not include adequate numbers of patients with inherited hemorrhagic disorders. However, the available data indicate that DAAs have an excellent safety profile with a sustained virological response rate of >90%.

Hepatitis C infection in patients with hereditary bleeding disorders: epidemiology, natural history, and management

PubMed Central

Papadopoulos, Nikolaos; Argiana, Vasiliki; Deutsch, Melanie

2018-01-01

Hereditary bleeding disorders include a group of diseases with abnormalities of coagulation. Prior to 1990, infection with hepatitis C virus (HCV) was mainly transmitted via pooled plasma products as a treatment for hereditary bleeding disorders. Anti-HCV positivity in these patients may be as high as >70% in some areas, while some of them have also been coinfected with human immunodeficiency virus. Since about 20% of HCV-infected patients clear the infection naturally, chronic HCV infection represents a significant health problem in this group of patients. Mortality due to chronic HCV infection is estimated to be >10 times higher in patients with hemophilia than in the general population, and is mainly due to liver cirrhosis and hepatocellular carcinoma. The antiviral treatment of HCV in patients with hereditary bleeding disorders is not different from that of any other infected patients. Nevertheless, many patients with hereditary bleeding disorders have declined (Peg)interferon-based treatment because of side effects. In recent years, multiple orally administrated direct-acting antivirals (DAAs) have been approved for HCV treatment. Unfortunately, there is not much experience from treating these patients with DAA regimens, as major studies and real-life data did not include adequate numbers of patients with inherited hemorrhagic disorders. However, the available data indicate that DAAs have an excellent safety profile with a sustained virological response rate of >90%. PMID:29333065

Genetics Home Reference: hereditary neuropathy with liability to pressure palsies

MedlinePlus

... PubMed Central Yilmaz U, Bird TT, Carter GT, Wang LH, Weiss MD. Pain in hereditary neuropathy with liability to pressure palsy: an association with fibromyalgia syndrome? Muscle Nerve. 2015 Mar;51(3):385-90. doi: 10.1002/ ...

Deferasirox pharmacokinetics evaluation in a woman with hereditary haemochromatosis and heterozygous β-thalassaemia.

PubMed

Allegra, Sarah; De Francia, Silvia; Longo, Filomena; Massano, Davide; Cusato, Jessica; Arduino, Arianna; Pirro, Elisa; Piga, Antonio; D'Avolio, Antonio

2016-12-01

We present the deferasirox pharmacokinetics evaluation of a female patient on iron chelation, for the interesting findings from her genetic background (hereditary haemochromatosis and heterozygous β-thalassaemia) and clinical history (ileostomy; iron overload from transfusions). Drug plasma concentrations were measured by an HPLC-UV validated method, before and after ileum resection. Area under deferasirox concentration curve over 24h (AUC) values were determined by the mixed log-linear rule, using Kinetica software. AUC was low also with high deferasirox dose as well as tolerability. Non invasive tissue iron quantification by magnetic resonance imaging or superconducting quantum interference device were prevented by a metal hip replacement. Good efficacy and normalisation of iron markers was obtained on long term. Therapeutic drug monitoring in patient in critical conditions may help to understand reasons for non response and set individualised treatment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Confronting "hereditary" disease: eugenic attempts to eliminate tuberculosis in progressive era America.

PubMed

Wilson, Philip K

2006-01-01

Tuberculosis was clearly one of the most predominant diseases of the early twentieth century. At this time, Americans involved in the eugenics movement grew increasingly interested in methods to prevent this disease's potential hereditary spread. To do so, as this essay examines, eugenicists' attempted to shift the accepted view that tuberculosis arose from infection and contagion to a view of its heritable nature. The methods that they employed to better understand the propagation and control of tuberculosis are also discussed. Finally, the essay explores the interpretative analyses of data that the Eugenics Record Office used in an attempt to convince contemporaries of the hereditary transmission of tuberculosis.

Genetics Home Reference: distal hereditary motor neuropathy, type V

MedlinePlus

... PubMed Irobi J, De Jonghe P, Timmerman V. Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet. 2004 Oct 1;13 Spec No 2:R195-202. Review. Citation on PubMed Ito D, Suzuki N. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. ...

Hereditary hemorrhagic telangiectasia patient presenting with brain abscess due to silent pulmonary arteriovenous malformation.

PubMed

Themistocleous, Marios; Giakoumettis, Dimitrios; Mitsios, Andreas; Anagnostopoulos, Christos; Kalyvas, Aristoteles; Koutsarnakis, Christos

2016-01-01

Hereditary hemorrhagic telangiectasia is a rare autosomal dominant inherited disease that is usually complicated by visceral vascular malformations. Patients harboring such malformations are at increased risk of brain abscess formation, which despite advances in diagnostic and surgical methods remains a life threatening medical emergency with high mortality and morbidity rates. In the present report we describe a case of cerebral abscess due to silent pulmonary arteriovenous malformation (AVM) in a young patient previously undiagnosed for hereditary hemorrhagic telangiectasia syndrome (HHT).

Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis

PubMed Central

Ye, Qi; Kim, Jonghan

2015-01-01

Manganese in excess promotes unstable emotional behavior. Our previous study showed that olfactory manganese uptake into the brain is altered in Hfe−/− mice, a model of iron overload hemochromatosis, suggesting that Hfe deficiency could modify the neurotoxicity of airborne manganese. We determined anxiety-related behavior and monoaminergic protein expression after repeated intranasal instillation of MnCl2 to Hfe−/− mice. Compared with manganese-instilled wild-type mice, Hfe−/− mice showed decreased manganese accumulation in the cerebellum. Hfe−/− mice also exhibited increased anxiety with decreased exploratory activity and elevated dopamine D1 receptor and norepinephrine transporter in the striatum. Moreover, Hfe deficiency attenuated manganese-associated impulsivity and modified the effect of manganese on the expression of tyrosine hydroxylase, vesicular monoamine transporter and serotonin transporter. Together, our data indicate that loss of HFE function alters manganese-associated emotional behavior and further suggest that HFE could be a potential molecular target to alleviate affective disorders induced by manganese inhalation. PMID:26189056

Endometrial cancers in mutation carriers from hereditary breast ovarian cancer syndrome kindreds: report from the Creighton University Hereditary Cancer Registry with review of the implications.

PubMed

Casey, Murray Joseph; Bewtra, Chhanda; Lynch, Henry T; Snyder, Carrie L; Stacey, Mark

2015-05-01

The aim of this study was to categorize and report endometrial cancers in mutation carriers from hereditary breast ovarian cancer families. Our Hereditary Cancer Registry was searched for gynecologic and peritoneal cancers linked to mutations in BRCA1 or BRCA2. Invasive cancers were registered in 101 mutation carriers with complete pathology reports. Efforts were made to secure diagnostic surgical pathology tissues for review. All records and available diagnostic slides were meticulously studied, and primary cancers were classified. Eight malignancies were classified as primary endometrial cancers. Five of these were low- or intermediate-grade endometrioid carcinomas, and 3 were pure serous carcinomas or contained serous carcinoma elements mixed with high-grade endometrioid carcinoma. Breast cancers were diagnosed in 5 patients before and in 1 patient after endometrial carcinoma. Three endometrioid carcinomas were preceded by estrogen treatment, 2 for many years and the other for only 2 months, and 2 of the patients with serous carcinoma had been treated with tamoxifen. The finding that 8 of gynecologic and peritoneal cancers in 101 mutation carriers were endometrial cancers with a smaller proportion of endometrioid carcinomas than reported in general populations is added to the current controversial literature on endometrial cancer, particularly regarding serous carcinomas, in hereditary breast ovarian cancer syndrome. Well-designed prospective programs for standardized surgical and pathologic handling, processing, and reporting are essential for working out the pathogenesis, true risks, and best management of this disease in carriers of deleterious BRCA1 and BRCA2 germline mutations.

Friedreich's ataxia mimicking hereditary motor and sensory neuropathy.

PubMed

Panas, Marios; Kalfakis, Nikolaos; Karadima, Georgia; Davaki, Panagiota; Vassilopoulos, Demetris

2002-11-01

Four patients from three unrelated families, with clinical and electrophysiological findings compatible with the diagnosis of hereditary motor and sensory neuropathy, are presented. The molecular analysis showed that the affected individuals were homozygous for the mutation in the X25 gene, characteristic of Friedreich's ataxia. These patients seem to represent a form of Friedreich's ataxia mimicking Charcot-Marie-Tooth disease.

Hereditary spastic paraplegia.

PubMed

Blackstone, Craig

2018-01-01

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurologic disorders with the common feature of prominent lower-extremity spasticity, resulting from a length-dependent axonopathy of corticospinal upper motor neurons. The HSPs exist not only in "pure" forms but also in "complex" forms that are associated with additional neurologic and extraneurologic features. The HSPs are among the most genetically diverse neurologic disorders, with well over 70 distinct genetic loci, for which about 60 mutated genes have already been identified. Numerous studies elucidating the molecular pathogenesis underlying HSPs have highlighted the importance of basic cellular functions - especially membrane trafficking, mitochondrial function, organelle shaping and biogenesis, axon transport, and lipid/cholesterol metabolism - in axon development and maintenance. An encouragingly small number of converging cellular pathogenic themes have been identified for the most common HSPs, and some of these pathways present compelling targets for future therapies. Copyright © 2018 Elsevier B.V. All rights reserved.

[Hereditary fructose intolerance].

PubMed

Rumping, Lynne; Waterham, Hans R; Kok, Irene; van Hasselt, Peter M; Visser, Gepke

2014-01-01

Hereditary fructose intolerance (HFI) is a rare metabolic disease affecting fructose metabolism. After ingestion of fructose, patients may present with clinical symptoms varying from indefinite gastrointestinal symptoms to life-threatening hypoglycaemia and hepatic failure. A 13-year-old boy was referred to the department of metabolic diseases because of an abnormal fructose loading test. He was known with persistent gastrointestinal symptoms since infancy. His dietary history revealed an avoidance of fruit and sweets. Because malabsorption was suspected, an oral fructose loading test was performed. During this test, he developed severe vagal symptoms which were probably caused by a potentially fatal hypoglycaemia. The diagnosis of HFI was confirmed by genetic analysis. A good dietary history may be of important help in the diagnosis of HFI. On suspicion of HFI, genetic analysis is easy and the first choice in the diagnostic work-up. With timely diagnosis and adequate dietary treatment patients have an excellent prognosis. Fructose loading tests as part of the diagnostics can be dangerous.

Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia.

PubMed

Newton, Timothy; Allison, Rachel; Edgar, James R; Lumb, Jennifer H; Rodger, Catherine E; Manna, Paul T; Rizo, Tania; Kohl, Zacharias; Nygren, Anders O H; Arning, Larissa; Schüle, Rebecca; Depienne, Christel; Goldberg, Lisa; Frahm, Christiane; Stevanin, Giovanni; Durr, Alexandra; Schöls, Ludger; Winner, Beate; Beetz, Christian; Reid, Evan

2018-05-01

Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.

Increased Retinal Expression of the Pro-Angiogenic Receptor GPR91 via BMP6 in a Mouse Model of Juvenile Hemochromatosis

PubMed Central

Arjunan, Pachiappan; Gnanaprakasam, Jaya P.; Ananth, Sudha; Romej, Michelle A.; Rajalakshmi, Veeranan-Karmegam; Prasad, Puttur D.; Martin, Pamela M.; Gurusamy, Mariappan; Thangaraju, Muthusamy; Bhutia, Yangzom D.; Ganapathy, Vadivel

2016-01-01

Purpose Hemochromatosis, an iron-overload disease, occurs as adult and juvenile types. Mutations in hemojuvelin (HJV), an iron-regulatory protein and a bone morphogenetic protein (BMP) coreceptor, underlie most of the juvenile type. Hjv−/− mice accumulate excess iron in retina and exhibit aberrant vascularization and angiomas. A succinate receptor, GPR91, is pro-angiogenic in retina. We hypothesized that Hjv−/− retinas have increased BMP signaling and increased GPR91 expression as the basis of angiomas. Methods Expression of GPR91 was examined by qPCR, immunofluorescence, and Western blot in wild-type and Hjv−/− mouse retinas and pRPE cells. Influence of excess iron and BMP6 on GPR91 expression was investigated in ARPE-19 cells, and wild-type and Hjv−/− pRPE cells. Succinate was used to activate GPR91 and determine the effects of GPR91 signaling on VEGF expression. Signaling of BMP6 was studied by the expression of Smad1/5/8 and pSmad4, and the BMP-target gene Id1. The interaction of pSmad4 with GPR91 promoter was studied by ChIP. Results Expression of GPR91 was higher in Hjv−/− retinas and RPE than in wild-type counterparts. Unexpectedly, BMP signaling was increased, not decreased, in Hjv−/− retinas and RPE. Bone morphogenetic protein 6 induced GPR91 in RPE, suggesting that increased BMP signaling in Hjv−/− retinas was likely responsible for GPR91 upregulation. Exposure of RPE to excess iron and succinate as well as BMP6 and succinate increased VEGF expression. Bone morphogenetic protein 6 promoted the interaction of pSmad4 with GPR91 promoter in RPE. Conclusions G-protein-coupled receptor 91 is a BMP6 target and Hjv deletion enhances BMP signaling in retina, thus underscoring a role for excess iron and hemochromatosis in abnormal retinal vascularization. PMID:27046124

Early ultrasonographic diagnosis of hereditary retinoblastoma.

PubMed

Pierro, L; Capoferri, C; Brancato, R

1991-01-01

A hereditary retinoblastoma (RTB) was identified by ocular echography in a newborn, whose predisposition to RTB had been assessed based on the family history and DNA testing of the chorionic villi at the eighth week of pregnancy. Ultrasonography was performed during pregnancies without an abnormality being demonstrated. On the third day of life a B-scan examination showed a small membranous lesion in the nasal parapapillary area, whilst on A-scan, the lesion appeared as a hyperreflective peak. Thanks to its early identification, the tumor was successfully treated by photocoagulation.

Towards a dietary prevention of hereditary breast cancer.

PubMed

Kotsopoulos, Joanne; Narod, Steven A

2005-03-01

Inheritance of a deleterious mutation in BRCA1 or BRCA2 confers a high lifetime risk of developing breast cancer. Variation in penetrance between individuals suggests that factors other than the gene mutation itself may influence the risk of cancer in susceptible women. Several risk factors have been identified which implicate estrogen-induced growth stimulation as a probable contributor to breast cancer pre-disposition. The protein products of both of these genes appear to help preserve genomic integrity via their participation in the DNA damage response and repair pathways. To date, the evidence for a cancer-protective role of dietary nutrients, for the most part those with antioxidant properties, has been based on women without any known genetic pre-disposition and it is important to identify and evaluate dietary factors which may modify the risk of cancer in BRCA carriers. Here we propose that diet modification may modulate the risk of hereditary breast cancer by decreasing DNA damage (possibly linked to estrogen exposure) or by enhancing DNA repair. The prevention of hereditary breast cancer through diet is an attractive complement to current management strategies and deserves exploration.

Socioeconomic burden of hereditary angioedema: results from the hereditary angioedema burden of illness study in Europe

PubMed Central

2014-01-01

Background Hereditary angioedema (HAE) due to C1 inhibitor deficiency is a rare but serious and potentially life-threatening disease marked by spontaneous, recurrent attacks of swelling. The study objective was to characterize direct and indirect resource utilization associated with HAE from the patient perspective in Europe. Methods The study was conducted in Spain, Germany, and Denmark to assess the real-world experience of HAE via a cross-sectional survey of HAE patients, including direct and indirect resource utilization during and between attacks for patients and their caregivers over the past 6 months. A regression model examined predictors of medical resource utilization. Results Overall, 164 patients had an attack in the past 6 months and were included in the analysis. The most significant predictor of medical resource utilization was the severity of the last attack (OR 2.6; p < 0.001). Among patients who sought medical care during the last attack (23%), more than half utilized the emergency department. The last attack prevented patients from their normal activities an average of 4–12 hours. Patient and caregiver absenteeism increased with attack severity and frequency. Among patients who were working or in school (n = 120), 72 provided work/school absenteeism data, resulting in an estimated 20 days missing from work/school on average per year; 51% (n = 84) indicated that HAE has hindered their career/educational advancement. Conclusion HAE poses a considerable burden on patients and their families in terms of direct medical costs and indirect costs related to lost productivity. This burden is substantial at the time of attacks and in between attacks. PMID:24996814

[Hereditary motor and sensory Lom-neuropathy--first Hungarian case report].

PubMed

Szabó, Antal; Siska, Eva; Molnár, Mária Judit

2007-01-20

Hereditary motor and sensory neuropathy-Lom is an autosomal recessive disorder of the peripheral nervous system, which occurs only in the european Roma population. The symptoms start in the first decade with slowly progressive gait disturbance, weakness and wasting of distal upper extremity muscles, joint deformities and hearing loss develop later in the second and third decades. This disorder is caused by a homozygous missense mutation of the NDRG1 gene, located in the 8q24 region. The Schwann cell dysfunction is most probably caused by altered lipid metabolism as a consequence of the NDRG1 mutation. Molecular genetic testing can be a first diagnostic step among roma individuals showing a Lom neuropathy phenotype, making evaluation of such patients and also genetic counselling faster and easier. Screening for hereditary neuromuscular disorders in this genetically isolated community may become an important public health issue in the near future.

Best practice guidelines for the molecular genetic diagnosis of Type 1 (HFE-related) hereditary haemochromatosis

PubMed Central

King, Caitriona; Barton, David E

2006-01-01

Background Hereditary haemochromatosis (HH) is a recessively-inherited disorder of iron over-absorption prevalent in Caucasian populations. Affected individuals for Type 1 HH are usually either homozygous for a cysteine to tyrosine amino acid substitution at position 282 (C282Y) of the HFE gene, or compound heterozygotes for C282Y and for a histidine to aspartic acid change at position 63 (H63D). Molecular genetic testing for these two mutations has become widespread in recent years. With diverse testing methods and reporting practices in use, there was a clear need for agreed guidelines for haemochromatosis genetic testing. The UK Clinical Molecular Genetics Society has elaborated a consensus process for the development of disease-specific best practice guidelines for genetic testing. Methods A survey of current practice in the molecular diagnosis of haemochromatosis was conducted. Based on the results of this survey, draft guidelines were prepared using the template developed by UK Clinical Molecular Genetics Society. A workshop was held to develop the draft into a consensus document. The consensus document was then posted on the Clinical Molecular Genetics Society website for broader consultation and amendment. Results Consensus or near-consensus was achieved on all points in the draft guidelines. The consensus and consultation processes worked well, and outstanding issues were documented in an appendix to the guidelines. Conclusion An agreed set of best practice guidelines were developed for diagnostic, predictive and carrier testing for hereditary haemochromatosis and for reporting the results of such testing. PMID:17134494

Urinary tract cancer in patients with hereditary non-polyposis colorectal cancer.

PubMed

Zachhau, Peter; Walter, Steen

2012-02-01

Hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome, is characterized as a hereditary colorectal cancer with an increased risk of cancer elsewhere in the body. In the Department of Urology at Odense University Hospital, screening for cancer in the urinary tract has been carried out on 20 patients with HNPCC since November 2001. Clinical records and pathology results were reviewed for all patients during the screening period. During screening two patients without urological symptoms were found to have cancer in the ureter. HNPCC patients with increased risk of urinary tract cancer should be referred for screening of the urinary tract. It is also important to discuss a rational strategy towards the screening of HNPCC patients for urinary tract cancer, and to initiate further investigation into this screening.

Orthodontic treatment for a patient with hereditary angiodema: a case report.

PubMed

Waldon, Kate; Barber, Sophy Kathleen; Spencer, Richard James

2015-05-01

Hereditary angiodema (HAE), also known as C1 esterase inhibitor deficiency, causes sufferers to experience episodic subcutaneous and submucosal oedema. These episodes can be triggered by dental treatment and manifest as life-threatening oedematous swelling in the head and neck region. This case report reviews an adolescent with hereditary angiodema whose malocclusion required orthodontic intervention. Due to her complex and unpredictable reaction to dental treatment, various options were explored before determining the appropriate care pathway for this patient. Trial placement of a sectional fixed appliance tested the tissue reaction prior to comprehensive treatment including extractions and fixed orthodontic appliances. This report demonstrates successful interdisciplinary management facilitating orthodontic care in a patient with HAE. © 2014 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hereditary non-polyposis colorectal cancer/Lynch syndrome in three dimensions.

PubMed

Kravochuck, Sara E; Church, James M

2017-12-01

Hereditary non-polyposis colorectal cancer (HNPCC) is defined by family history, and Lynch syndrome (LS) is defined genetically. However, universal tumour testing is now increasingly used to screen for patients with defective mismatch repair. This mixing of the results of family history, tumour testing and germline testing produces multiple permutations and combinations that can foster confusion. We wanted to clarify hereditary colorectal cancer using the three dimensions of classification: family history, tumour testing and germline testing. Family history (Amsterdam I or II criteria versus not Amsterdam criteria) was used to define patients and families with HNPCC. Tumour testing and germline testing were then performed to sub-classify patients and families. The permutations of these classifications are applied to our registry. There were 234 HNPCC families: 129 had LS of which 55 were three-dimensional Lynch (family history, tumour testing and germline testing), 66 were two-dimensional Lynch and eight were one-dimensional Lynch. A total of 10 families had tumour Lynch (tumours with microsatellite instability or loss of expression of a mismatch repair protein but an Amsterdam-negative family and negative germline testing), five were Lynch like (Amsterdam-positive family, tumours with microsatellite instability or loss of expression of a mismatch repair protein on immunohistochemistry but negative germline testing), 26 were familial colorectal cancer type X and 95 were HNPCC. Hereditary colorectal cancer can be confusing. Sorting families in three dimensions can clarify the confusion and may direct further testing and, ultimately, surveillance. © 2016 Royal Australasian College of Surgeons.

ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

PubMed

Syngal, Sapna; Brand, Randall E; Church, James M; Giardiello, Francis M; Hampel, Heather L; Burt, Randall W

2015-02-01

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes

PubMed Central

Syngal, Sapna; Brand, Randall E.; Church, James M.; Giardiello, Francis M.; Hampel, Heather L.; Burt, Randall W.

2015-01-01

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer. PMID:25645574

Prophylactic Therapy for Hereditary Angioedema.

PubMed

Longhurst, Hilary; Zinser, Emily

2017-08-01

Long-term prophylaxis is needed in many patients with hereditary angioedema and poses many challenges. Attenuated androgens are effective in many but are limited by side effect profiles. There is less evidence for efficacy of tranexamic acid and progestagens; however, the small side effect profile makes tranexamic acid an option for prophylaxis in children and progestagens an option for women. C1 inhibitor is beneficial, but at present requires intravenous delivery and may need dose titration for maximum efficacy. Short-term prophylaxis should be considered for all procedures. New therapies are promising in overcoming many problems encountered with current options for long-term prophylaxis. Copyright © 2017 Elsevier Inc. All rights reserved.

[Hereditary optic neuropathies in pediatric ophthalmology].

PubMed

Orssaud, C; Robert, M P; Bremond Gignac, D

2018-05-17

Hereditary optic neuropathies (HON) often begin in adulthood. However, some of them can have an early onset. These may have specific clinical features and natural histories. Retrospective study of HON patients with onset before the age of 14 years seen in a referral center. In addition to the age of onset, we evaluated the genetic etiology, visual acuity at 15 years, last best corrected visual acuity, optic disc appearance, visual field and extra-ophthalmological manifestations. Forty-four patients (16 women) were included; i.e. 27.8% of all patients followed for HON. The mean age of onset was 8.5±3.3 years, with an onset earlier than 3 years in 5 patients. An etiology was not found in 8 patients. Of the remaining 36 patients, 12 had Leber's hereditary optic neuropathy (LHON), 11 had dominant optic atrophy, 12 had WS/WS-like syndrome, 2 had recessive optic atrophy and 1 had spastic paraplegia type 7. For 78 eyes of 40 patients (mean age 26.9±14.5 years), the mean last visual acuity was 0.80±0.33 LogMAR, with differences according to genetic forms. Visual acuity was less than or equal to counting fingers for 7 eyes (29.1%) of 4 WS/WS-like patients and one LHON patient. Early onset NOH are not unusual. Their visual prognosis is as severe as adult onset NOH, with variations depending on the underlying genetic causes. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Cellular pathways of hereditary spastic paraplegia.

PubMed

Blackstone, Craig

2012-01-01

Human voluntary movement is controlled by the pyramidal motor system, a long CNS pathway comprising corticospinal and lower motor neurons. Hereditary spastic paraplegias (HSPs) are a large, genetically diverse group of inherited neurologic disorders characterized by a length-dependent distal axonopathy of the corticospinal tracts, resulting in lower limb spasticity and weakness. A range of studies are converging on alterations in the shaping of organelles, particularly the endoplasmic reticulum, as well as intracellular membrane trafficking and distribution as primary defects underlying the HSPs, with clear relevance for other long axonopathies affecting peripheral nerves and lower motor neurons.

Visual Rehabilitation of Persons with Leber's Hereditary Optic Neuropathy.

ERIC Educational Resources Information Center

Rudanko, S.-L.

1995-01-01

This article presents results of a noncontrolled clinical study of 20 persons with Leber's hereditary optic neuropathy who were treated from 1976 to 1990 at the Low Vision Centre of the Finnish Federation of the Visually Handicapped. The importance of early functional visual rehabilitation is emphasized, as is the use of low vision aids to help…

Hereditary pancreatitis of 3 Chinese children

PubMed Central

Dai, Li-Na; Chen, Ying-Wei; Yan, Wei-Hui; Lu, Li-Na; Tao, Yi-Jing; Cai, Wei

2016-01-01

Abstract Background: Hereditary pancreatitis (HP) is quite rare and is distinguished by incomplete penetrance presentation as early-onset relapsing pancreatitis, usually beginning in childhood. HP is now known to be commonly relevant to mutations in the PRSS1 (gene-encoding cationic trypsinogen), SPINK1 (serine protease inhibitor, Kazal type 1), CFTR (cystic fibrosis), carboxypeptidase A1 (CPA1), and chymotrypsin C (CTRC) genes as reported in some Caucasian studies. HP has a variable spectrum of severity and may develop complications. Methods & Results: We describe the clinical course of 3 preschool children, hospitalized with postprandial abdominal pain, whose laboratory tests showed high serum amylase. Similar episodes of abdominal pain led to readmission, and the patients recovered quickly after using symptomatic therapy. The condition of the first boy, who developed a pancreatic tail pseudocyst and splenic infarction, was especially complicated. The boy underwent 2 endoscopic retrograde cholangiopancreatographies and stenting, along with a surgical procedure that completely relieved his symptoms for 3 months. The 3 patients and their parents were given genetic testing. All of the patients carried 1 or more gene mutations inherited from their mothers, fathers, or both parents; however, none of the parents were affected. Conclusion: For children with repeated pancreatitis, clinicians should consider HP in the differential diagnosis. It is reliable to perform gene sequencing on suspicious patients and their parents. Multidisciplinary and comprehensive treatment should be recommended to manage HP and its complications. Cholangiopancreatography and stenting is a relatively minimally invasive approach when compared with surgery and can be tried as an early intervention. Surgical procedures should be reserved for patients with complications. PMID:27603351

Atypical hereditary sensory and autonomic neuropathy type IV with neither mental retardation nor pain insensitivity.

PubMed

Jung, Chae Lim; Ki, Chang-Seok; Kim, Byoung Joon; Lee, Jong-Hyuck; Sung, Ki-Sun; Kim, Jong-Won; Park, Youn-Soo

2013-12-01

Hereditary sensory and autonomic neuropathy type IV is an autosomal recessive disorder characterized by severe mental retardation and self-mutilation-related complications. Recently, we investigated a 16-year-old Korean boy with normal intelligence. He had preserved pain sensation but was suspected of having hereditary sensory and autonomic neuropathy type IV because of the recurrent bone fractures and painless joint destruction in the absence of any predisposing medical conditions. Genetic analysis of the NTRK1 gene revealed compound heterozygous mutations including c.851-33T>A and c.2303C>T (p.Pro768Leu) in the NTRK1 gene. The p.Pro768Leu mutation has been identified in 2 Japanese patients with a mild phenotype. Therefore, although it is rare, hereditary sensory and autonomic neuropathy type IV should be considered in patients with recurrent bone fractures and painless joint destruction who do not have any predisposing conditions even when they do not have typical clinical features such as mental retardation or pain insensitivity.

Evaluation of an online family history tool for identifying hereditary and familial colorectal cancer.

PubMed

Kallenberg, F G J; Aalfs, C M; The, F O; Wientjes, C A; Depla, A C; Mundt, M W; Bossuyt, P M M; Dekker, E

2017-09-21

Identifying a hereditary colorectal cancer (CRC) syndrome or familial CRC (FCC) in a CRC patient may enable the patient and relatives to enroll in surveillance protocols. As these individuals are insufficiently recognized, we evaluated an online family history tool, consisting of a patient-administered family history questionnaire and an automated genetic referral recommendation, to facilitate the identification of patients with hereditary CRC or FCC. Between 2015 and 2016, all newly diagnosed CRC patients in five Dutch outpatient clinics, were included in a trial with a stepped-wedge design, when first visiting the clinic. Each hospital continued standard procedures for identifying patients at risk (control strategy) and then, after a predetermined period, switched to offering the family history tool to included patients (intervention strategy). After considering the tool-based recommendation, the health care provider could decide on and arrange the referral. Primary outcome was the relative number of CRC patients who received screening or surveillance recommendations for themselves or relatives because of hereditary CRC or FCC, provided by genetic counseling. The intervention effect was evaluated using a logit-linear model. With the tool, 46/489 (9.4%) patients received a screening or surveillance recommendation, compared to 35/292 (12.0%) in the control group. In the intention-to-treat-analysis, accounting for time trends and hospital effects, this difference was not statistically significant (p = 0.58). A family history tool does not necessarily assist in increasing the number of CRC patients and relatives enrolled in screening or surveillance recommendations for hereditary CRC or FCC. Other interventions should be considered.

Hereditary melanoma and predictive genetic testing: why not?

PubMed

Riedijk, S R; de Snoo, F A; van Dijk, S; Bergman, W; van Haeringen, A; Silberg, S; van Elderen, T M T; Tibben, A

2005-09-01

Since p16-Leiden presymptomatic testing for hereditary melanoma has become available in the Netherlands, the benefits and risks of offering such testing are evaluated. The current paper investigated why the non-participants were reluctant to participate in genetic testing. Sixty six eligible individuals, who were knowledgeable about the test but had not participated in genetic testing by January 2003, completed a self-report questionnaire assessing motivation, anxiety, family dynamics, risk knowledge and causal attributions. Non-participants reported anxiety levels below clinical significance. A principal components analysis on reasons for non-participation distinguished two underlying motives: emotional and rational motivation. Rational motivation for non-participation was associated with more accurate risk knowledge, the inclination to preselect mutation carriers within the family and lower scores on anxiety. Emotional motivation for non-participation was associated with disease misperceptions, hesitation to communicate unfavourable test results within the family and higher scores on anxiety. Rational and emotional motivation for non-participation in the genetic test for hereditary melanoma was found. Emotionally motivated individuals may be reluctant to disseminate genetic risk information. Rationally motivated individuals were better informed than emotionally motivated individuals. It is suggested that a leaflet is added to the invitation letter to enhance informed decision-making about genetic testing.

Effective Referral of Low-Income Women at Risk for Hereditary Breast and Ovarian Cancer to Genetic Counseling: A Randomized Delayed Intervention Control Trial.

PubMed

Pasick, Rena J; Joseph, Galen; Stewart, Susan; Kaplan, Celia; Lee, Robin; Luce, Judith; Davis, Sharon; Marquez, Titas; Nguyen, Tung; Guerra, Claudia

2016-10-01

To determine the effectiveness of a statewide telephone service in identifying low-income women at risk for hereditary breast and ovarian cancer and referring them to free genetic counseling. From June 2010 through August 2011, eligible callers to California's toll-free breast and cervical cancer telephone service were screened for their family histories of breast and ovarian cancer. High-risk women were identified and called for a baseline survey and randomization to an immediate offer of genetic counseling or a mailed brochure on how to obtain counseling. Clinic records were used to assess receipt of genetic counseling after 2 months. Among 1212 eligible callers, 709 (58.5%) agreed to answer family history questions; 102 (14%) were at high risk (25% Hispanic, 46% White, 10% Black, 16% Asian, 3% of other racial/ethnic backgrounds). Of the high-risk women offered an immediate appointment, 39% received counseling during the intervention period, as compared with 4.5% of those receiving the brochure. A public health approach to the rare but serious risk of hereditary breast and ovarian cancer can be successful when integrated into the efforts of existing safety net organizations.

Effective Referral of Low-Income Women at Risk for Hereditary Breast and Ovarian Cancer to Genetic Counseling: A Randomized Delayed Intervention Control Trial

PubMed Central

Joseph, Galen; Stewart, Susan; Kaplan, Celia; Lee, Robin; Luce, Judith; Davis, Sharon; Marquez, Titas; Nguyen, Tung; Guerra, Claudia

2016-01-01

Objectives. To determine the effectiveness of a statewide telephone service in identifying low-income women at risk for hereditary breast and ovarian cancer and referring them to free genetic counseling. Methods. From June 2010 through August 2011, eligible callers to California’s toll-free breast and cervical cancer telephone service were screened for their family histories of breast and ovarian cancer. High-risk women were identified and called for a baseline survey and randomization to an immediate offer of genetic counseling or a mailed brochure on how to obtain counseling. Clinic records were used to assess receipt of genetic counseling after 2 months. Results. Among 1212 eligible callers, 709 (58.5%) agreed to answer family history questions; 102 (14%) were at high risk (25% Hispanic, 46% White, 10% Black, 16% Asian, 3% of other racial/ethnic backgrounds). Of the high-risk women offered an immediate appointment, 39% received counseling during the intervention period, as compared with 4.5% of those receiving the brochure. Conclusions. A public health approach to the rare but serious risk of hereditary breast and ovarian cancer can be successful when integrated into the efforts of existing safety net organizations. PMID:27552275

Genetic spectrum of hereditary neuropathies with onset in the first year of life

PubMed Central

Baets, Jonathan; Deconinck, Tine; De Vriendt, Els; Zimoń, Magdalena; Yperzeele, Laetitia; Van Hoorenbeeck, Kim; Peeters, Kristien; Spiegel, Ronen; Parman, Yesim; Ceulemans, Berten; Van Bogaert, Patrick; Pou-Serradell, Adolf; Bernert, Günther; Dinopoulos, Argirios; Auer-Grumbach, Michaela; Sallinen, Satu-Leena; Fabrizi, Gian Maria; Pauly, Fernand; Van den Bergh, Peter; Bilir, Birdal; Battaloglu, Esra; Madrid, Ricardo E.; Kabzińska, Dagmara; Kochanski, Andrzej; Topaloglu, Haluk; Miller, Geoffrey; Jordanova, Albena; Timmerman, Vincent

2011-01-01

Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine–Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot–Marie–Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot–Marie–Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot–Marie–Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset. PMID:21840889

Mouse homologues of human hereditary disease.

PubMed Central

Searle, A G; Edwards, J H; Hall, J G

1994-01-01

Details are given of 214 loci known to be associated with human hereditary disease, which have been mapped on both human and mouse chromosomes. Forty two of these have pathological variants in both species; in general the mouse variants are similar in their effects to the corresponding human ones, but exceptions include the Dmd/DMD and Hprt/HPRT mutations which cause little, if any, harm in mice. Possible reasons for phenotypic differences are discussed. In most pathological variants the gene product seems to be absent or greatly reduced in both species. The extensive data on conserved segments between human and mouse chromosomes are used to predict locations in the mouse of over 50 loci of medical interest which are mapped so far only on human chromosomes. In about 80% of these a fairly confident prediction can be made. Some likely homologies between mapped mouse loci and unmapped human ones are also given. Sixty six human and mouse proto-oncogene and growth factor gene homologies are also listed; those of confirmed location are all in known conserved segments. A survey of 18 mapped human disease loci and chromosome regions in which the manifestation or severity of pathological effects is thought to be the result of genomic imprinting shows that most of the homologous regions in the mouse are also associated with imprinting, especially those with homologues on human chromosomes 11p and 15q. Useful methods of accelerating the production of mouse models of human hereditary disease include (1) use of a supermutagen, such as ethylnitrosourea (ENU), (2) targeted mutagenesis involving ES cells, and (3) use of gene transfer techniques, with production of 'knockout mutations'. PMID:8151633

Genetics of Hereditary Ataxia in Scottish Terriers.

PubMed

Urkasemsin, G; Nielsen, D M; Singleton, A; Arepalli, S; Hernandez, D; Agler, C; Olby, N J

2017-07-01

Scottish Terriers have a high incidence of juvenile onset hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex and causing slowly progressive cerebellar dysfunction. To identify chromosomal regions associated with hereditary ataxia in Scottish Terriers. One hundred and fifty-three Scottish Terriers were recruited through the Scottish Terrier Club of America. Prospective study. Dogs were classified as affected if they had slowly progressive cerebellar signs. When possible, magnetic resonance imaging and histopathological evaluation of the brain were completed as diagnostic aids. To identify genomic regions connected with the disease, genome-wide mapping was performed using both linkage- and association-based approaches. Pedigree evaluation and homozygosity mapping were also performed to examine mode of inheritance and to investigate the region of interest, respectively. Linkage and genome-wide association studies in a cohort of Scottish Terriers both identified a region on CFA X strongly associated with the disease trait. Homozygosity mapping revealed a 4 Mb region of interest. Pedigree evaluation failed to identify the possible mode of inheritance due to the lack of complete litter information. This finding suggests that further genetic investigation of the potential region of interest on CFA X should be considered in order to identify the causal mutation as well as develop a genetic test to eliminate the disease from this breed. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

New insights on hereditary erythrocyte membrane defects.

PubMed

Andolfo, Immacolata; Russo, Roberta; Gambale, Antonella; Iolascon, Achille

2016-11-01

After the first proposed model of the red blood cell membrane skeleton 36 years ago, several additional proteins have been discovered during the intervening years, and their relationship with the pathogenesis of the related disorders have been somewhat defined. The knowledge of erythrocyte membrane structure is important because it represents the model for spectrin-based membrane skeletons in all cells and because defects in its structure underlie multiple hemolytic anemias. This review summarizes the main features of erythrocyte membrane disorders, dividing them into structural and altered permeability defects, focusing particularly on the most recent advances. New proteins involved in alterations of the red blood cell membrane permeability were recently described. The mechanoreceptor PIEZO1 is the largest ion channel identified to date, the fundamental regulator of erythrocyte volume homeostasis. Missense, gain-of-function mutations in the PIEZO1 gene have been identified in several families as causative of dehydrated hereditary stomatocytosis or xerocytosis. Similarly, the KCNN4 gene, codifying the so called Gardos channel, has been recently identified as a second causative gene of hereditary xerocytosis. Finally, ABCB6 missense mutations were identified in different pedigrees of familial pseudohyperkalemia. New genomic technologies have improved the quality and reduced the time of diagnosis of these diseases. Moreover, they are essential for the identification of the new causative genes. However, many questions remain to solve, and are currently objects of intensive studies. Copyright© Ferrata Storti Foundation.

New insights on hereditary erythrocyte membrane defects

PubMed Central

Andolfo, Immacolata; Russo, Roberta; Gambale, Antonella; Iolascon, Achille

2016-01-01

After the first proposed model of the red blood cell membrane skeleton 36 years ago, several additional proteins have been discovered during the intervening years, and their relationship with the pathogenesis of the related disorders have been somewhat defined. The knowledge of erythrocyte membrane structure is important because it represents the model for spectrin-based membrane skeletons in all cells and because defects in its structure underlie multiple hemolytic anemias. This review summarizes the main features of erythrocyte membrane disorders, dividing them into structural and altered permeability defects, focusing particularly on the most recent advances. New proteins involved in alterations of the red blood cell membrane permeability were recently described. The mechanoreceptor PIEZO1 is the largest ion channel identified to date, the fundamental regulator of erythrocyte volume homeostasis. Missense, gain-of-function mutations in the PIEZO1 gene have been identified in several families as causative of dehydrated hereditary stomatocytosis or xerocytosis. Similarly, the KCNN4 gene, codifying the so called Gardos channel, has been recently identified as a second causative gene of hereditary xerocytosis. Finally, ABCB6 missense mutations were identified in different pedigrees of familial pseudohyperkalemia. New genomic technologies have improved the quality and reduced the time of diagnosis of these diseases. Moreover, they are essential for the identification of the new causative genes. However, many questions remain to solve, and are currently objects of intensive studies. PMID:27756835

Rare hereditary cause of chronic pancreatitis in a young male: SPINK1 mutation

PubMed Central

Patel, Janaki; Madan, Arina; Gammon, Amanda; Sossenheimer, Michael; Samadder, Niloy Jewel

2017-01-01

Hereditary chronic pancreatitis associated with a mutation in the serine protease inhibitor, Kazal Type-1 (SPINK-1 gene) is extremely rare. The SPINK1 mutation results in trypsinogen activation which predisposes to chronic pancreatitis predominately when combined with CFTR gene mutations. It presents as either chronic or recurrent acute pancreatitis. Symptom control and management of complications is important. Active surveillance with cross-sectional imaging for pancreatic malignancy in individuals with hereditary pancreatitis is advocated due to individuals being high risk. We present an unusual case of a young male who initially presented with renal colic and was incidentally diagnosed with severe chronic pancreatitis on abdominal imaging, with genetic testing confirming a homozygous SPINK1 mutation. PMID:29515728

Rare hereditary cause of chronic pancreatitis in a young male: SPINK1 mutation.

PubMed

Patel, Janaki; Madan, Arina; Gammon, Amanda; Sossenheimer, Michael; Samadder, Niloy Jewel

2017-01-01

Hereditary chronic pancreatitis associated with a mutation in the serine protease inhibitor, Kazal Type-1 (SPINK-1 gene) is extremely rare. The SPINK1 mutation results in trypsinogen activation which predisposes to chronic pancreatitis predominately when combined with CFTR gene mutations. It presents as either chronic or recurrent acute pancreatitis. Symptom control and management of complications is important. Active surveillance with cross-sectional imaging for pancreatic malignancy in individuals with hereditary pancreatitis is advocated due to individuals being high risk. We present an unusual case of a young male who initially presented with renal colic and was incidentally diagnosed with severe chronic pancreatitis on abdominal imaging, with genetic testing confirming a homozygous SPINK1 mutation.

Frequency of breast cancer with hereditary risk features in Spain: Analysis from GEICAM "El Álamo III" retrospective study.

PubMed

Márquez-Rodas, Iván; Pollán, Marina; Escudero, María José; Ruiz, Amparo; Martín, Miguel; Santaballa, Ana; Martínez Del Prado, Purificación; Batista, Norberto; Andrés, Raquel; Antón, Antonio; Llombart, Antonio; Fernandez Aramburu, Antonio; Adrover, Encarnación; González, Sonia; Seguí, Miguel Angel; Calvo, Lourdes; Lizón, José; Rodríguez Lescure, Álvaro; Ramón Y Cajal, Teresa; Llort, Gemma; Jara, Carlos; Carrasco, Eva; López-Tarruella, Sara

2017-01-01

To determine the frequency of breast cancer (BC) patients with hereditary risk features in a wide retrospective cohort of patients in Spain. a retrospective analysis was conducted from 10,638 BC patients diagnosed between 1998 and 2001 in the GEICAM registry "El Álamo III", dividing them into four groups according to modified ESMO and SEOM hereditary cancer risk criteria: Sporadic breast cancer group (R0); Individual risk group (IR); Familial risk group (FR); Individual and familial risk group (IFR) with both individual and familial risk criteria. 7,641 patients were evaluable. Of them, 2,252 patients (29.5%) had at least one hereditary risk criteria, being subclassified in: FR 1.105 (14.5%), IR 970 (12.7%), IFR 177 (2.3%). There was a higher frequency of newly diagnosed metastatic patients in the IR group (5.1% vs 3.2%, p = 0.02). In contrast, in RO were lower proportion of big tumors (> T2) (43.8% vs 47.4%, p = 0.023), nodal involvement (43.4% vs 48.1%, p = 0.004) and lower histological grades (20.9% G3 for the R0 vs 29.8%) when compared to patients with any risk criteria. Almost three out of ten BC patients have at least one hereditary risk cancer feature that would warrant further genetic counseling. Patients with hereditary cancer risk seems to be diagnosed with worse prognosis factors.

Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus.

PubMed

La Morgia, C; Achilli, A; Iommarini, L; Barboni, P; Pala, M; Olivieri, A; Zanna, C; Vidoni, S; Tonon, C; Lodi, R; Vetrugno, R; Mostacci, B; Liguori, R; Carroccia, R; Montagna, P; Rugolo, M; Torroni, A; Carelli, V

2008-03-04

To investigate the mechanisms underlying myoclonus in Leber hereditary optic neuropathy (LHON). Five patients and one unaffected carrier from two Italian families bearing the homoplasmic 11778/ND4 and 3460/ND1 mutations underwent a uniform investigation including neurophysiologic studies, muscle biopsy, serum lactic acid after exercise, and muscle ((31)P) and cerebral ((1)H) magnetic resonance spectroscopy (MRS). Biochemical investigations on fibroblasts and complete mitochondrial DNA (mtDNA) sequences of both families were also performed. All six individuals had myoclonus. In spite of a normal EEG background and the absence of giant SEPs and C reflex, EEG-EMG back-averaging showed a preceding jerk-locked EEG potential, consistent with a cortical generator of the myoclonus. Specific comorbidities in the 11778/ND4 family included muscular cramps and psychiatric disorders, whereas features common to both families were migraine and cardiologic abnormalities. Signs of mitochondrial proliferation were seen in muscle biopsies and lactic acid elevation was observed in four of six patients. (31)P-MRS was abnormal in five of six patients and (1)H-MRS showed ventricular accumulation of lactic acid in three of six patients. Fibroblast ATP depletion was evident at 48 hours incubation with galactose in LHON/myoclonus patients. Sequence analysis revealed haplogroup T2 (11778/ND4 family) and U4a (3460/ND1 family) mtDNAs. A functional role for the non-synonymous 4136A>G/ND1, 9139G>A/ATPase6, and 15773G>A/cyt b variants was supported by amino acid conservation analysis. Myoclonus and other comorbidities characterized our Leber hereditary optic neuropathy (LHON) families. Functional investigations disclosed a bioenergetic impairment in all individuals. Our sequence analysis suggests that the LHON plus phenotype in our cases may relate to the synergic role of mtDNA variants.

Longitudinal Cerebral Blood Flow Changes during Speech in Hereditary Ataxia

ERIC Educational Resources Information Center

Sidtis, John J.; Strother, Stephen C.; Naoum, Ansam; Rottenberg, David A.; Gomez, Christopher

2010-01-01

The hereditary ataxias constitute a group of degenerative diseases that progress over years or decades. With principal pathology involving the cerebellum, dysarthria is an early feature of many of the ataxias. Positron emission tomography was used to study regional cerebral blood flow changes during speech production over a 21 month period in a…

HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum.

PubMed

Gess, Burkhard; Auer-Grumbach, Michaela; Schirmacher, Anja; Strom, Tim; Zitzelsberger, Manuela; Rudnik-Schöneborn, Sabine; Röhr, Dominik; Halfter, Hartmut; Young, Peter; Senderek, Jan

2014-11-04

To determine the nature and frequency of HSJ1 mutations in patients with hereditary motor and hereditary motor and sensory neuropathies. Patients were screened for mutations by genome-wide or targeted linkage and homozygosity studies, whole-exome sequencing, and Sanger sequencing. RNA and protein studies of skin fibroblasts were used for functional characterization. We describe 2 additional mutations in the HSJ1 gene in a cohort of 90 patients with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 (CMT2). One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression. Another family, presenting with a CMT2 phenotype, carried the homozygous missense mutation c.14A>G (p.Tyr5Cys). This mutation was classified as likely disease-related by several automatic algorithms for prediction of possible impact of an amino acid substitution on the structure and function of proteins. Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population. Taken together, in our cohort of 90 probands, we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. We provide clinical and functional information on an HSJ1 splice-site mutation and report the detailed phenotype of 2 patients with CMT2, broadening the phenotypic spectrum of HSJ1-related neuropathies. © 2014 American Academy of Neurology.

Genotype-Phenotype Correlation of Hereditary Erythrocytosis Mutations, a single center experience.

PubMed

Oliveira, Jennifer L; Coon, Lea M; Frederick, Lori A; Hein, Molly; Swanson, Kenneth C; Savedra, Michelle E; Porter, Tavanna R; Patnaik, Mrinal M; Tefferi, Ayalew; Pardanani, Animesh; Grebe, Stefan K; Viswanatha, David S; Hoyer, James D

2018-05-23

Hereditary erythrocytosis is associated with high oxygen affinity hemoglobin variants (HOAs), 2,3-bisphosphoglycerate deficiency and abnormalities in EPOR and the oxygen-sensing pathway proteins PHD, HIF2α, and VHL. Our laboratory has 40 years of experience with hemoglobin disorder testing and we have characterized HOAs using varied protein and molecular techniques including functional assessment by p50 analysis. In addition, we have more recently commenced adding the assessment of clinically relevant regions of the VHL, BPGM, EPOR, EGLN1 (PHD2), and EPAS1 (HIF2A) genes in a more comprehensive hereditary erythrocytosis panel of tests. Review of our experience confirms a wide spectrum of alterations associated with erythrocytosis which we have correlated with phenotypic and clinical features. Through generic hemoglobinopathy testing we have identified 762 patients with 81 distinct HOA Hb variants (61 β, 20 α), including 12 that were first identified by our laboratory. Of the 1192 cases received for an evaluation specific for hereditary erythrocytosis, approximately 12% had reportable alterations: 85 pathogenic/likely pathogenic mutations and 58 variants of unknown significance. Many have not been previously reported. Correlation with clinical and phenotypic data supports an algorithmic approach to guide economical evaluation; although, testing is expanded if the suspected causes are negative or of uncertain significance. Clinical features are similar and range from asymptomatic to recurrent headaches, fatigue, restless legs, chest pain, exertional dyspnea and thrombotic episodes. Many patients were chronically phlebotomized with reported relief of symptoms. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3

PubMed Central

Demir, Korcan; Al-Rijjal, Roua A.; Zou, Minjing; Çatli, Gönül; Anık, Ahmet; Al-Enezi, Anwar F.; Özışık, Seçil; Al-Faham, Manar S. A.; Abacı, Ayhan; Dündar, Bumin; Kattan, Walaa E.; Alsagob, Maysoon; Kavukçu, Salih; Tamimi, Hamdi E.; Meyer, Brian F.; Böber, Ece

2018-01-01

Background Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed. Methodology Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions. Results Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887–22,395,767del (179880 bp deletion including exon 16–22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families. Conclusions This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood. PMID:29505567

New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes.

PubMed

Devos, David; Vuillaume, Isabelle; de Becdelievre, Alix; de Martinville, Berengère; Dhaenens, Claire-Marie; Cuvellier, Jean-Christophe; Cuisset, Jean-Marie; Vallée, Louis; Lemaitre, Marie-Pierre; Bourteel, Hélène; Hachulla, Eric; Wallaert, Benoit; Destée, Alain; Defebvre, Luc; Sablonnière, Bernard

2006-12-01

Benign hereditary chorea is a rare autosomal dominant disorder presenting with a childhood-onset and slowly progressive chorea. The objective of this study was to describe the clinical and genetic features of 3 patients who developed childhood-onset chorea. Three affected patients from three generations of a family with benign hereditary chorea associated with a multisystemic disorder of the basal ganglia, thyroid, lungs, salivary glands, bowels, and teeth. The TITF-1 gene was screened by microsatellite analysis, gene sequencing, and fluorescence in situ hybridization. Genetic analysis revealed a novel 0.9-Mb deletion on chromosome 14, which includes the TITF-1 and PAX9 genes. We have identified a novel deletion responsible for a new syndrome of benign hereditary chorea, including symptoms of brain-thyroid-lung syndrome associated with bowels, salivary glands, and teeth disorders. Associated signs, sometimes of slight expression, remain of high interest for the clinical and genetic diagnosis of benign hereditary chorea. Copyright 2006 Movement Disorder Society.

Shifting the closed-loop spectrum in the optimal linear quadratic regulator problem for hereditary systems

NASA Technical Reports Server (NTRS)

Gibson, J. S.; Rosen, I. G.

1985-01-01

In the optimal linear quadratic regulator problem for finite dimensional systems, the method known as an alpha-shift can be used to produce a closed-loop system whose spectrum lies to the left of some specified vertical line; that is, a closed-loop system with a prescribed degree of stability. This paper treats the extension of the alpha-shift to hereditary systems. As infinite dimensions, the shift can be accomplished by adding alpha times the identity to the open-loop semigroup generator and then solving an optimal regulator problem. However, this approach does not work with a new approximation scheme for hereditary control problems recently developed by Kappel and Salamon. Since this scheme is among the best to date for the numerical solution of the linear regulator problem for hereditary systems, an alternative method for shifting the closed-loop spectrum is needed. An alpha-shift technique that can be used with the Kappel-Salamon approximation scheme is developed. Both the continuous-time and discrete-time problems are considered. A numerical example which demonstrates the feasibility of the method is included.

Shifting the closed-loop spectrum in the optimal linear quadratic regulator problem for hereditary systems

NASA Technical Reports Server (NTRS)

Gibson, J. S.; Rosen, I. G.

1987-01-01

In the optimal linear quadratic regulator problem for finite dimensional systems, the method known as an alpha-shift can be used to produce a closed-loop system whose spectrum lies to the left of some specified vertical line; that is, a closed-loop system with a prescribed degree of stability. This paper treats the extension of the alpha-shift to hereditary systems. As infinite dimensions, the shift can be accomplished by adding alpha times the identity to the open-loop semigroup generator and then solving an optimal regulator problem. However, this approach does not work with a new approximation scheme for hereditary control problems recently developed by Kappel and Salamon. Since this scheme is among the best to date for the numerical solution of the linear regulator problem for hereditary systems, an alternative method for shifting the closed-loop spectrum is needed. An alpha-shift technique that can be used with the Kappel-Salamon approximation scheme is developed. Both the continuous-time and discrete-time problems are considered. A numerical example which demonstrates the feasibility of the method is included.

Genes for Hereditary Sensory and Autonomic Neuropathies: A Genotype-Phenotype Correlation

ERIC Educational Resources Information Center

Rotthier, Annelies; Baets, Jonathan; De Vriendt, Els; Jacobs, An; Auer-Grumbach, Michaela; Levy, Nicolas; Bonello-Palot, Nathalie; Kilic, Sara Sebnem; Weis, Joachim; Nascimento, Andres; Swinkels, Marielle; Kruyt, Moyo C.; Jordanova, Albena; De Jonghe, Peter; Timmerman, Vincent

2009-01-01

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant ("SPTLC1"…

Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma.

PubMed

Comino-Méndez, Iñaki; Gracia-Aznárez, Francisco J; Schiavi, Francesca; Landa, Iñigo; Leandro-García, Luis J; Letón, Rocío; Honrado, Emiliano; Ramos-Medina, Rocío; Caronia, Daniela; Pita, Guillermo; Gómez-Graña, Alvaro; de Cubas, Aguirre A; Inglada-Pérez, Lucía; Maliszewska, Agnieszka; Taschin, Elisa; Bobisse, Sara; Pica, Giuseppe; Loli, Paola; Hernández-Lavado, Rafael; Díaz, José A; Gómez-Morales, Mercedes; González-Neira, Anna; Roncador, Giovanna; Rodríguez-Antona, Cristina; Benítez, Javier; Mannelli, Massimo; Opocher, Giuseppe; Robledo, Mercedes; Cascón, Alberto

2011-06-19

Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.

Hepatic and renal failure associated with amiodarone infusion in a patient with hereditary fructose intolerance.

PubMed

Curran, B J; Havill, J H

2002-06-01

Hereditary fructose intolerance is a rare inherited metabolic disorder. Although fructose intolerance usually presents in the paediatric age group, individuals can survive into adulthood by self.manipulation of diet. Hospitalisation can become a high.risk environment for these individuals because of loss of control of their strict dietary constraints and the added danger of administration of medications containing fructose, sucrose and sorbitol. We report a case of hereditary fructose intolerance in an adult presenting with hepatic and renal failure associated with an amiodarone infusion and explore the possibility of polysorbate 80 as a cause of this patient's hepatic and renal failure.

Novel Bioimaging Techniques of Metals by Laser Ablation Inductively Coupled Plasma Mass Spectrometry for Diagnosis Of Fibrotic and Cirrhotic Liver Disorders

PubMed Central

Gassler, Nikolaus; Bosserhoff, Anja K.; Becker, J. Sabine

2013-01-01

Background and Aims Hereditary disorders associated with metal overload or unwanted toxic accumulation of heavy metals can lead to morbidity and mortality. Patients with hereditary hemochromatosis or Wilson disease for example may develop severe hepatic pathology including fibrosis, cirrhosis or hepatocellular carcinoma. While relevant disease genes are identified and genetic testing is applicable, liver biopsy in combination with metal detecting techniques such as energy-dispersive X-ray spectroscopy (EDX) is still applied for accurate diagnosis of metals. Vice versa, several metals are needed in trace amounts for carrying out vital functions and their deficiency due to rapid growth, pregnancy, excessive blood loss, and insufficient nutritional or digestive uptake results in organic and systemic shortcomings. Established in situ techniques, such as EDX-ray spectroscopy, are not sensitive enough to analyze trace metal distribution and the quantification of metal images is difficult. Methods In this study, we developed a quantitative biometal imaging technique of human liver tissue by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) in order to compare the distribution of selected metals in cryo-sections of healthy and fibrotic/cirrhotic livers. Results Most of the metals are homogeneous distributed within the normal tissue, while they are redirected within fibrotic livers resulting in significant metal deposits. Moreover, total iron and copper concentrations in diseased liver were found about 3-5 times higher than in normal liver samples. Conclusions Biometal imaging via LA-ICP-MS is a sensitive innovative diagnostic tool that will impact clinical practice in identification and evaluation of hepatic metal disorders and to detect subtle metal variations during ongoing hepatic fibrogenesis. PMID:23505552

Management of women at high risk of hereditary breast cancer in the Veneto Regional Program for Prevention.

PubMed

Del Sole, Annamaria; Cinquetti, Sandro; Fedato, Chiara; Montagna, Marco; Russo, Francesca; Sbrogiò, Luca Gino; Zorzi, Manuel

2015-01-01

Today it is well-known that high risk of genetic breast cancer concerns a very limited part of the population: no more than 2-3 women are affected every thousand and this condition as a whole accounts for no more than 3%-5% of all breast cancers. Following the directions contained in the 2014-2018 National Prevention Plan, Veneto's 2014-2018 Regional Program of Prevention (PRP), approved by Regional Council Resolution (DGR) No. 749 of 14.5.2015, consolidation of a pathway of diagnosis, observation, and prophylaxis for women at high risk of hereditary breast carcinoma is thus proposed. The principal activities of this policy will be the following: creation of a regional working group, survey of currently existing pathways for the identification of women at risk of hereditary breast cancer and adoption of the same, approval and consolidation of a structured regional pathway for women at high risk of hereditary breast and/or ovarian cancer, from paths of oncogenetic consultation and genetic testing to management of disease risk. Subsequent to the recognition of the pathway of diagnosis, observation, and prophylaxis for women at high risk of hereditary breast carcinoma, the Veneto region undertakes to develop a co-ordinated program of information and training on this pathway directed at the population and healthcare workers. It is firmly hoped that with the inclusion of a program for the management of women at high risk of hereditary breast cancer within the Veneto PRP this topic may become more defined and structured in terms of sustainability, integration with the existing regional networks (mammography network, Breast Unit), contrasting inequality, monitoring and evaluation, in this way pursuing the objectives of a reduction of cause-specific mortality and improvement of quality of life.

Family history record and hereditary cancer risk perception according to National Cancer Institute criteria in a Spanish medical oncology service: a retrospective study.

PubMed

Márquez-Rodas, Iván; López-Trabada, Daniel; Rupérez Blanco, Ana Belén; Custodio Cabello, Sara; Peligros Gómez, María Isabel; Orera Clemente, María; Calvo, Felipe A; Martín, Miguel

2012-01-01

Identification of patients at risk of hereditary cancer is an essential component of oncology practice, since it enables clinicians to offer early detection and prevention programs. However, the large number of hereditary syndromes makes it difficult to take them all into account in daily practice. Consequently, the National Cancer Institute (NCI) has suggested a series of criteria to guide initial suspicion. It was the aim of this study to assess the perception of the risk of hereditary cancer according to the NCI criteria in our medical oncology service. We retrospectively analyzed the recordings of the family history in new cancer patients seen in our medical oncology service from January to November 2009, only 1 year before the implementation of our multidisciplinary hereditary cancer program. The family history was recorded in only 175/621 (28%) patients. A total of 119 (19%) patients met 1 or more NCI criteria (1 criterion, n = 91; 2 criteria, n = 23; 3 criteria, n = 4; and 4 criteria, n = 1), and only 14 (11.4%) patients were referred to genetic counseling. This study shows that few clinicians record the family history. The perception of the risk of hereditary cancer is low according to the NCI criteria in our medical oncology service. These findings can be explained by the lack of a multidisciplinary hereditary cancer program when the study was performed. Copyright © 2012 S. Karger AG, Basel.

Ethical dilemmas in genetic testing: examples from the Cuban program for predictive diagnosis of hereditary ataxias.

PubMed

Mariño, Tania Cruz; Armiñán, Rubén Reynaldo; Cedeño, Humberto Jorge; Mesa, José Miguel Laffita; Zaldivar, Yanetza González; Rodríguez, Raúl Aguilera; Santos, Miguel Velázquez; Mederos, Luis Enrique Almaguer; Herrera, Milena Paneque; Pérez, Luis Velázquez

2011-06-01

Predictive testing protocols are intended to help patients affected with hereditary conditions understand their condition and make informed reproductive choices. However, predictive protocols may expose clinicians and patients to ethical dilemmas that interfere with genetic counseling and the decision making process. This paper describes ethical dilemmas in a series of five cases involving predictive testing for hereditary ataxias in Cuba. The examples herein present evidence of the deeply controversial situations faced by both individuals at risk and professionals in charge of these predictive studies, suggesting a need for expanded guidelines to address such complexities.

CARCINOGENICITY OF INDIVIDUAL AND A MIXTURE OF DRINKING WATER DISINFECTION BY-PRODUCTS IN A RAT MODEL OF HEREDITARY RENAL CELL CARCINOMA

EPA Science Inventory

Carcinogenicity of Individual and a Mixture of Drinking Water Disinfection By-Products in a Rat Model of Hereditary Renal Cell Carcinoma

Eker rats develop hereditary renal cell carcinoma secondary to a germline mutation in the tuberous sclerosis 2 (Tsc2) gene and are ligh...

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis.

PubMed

Giavina-Bianchi, Pedro; Arruda, Luisa Karla; Aun, Marcelo V; Campos, Regis A; Chong-Neto, Herberto J; Constantino-Silva, Rosemeire N; Fernandes, Fátima R; Ferraro, Maria F; Ferriani, Mariana P L; França, Alfeu T; Fusaro, Gustavo; Garcia, Juliana F B; Komninakis, Shirley; Maia, Luana S M; Mansour, Eli; Moreno, Adriana S; Motta, Antonio A; Pesquero, João B; Portilho, Nathalia; Rosário, Nelson A; Serpa, Faradiba S; Solé, Dirceu; Takejima, Priscila; Toledo, Eliana; Valle, Solange O.R; Veronez, Camila L; Grumach, Anete S

2018-01-01

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associação Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Advantages and disadvantages of an iron-rich diet.

PubMed

Hallberg, L

2002-03-01

A review by invitation about advantages and disadvantages of an iron-rich diet by analyzing physiological iron requirements, dietary factors influencing iron absorption and the regulatory systems available to control iron absorption according to needs. The control to prevent iron deficiency is good but not perfect, as observed in previously described studies on relationships between individual iron requirements and the probability of iron deficiency developing in relation to diet. The control to prevent iron overload seems to be perfect except in the few subjects being homozygotes for hereditary hemochromatosis. A diet rich in easily available iron is important for covering basal iron losses, menstrual iron losses and the high iron requirements for growth from infancy to adolescence and for pregnancy.

[Hereditary motor and sensory neuropathy type 4A].

PubMed

2010-01-01

The first in the Russian Federation clinical cases of patients with autosomal-recessive type of hereditary motor and sensory neuropathy, type 4A, (HMSN 4A) are presented. In all cases, the diagnosis has been verified using molecular-genetic methods (DNA diagnostics). An analysis of features of clinical manifestations was performed in patients, aged from 5 to 34 years, with different disease duration (from 3-to 29 years). Criteria of selection of patients for DNA diagnostics for searching mutations in the GDAP1 gene are specified.

Hereditary spastic paraplegia: clinical principles and genetic advances.

PubMed

Fink, John K

2014-07-01

Hereditary spastic paraplegia (HSP) refers to inherited disorders in which spastic gait is either the only feature or is a major syndrome feature. There are more than 70 genetic types of HSP. Neuropathological studies, albeit limited to only a few genetic types of HSP, have identified axon degeneration involving the distal ends of the corticospinal tracts and fasciculus gracilis fibers. In this review, the author highlights the clinical and genetic features of HSP. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

[Mutation analysis of FGFR3 gene in a family featuring hereditary dwarfism].

PubMed

Zhang, Qiong; Jiang, Hai-ou; Quan, Qing-li; Li, Jun; He, Ting; Huang, Xue-shuang

2011-12-01

To investigate the clinical symptoms and potential mutation in FGFR3 gene for a family featuring hereditary dwarfism in order to attain diagnosis and provide prenatal diagnosis. Five patients and two unaffected relatives from the family, in addition with 100 healthy controls, were recruited. Genome DNA was extracted. Exons 10 and 13 of the FGFR3 gene were amplified using polymerase chain reaction (PCR). PCR products were sequenced in both directions. All patients had similar features including short stature, short limbs, lumbar hyperlordosis but normal craniofacial features. A heterozygous mutation G1620T (N540K) was identified in the cDNA from all patients but not in the unaffected relatives and 100 control subjects. A heterozygous G380R mutation was excluded. The hereditary dwarfism featured by this family has been caused by hypochondroplasia (HCH) due to a N540K mutation in the FGFR3 gene.

MRI screening of kindred at risk of developing paragangliomas: support for genomic imprinting in hereditary glomus tumours.

PubMed Central

van Gils, A. P.; van der Mey, A. G.; Hoogma, R. P.; Sandkuijl, L. A.; Maaswinkel-Mooy, P. D.; Falke, T. H.; Pauwels, E. K.

1992-01-01

Paragangliomas of the head and neck (glomus tumours) can occur in a hereditary pattern and may be hormonally active as well as being associated with paragangliomas elsewhere. A number of these tumours may be present without symptoms. To detect the presence of subclinical paragangliomas we screened 83 members of a family at risk of developing hereditary paragangliomas using whole body MRI and urinary catecholamine testing. In eight previously diagnosed members, eight known glomus tumours of which one functioning, and two unknown glomus tumours and one unknown pheochromocytoma were present. Six unsuspected members showed ten glomus tumours and one pheochromocytoma. It has been suggested that the manifestation of hereditary glomus tumours is determined by the sex of the transmitting parent. There were no tumours in the descendants of female gene carriers. Comparing the likelihood of inheritance with genomic imprinting versus inheritance without genomic imprinting we found an odds ratio of 23375 in favour of genomic imprinting. PMID:1616861

Hereditary hypohidrotic ectodermal dysplasia: report of a rare case.

PubMed

Paramkusam, Geetha; Meduri, Venkateswarlu; Nadendla, Lakshmi Kavitha; Shetty, Namratha

2013-09-01

Hereditary Hypohidrotic Ectodermal Dysplasia (HHED), an X-linked, recessive, Mendelian character, is seen usually in males and it is inherited through female carriers. It is characterised by congenital dysplasia of one or more ectodermal structures and it is manifested by hypohidrosis, hypotrichosis and hypodontia. It results from abnormal morphogenesis of cutaneous and oral embryonic ectoderm. Here, we are presenting a rare case of HHED in a 19 year female with classic features of this condition.

Radiosurgery for cerebral arteriovenous malformations in hereditary hemorrhagic telangiectasia.

PubMed

Maarouf, M; Runge, M; Kocher, M; Zähringer, M; Treuer, H; Sturm, V

2004-07-27

The authors evaluated the efficacy of radiosurgery (RS) for cerebral arteriovenous malformations in hereditary hemorrhagic telangiectasia (HHT AVMs). Two patients with seven HHT AVMs were treated by linear accelerator-RS. Complete obliteration was achieved 18 to 24 months post-treatment without side effects. Because HHT AVMs are small and multiple, RS is superior to microsurgery because it is noninvasive and all AVMs can be treated in one session regardless of their location.

Cardiac arrest after anesthetic management in a patient with hereditary sensory autonomic neuropathy type IV.

PubMed

Ergül, Yakup; Ekici, Bariş; Keskin, Sabiha

2011-01-01

Hereditary sensory autonomic neuropathy type IV is a rare disorder with an autosomal recessive transmission and characterized by self-mutilation due to a lack in pain and heat sensation. Recurrent hyperpyrexia and anhydrosis are seen in patients as a result of a lack of sweat gland innervation. Self-mutilation and insensitivity to pain result in orthopedic complications and patients undergone recurrent surgical interventions with anesthesia. However, these patients are prone to perioperative complications such as hyperthermia, hypothermia, and cardiac complications like bradycardia and hypotension. We report a 5-year-old boy with hereditary sensory autonomic neuropathy type IV, developing hyperpyrexia and cardiac arrest after anesthesia.

Advances in Sequencing Technologies for Understanding Hereditary Ataxias A Review

PubMed Central

Didonna, Alessandro; Opal, Puneet

2017-01-01

IMPORTANCE The hereditary progressive ataxias comprise genetic disorders that affect the cerebellum and its connections. Even though these diseases historically have been among the first familial disorders of the nervous system to have been recognized, progress in the field has been challenging because of the large number of ataxic genetic syndromes, many of which overlap in their clinical features. OBSERVATIONS We have taken a historical approach to demonstrate how our knowledge of the genetic basis of ataxic disorders has come about by novel techniques in gene sequencing and bioinformatics. Furthermore, we show that the genes implicated in ataxia, although seemingly unrelated, appear to encode for proteins that interact with each other in connected functional modules. CONCLUSIONS AND RELEVANCE It has taken approximately 150 years for neurologists to comprehensively unravel the genetic diversity of ataxias. There has been an explosion in our understanding of their molecular basis with the arrival of next-generation sequencing and computer-driven bioinformatics; this in turn has made hereditary ataxias an especially well-developed model group of diseases for gaining insights at a systems level into genes and cellular pathways that result in neurodegeneration. PMID:27749953

Ultrastructural evaluation of gingival connective tissue in hereditary gingival fibromatosis.

PubMed

Pêgo, Sabina Pena B; de Faria, Paulo Rogério; Santos, Luis Antônio N; Coletta, Ricardo D; de Aquino, Sibele Nascimento; Martelli-Júnior, Hercílio

2016-07-01

To describe the ultrastructural features of hereditary gingival fibromatosis (HGF) in affected family members and compare microscopic findings with normal gingival (NG) tissue. Gingival tissue samples from nine patients with HGF from five unrelated families were evaluated by transmission electron microscopy. Nine NG tissue samples were used for comparison. Areas containing collagen fibrils forming loops and folds were observed in both groups, whereas oxytalan fibers were frequently identified in the HGF group. The diameter of collagen fibrils and the interfibrillar space among them were more uniform in the NG group than in the HGF group. Fibroblasts were the most common cells found in both the HGF and NG groups and exhibited enlarged, rough endoplasmic reticulum, mitochondria with well-preserved crests, conspicuous nucleoli, and euchromatic chromatin. Other cells, such as mast cells, plasma cells, and macrophages, were also observed. HGF tissues had ultrastructural characteristics that were very similar to those of NG tissues. Oxytalan fibers were observed more frequently in the HGF samples than in the NG samples. Other studies of HGF in patients from different families should be performed to better understand the pathogenesis of this hereditary condition. Copyright © 2016 Elsevier Inc. All rights reserved.

H63D mutation in hemochromatosis alters cholesterol metabolism and induces memory impairment.

PubMed

Ali-Rahmani, Fatima; Grigson, Patricia S; Lee, Sang; Neely, Elizabeth; Connor, James R; Schengrund, Cara-Lynne

2014-06-01

The H63D variant of the hemochromatosis (HFE) gene, when expressed in carriers of the apolipoprotein E4 allele, is implicated as a risk factor for earlier onset of Alzheimer's disease (AD). We tested the hypothesis that like expression of apolipoprotein E4, expression of H63D-HFE disrupts cholesterol metabolism contributing to an increase in neurodegeneration and memory deficits. Analysis of SH-SY5Y human neuroblastoma cells transfected to stably express either wild type- (WT) or H63D-HFE indicated about a 50% reduction in cholesterol content in cells expressing H63D-HFE. This was accompanied by a significant decrease in expression of 3-hydroxy-3-methyl-glutaryl-CoA reductase, and a significant increase in expression of cholesterol 24-hydroxylase. Consistent with these studies, H67D-HFE (orthologous to human H63D-HFE) knock-in mice, showed a greater age dependent decline in brain cholesterol than WT-HFE animals and changes in expression of proteins regulating cholesterol metabolism. Brains of aged H67D-HFE mice also exhibited a significant decrease in expression of synapse proteins and a significant increase in caspase-3 expression relative to WT-HFE controls. H67D-HFE mice also had a greater reduction in brain volume and poorer recognition and spatial memory than WT-HFE mice, symptoms associated with AD. These results indicate that the alterations in cholesterol metabolism associated with expression of H63D-HFE may contribute to the development of AD. Copyright © 2014 Elsevier Inc. All rights reserved.

Hereditary Deafness in a Former Fishing Village on the Dutch Coast

ERIC Educational Resources Information Center

Nyst, Victoria A. S.

2016-01-01

In communities with an increased prevalence of hereditary deafness, social, and linguistic adaptations are found in response. Aulbers (1959) describes a high prevalence of deafness in a fishing village on the Dutch coast: Katwijk aan Zee. This article aims to assess the current prevalence of deafness in Katwijk, as well as the current sign…

Converging cellular themes for the hereditary spastic paraplegias.

PubMed

Blackstone, Craig

2018-05-10

Hereditary spastic paraplegias (HSPs) are neurologic disorders characterized by prominent lower-extremity spasticity, resulting from a length-dependent axonopathy of corticospinal upper motor neurons. They are among the most genetically-diverse neurologic disorders, with >80 distinct genetic loci and over 60 identified genes. Studies investigating the molecular pathogenesis underlying HSPs have emphasized the importance of converging cellular pathogenic themes in the most common forms of HSP, providing compelling targets for therapy. Most notably, these include organelle shaping and biogenesis as well as membrane and cargo trafficking. Published by Elsevier Ltd.

Incidence and survival in non-hereditary amyloidosis in Sweden

PubMed Central

2012-01-01

Background Amyloidosis is a heterogeneous disease caused by deposition of amyloid fibrils in organs and thereby interfering with physiological functions. Hardly any incidence data are available and most survival data are limited to specialist clinics. Methods Amyloidosis patients were identified from the Swedish Hospital Discharge and Outpatients Registers from years 2001 through 2008. Results The incidence of non-hereditary amyloidosis in 949 patients was 8.29 per million person-years and the diagnostic age with the highest incidence was over 65 years. Secondary systemic amyloidosis showed an incidence of 1 per million and a female excess and the largest number of subsequent rheumatoid arthritis deaths; the median survival was 4 years. However, as rheumatoid arthritis deaths also occurred in other diagnostic subtypes, the incidence of secondary systemic amyloidosis was likely to be about 2.0 per million. The median survival of patients with organ-limited amyloidosis was 6 years. Most myeloma deaths occurred in patients diagnosed with unspecified or ‘other’ amyloidosis. These subtypes probably accounted for most of immunoglobulin light chain (AL) amyloidosis cases; the median survival time was 3 years. Conclusions The present diagnostic categorization cannot single out AL amyloidosis in the Swedish discharge data but, by extrapolation from myeloma cases, an incidence of 3.2 per million could be ascribed to AL amyloidosis. Similarly, based on rheumatoid arthritis death rates, an incidence of 2.0 could be ascribed to secondary systemic amyloidosis. PMID:23148499

Hereditary sensory neuropathy type I.

PubMed

Auer-Grumbach, Michaela

2008-03-18

Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin

Hereditary sensory neuropathy type I

PubMed Central

Auer-Grumbach, Michaela

2008-01-01

Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin

Hereditary Hypohidrotic Ectodermal Dysplasia: Report of a Rare Case

PubMed Central

Paramkusam, Geetha; Meduri, Venkateswarlu; Nadendla, Lakshmi Kavitha; Shetty, Namratha

2013-01-01

Hereditary Hypohidrotic Ectodermal Dysplasia (HHED), an X-linked, recessive, Mendelian character, is seen usually in males and it is inherited through female carriers. It is characterised by congenital dysplasia of one or more ectodermal structures and it is manifested by hypohidrosis, hypotrichosis and hypodontia. It results from abnormal morphogenesis of cutaneous and oral embryonic ectoderm. Here, we are presenting a rare case of HHED in a 19 year female with classic features of this condition. PMID:24179947

HFE gene polymorphism defined by sequence-based typing of the Brazilian population and a standardized nomenclature for HFE allele sequences.

PubMed

Campos, W N; Massaro, J D; Martinelli, A L C; Halliwell, J A; Marsh, S G E; Mendes-Junior, C T; Donadi, E A

2017-10-01

The HFE molecule controls iron uptake from gut, and defects in the molecule have been associated with iron overload, particularly in hereditary hemochromatosis. The HFE gene including both coding and boundary intronic regions were sequenced in 304 Brazilian individuals, encompassing healthy individuals and patients exhibiting hereditary or acquired iron overload. Six sites of variation were detected: (1) H63D C>G in exon 2, (2) IVS2 (+4) T>C in intron 2, (3) a C>G transversion in intron 3, (4) C282Y G>A in exon 4, (5) IVS4 (-44) T>C in intron 4, and (6) a new guanine deletion (G>del) in intron 5, which were used for haplotype inference. Nine HFE alleles were detected and six of these were officially named on the basis of the HLA Nomenclature, defined by the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System, and published via the IPD-IMGT/HLA website. Four alleles, HFE*001, *002, *003, and *004 exhibited variation within their exon sequences. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough.

PubMed

Miura, Shiroh; Shibata, Hiroki; Kida, Hiroshi; Noda, Kazuhito; Tomiyasu, Katsuro; Yamamoto, Ken; Iwaki, Akiko; Ayabe, Mitsuyoshi; Aizawa, Hisamichi; Taniwaki, Takayuki; Fukumaki, Yasuyuki

2008-10-15

We studied a four-generation pedigree of a Japanese family with hereditary neuropathy to elucidate the genetic basis of this disease. Twelve members of the family were enrolled in this study. The clinical features were neurogenic muscle weakness with proximal dominancy in the lower extremities, sensory involvement, areflexia, fine postural tremors, painful muscle cramps, elevated creatine kinase levels, recurrent paroxysmal dry cough, and neurogenic bladder. We performed a genome-wide search using genetic loci spaced at about 13 Mb intervals. Although nine chromosomes (1, 3, 4, 5, 6, 10, 17, 19, and 22) had at least one region in which the logarithm of odds (LOD) score was over 1.0, no loci fulfilled the criteria for significant evidence of linkage. Moreover, we analyzed an extra 14 markers on 3p12-q13 (the locus of hereditary motor and sensory neuropathy, proximal dominant form) and an extra five markers on 3p22-p24 (the locus of hereditary sensory neuropathy with chronic cough) and observed LOD scores of <-3 on both 3p12-q13 and 3p22-p24. Mutation scanning of the entire coding regions of the MPZ and PMP22 genes revealed no mutations. We conclude that the disorder described here is a newly classified hereditary motor and sensory neuropathy with autosomal dominant inheritance.

Genetic disorder in carbohydrates metabolism: hereditary fructose intolerance associated with celiac disease.

PubMed

Păcurar, Daniela; Leşanu, Gabriela; Dijmărescu, Irina; Ţincu, Iulia Florentina; Gherghiceanu, Mihaela; Orăşeanu, Dumitru

2017-01-01

Celiac disease (CD) has been associated with several genetic and immune disorders, but association between CD and hereditary fructose intolerance (HFI) is extremely rare. HFI is an autosomal recessive disease caused by catalytic deficiency of aldolase B (fructose-1,6-bisphosphate aldolase). We report the case of a 5-year-old boy suffering from CD, admitted with an initial diagnosis of Reye's-like syndrome. He presented with episodic unconsciousness, seizures, hypoglycemia, hepatomegaly and abnormal liver function. The patient has been on an exclusion diet for three years, but he still had symptoms: stunting, hepatomegaly, high transaminases, but tissue transglutaminase antibodies were negative. Liver biopsy showed hepatic steatosis and mitochondrial damage. The dietary history showed an aversion to fruits, vegetables and sweet-tasting foods. The fructose tolerance test was positive, revealing the diagnostic of hereditary fructose intolerance. Appropriate dietary management and precautions were recommended. The patient has been symptom-free and exhibited normal growth and development until 10 years of age.

[Indicators of lipid peroxidation in the blood in hereditary predisposition to arteriosclerosis].

PubMed

Davidenkova, E F; Shafran, M G; Veksler, B M

1990-02-01

In members of the families whose parents had atherosclerosis complicated by macrofocal myocardial infarction or stroke, the serum level of lipid peroxidation products was correlated to enzymatic activity of neutrophil and red blood cells oxidation-antioxidation. In persons with hereditary predisposition to atherosclerosis both with clinical signs of atherosclerosis and phenotypically healthy against the control group there was elevated content of plasma acylhydroperoxides and hypoactivity of neutrophil myeloperoxidase. Determination of lipid peroxidation products by malonic dealdehyde showed this parameter to be higher in members of the families of the study group and in those with cardiovascular disorders. For those whose parents had atherosclerosis versus control subjects there were no differences in the activity of superoxide dismutase, glutation peroxidase and catalase in the blood red cells. Shifts in lipid peroxidation and activity of blood myeloperoxidase are identical in type and may represent a pathogenetic ling in formation of hereditary predisposition to cardiovascular disorders of atherosclerotic origin, the detection of which becomes feasible in a subclinical period.

[Hereditary breast and ovarian cancers].

PubMed

Gevensleben, H; Serçe, N; Büttner, R

2010-10-01

Hereditary factors are responsible for 5-10% of all breast cancers and 10% of all ovarian cancer cases and are predominantly caused by mutations in the high risk genes BRCA1 and BRCA2 (BRCA: breast cancer). Additional moderate and low penetrance gene variants are currently being analyzed via whole genome association studies. Interdisciplinary counseling, quality managed genetic testing and intensified prevention efforts in specialized medical centres are essential for members of high risk families considering the high prevalence of malignant tumors and the early age of onset. Furthermore, the identification of BRCA-deficient carcinomas is of particular clinical interest, especially regarding new specific therapeutic options, e.g. treatment with poly (ADP-ribose) polymerase (PARP) inhibitors. There are presently no valid surrogate markers verifying the association of BRCA1/BRC2 in tumors. However, breast cancers harboring pathogenic BRCA1 mutations in particular display specific histopathological features.

Human parvovirus B19-induced aplastic crisis in an adult patient with hereditary spherocytosis: a case report and review of the literature.

PubMed

Kobayashi, Yujin; Hatta, Yoshihiro; Ishiwatari, Yusaku; Kanno, Hitoshi; Takei, Masami

2014-03-11

Although there are several case reports of human parvovirus B19 infection in patients with hereditary spherocytosis, no systematic reviews of adult patients with hereditary spherocytosis with human parvovirus B19 infection have been published as clinical case reports. In this study, we report a case of aplastic crisis due to human parvovirus B19 infection in an adult patient with hereditary spherocytosis. A 33-year-old woman with hereditary spherocytosis and gallstones was admitted because of rapid progress in marked anemia and fever. Although empiric antibiotic therapy was prescribed, her clinical symptoms and liver function test worsened. Because the anti-human parvovirus B19 antibody and deoxyribonucleic acid levels assessed by polymerase chain reaction were positive, the patient was diagnosed with aplastic crisis due to the human parvovirus B19 infection. We collected and reviewed several case reports of patients with hereditary spherocytosis aged > 18 years with human parvovirus B19 infection between 1984 and 2010. A total of 19 reports with 22 cases [median age, 28 years (range, 18-43 range); male: female ratio, 6:16], including the present case were identified. The male-to-female ratio of 6:16 implied that younger females were predominantly affected. Although fever and abdominal symptoms were common initial symptoms, liver dysfunction or skin eruptions were less commonly documented. Anti-human parvovirus B19 antibody or deoxyribonucleic acid levels assessed by polymerase chain reaction was commonly used to diagnose human parvovirus B19 infection and may be useful to distinguish human parvovirus B19 infection from other abdominal infection in patients with hereditary spherocytosis.

Hereditary neuropathy with liability to pressure palsies occurring during military training.

PubMed

Delacour, H; Bompaire, F; Biale, L; Sallansonnet-Froment, M; Ceppa, F; Burnat, P

2012-03-01

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant peripheral neuropathy characterized by recurrent isolated nerve palsies, which are precipitated by trivial compression and trauma. Although HNPP has been well-described in literature, it often goes unrecognized. We report a case of HNPP occurring during military training to promote recognition and proper management of this entity.

DNA repair and tumorigenesis: lessons from hereditary cancer syndromes.

PubMed

Heinen, Christopher D; Schmutte, Christoph; Fishel, Richard

2002-01-01

The discovery that alterations of the DNA mismatch repair system (MMR) were linked to the common human cancer susceptibility syndrome hereditary nonpolyposis colon cancer (HNPCC) resulted in the declaration of a third class of genes involved in tumor development. In addition to oncogenes and tumor suppressors, alterations of DNA repair genes involved in maintaining genomic stability were found to be a clear cause of tum the level of the single nucleotides or chromosomes. This observation suggested that the establishment of genomic instability, termed the Mutator Phenotype, was an important aspect of tumor development.(1,2) Since the initial identification of the human MutS homolog hMSH2 nearly a decade ago,(3,4) more links have been described between human cancers and genes involved in maintaining genomic stability. Work in recent years has revealed that DNA repair proteins may also function in signaling pathways that provoke cell cycle arrest and apoptosis. This review will focus on the genetic and biochemical functions of DNA repair genes linked to hereditary cancer predisposition characterized by genomic instability (Table 1). Interestingly, the protein products of these genes have been directly or indirectly linked to the DNA damage-induce cell cycle arrest and apoptosis. We conclude that a robust connection between DNA repair proteins and damage-induced apoptosis may be as important for tumorigenesis as their role in maintaining genome stability.

Hereditary cancer genes are highly susceptible to splicing mutations

PubMed Central

Soemedi, Rachel; Maguire, Samantha; Murray, Michael F.; Monaghan, Sean F.

2018-01-01

Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5′ and 3′ splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36%) of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we found that three main causal genes of Lynch Syndrome, MLH1, MSH2, and PMS2, belonged to a class of 86 disease genes which are enriched for splicing mutations. Other cancer genes were also enriched in the 86 susceptible genes. The enrichment of splicing mutations in hereditary cancers strongly argues for additional priority in interpreting clinical sequencing data in relation to cancer and splicing. PMID:29505604

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy

PubMed Central

Iommarini, Luisa; Giordano, Luca; Maresca, Alessandra; Pisano, Annalinda; Valentino, Maria Lucia; Caporali, Leonardo; Liguori, Rocco; Deceglie, Stefania; Roberti, Marina; Fanelli, Francesca; Fracasso, Flavio; Ross-Cisneros, Fred N.; D’Adamo, Pio; Hudson, Gavin; Pyle, Angela; Yu-Wai-Man, Patrick; Chinnery, Patrick F.; Zeviani, Massimo; Salomao, Solange R.; Berezovsky, Adriana; Belfort, Rubens; Ventura, Dora Fix; Moraes, Milton; Moraes Filho, Milton; Barboni, Piero; Sadun, Federico; De Negri, Annamaria; Sadun, Alfredo A.; Tancredi, Andrea; Mancini, Massimiliano; d’Amati, Giulia; Loguercio Polosa, Paola; Cantatore, Palmiro

2014-01-01

Leber’s hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber’s hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber’s hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies. PMID:24369379

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

PubMed

Longhurst, Hilary; Cicardi, Marco; Craig, Timothy; Bork, Konrad; Grattan, Clive; Baker, James; Li, Huamin H; Reshef, Avner; Bonner, James; Bernstein, Jonathan A; Anderson, John; Lumry, William R; Farkas, Henriette; Katelaris, Constance H; Sussman, Gordon L; Jacobs, Joshua; Riedl, Marc; Manning, Michael E; Hebert, Jacques; Keith, Paul K; Kivity, Shmuel; Neri, Sergio; Levy, Donald S; Baeza, Maria L; Nathan, Robert; Schwartz, Lawrence B; Caballero, Teresa; Yang, William; Crisan, Ioana; Hernandez, María D; Hussain, Iftikhar; Tarzi, Michael; Ritchie, Bruce; Králíčková, Pavlina; Guilarte, Mar; Rehman, Syed M; Banerji, Aleena; Gower, Richard G; Bensen-Kennedy, Debra; Edelman, Jonathan; Feuersenger, Henrike; Lawo, John-Philip; Machnig, Thomas; Pawaskar, Dipti; Pragst, Ingo; Zuraw, Bruce L

2017-03-23

Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU

Genetics, biomarkers, hereditary cancer syndrome diagnosis, heterogeneity and treatment: a review.

PubMed

Lynch, Henry T; Drescher, Kristen; Knezetic, Joseph; Lanspa, Stephen

2014-09-01

Molecular genetic pathways that drive the phenotypic and genotypic heterogeneity of hereditary colorectal cancer also can affect response to chemotherapy and chemoprevention. These mutations also can alter patients' response to therapy. Environmental differences can affect this highly complex conundrum. We will use Lynch syndrome as a model to explore this issue. However, to begin with, after more than a century of documentation, we must ask what is meant by the eponym "Lynch syndrome". Germline mutations may act as drivers of chemoprevention and chemotherapy and therein may act positively or conversely they may have a negative effect in terms of inhibiting the inactivation of cancer-causing germline mutations. A relatively new field of hereditary cancer therapeutics has significantly impacted cancer care, from the standpoint of the sensitivity or resistance to a particular form of chemotherapy and/or chemoprevention. The question for the diagnostician and therapist must always concern what is the best possible management approach for the patient, particularly when he or she harbors a cancer-causing germline mutation, which, in this case, causes Lynch syndrome. Continued molecular genetic research might yield a more tailored effective treatment for Lynch syndrome. The ultimate goal of such hereditary oncologic research is to better understand the mutation's therapeutic task, namely, its potential to benefit the patient in terms of its treatment goal, thereby fulfilling the essence of personalized medicine. However, this goal may be exceedingly complicated. For example, in the natural clinical and molecular genetic history of hereditary forms of cancer, there will be a predominance of early-onset cancers of multiple anatomic sites. In our Lynch syndrome model, these will be most commonly colorectal, endometrial, and ovarian cancer. Attention must initially be focused upon cancer's early age of onset coupled with the tendency to multiple primary cancers so that, in

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

PubMed Central

Estrada-Cuzcano, Alejandro; Martin, Shaun; Chamova, Teodora; Synofzik, Matthis; Timmann, Dagmar; Holemans, Tine; Andreeva, Albena; Reichbauer, Jennifer; De Rycke, Riet; Chang, Dae-In; van Veen, Sarah; Samuel, Jean; Schöls, Ludger; Pöppel, Thorsten; Mollerup Sørensen, Danny; Asselbergh, Bob; Klein, Christine; Zuchner, Stephan; Jordanova, Albena; Vangheluwe, Peter; Tournev, Ivailo; Schüle, Rebecca

2017-01-01

Abstract Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower

Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda.

PubMed

Stölzel, Ulrich; Köstler, Erich; Schuppan, Detlef; Richter, Matthias; Wollina, Uwe; Doss, Manfred O; Wittekind, Christian; Tannapfel, Andrea

2003-03-01

To examine the role of hemochromatosis (HFE) gene mutations, which are associated with porphyria cutanea tarda (PCT), in the therapeutic response to chloroquine. We retrospectively analyzed a database (Excel version 2001 [Microsoft Excel, Redmond, Wash]; date range of search, 1985-1999) of chloroquine-treated patients with PCT on whether HFE mutations (C282Y and H63D) might have influenced the clinical response, urinary porphyrin excretion, liver enzyme activities, and serum iron markers. Serum samples and corresponding complete sets of data before and after therapy were available in 62 of 207 patients with PCT who were treated exclusively with chloroquine. Academic teaching hospital. For treatment, low-dose chloroquine diphosphate, 125 to 250 mg twice weekly, was used during a median time of 16 months (range, 12-26 months). Of the 62 German patients with PCT, 37 (60%) carries HFE mutations. Chloroquine therapy was accompanied by clinical remission and reduced urinary porphyrin excretion (P<.001) in the 24 patients (39%) with HFE wild type as well as in 35 HFE heterozygous patients with PCT (56%). Decreases of serum iron markers following chloroquine therapy were limited to patients with PCT and HFE wild type. All patients homozygous for the C282Y mutation (3 [5%] of 62) had high serum iron, ferritin, and transferrin saturation and failed to respond to chloroquine treatment. The therapeutic response to chloroquine was not compromised by C282Y heterozygosity and compound heterozygosity of HFE mutations. Because HFE C282Y homozygotes (+/+) did not respond to chloroquine and a decrease in serum iron concentration was limited to patients with PCT and HFE wild type, phlebotomy should be first-line therapy in patients with PCT and HFE mutations.

Deprivation amblyopia and congenital hereditary cataract.

PubMed

Mansouri, Behzad; Stacy, Rebecca C; Kruger, Joshua; Cestari, Dean M

2013-01-01

Amblyopia is a neurodevelopmental disorder of vision associated with decreased visual acuity, poor or absent stereopsis, and suppression of information from one eye.(1,2) Amblyopia may be caused by strabismus (strabismic amblyopia), refractive error (anisometropic amblyopia), or deprivation from obstructed vision (deprivation amblyopia). 1 In the developed world, amblyopia is the most common cause of childhood visual impairment, 3 which reduces quality of life 4 and also almost doubles the lifetime risk of legal blindness.(5, 6) Successful treatment of amblyopia greatly depends on early detection and treatment of predisposing disorders such as congenital cataract, which is the most common cause of deprivational amblyopia. Understanding the genetic causes of congenital cataract leads to more effective screening tests, early detection and treatment of infants and children who are at high risk for hereditary congenital cataract.

Knowledge about hereditary cancer of women with family histories of breast, colorectal, or both types of cancer.

PubMed

Campacci, N; de Lima, J O; Ramadan, L; Palmero, E I

2015-03-01

Usually, the mass media do not address hereditary cancer and their risk factors, nor are these topics discussed at the community level. We used an informative guide on cancer and hereditary cancer, followed by a questionnaire on these topics to investigate the relevant knowledge among women at high risk for hereditary breast and/or colorectal cancer from a population-based cohort. The cohort was composed of 81 Brazilian women with positive family histories of breast and/or colorectal cancer. Strauss and Corbin's Grounded Theory was used for qualitative analysis. The average age of the cohort was 49.9 years old. Three participants (3.9%) were illiterate, 45 (59.2%) had attended elementary school, 14 (18.4%) had secondary school, and 14 (18.4%) held higher education degrees. A total of 47 (54.3%) volunteers were unable to fully understand the information provided in the guide because they did not know the meaning of words such as metastasis, malignant, hereditary, sporadic, or oncogenetics. Notwithstanding, the acceptance of the educational tool utilized was satisfactory, and it enhanced the volunteers' interest in a better understanding of cancer and heredity. Thereby, we concluded that the low knowledge of this important subject and the unawareness about fundamental terms required for the comprehension of this specific type of neoplasm made us believe that the use of the informative guide can provide a great value when used previously to the genetic counseling consultations. Besides, educational tools of easy understanding should be part of everyday clinical practice, from primary to specialized patient care.

Imaging of Hereditary Hemorrhagic Telangiectasia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carette, Marie-France, E-mail: marie-france.carette@tnn.aphp.fr; Nedelcu, Cosmina; Tassart, Marc

This pictorial review is based on our experience of the follow-up of 120 patients at our multidisciplinary center for hereditary hemorrhagic telangiectasia (HHT). Rendu-Osler-Weber disease or HHT is a multiorgan autosomal dominant disorder with high penetrance, characterized by epistaxis, mucocutaneous telangiectasis, and visceral arteriovenous malformations (AVMs). The research on gene mutations is fundamental and family screening by clinical examination, chest X-ray, research of pulmonary shunting, and abdominal color Doppler sonography is absolutely necessary. The angioarchitecture of pulmonary AVMs can be studied by unenhanced multidetector computed tomography; however, all other explorations of liver, digestive bowels, or brain require administration of contrastmore » media. Magnetic resonance angiography is helpful for central nervous system screening, in particular for the spinal cord, but also for pulmonary, hepatic, and pelvic AVMs. Knowledge of the multiorgan involvement of HHT, mechanism of complications, and radiologic findings is fundamental for the correct management of these patients.« less

Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy

NASA Astrophysics Data System (ADS)

Wallace, Douglas C.; Singh, Gurparkash; Lott, Marie T.; Hodge, Judy A.; Schurr, Theodore G.; Lezza, Angela M. S.; Elsas, Louis J.; Nikoskelainen, Eeva K.

1988-12-01

Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

Hereditary motor and sensory neuropathy Lom type in a Serbian family.

PubMed

Dacković, J; Keckarević-Marković, M; Komazec, Z; Rakocević-Stojanović, V; Lavrnić, D; Stević, Z; Ribarić, K; Romac, S; Apostolski, S

2008-10-01

Hereditary motor and sensory neuropathy Lom type (HMSNL), also called CMT 4D, a hereditary autosomal recessive neuropathy, caused by mutation in N-Myc downstream regulated gene 1 (NDRG1 gene), was first described in a Bulgarian Gypsy population near Lom and later has been found in Gypsy communities in Italy, Spain, Slovenia and Hungary. We present two siblings with HMSNL, female and male, aged 30 and 26, respectively in a Serbian non-consanguineous family of Gypsy ethnic origin. They had normal developmental milestones. Both had symptoms of lower limb muscle weakness and walking difficulties with frequent falls, which began at the age of seven. At the age of 12, they developed hearing problems and at the age of 15 hand muscle weakness. Neurological examination revealed sensorineural hearing loss, dysarthria, severe distal and mild proximal muscle wasting and weakness, areflexia and impairment of all sensory modalities of distal distribution. Electrophysiological study revealed denervation with severe and early axonal loss. Sensorineural hearing loss was confirmed on electrocochleography and brainstem evoked potentials. Molecular genetic testing confirmed homozygote C564t (R148X) mutation in NDRG1 gene.

Genetics Home Reference: hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis

MedlinePlus

... which scar tissue forms in the lungs . Pulmonary fibrosis eventually causes difficulty breathing and can be life-threatening within ... Keavney B, Bézieau S, Mayosi BM. Mutations in FAM111B cause hereditary fibrosing ... myopathy, and pulmonary fibrosis. Am J Hum Genet. 2013 Dec 5;93( ...

Further Validation of the SIGMAR1 c.151+1G>T Mutation as Cause of Distal Hereditary Motor Neuropathy

PubMed Central

Lee, Jessica J. Y.; Drögemoller, Britt; Shyr, Casper; Tarailo-Graovac, Maja; Eydoux, Patrice; Ross, Colin J.; Wasserman, Wyeth W.; Björnson, Bruce; Wu, John K.

2016-01-01

Distal hereditary motor neuropathies represent a group of rare genetic disorders characterized by progressive distal motor weakness without sensory loss. Their genetic heterogeneity is high and thus eligible for diagnostic whole exome sequencing. The authors report successful application of whole exome sequencing in diagnosing a second consanguineous family with distal hereditary motor neuropathy due to a homozygous c.151+1G>T variant in SIGMAR1. This variant was recently proposed as causal for the same condition in a consanguineous Chinese family. Compared to this family, the Afghan ethnic origin of our patient is distinct, yet the features are identical, validating the SIGMAR1 deficiency phenotype: progressive muscle wasting/weakness in lower and upper limbs without sensory loss. Rapid disease progression during adolescent growth is similar and may be due to SIGMAR1’s role in regulating axon elongation and tau phosphorylation. Finally, the authors conclude that SIGMAR1 deficiency should be added to the differential diagnosis of distal hereditary motor neuropathies. PMID:28503617

Early Detection Research Network Registry for Hereditary Cancer — EDRN Public Portal

Cancer.gov

The EDRN High Risk Registry (HRR)recruits individuals that carry germline mutations for hereditary cancer syndromes, who are willing to participate in biomarker studies. Recruitment is pursued through distribution of recruitment packets. The recruitment packet includes a cover letter, EDRN HRR brochure, consent form, HIPAA authorization, and baseline questionnaire. Upon completion of enrollment materials, each Registry member is provided a Certificate of Confidentiality, which has been issued by the NCI for the EDRN HRR. The EDRN HRR has a website (http://medicine2.creighton.edu/EDRN-Registry). It provides eligibilty, enrollment educational information for individuals who are at high risk of developing hereditary cancer. The EDRN HRR newsletter is published twice each year. These are distributed to EDRN HRR members on an annual basis. Follow-up questionnaires are sent to Registry participants each year. An EDRN HRR database has been established to store demographic data, personal and family history of cancer diagnoses, personal smoking history, female specific history, as well as cancer prevention, detection and treatment information collected on questionnaires. All EDRN HRR questionnaires and database use the EDRN CDEs.

Hemochromatosis Enhances Tumor Progression via Upregulation of Intracellular Iron in Head and Neck Cancer

PubMed Central

Lenarduzzi, Michelle; Hui, Angela B. Y.; Yue, Shijun; Ito, Emma; Shi, Wei; Williams, Justin; Bruce, Jeff; Sakemura-Nakatsugawa, Noriko; Xu, Wei; Schimmer, Aaron; Liu, Fei-Fei

2013-01-01

Introduction Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), outcomes have not significantly improved; highlighting the importance of identifying novel therapeutic approaches to target this disease. To address this challenge, we proceeded to evaluate the role of iron in HNSCC. Experimental Design Expression levels of iron-related genes were evaluated in HNSCC cell lines using quantitative RT-PCR. Cellular phenotypic effects were assessed using viability (MTS), clonogenic survival, BrdU, and tumor formation assays. The prognostic significance of iron-related proteins was determined using immunohistochemistry. Results In a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. In vitro knockdown of HFE in HNSCC cell lines significantly decreased hepcidin (HAMP) expression and intracellular iron level. This in turn, resulted in a significant decrease in HNSCC cell viability, clonogenicity, DNA synthesis, and Wnt signalling. These cellular changes were reversed by re-introducing iron back into HNSCC cells after HFE knockdown, indicating that iron was mediating this phenotype. Concordantly, treating HNSCC cells with an iron chelator, ciclopirox olamine (CPX), significantly reduced viability and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression. Conclusions Our data identify HFE as potentially novel prognostic marker in HNSCC that promotes tumour progression via HAMP and elevated intracellular iron levels, leading to increased cellular proliferation and tumour formation. Hence, these findings suggest that iron chelators might have a therapeutic role in HNSCC management. PMID:23991213

[Hereditary sensory and autonomic neuropathy type II A: early neurological and skeletal findings].

PubMed

Esmer, C; Díaz Zambrano, S; Santos Díaz, M A; González Huerta, L M; Cuevas Covarrubias, S A; Bravo Oro, A

2014-04-01

The hereditary sensory and autonomic neuropathies are genetic disorders characterized by the loss of sensation including pain, tactile and temperature. Its clinical and molecular features vary widely; the symptoms may begin from birth or be noticed in the first or second decade, with different types of complications of trauma to the extremities such as ulcers, mutilations and acral amputations. They are classified into six groups from I to VI, determined by the abnormality in eleven genes leading to phenotypic variations in the age of onset and the presence or absence of dysautonomia signs. With the exception of type I, all are autosomal recessive. The type II of these neuropathies is characterized by insensitivity to pain, heat and proprioception. We describe three members of a Mexican family with WNK1 gene mutation that caused hereditary neuropathy IIA. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Hereditary Syndromes Manifesting as Endometrial Carcinoma: How Can Pathological Features Aid Risk Assessment?

PubMed Central

Wong, Adele; Ngeow, Joanne

2015-01-01

Endometrial carcinoma is the most common gynecological tumor worldwide. It can be the presenting malignancy, acting as the harbinger, of an undiagnosed hereditary syndrome. Up to 50% of females with Lynch syndrome present in this manner. Differentiation between Lynch, Muir-Torre, and Cowden syndromes can at times be challenging due to the overlapping features. Our review emphasizes on the strengths, pitfalls, and limitations of microscopic features as well as immunohistochemical and polymerase chain reaction- (PCR-) based tests used by laboratories to screen for DNA mismatch repair (MMR) and PTEN gene mutations in patients to enable a more targeted and cost effective approach in the use of confirmatory gene mutational analysis tests. This is crucial towards initiating timely and appropriate surveillance measures for the patient and affected family members. We also review the evidence postulating on the possible inclusion of uterine serous carcinoma as part of the spectrum of malignancies seen in hereditary breast and ovarian carcinoma syndrome, driven by mutations in BRCA1/2. PMID:26161390

Inflammation and neuropathic attacks in hereditary brachial plexus neuropathy

PubMed Central

Klein, C; Dyck, P; Friedenberg, S; Burns, T; Windebank, A; Dyck, P

2002-01-01

Objective: To study the role of mechanical, infectious, and inflammatory factors inducing neuropathic attacks in hereditary brachial plexus neuropathy (HBPN), an autosomal dominant disorder characterised by attacks of pain and weakness, atrophy, and sensory alterations of the shoulder girdle and upper limb muscles. Methods: Four patients from separate kindreds with HBPN were evaluated. Upper extremity nerve biopsies were obtained during attacks from a person of each kindred. In situ hybridisation for common viruses in nerve tissue and genetic testing for a hereditary tendency to pressure palsies (HNPP; tomaculous neuropathy) were undertaken. Two patients treated with intravenous methyl prednisolone had serial clinical and electrophysiological examinations. One patient was followed prospectively through pregnancy and during the development of a stereotypic attack after elective caesarean delivery. Results: Upper extremity nerve biopsies in two patients showed prominent perivascular inflammatory infiltrates with vessel wall disruption. Nerve in situ hybridisation for viruses was negative. There were no tomaculous nerve changes. In two patients intravenous methyl prednisolone ameliorated symptoms (largely pain), but with tapering of steroid dose, signs and symptoms worsened. Elective caesarean delivery did not prevent a typical postpartum attack. Conclusions: Inflammation, probably immune, appears pathogenic for some if not all attacks of HBPN. Immune modulation may be useful in preventing or reducing the neuropathic attacks, although controlled trials are needed to establish efficacy, as correction of the mutant gene is still not possible. The genes involved in immune regulation may be candidates for causing HBPN disorders. PMID:12082044

Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies.

PubMed

Tey, S; Ahmad-Annuar, A; Drew, A P; Shahrizaila, N; Nicholson, G A; Kennerson, M L

2016-08-01

The cytoplasmic dynein-dynactin genes are attractive candidates for neurodegenerative disorders given their functional role in retrograde transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) gene has been implicated in various neurodegenerative disorders, and dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of disorders including motor neuron disease, Parkinson's disease, spinobulbar muscular atrophy and hereditary spastic paraplegia. However, the involvement of other dynactin genes with inherited peripheral neuropathies (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy and Charcot-Marie-Tooth disease is under reported. We screened eight genes; DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using whole-exome sequencing and high-resolution melt (HRM) analysis. Eight non-synonymous variants (including one novel variant) and three synonymous variants were identified. Four variants have been reported previously in other studies, however segregation analysis within family members excluded them from causing IPN in these families. No variants of disease significance were identified in this study suggesting the dynactin genes are unlikely to be a common cause of IPNs. However, with the ease of querying gene variants from exome data, these genes remain worthwhile candidates to assess unsolved IPN families for variants that may affect the function of the proteins. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinical germline diagnostic exome sequencing for hereditary cancer: Findings within novel candidate genes are prevalent.

PubMed

Powis, Zöe; Espenschied, Carin R; LaDuca, Holly; Hagman, Kelly D; Paudyal, Tripti; Li, Shuwei; Inaba, Hiroto; Mauer, Ann; Nathanson, Katherine L; Knost, James; Chao, Elizabeth C; Tang, Sha

2018-08-01

Clinical diagnostic exome sequencing (DES) has been effective in diagnosing individuals with suspected genetic conditions; nevertheless little has been described regarding its clinical utility in individuals with a personal and family history of cancer. This study aimed to assess diagnostic yield and clinical characteristics of pediatric and adult patients undergoing germline DES for hereditary cancer. We retrospectively reviewed 2171 patients referred for DES; cases with a personal and/or family history of cancer were further studied. Of 39 cancer patients, relevant alterations were found in eight individuals (21%), including one (3%) positive pathogenic alteration within a characterized gene, two (5%) uncertain findings in characterized genes, and five (13%) alterations in novel candidate genes. Two of the 5 pediatric patients, undergoing testing, (40%) had findings in novel candidate genes, with the remainder being negative. We include brief case studies to illustrate the variety of challenging issues related to these patients. Our observations demonstrate utility of family-based exome sequencing in patients for suspected hereditary cancer, including familial co-segregation analysis, and comprehensive medical review. DES may be particularly useful when traditional approaches do not result in a diagnosis or in families with unique phenotypes. This work also highlights the importance and complexity of analysis of uncharacterized genes in exome sequencing for hereditary cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

HEREDITARY PREMATURE SENESCENCE OF THE RABBIT

PubMed Central

Pearce, Louise; Brown, Wade H.

1960-01-01

The occurrence of hereditary premature senescence in a family of pure bred Belgian hares belonging to a rabbit-breeding colony organized for the investigation of constitutional problems, has been described. Representatives of 20 generations of the complex have been studied. The condition was a degeneration of variable degrees of severity and two principal forms were recognized, the acute and the chronic, the chronic being the more frequent. The chronic form has now been described in terms of the principal local or external manifestations; that is, degeneration of the coat and skin, lesions of the eyes and feet, and reproductive abnormalities, and of the general deterioration which in severe cases pursued a progressive course characterized by muscle wasting, fat reduction, emaciation, weakness, and death. The acute form will be described in the next paper (2). PMID:13733754

Hereditary stomatocytosis: association of low 2,3-diphosphoglycerate with increased cation pumping by the red cell.

PubMed

Wiley, J S; Cooper, R A; Adachi, K; Asakura, T

1979-01-01

The levels of glycolytic intermediates have been measured in red cells from patients with both overhydrated and dehydrated varieties of the hereditary stomatocytosis syndrome. Red cell 2,3-diphosphoglycerate was reduced by 33% below normal in all patients with either stomatocyte or target cell morphologies (i.e. over or under hydrated varieties respectively). The relative decrement in 2,3-diphosphoglycerate was even greater when abnormal cells were compared with control cells with similar reticulocytosis. Red cell ADP concentrations in stomatocytosis were significantly increased above normal but ATP concentrations were not significantly changed. Whole blood oxygen affinity in stomatocytosis was increased in proportion to the lowered content of diphosphoglycerate. Some new parameters of membrane transport in hereditary stomatocytosis have been measured. Platelet K+ and Na+ concentrations and platelet K+ permeability were normal in stomatocytosis. The number of 3H-uridine transport sites in stomatocytes were increased by 9-39% above normal and this increment was the same as the increment in red cell lipids (0-38%). Hereditary stomatocytes contain 2-10-fold more cation pumps than normal and the increased active cation pumping may explain the high ADP, the low 2,3-diphosphoglycerate concentration and the increased oxygen affinity in this syndrome.

Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome

PubMed Central

Menendez, Javier A.; Folguera-Blasco, Núria; Cuyàs, Elisabet; Fernández-Arroyo, Salvador; Joven, Jorge; Alarcón, Tomás

2016-01-01

The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a “field effect” predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger “accelerated geroncogenesis” in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes “permissive” with survival and expansion of genomically unstable pre-tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, α-ketoglutarate, NAD+, FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the “install phase” that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the “geroncogenic risk” of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited “one-hit” metabolic “field effect” might offer new strategies to therapeutically revisit the apparently irreversible genetic-hereditary fate of women with hereditary breast-ovarian cancer syndrome. PMID:26943589

Inherited focal, episodic neuropathies: hereditary neuropathy with liability to pressure palsies and hereditary neuralgic amyotrophy.

PubMed

Chance, Phillip F

2006-01-01

Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or "sausage-like" formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often

Serial casting for neuromuscular flatfoot and vertical talus in an adolescent with hereditary spastic paraplegia.

PubMed

Sweet, Laurene A; OʼNeill, Lindsey M; Dobbs, Matthew B

2014-01-01

The purpose of this report is to explore assessment and serial casting intervention for painful rigid flatfoot deformities with vertical talus in an adolescent girl with hereditary spastic paraplegia who was nonambulatory. The participant's right foot underwent 2 phases of casting with correction first toward hindfoot inversion and then dorsiflexion. Because of a vertical talus, her left foot required an intermediate casting toward plantar flexion, inversion, and forefoot adduction prior to casting toward dorsiflexion. The patient improved despite the underlying progressive neuromuscular disorder. Pain ameliorated and she returned to supported standing and transfers. Spasticity decreased bilaterally and the flexibility of her foot deformities improved to allow orthotic fabrication in subtalar neutral. Results were maintained at 12 and 16 months. Individualized multiphase serial casting requires further investigation with patients such as those with hereditary spastic paraplegia.

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

PubMed Central

Craggs, Lucinda JL; Yamamoto, Yumi; Deramecourt, Vincent; Kalaria, Raj N

2014-01-01

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology. PMID:25323665

Hereditary Angioedema: The Economics of Treatment of an Orphan Disease.

PubMed

Lumry, William Raymond

2018-01-01

This review will discuss the cost burden of hereditary angioedema on patients, healthcare systems, and society. The impact of availability of and access to novel and specific therapies on morbidity, mortality, and the overall burden of disease will be explored along with potential changes in treatment paradigms to improve effectiveness and reduce cost of treatment. The prevalence of orphan diseases, legislative incentives to encourage development of orphan disease therapies and the impact of orphan disease treatment on healthcare payment systems will be discussed.

Circular RNAs and hereditary bone diseases.

PubMed

Zhai, Naixiang; Lu, Yanqin; Wang, Yanzhou; Ren, Xiuzhi; Han, Jinxiang

2018-02-01

Circular RNA (circRNA) is a non-linear form of RNA derived from exonic, intronic, and exon-intron gene regions. circRNAs are characterized by covalent closed loops, highly stable nuclease resistance, and specific expression in species and developmental stages. CircRNA molecules have been identified as playing roles in the regulation of cell transcription, transcriptional expression after translation, interactions with microRNAs, and protein coding. A high stability and tissue- and disease-specific expression allow circRNAs to serve as potential biomarkers both for diseases and prognosis. CircRNAs function in bone remodeling by directly participating in bone-related signaling pathways and by forming the circRNA-miRNA-mRNA axis. Studies have seldom reported on the low incidence of circRNAs in genetic bone disorders. The current study reviews the characteristics of circRNAs and recent research on their role in rare hereditary bone diseases.

'Gardos Channelopathy': a variant of hereditary Stomatocytosis with complex molecular regulation.

PubMed

Fermo, Elisa; Bogdanova, Anna; Petkova-Kirova, Polina; Zaninoni, Anna; Marcello, Anna Paola; Makhro, Asya; Hänggi, Pascal; Hertz, Laura; Danielczok, Jens; Vercellati, Cristina; Mirra, Nadia; Zanella, Alberto; Cortelezzi, Agostino; Barcellini, Wilma; Kaestner, Lars; Bianchi, Paola

2017-05-11

The Gardos channel is a Ca 2+ sensitive, K + selective channel present in several tissues including RBCs, where it is involved in cell volume regulation. Recently, mutations at two different aminoacid residues in KCNN4 have been reported in patients with hereditary xerocytosis. We identified by whole exome sequencing a new family with two members affected by chronic hemolytic anemia carrying mutation R352H in the KCNN4 gene. No additional mutations in genes encoding for RBCs cytoskeletal, membrane or channel proteins were detected. We performed functional studies on patients' RBCs to evaluate the effects of R352H mutation on the cellular properties and eventually on the clinical phenotype. Gardos channel hyperactivation was demonstrated in circulating erythrocytes and erythroblasts differentiated ex-vivo from peripheral CD34+ cells. Pathological alterations in the function of multiple ion transport systems were observed, suggesting the presence of compensatory effects ultimately preventing cellular dehydration in patient's RBCs; moreover, flow cytometry and confocal fluorescence live-cell imaging showed Ca 2+ overload in the RBCs of both patients and hypersensitivity of Ca 2+ uptake by RBCs to swelling. Altogether these findings suggest that the 'Gardos channelopathy' is a complex pathology, to some extent different from the common hereditary xerocytosis.

Fractional hereditariness of lipid membranes: Instabilities and linearized evolution.

PubMed

Deseri, L; Pollaci, P; Zingales, M; Dayal, K

2016-05-01

In this work lipid ordering phase changes arising in planar membrane bilayers is investigated both accounting for elasticity alone and for effective viscoelastic response of such assemblies. The mechanical response of such membranes is studied by minimizing the Gibbs free energy which penalizes perturbations of the changes of areal stretch and their gradients only (Deseri and Zurlo, 2013). As material instabilities arise whenever areal stretches characterizing homogeneous configurations lie inside the spinoidal zone of the free energy density, bifurcations from such configurations are shown to occur as oscillatory perturbations of the in-plane displacement. Experimental observations (Espinosa et al., 2011) show a power-law in-plane viscous behavior of lipid structures allowing for an effective viscoelastic behavior of lipid membranes, which falls in the framework of Fractional Hereditariness. A suitable generalization of the variational principle invoked for the elasticity is applied in this case, and the corresponding Euler-Lagrange equation is found together with a set of boundary and initial conditions. Separation of variables allows for showing how Fractional Hereditariness owes bifurcated modes with a larger number of spatial oscillations than the corresponding elastic analog. Indeed, the available range of areal stresses for material instabilities is found to increase with respect to the purely elastic case. Nevertheless, the time evolution of the perturbations solving the Euler-Lagrange equation above exhibits time-decay and the large number of spatial oscillation slowly relaxes, thereby keeping the features of a long-tail type time-response. Copyright © 2015 Elsevier Ltd. All rights reserved.

[A Case of Hereditary Medullary Thyroid Cancer (MEN2A/FMTC) Diagnosed at the Time of Recurrence].

PubMed

Enomoto, Keisuke; Shimizu, Kotaro; Hirose, Masayuki; Miyabe, Haruka; Morizane, Natsue; Takenaka, Yukinori; Shimazu, Kohki; Fushimi, Hiroaki; Uno, Atsuhiko

2015-03-01

We report a 42-year-old man with hereditary medullary thyroid cancer (multiple endocrine neoplasia, MEN2A/familial medullary thyroid carcinoma, FMTC), which was diagnosed at the time of tumor recurrence. He had a past history of a left thyroidectomy with neck dissection 7 years previously. A RET gene analysis revealed a point mutation (codon 618), and we diagnosed him as having hereditary medullary thyroid cancer. We resected the recurrent tumor in the right thyroid lobe together with performing a right lateral and central neck dissection. A RET gene analysis should be performed for patients with medullary thyroid cancer. When a RET gene mutation is present, a total thyroidectomy must be performed for the medullary thyroid cancer.

[Review of the recent literature on hereditary neuropathies].

PubMed

Birouk, N

2014-12-01

The recent literature included interesting reports on the pathogenic mechanisms of hereditary neuropathies. The axonal traffic and its abnormalities in some forms of Charcot-Marie-Tooth (CMT) disease were particularly reviewed by Bucci et al. Many genes related to CMT disease code for proteins that are involved directly or not in intracellular traffic. KIF1B controls vesicle motility on microtubules. MTMR2, MTMR13 and FIG4 regulate the metabolism of phosphoinositide at the level of endosomes. The HSPs are involved in the proteasomal degradation. GDAP1 and MFN2 regulate the mitochondrial fission and fusion respectively and the mitochondial transport within the axon. Pareyson et al. reported a review on peripheral neuropathies in mitochondrial disorders. They used the term of "mitochondrial CMT" for the forms of CMT with abnormal mitochondrial dynamic or structure. Among the new entities, we can draw the attention to a proximal form of hereditary motor and sensory neuropathy with autosomal dominant inheritance, which is characterized by motor deficit with cramps and fasciculations predominating in proximal muscles. Distal sensory deficit can be present. The gene TFG on chromosome 3 has been recently identified to be responsible for this form. Another rare form of axonal autosomal recessive neuropathy due to HNT1 gene mutation is characterized by the presence of hands myotonia that appears later than neuropathy but constitute an interesting clinical hallmark to orientate the diagnosis of this form. In terms of differential diagnosis, CMT4J due to FIG4 mutation can present with a rapidly progressive and asymmetric weakness that resembles CIDP. Bouhy et al. made an interesting review on the therapeutic trials, animal models and the future therapeutic strategies to be developed in CMT disease. Copyright © 2014. Published by Elsevier Masson SAS.

Recent results of nonlinear estimators applied to hereditary systems.

NASA Technical Reports Server (NTRS)

Schiess, J. R.; Roland, V. R.; Wells, W. R.

1972-01-01

An application of the extended Kalman filter to delayed systems to estimate the state and time delay is presented. Two nonlinear estimators are discussed and the results compared with those of the Kalman filter. For all the filters considered, the hereditary system was treated with the delay in the pure form and by using Pade approximations of the delay. A summary of the convergence properties of the filters studied is given. The results indicate that the linear filter applied to the delayed system performs inadequately while the nonlinear filters provide reasonable estimates of both the state and the parameters.

Longer survival associated with HLA-A*03, B*14 among 212 hemochromatosis probands with HFE C282Y homozygosity and HLA-A and -B typing and haplotyping.

PubMed

Barton, James C; Barton, J Clayborn; Acton, Ronald T

2010-11-01

Human leukocyte antigen (HLA) haplotypes may influence iron phenotypes in patients with HFE hemochromatosis and could affect survival. We tabulated general characteristics of HLA-A and -B types and haplotypes of HFE C282Y/C282Y probands diagnosed in medical care and analyzed these data to identify HLA survival modifiers. There were 212 probands (130 men, 82 women). Mean follow-up was 12.0 ± 6.4 yr (0.1-41.2 yr; 34 deaths). HLA-A*03 was more prevalent in men (76.9% vs. 61.0% women; P = 0.0129); 35.4% of men and 29.3% of women had A*03, B*07; and 7.7% of men and 8.5% of women had A*03, B*14. Twenty-three probands had cirrhosis; none had A*03, B*14. Positivity for A*03 or A*03, B*07 was not a significant predictor or modifier of survival. In multiple regression analyses, A*03, B*14 predicted longer survival (P = 0.0004). Kaplan-Meier analysis confirmed longer survival in probands with A*03, B*14 (P = 0.0199, log-rank test). After excluding the 23 non-A*03, B*14 probands with cirrhosis, survival of probands with A*03, B*14 was still greater than that of probands without A*03, B*14 (P = 0.0254; log-rank test). Twenty-four years after diagnosis, cumulative survival of probands with and without A*03, B*14 was 100% and 58%, respectively. The percentage of deaths due to iron overload was lower in probands with A*03, B*14 (0% vs. 21.9%; P = 0.0392). In hemochromatosis probands with HFE C282Y/C282Y, survival was longer in those with HLA-A*03, B*14. Earlier age at diagnosis and less severe iron overload in probands with A*03, B*14 could explain this difference. © 2010 John Wiley & Sons A/S.

Hereditary neuropathy with liability to pressure palsy: a brief review with a case report.

PubMed

Rana, Abdul Qayyum; Masroor, Mohamed Sufian

2012-03-01

Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) is an autosomal dominant disorder and is usually characterized by episodes of recurrent and painless focal motor and sensory peripheral mononeuropathy. This condition is usually localized around areas of entrapment (predominantly the wrists, knees, elbows, and shoulders). The genetic locus of the disease is chromosome 17p12. A deletion of the PMP22 gene results in the lack of peripheral myelin protein, a key component to the myelin sheet of peripheral nerves. However, this disease may be completely asymptomatic until an event, such as a minor trauma, triggers these episodes, as seen in our presented case report. The diagnosis of HNPP can be somewhat challenging, as other diseases, such as Charcot-Marie-Tooth disease type 1A (CMT) and Hereditary Neuralgic Amyotrophy (HNA) must be included in the differential diagnosis due to their overlapping clinical features. There are currently no treatments to cure the disease, but therapies seek to alleviate the symptoms and recurring episodes.

The contribution of self-esteem and self-concept in psychological distress in women at risk of hereditary breast cancer.

PubMed

den Heijer, Mariska; Seynaeve, Caroline; Vanheusden, Kathleen; Duivenvoorden, Hugo J; Vos, Joël; Bartels, Carina C M; Menke-Pluymers, Marian B E; Tibben, Aad

2011-11-01

Clarification of the role of several aspects of self-concept regarding psychological distress in women at risk of hereditary breast cancer will help to target counselling and psychosocial interventions more appropriately. In this study, we aimed (1) to examine the role of general self-esteem and specific aspects of self-concept (i.e. stigma, vulnerability, and mastery) in psychological distress in women at risk of hereditary breast cancer and (2) to compare the relative importance of these self-concept aspects in psychological distress in women with low versus high self-esteem. General and breast-cancer-specific distress, self-esteem, self-concept, and demographics were assessed in 246 women being at risk of hereditary breast cancer, who opted either for regular breast surveillance or prophylactic surgery. In the total study group, self-esteem was negatively associated with general distress. Furthermore, feeling stigmatized was strongly associated with more breast-cancer-specific distress, and to a lesser degree with general distress. In women with low-self esteem, feelings of stigmatization were strongly associated with higher levels of both breast-cancer-specific and general distress, while a sense of mastery was associated with less general distress. For women with high self-esteem, feelings of both stigmatization and vulnerability were associated with more breast-cancer-specific distress, whereas there were no significant associations with general distress. Psychosocial interventions or support groups for women at risk of hereditary breast cancer should focus on self-esteem and feelings of stigmatization and isolation, and consequently tailor the interventions on specific items for respective women. Copyright © 2010 John Wiley & Sons, Ltd.

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure.

PubMed

Beetz, Christian; Johnson, Adam; Schuh, Amber L; Thakur, Seema; Varga, Rita-Eva; Fothergill, Thomas; Hertel, Nicole; Bomba-Warczak, Ewa; Thiele, Holger; Nürnberg, Gudrun; Altmüller, Janine; Saxena, Renu; Chapman, Edwin R; Dent, Erik W; Nürnberg, Peter; Audhya, Anjon

2013-03-26

Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.

Hereditary angioedema with C1 inhibitor deficiency: delay in diagnosis in Europe

PubMed Central

2013-01-01

Background Hereditary angioedema (HAE) is a rare, debilitating, and potentially life-threatening disease characterized by recurrent edema attacks. Important advances in HAE treatment have been made, including the development of new therapies for treating or preventing attacks. Nevertheless, the disease is still frequently misdiagnosed and inappropriately treated, potentially exposing patients with laryngeal attacks to the risk of asphyxiation. Methods The Icatibant Outcome Survey (IOS) is an international, observational study that documents the clinical outcome of HAE patients eligible for treatment with icatibant. Patient ages at first symptoms and at diagnosis were recorded at enrolment, and the delay between first symptoms and diagnosis was calculated. Results The median [range] diagnostic delay in HAE type I and II patients across eight countries was 8.5 years [0–62.0]. The median delay in diagnosis was longer for HAE type II versus type I (21 versus 8 years, respectively), although this did not quite reach statistical significance. Conclusions Although it can be difficult to differentiate HAE symptoms from those of more common angioedema sub-types (e.g. idiopathic or acquired angioedema), our results show that HAE type I and II patients have an unacceptable delay in diagnosis, even those with a family history of the disease. Raising physician awareness of this disabling and potentially fatal disease may lead to a more accurate diagnosis and timely treatment. PMID:23937903

Aplastic crisis in occult hereditary spherocytosis caused by human parvovirus (HPV B19).

PubMed

Rappaport, E S; Quick, G; Ransom, D; Helbert, B; Frankel, L S

1989-02-01

We have reported a case of aplastic crisis occurring in an 11-year-old black boy with occult hereditary spherocytosis. An etiologic diagnosis of human parvovirus (HPV) B19 infection was confirmed serologically. The Coulter Model S + IV proved useful for both diagnosis and treatment monitoring through serial histograms. The relationship of HPV infection and aplastic crisis is discussed.

Identification of a Comprehensive Spectrum of Genetic Factors for Hereditary Breast Cancer in a Chinese Population by Next-Generation Sequencing

PubMed Central

Yang, Xiaochen; Wu, Jiong; Lu, Jingsong; Liu, Guangyu; Di, Genhong; Chen, Canming; Hou, Yifeng; Sun, Menghong; Yang, Wentao; Xu, Xiaojing; Zhao, Ying; Hu, Xin; Li, Daqiang; Cao, Zhigang; Zhou, Xiaoyan; Huang, Xiaoyan; Liu, Zhebin; Chen, Huan; Gu, Yanzi; Chi, Yayun; Yan, Xia; Han, Qixia; Shen, Zhenzhou; Shao, Zhimin; Hu, Zhen

2015-01-01

The genetic etiology of hereditary breast cancer has not been fully elucidated. Although germline mutations of high-penetrance genes such as BRCA1/2 are implicated in development of hereditary breast cancers, at least half of all breast cancer families are not linked to these genes. To identify a comprehensive spectrum of genetic factors for hereditary breast cancer in a Chinese population, we performed an analysis of germline mutations in 2,165 coding exons of 152 genes associated with hereditary cancer using next-generation sequencing (NGS) in 99 breast cancer patients from families of cancer patients regardless of cancer types. Forty-two deleterious germline mutations were identified in 21 genes of 34 patients, including 18 (18.2%) BRCA1 or BRCA2 mutations, 3 (3%) TP53 mutations, 5 (5.1%) DNA mismatch repair gene mutations, 1 (1%) CDH1 mutation, 6 (6.1%) Fanconi anemia pathway gene mutations, and 9 (9.1%) mutations in other genes. Of seven patients who carried mutations in more than one gene, 4 were BRCA1/2 mutation carriers, and their average onset age was much younger than patients with only BRCA1/2 mutations. Almost all identified high-penetrance gene mutations in those families fulfill the typical phenotypes of hereditary cancer syndromes listed in the National Comprehensive Cancer Network (NCCN) guidelines, except two TP53 and three mismatch repair gene mutations. Furthermore, functional studies of MSH3 germline mutations confirmed the association between MSH3 mutation and tumorigenesis, and segregation analysis suggested antagonism between BRCA1 and MSH3. We also identified a lot of low-penetrance gene mutations. Although the clinical significance of those newly identified low-penetrance gene mutations has not been fully appreciated yet, these new findings do provide valuable epidemiological information for the future studies. Together, these findings highlight the importance of genetic testing based on NCCN guidelines and a multi-gene analysis using NGS

Autosomal recessive type II hereditary motor and sensory neuropathy with acrodystrophy.

PubMed

Thomas, P K; Claus, D; King, R H

1999-02-01

A family is described with presumed autosomal recessive inheritance in which three siblings developed a progressive neuropathy that combined limb weakness and severe distal sensory loss leading to prominent mutilating changes. Electrophysiological and nerve biopsy findings indicated an axonopathy. The disorder is therefore classifiable as type II hereditary motor and sensory neuropathy (HMSN II). The clinical features differ from those reported in previously described cases of autosomal recessive HMSN II. This disorder may therefore represent a new variant.

Effect of epithalon on age-specific changes in the retina in rats with hereditary pigmentary dystrophy.

PubMed

Khavinson, V Kh; Razumovskii, M I; Trofimova, S V; Grigor'yan, R A; Chaban, T V; Oleinik, T L; Razumovskaya, A M

2002-01-01

The effect of peptide bioregulator Epithalon on the course of hereditary pigmentary retinal degeneration was studied in Campbell rats. Administration of epithalon starting from birth protected morphological structure, increased its bioelectrical activity, and improved its function.

UOK 268 Cell Line for Hereditary Leiomyomatosis and Renal Cell Carcinoma | NCI Technology Transfer Center | TTC

Cancer.gov

The National Cancer Institute’s Urologic Oncology Branch seeks parties to co-develop the UOK 262 immortalized cell line as research tool to study aggressive hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated recurring kidney cancer.

Hereditary sensory and autonomic neuropathy type IV and orthopaedic complications.

PubMed

Kim, W; Guinot, A; Marleix, S; Chapuis, M; Fraisse, B; Violas, P

2013-11-01

Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is a very rare autosomal recessive disorder characterized by recurrent episodes of unexplained fever, extensive anhidrosis, total insensitivity to pain, hypotonia, and mental retardation. The most frequent complications of this disease are corneal scarring, multiple fractures, joint deformities, osteomyelitis, and disabling self-mutilations. We reported the case of a 12-year-old boy. The goal was to discuss our decision-making and compare this case with cases described in the literature. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Quantification of Liver Iron with MRI: State of the Art and Remaining Challenges

PubMed Central

Hernando, Diego; Levin, Yakir S; Sirlin, Claude B; Reeder, Scott B

2015-01-01

Liver iron overload is the histological hallmark of hereditary hemochromatosis and transfusional hemosiderosis, and can also occur in chronic hepatopathies. Iron overload can result in liver damage, with the eventual development of cirrhosis, liver failure and hepatocellular carcinoma. Assessment of liver iron levels is necessary for detection and quantitative staging of iron overload, and monitoring of iron-reducing treatments. This article discusses the need for non-invasive assessment of liver iron, and reviews qualitative and quantitative methods with a particular emphasis on MRI. Specific MRI methods for liver iron quantification include signal intensity ratio as well as R2 and R2* relaxometry techniques. Methods that are in clinical use, as well as their limitations, are described. Remaining challenges, unsolved problems, and emerging techniques to provide improved characterization of liver iron deposition are discussed. PMID:24585403

Developing an item bank to measure the coping strategies of people with hereditary retinal diseases.

PubMed

Prem Senthil, Mallika; Khadka, Jyoti; De Roach, John; Lamey, Tina; McLaren, Terri; Campbell, Isabella; Fenwick, Eva K; Lamoureux, Ecosse L; Pesudovs, Konrad

2018-05-05

Our understanding of the coping strategies used by people with visual impairment to manage stress related to visual loss is limited. This study aims to develop a sophisticated coping instrument in the form of an item bank implemented via Computerised adaptive testing (CAT) for hereditary retinal diseases. Items on coping were extracted from qualitative interviews with patients which were supplemented by items from a literature review. A systematic multi-stage process of item refinement was carried out followed by expert panel discussion and cognitive interviews. The final coping item bank had 30 items. Rasch analysis was used to assess the psychometric properties. A CAT simulation was carried out to estimate an average number of items required to gain precise measurement of hereditary retinal disease-related coping. One hundred eighty-nine participants answered the coping item bank (median age = 58 years). The coping scale demonstrated good precision and targeting. The standardised residual loadings for items revealed six items grouped together. Removal of the six items reduced the precision of the main coping scale and worsened the variance explained by the measure. Therefore, the six items were retained within the main scale. Our CAT simulation indicated that, on average, less than 10 items are required to gain a precise measurement of coping. This is the first study to develop a psychometrically robust coping instrument for hereditary retinal diseases. CAT simulation indicated that on an average, only four and nine items were required to gain measurement at moderate and high precision, respectively.

NCAM is hyposialylated in hereditary inclusion body myopathy due to GNE mutations.

PubMed

Ricci, E; Broccolini, A; Gidaro, T; Morosetti, R; Gliubizzi, C; Frusciante, R; Di Lella, G M; Tonali, P A; Mirabella, M

2006-03-14

The authors found that the neural cell adhesion molecule (NCAM) is hyposialylated in hereditary inclusion body myopathy (HIBM) muscle, as suggested by its decreased molecular weight by Western blot. This abnormality represented the only pathologic feature differentiating HIBM due to GNE mutations from other myopathies with similar clinical and pathologic characteristics. If further confirmed in larger series of patients, this may be a useful diagnostic marker of GNE-related HIBM.

Quantitative and Functional Analyses of Spastin in the Nervous System: Implications for Hereditary Spastic Paraplegia

DTIC Science & Technology

2008-02-27

equivalent levels of expression of the spastin constructs, as assessed by fluorescence intensity of the Sp/AAA antibody staining. Microtu- bule levels...Errico A, Ballabio A, Rugarli EI (2002) Spastin, the protein mutated in au- tosomal dominant hereditary spastic paraplegia, is involved in microtu- bule

[Double mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostoses].

PubMed

Cammarata-Scalisi, Francisco; Cozar, Mónica; Grinberg, Daniel; Balcells, Susana; Asteggiano, Carla G; Martínez-Domenech, Gustavo; Bracho, Ana; Sánchez, Yanira; Stock, Frances; Delgado-Luengo, Wilmer; Zara-Chirinos, Carmen; Chacín, José Antonio

2015-04-01

Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage-capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the disease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18,000 to 1/50,000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses.

Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice

PubMed Central

Alsulimani, Helal Hussain; Ye, Qi

2015-01-01

Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe-/-) and their control wild-type (Hfe+/+) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe+/+ mice, but not in Hfe-/- mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe+/+ compared with water-drinking Hfe+/+ mice. However, Mn-exposed Hfe-/- mice spent more time to find the target hole than Mn-drinking Hfe+/+ mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and other iron overload

Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice.

PubMed

Alsulimani, Helal Hussain; Ye, Qi; Kim, Jonghan

2015-12-01

Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe (-/-)) and their control wild-type (Hfe (+/+)) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe (+/+) mice, but not in Hfe (-/-) mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe (+/+) compared with water-drinking Hfe (+/+) mice. However, Mn-exposed Hfe (-/-) mice spent more time to find the target hole than Mn-drinking Hfe (+/+) mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and

Integrated Computational Analysis of Genes Associated with Human Hereditary Insensitivity to Pain. A Drug Repurposing Perspective

PubMed Central

Lötsch, Jörn; Lippmann, Catharina; Kringel, Dario; Ultsch, Alfred

2017-01-01

Genes causally involved in human insensitivity to pain provide a unique molecular source of studying the pathophysiology of pain and the development of novel analgesic drugs. The increasing availability of “big data” enables novel research approaches to chronic pain while also requiring novel techniques for data mining and knowledge discovery. We used machine learning to combine the knowledge about n = 20 genes causally involved in human hereditary insensitivity to pain with the knowledge about the functions of thousands of genes. An integrated computational analysis proposed that among the functions of this set of genes, the processes related to nervous system development and to ceramide and sphingosine signaling pathways are particularly important. This is in line with earlier suggestions to use these pathways as therapeutic target in pain. Following identification of the biological processes characterizing hereditary insensitivity to pain, the biological processes were used for a similarity analysis with the functions of n = 4,834 database-queried drugs. Using emergent self-organizing maps, a cluster of n = 22 drugs was identified sharing important functional features with hereditary insensitivity to pain. Several members of this cluster had been implicated in pain in preclinical experiments. Thus, the present concept of machine-learned knowledge discovery for pain research provides biologically plausible results and seems to be suitable for drug discovery by identifying a narrow choice of repurposing candidates, demonstrating that contemporary machine-learned methods offer innovative approaches to knowledge discovery from available evidence. PMID:28848388

Hereditary spastic paraplegias: membrane traffic and the motor pathway

PubMed Central

Blackstone, Craig; O’Kane, Cahir J.; Reid, Evan

2017-01-01

Voluntary movement is a fundamental way in which animals respond to, and interact with, their environment. In mammals, the main CNS pathway controlling voluntary movement is the corticospinal tract, which encompasses connections between the cerebral motor cortex and the spinal cord. Hereditary spastic paraplegias (HSPs) are a group of genetic disorders that lead to a length-dependent, distal axonopathy of fibres of the corticospinal tract, causing lower limb spasticity and weakness. Recent work aimed at elucidating the molecular cell biology underlying the HSPs has revealed the importance of basic cellular processes — especially membrane trafficking and organelle morphogenesis and distribution — in axonal maintenance and degeneration. PMID:21139634

Hereditary spastic paraplegias: membrane traffic and the motor pathway.

PubMed

Blackstone, Craig; O'Kane, Cahir J; Reid, Evan

2011-01-01

Voluntary movement is a fundamental way in which animals respond to, and interact with, their environment. In mammals, the main CNS pathway controlling voluntary movement is the corticospinal tract, which encompasses connections between the cerebral motor cortex and the spinal cord. Hereditary spastic paraplegias (HSPs) are a group of genetic disorders that lead to a length-dependent, distal axonopathy of fibres of the corticospinal tract, causing lower limb spasticity and weakness. Recent work aimed at elucidating the molecular cell biology underlying the HSPs has revealed the importance of basic cellular processes — especially membrane trafficking and organelle morphogenesis and distribution— in axonal maintenance and degeneration.

[Distal hereditary motor neuropathy].

PubMed

Devic, P; Petiot, P

2011-11-01

Distal hereditary motor neuropathy (dHMN), also known as spinal muscular atrophy, represents a group of clinically and genetically heterogeneous diseases caused by degenerations of spinal motor neurons and leading to distal muscle weakness and wasting. Nerve conduction studies reveal a pure motor axonopathy and needle examination shows chronic denervation. dHMN were initially subdivided into seven subtypes according to mode of inheritance, age at onset, and clinical evolution. Recent studies have shown that these subtypes are still heterogeneous at the molecular genetic level and novel clinical and genetic entities have been characterized. To date, mutations in 11 different genes have been identified for autosomal-dominant, autosomal-recessive, and X-linked recessive dHMN. Most of the genes encode protein involved in housekeeping functions, endosomal trafficking, axonal transport, translation synthesis, RNA processing, oxidative stress response and apoptosis. The pathophysiological mechanisms underlying dHMN seem to be related to the "length-dependent" death of motor neurons of the anterior horn of the spinal cord, likely because their large axons have higher metabolic requirements for maintenance. dHMN remain heterogeneous at the clinical and molecular genetic level. The molecular pathomechanisms explaining why mutations in these ubiquitously expressed housekeeping genes result in the selective involvement of spinal motor neurons remain to be unravelled. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

[Hereditary eye dieseas in the Entlebucher Mountaindog in Switzerland: a retrospective study from 1999 to 2009].

PubMed

Kuster, N; Hässig, M; Spiess, B

2011-06-01

The aim of this study was to analyze the prevalence and the incidence of hereditary cataract and progressive retinal atrophy (PRA) in the Entlebucher Mountaindog (EMD) and to evaluate possible changes over time. In addition, the influence of selective breeding programs and DNA-testing for PRA was also investigated. Data of eye certifications for hereditary eye diseases was used. Between 1999 and 2009 a total of 798 ocular examinations were carried out in 285 EMD. 20.4 % had cataracts and 69 % of these were of the posterior polar type. PRA was diagnosed in 6.3 % of the dogs. Cataracts were diagnosed at 5.24 ± 2.71 years (mean ± standard error), while PRA was diagnosed at 4.93 ± 1.32 years of age. The incidence of PRA and cataract showed a decreasing trend (p-value > 0.2) without being significant.

Bilateral vision loss due to Leber's hereditary optic neuropathy after long-term alcohol, nicotine and drug abuse.

PubMed

Maass, Johanna; Matthé, Egbert

2018-04-01

Leber's hereditary optic neuropathy is relatively rare, and no clinical pathognomonic signs exist. We present a rare case of bilateral vision loss of a patient with multiple drug abuse in the history. A 31-year-old man presented with a history of progressive, decreased vision in both eyes for 6 month. On examination, his visual acuity was hand motion in both eyes. Funduscopy demonstrated a temporal pallor of the optic disc. Goldmann visual field perimetry showed a crescent visual field in the right eye and a circular decrease to less than 50 ° in the left eye. Electroretinogram showed a scotopic b-wave amplitude reduction. Optical coherence tomographies, Heidelberg Retina tomography, visual evoked potentials, and magnetic resonance imaging with contrast as well as blood tests were normal. The patient reported to consume various kinds of drugs as well as recreational drug use and alcohol consumption since he was 16 years old. We started a hemodilution therapy, believing the patient suffered from a bilateral, toxic optic neuropathy due to his lifestyle. Laboratory results later on showed Leber's hereditary optic neuropathy. Leber's hereditary optic neuropathy is a rare disease without a typical, pathognomonic presentation. Even though the patient gave good reasons for a toxic optic neuropathy, one should never stop to test for other diseases.

CHEK2 1100DELC germline mutation: a frequency study in hereditary breast and colon cancer Brazilian families.

PubMed

Abud, Jamile; Koehler-Santos, Patricia; Ashton-Prolla, Patricia; Prolla, João Carlos

2012-12-01

CHEK2 encodes a cell cycle checkpoint kinase that plays an important role in the DNA damage repair pathway, activated mainly by ATM (Ataxia Telangiectasia Mutated) in response to double-stranded DNA breaks. A germline mutation in CHEK2, 1100delC, has been described as a low penetrance allele in a significant number of families with breast and colorectal cancer in certain countries and is also associated with increased risk of contralateral breast cancer in women previously affected by the disease. About 5%-10% of all breast and colorectal cancers are associated with hereditary predisposition and its recognition is of great importance for genetic counseling and cancer risk management. Here, we have assessed the frequency of the CHEK2 1100delC mutation in the germline of 59 unrelated Brazilian individuals with clinical criteria for the hereditary breast and colorectal cancer syndrome. A long-range PCR strategy followed by gene sequencing was used. The 1100delC mutation was encountered in the germline of one (1.7%) individual in this high risk cohort. This indicates that the CHEK2 1100delC is not commonly encountered in Brazilian families with multiple diagnoses of breast and colorectal cancer. These results should be confirmed in a larger series of families and further testing should be undertaken to investigate the molecular mechanisms underlying the hereditary breast and colorectal cancer phenotype.

Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.

PubMed

Guelly, Christian; Zhu, Peng-Peng; Leonardis, Lea; Papić, Lea; Zidar, Janez; Schabhüttl, Maria; Strohmaier, Heimo; Weis, Joachim; Strom, Tim M; Baets, Jonathan; Willems, Jan; De Jonghe, Peter; Reilly, Mary M; Fröhlich, Eleonore; Hatz, Martina; Trajanoski, Slave; Pieber, Thomas R; Janecke, Andreas R; Blackstone, Craig; Auer-Grumbach, Michaela

2011-01-07

Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders.

Dog as a model in studies on human hereditary diseases and their gene therapy.

PubMed

Switonski, Marek

2014-03-01

During the last 15 years spectacular progress has been achieved in knowledge on the dog genome organization and the molecular background of hereditary diseases in this species. A majority of canine genetic diseases have their counterparts in humans and thus dogs are considered as a very important large animal model in human biomedicine. Among canine monogenic diseases with known causative gene mutations there are two large groups classified as retinal dystrophies and lysosomal storage diseases. Specific types of these diseases are usually diagnosed in a single or several breeds. A well known disorder, restricted to a single breed, is congenital stationary night blindness described in Briards. This disease is a counterpart of Leber amaurosis in children. On the other hand, one of the most common monogenic human diseases (Duchenne muscular dystrophy), has its canine counterparts in several breeds (e.g., the Golden retriever, Beagle and German short-haired pointer). For some of the canine diseases gene therapy strategy was successfully applied, e.g., for congenital stationary night blindness, rod-cone dystrophy and muccopolysaccharydoses type I, IIIB and VII. Since phenotypic variability between the breeds is exceptionally high, the dog is an interesting model to study the molecular background of congenital malformations (e.g., dwarfism and osteoporosis imperfecta). Also disorders of sexual development (DSD), especially testicular or ovotesticular DSD (78,XX; SRY-negative), which is widely distributed across dozens of breeds, are of particular interest. Studies on the genetic background of canine cancers, a major health problem in this species, are also quite advanced. On the other hand, genetic studies on canine counterparts of major human complex diseases (e.g., obesity, the metabolic syndrome and diabetes mellitus) are still in their infancy. Copyright © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish

[Evaluation of fundus autofluorescence in hereditary retinal diseases using Heidelberg Retina Angiograph2].

PubMed

Côco, Monique; Baba, Natalia Tamie; Sallum, Juliana Maria Ferraz

2007-01-01

To define characteristics of the fundus autofluorescence examination, verifying usefulness in the diagnosis and care of hereditary retinal diseases. 28 patients, adults, divided equally into four groups with diagnoses of Stargardt macular dystrophy, cone dystrophy, retinitis pigmentosa and healthy volunteers for the establishment of the normality pattern. An average of nine images with the filter for fluorescein angiography was obtained for the formation of the image autofluorescence using Heidelberg Retina Angiograph2. The images of each group of patients were analyzed to verify common characteristics. The fundus autofluorescence of healthy volunteers showed the foveal area darker than the surrounding retina. The images of Stargardt macular dystrophy, in general, presented an oval central lesion, with reduced autofluorescence. The main alterations of the autofluorescence in patients with cone dystrophy were reduced foveal autofluorescence with a parafoveal ring of increased autofluorescence. In general, the images of retinitis pigmentosa showed outlying pigments with reduced autofluorescence, and of the foveal area, in some cases disorganization or reduced autofluorescence. The study showed the existence of patterns of fundus autofluorescence in the hereditary retinal diseases that allow the diagnosis and better interpretation of the pathogenesis of these diseases.

Men in the women's world of hereditary breast and ovarian cancer--a systematic review.

PubMed

Strømsvik, Nina; Råheim, Målfrid; Oyen, Nina; Gjengedal, Eva

2009-01-01

Little is known about men seeking genetic counseling for hereditary breast and ovarian cancer (HBOC). We review the sparse literature on men attending such genetic consultations. Two main themes are identified: the women's influence on the genetic counseling process, and the psychological impact on men. The women in the HBOC families have an influence on the men's decision to request genetic testing, and they take the leading role in communicating genetic information. With respect to psychological impact, the men suffer from grief and fear of developing cancer, and they seem to use avoidance as a coping strategy. Carrier males experience feelings of guilt because they might have passed on a mutation to their children. Non-carriers experience test-related stress if their siblings tested positive. Mutation status may have an impact on reproductive issues. These findings are discussed in light of gender issues and literature concerning men's health behavior. Further studies are needed to provide optimal care for men seeking genetic counseling for hereditary breast and ovarian cancer.

Accessory mammary tissue associated with congenital and hereditary nephrourinary malformations.

PubMed

Urbani, C E; Betti, R

1996-05-01

The association between polythelia (supernumerary nipple) and kidney and urinary tract malformations (KUTM) is controversial. Some authors reported this association in newborns and infants. Case-control studies dealing with adult subjects are not found in the literature. The purpose of this study is to determine the frequency of the association between accessory mammary tissue (AMT) and congenital and hereditary nephrourinary defects in an adult population compared to a control group. The study was performed in 146 white patients (123 men, 23 women) with AMT out of 2645 subjects consecutively referred to us for physical examination. The following investigations were undertaken: ultrasonographic examination of the abdomen and the kidneys, ECG, echocardiogram, roentgenogram of the vertebral column, urinalysis, and other laboratory tests. A sex- and age-matched control group without any evidence of AMT or lateral displacement of the nipples underwent the same examinations. Kidney and urinary tract malformations were detected in 11 patients with AMT (nine men, two women) and in one control. These data indicate a significantly higher frequency of KUTM in the AMT-affected patients compared to controls (7.53% vs. 0.68%, P < 0.001). A broad spectrum of KUTM was discovered in association with AMT: adult dominant polycystic kidney disease, unilateral renal agenesis, cystic renal dysplasia, familial renal cysts, and congenital stenosis of the pyeloureteral joint. Accessory mammary tissue offers an important clue for congenital and hereditary anomalies of the kidneys and urinary collecting systems. Patients with AMT should, therefore, be extensively examined for the presence of occult nephrouropathies.

Efficacy, safety and pharmacokinetics of a new high-purity factor X concentrate in women and girls with hereditary factor X deficiency.

PubMed

Kulkarni, R; James, A H; Norton, M; Shapiro, A

2018-05-01

Essentials Plasma-derived factor X concentrate (pdFX) is used to treat hereditary factor X deficiency. pdFX pharmacokinetics, safety and efficacy were assessed in factor X-deficient women/girls. Treatment success rate was 98%; only 6 adverse events in 2 subjects were possibly pdFX related. On-demand pdFX 25 IU kg -1 was effective and safe in women/girls with factor X deficiency. Background A high-purity, plasma-derived factor X concentrate (pdFX) has been approved for the treatment of hereditary FX deficiency, an autosomal recessive disorder. Objective To perform post hoc assessments of pdFX pharmacokinetics, safety and efficacy in women and girls with hereditary FX deficiency. Patients/Methods Subjects aged ≥ 12 years with moderate/severe FX deficiency (plasma FX activity of < 5 IU dL -1 ) received on-demand or preventive pdFX (25 IU kg -1 ) for ≤ 2 years. Results Of 16 enrolled subjects, 10 women and girls (aged 14-58 years [median, 25.5 years]) received 267 pdFX infusions. Mean monthly infusions per subject were higher among women and girls (2.48) than among men and boys (1.62). In women and girls, 132 assessable bleeding episodes (61 heavy menstrual bleeds, 47 joint bleeds, 15 muscle bleeds, and nine other bleeds) were treated with pdFX, with a 98% treatment success rate versus 100% in men and boys. Mean pdFX incremental recovery was similar in the two groups (2.05 IU dL -1 versus 1.91 IU dL -1 per IU kg -1 ), as was the mean half-life (29.3 h versus 29.5 h). Of 142 adverse events in women and girls, headache was the most common (12 events in six subjects). Six events (two infusion-site erythema, two fatigue, one back pain, one infusion-site pain) in two subjects were considered to be possibly pdFX-related. Following the trial, pdFX was used to successfully maintain hemostasis in two subjects undergoing obstetric delivery. Conclusions pdFX was well tolerated and effective in women and girls with FX deficiency. Although women and girls had different bleeding

REEP1 Mutation Spectrum and Genotype/Phenotype Correlation in Hereditary Spastic Paraplegia Type 31

ERIC Educational Resources Information Center

Beetz, Christian; Schule, Rebecca; Deconinck, Tine; Tran-Viet, Khanh-Nhat; Zhu, Hui; Kremer, Berry P. H.; Frints, Suzanna G. M.; van Zelst-Stams, Wendy A. G.; Byrne, Paula; Otto, Susanne; Nygren, Anders O. H.; Baets, Jonathan; Smets, Katrien; Ceulemans, Berten; Dan, Bernard; Nagan, Narasimhan; Kassubek, Jan; Klimpe, Sven; Klopstock, Thomas; Stolze, Henning; Smeets, Hubert J. M.; Schrander-Stumpel, Constance T. R. M.; Hutchinson, Michael; van de Warrenburg, Bart P.; Braastad, Corey; Deufel, Thomas; Pericak-Vance, Margaret; Schols, Ludger; de Jonghe, Peter; Zuchner, Stephan

2008-01-01

Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for "REEP1" mutations and copy number variations. We identified 13 novel and 2 known "REEP1"…

Calcium absorption, kinetics, bone density, and bone structure in patients with hereditary vitamin D-resistant rickets

USDA-ARS?s Scientific Manuscript database

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by mutations in the vitamin D receptor gene. Children with HVDRR suffer from severe hypocalcemia and rickets that are treatable with extremely high-dose calcium supplements. Surprisingly, spontaneous recovery of calcium metabolis...

A new hereditary colorectal cancer network in the Middle East and eastern mediterranean countries to improve care for high-risk families.

PubMed

Ghorbanoghli, Zeinab; Jabari, Carol; Sweidan, Walid; Hammoudeh, Wail; Cortas, George; Sharara, Ala I; Abedrabbo, Amal; Hourani, Ijad; Mahjoubi, Bahareh; Majidzadeh, Keivan; Tözün, Nurdan; Ziada-Bouchaar, Hadia; Hamoudi, Waseem; Diab, Osama; Khorshid, Hamid Reza Khorram; Lynch, Henry; Vasen, Hans

2018-04-01

Colorectal cancer (CRC) has a very high incidence in the western world. Data from registries in the Middle East showed that the incidence of CRC is relatively low in these countries. However, these data also showed that CRC incidence has increased substantially over the past three decades and that a high proportion of cases are diagnosed at an early age (<50 years). In view of these findings, more attention should be paid to prevention. Because of the often limited financial resources, focused screening of individuals with hereditary CRC, in particular those with Lynch syndrome, appears to be the most cost-effective strategy. During recent meetings of the Palestinian Society of Gastroenterology and the Mediterranean Task force for Cancer Control (MTCC) in Jericho, and the Patient's Friends Society of Jerusalem in Hebron the issue of hereditary CRC in the Middle East was discussed and the idea was conceived to establish a network on hereditary colorectal cancer (HCCN-ME) with the goal of improving care for high-risk groups in the Middle East and (Eastern) Mediterranean Countries.

Multiple Hereditary Osteochondromatosis: A Case Report

PubMed Central

Küçükesmen, Çiḡdem; Özen, Buḡra; Akçam, Mustafa

2007-01-01

Objectives Common carious lesions owing to vomiting are not widespread in children. In this case, we aimed to report an 11-years-old male patient with common carious lesions due to repeated vomitings, chewing and eating difficulty and retarded growth with Multiple Hereditary Osteochondromatosis (MHO). Case Report An 11-years-old boy was referred to Department of Pediatric Dentistry in Faculty of Dentistry because of eating difficulty owing to common carious lesions. It was seen that the patient growth was generally retarded in extra-oral examination. Some exostoses were also present on the extremities. It was learned that he was previously diagnosed as MHO in Faculty of Medicine. Nausea and vomiting have been commonly occurring after taking of Didronat. Chewing and eating difficulty and inadequate nutrition were present because of bad oral hygiene, carious lesions and remained roots. Growth was negatively affected by malnutrition and MHO. Results Diet recommendations were given and oral hygiene behaviors were rearranged. Preventive, surgical, restorative and prosthetical dental applications were applied for dental treatments. PMID:19212564

Hereditary angioedema: management of laryngeal attacks.

PubMed

Christiansen, Sandra C; Zuraw, Bruce L

2011-01-01

Hereditary angioedema (HAE) patients suffering from laryngeal attacks in the United States faced severely limited treatment options until 2008. These potentially life-threatening episodes occur in over one-half of the patients affected by HAE during their lifetimes. Acute therapy had been relegated to supportive care, intubation, and consideration of fresh frozen plasma (FFP)--the latter with the potential for actually accelerating the speed and severity of the swelling. In this article we will review the recently approved and emerging HAE treatments that have evolved from the recognition that bradykinin generation is the fundamental abnormality leading to attacks of angioedema. Acute therapy for laryngeal attacks will be discussed including purified plasma-derived C1 inhibitor (C1INH), recombinant C1INH, an inhibitor of plasma kallikrein (ecallantide), and a B2 receptor antagonist (icatibant). Prophylactic care has also been transformed from a reliance on attenuated androgens with their attendant side effects to C1INH replacement. The arrival of these novel therapies promises to transform the future management of HAE.

Molecular genetics analysis of hereditary breast and ovarian cancer patients in India

PubMed Central

Soumittra, Nagasamy; Meenakumari, Balaiah; Parija, Tithi; Sridevi, Veluswami; Nancy, Karunakaran N; Swaminathan, Rajaraman; Rajalekshmy, Kamalalayam R; Majhi, Urmila; Rajkumar, Thangarajan

2009-01-01

Background Hereditary cancers account for 5–10% of cancers. In this study BRCA1, BRCA2 and CHEK2*(1100delC) were analyzed for mutations in 91 HBOC/HBC/HOC families and early onset breast and early onset ovarian cancer cases. Methods PCR-DHPLC was used for mutation screening followed by DNA sequencing for identification and confirmation of mutations. Kaplan-Meier survival probabilities were computed for five-year survival data on Breast and Ovarian cancer cases separately, and differences were tested using the Log-rank test. Results Fifteen (16%) pathogenic mutations (12 in BRCA1 and 3 in BRCA2), of which six were novel BRCA1 mutations were identified. None of the cases showed CHEK2*1100delC mutation. Many reported polymorphisms in the exonic and intronic regions of BRCA1 and BRCA2 were also seen. The mutation status and the polymorphisms were analyzed for association with the clinico-pathological features like age, stage, grade, histology, disease status, survival (overall and disease free) and with prognostic molecular markers (ER, PR, c-erbB2 and p53). Conclusion The stage of the disease at diagnosis was the only statistically significant (p < 0.0035) prognostic parameter. The mutation frequency and the polymorphisms were similar to reports on other ethnic populations. The lack of association between the clinico-pathological variables, mutation status and the disease status is likely to be due to the small numbers. PMID:19656415

WAO Guideline for the Management of Hereditary Angioedema

PubMed Central

2012-01-01

Hereditary Angioedema (HAE) is a rare disease and for this reason proper diagnosis and appropriate therapy are often unknown or not available for physicians and other health care providers. For this reason we convened a group of specialists that focus upon HAE from around the world to develop not only a consensus on diagnosis and management of HAE, but to also provide evidence based grades, strength of evidence and classification for the consensus. Since both consensus and evidence grading were adhered to the document meets criteria as a guideline. The outcome of the guideline is to improve diagnosis and management of patients with HAE throughout the world and to help initiate uniform care and availability of therapies to all with the diagnosis no matter where the residence of the individual with HAE exists. PMID:23282420

Multigeneration family with dominant SPG30 hereditary spastic paraplegia.

PubMed

Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig

2017-11-01

Autosomal recessive KIF1A missense mutations cause hereditary spastic paraplegia (HSP) type SPG30, while recessive truncations lead to sensory and autonomic neuropathy (HSN2C) and many de novo missense mutations are associated with cognitive impairment. Here, we describe family members across three generations with pure HSP. A heterozygous p.Ser69Leu KIF1A mutation segregates with those afflicted. The same variant was previously reported in a Finnish father and son with pure HSP as well as four members of a Sicilian kindred with more intrafamilial phenotypic variability. This further validates the pathogenicity of the p.Ser69Leu mutation and suggests that it may represent a mutation hot spot.

CHEK2 contribution to hereditary breast cancer in non-BRCA families

PubMed Central

2011-01-01

Background Mutations in the BRCA1 and BRCA2 genes are responsible for only a part of hereditary breast cancer (HBC). The origins of "non-BRCA" HBC in families may be attributed in part to rare mutations in genes conferring moderate risk, such as CHEK2, which encodes for an upstream regulator of BRCA1. Previous studies have demonstrated an association between CHEK2 founder mutations and non-BRCA HBC. However, very few data on the entire coding sequence of this gene are available. Methods We investigated the contribution of CHEK2 mutations to non-BRCA HBC by direct sequencing of its whole coding sequence in 507 non-BRCA HBC cases and 513 controls. Results We observed 16 mutations in cases and 4 in controls, including 9 missense variants of uncertain consequence. Using both in silico tools and an in vitro kinase activity test, the majority of the variants were found likely to be deleterious for protein function. One variant present in both cases and controls was proposed to be neutral. Removing this variant from the pool of potentially deleterious variants gave a mutation frequency of 1.48% for cases and 0.29% for controls (P = 0.0040). The odds ratio of breast cancer in the presence of a deleterious CHEK2 mutation was 5.18. Conclusions Our work indicates that a variety of deleterious CHEK2 alleles make an appreciable contribution to breast cancer susceptibility, and their identification could help in the clinical management of patients carrying a CHEK2 mutation. PMID:22114986

Association of recurrent pregnancy loss with chromosomal abnormalities and hereditary thrombophilias.

PubMed

Ocak, Z; Özlü, T; Ozyurt, O

2013-06-01

Recurrent pregnancy loss (RPL) which is generally known as >3 consecutive pregnancy losses before 20 weeks' gestation is seen in 0.5-2% of women. To evaluate the association of parental and fetal chromosomal abnormalities with recurrent pregnancy loss in our area and to analyze the frequency of three types of hereditary thrombophilia's; (MTHFR C677T polymorphisms, FV Leiden G1691A mutation and Prothrombin (factor II) G20210A mutation) in these female patients. The present case-control retrospective study was performed between February 2007 and December 2011 on 495 couples, who had two or more consecutive pregnancy losses before 20 weeks' gestation. We used conventional cytogenetic analysis and polymerase chain reaction-restriction fragment length polymorphism. Parental chromosomal abnormality was detected in 28 cases (2.8% of all cases, 5.7% of the couples) most of which (92.9%) were structural abnormalities. All of the structural abnormalities were balanced chromosomal translocations. Chromosomal analysis performed from the abortion materials detected a major chromosomal abnormality in 31.9% of the cases. The most frequently observed alteration in the hereditary thrombophilia genes was heterozygote mutation for the MTHFR C677T polymorphisms (n=55). Balanced translocations are the most commonly detected chromosomal abnormalities in couples being evaluated for recurrent pregnancy loss and these patients are the best candidates for offering prenatal genetic diagnosis by the help of which there is a possibility of obtaining a better reproductive outcome.

Critical appraisal of androgen use in hereditary angioedema: a systematic review.

PubMed

Riedl, Marc A

2015-04-01

To provide an objective basis for evaluating the risk-benefit ratio of long-term androgen use in patients with hereditary angioedema (HAE). PubMed was searched with no time limitations using the keywords hereditary angioedema or angio-oedema combined with danazol, stanozolol, and androgen. Qualifying articles were English-language reports of androgen use in patients with HAE, with relevant safety and/or efficacy information. Reports were categorized according to level of evidence (LOE). The search process identified 153 citations, 63 of which contained relevant information; 2 additional publications were identified while other citations were being reviewed. Fifteen LOE 2 studies and multiple LOE 4 reports provided efficacy data, confirming a high level of prophylactic efficacy for androgen therapy in HAE, with occasional reports of poor prophylactic response. Common adverse events include weight gain, menstrual irregularities, virilization, headaches, myalgias or cramps, mood changes, and elevations in creatine phosphokinase level, liver function test results, and serum lipid level. The risk of adverse events is often correlated with dose and/or treatment duration. Rare cases of hepatic adenomas and hepatocellular carcinoma associated with long-term androgen use often had no preceding changes in liver function test results. Androgen therapy may be effective for most patients with HAE; however, potential risks and adverse effects must be carefully considered and discussed with patients when considering options for long-term HAE prophylaxis. Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Population prevalence of hereditary breast cancer phenotypes and implementation of a genetic cancer risk assessment program in southern Brazil

PubMed Central

2009-01-01

In 2004, a population-based cohort (the Núcleo Mama Porto Alegre - NMPOA Cohort) was started in Porto Alegre, southern Brazil and within that cohort, a hereditary breast cancer study was initiated, aiming to determine the prevalence of hereditary breast cancer phenotypes and evaluate acceptance of a genetic cancer risk assessment (GCRA) program. Women from that cohort who reported a positive family history of cancer were referred to GCRA. Of the 9218 women enrolled, 1286 (13.9%) reported a family history of cancer. Of the 902 women who attended GCRA, 55 (8%) had an estimated lifetime risk of breast cancer ≥ 20% and 214 (23.7%) had pedigrees suggestive of a breast cancer predisposition syndrome; an unexpectedly high number of these fulfilled criteria for Li-Fraumeni-like syndrome (122 families, 66.7%). The overall prevalence of a hereditary breast cancer phenotype was 6.2% (95%CI: 5.67-6.65). These findings identified a problem of significant magnitude in the region and indicate that genetic cancer risk evaluation should be undertaken in a considerable proportion of the women from this community. The large proportion of women who attended GCRA (72.3%) indicates that the program was well-accepted by the community, regardless of the potential cultural, economic and social barriers. PMID:21637504

Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a Cause of Hereditary Sensory Neuropathy Type I

PubMed Central

Guelly, Christian; Zhu, Peng-Peng; Leonardis, Lea; Papić, Lea; Zidar, Janez; Schabhüttl, Maria; Strohmaier, Heimo; Weis, Joachim; Strom, Tim M.; Baets, Jonathan; Willems, Jan; De Jonghe, Peter; Reilly, Mary M.; Fröhlich, Eleonore; Hatz, Martina; Trajanoski, Slave; Pieber, Thomas R.; Janecke, Andreas R.; Blackstone, Craig; Auer-Grumbach, Michaela

2011-01-01

Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders. PMID:21194679

[Hereditary phaeochromocytoma in twins].

PubMed

Tóth, Géza; Patócs, Attila; Tóth, Miklós

2016-08-01

Phaeochromocytoma is a tumor of the catecholamine-producing cells of the adrenal gland. Extraadrenal phaeochromocytomas are frequently called paragangliomas. The majority of phaeochromocytomas are sporadic, however, about 25-30% are caused by genetic mutation. These tumor are frequently referred as hereditary phaeochromocytomas/paragangliomas. Their incidence increases continuously which can be attributed to availability of genetic examination and to the discovery of novel genes. The 47-year-old female patient underwent abdominal computed tomography which revealed bilateral adrenal gland enlargement. Abdominal magnetic resonance imaging, the 131-I- metaiodobenzylguanidine scintigraphy, urinary catecholamines and serum chomogranin A measurements confirmed the diagnosis of bilateral phaeochromocytomas. The genetically identical twin sister of the patient was also diagnosed with hormonally active bilateral phaechromocytoma, suggesting the genetic origin of phaeochromocytoma. Mutation screening confirmed a germline mutation of the transmembrane protein 127 tumorsupressor gene in both patients. Both patients underwent cortical-sparing adrenalectomy. The adrenal gland with the larger tumor was totally resected, while in the opposite side only the tumor was resected and a small part of the cortex was saved. After the operation urinary catecholamines and serum chromogranin A returned to normal in both patients. Adrenocortical deficiency was absent in the first patient, but her sister developed adrenal insufficiency requiring glucocorticoid replacement. To the best of the authors' knowledge phaeochromocytoma affecting twins has never been described earlier. Genetic examination performed in siblings confirmed the presence of the mutant gene through four generations. Orv. Hetil., 2016, 157(33), 1326-1330.

Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study.

PubMed

Fewings, Eleanor; Larionov, Alexey; Redman, James; Goldgraben, Mae A; Scarth, James; Richardson, Susan; Brewer, Carole; Davidson, Rosemarie; Ellis, Ian; Evans, D Gareth; Halliday, Dorothy; Izatt, Louise; Marks, Peter; McConnell, Vivienne; Verbist, Louis; Mayes, Rebecca; Clark, Graeme R; Hadfield, James; Chin, Suet-Feung; Teixeira, Manuel R; Giger, Olivier T; Hardwick, Richard; di Pietro, Massimiliano; O'Donovan, Maria; Pharoah, Paul; Caldas, Carlos; Fitzgerald, Rebecca C; Tischkowitz, Marc

2018-04-26

Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants. We did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer. Protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN. Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant. The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families. UK Medical

Medical treatment of epistaxis in hereditary hemorrhagic telangiectasia: an evidence-based review.

PubMed

Halderman, Ashleigh A; Ryan, Matthew W; Clark, Christopher; Sindwani, Raj; Reh, Douglas D; Poetker, David M; Invernizzi, Rosangela; Marple, Bradley F

2018-06-01

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant hereditary disorder resulting in vascular dysplasia and formation of arteriovenous malformations. Recurrent epistaxis is a hallmark of the disease. An array of medical therapies are used in this patient population, but robust evidence-based recommendations regarding the medical treatment of epistaxis are lacking. This systematic review was performed to look at the current literature and make meaningful evidence-based recommendations. A search of the Ovid MEDLINE, Embase, and Cochrane databases was conducted by a research librarian. Abstracts in the English language and published in a peer-review journal were reviewed for relevance and inclusion. PRISMA guidelines were followed. Eighteen studies met the inclusion criteria. In a few small studies, thalidomide was shown to consistently improve severity and frequency of epistaxis and improve hemoglobin concentrations while decreasing the need for transfusion. Tranexamic acid appeared to only impact the epistaxis severity score and not other clinical outcomes. Selective estrogen modulators (SERMs), propranolol, rose geranium oil, and N-acetylcysteine, have demonstrated promising efficacy in small trials. Appropriate medical therapies for epistaxis outcomes in HHT remain undefined, and there is no "gold standard." Many of the studies are small and the data reported are heterogeneous, and therefore the ability to make strong evidence-based recommendations is limited. However, many different medications appear to be promising options. © 2018 ARS-AAOA, LLC.

Advances in the diagnosis of hereditary kidney cancer: Initial results of a multigene panel test.

PubMed

Nguyen, Kevin A; Syed, Jamil S; Espenschied, Carin R; LaDuca, Holly; Bhagat, Ansh M; Suarez-Sarmiento, Alfredo; O'Rourke, Timothy K; Brierley, Karina L; Hofstatter, Erin W; Shuch, Brian

2017-11-15

Panel testing has been recently introduced to evaluate hereditary cancer; however, limited information is available regarding its use in kidney cancer. The authors retrospectively reviewed test results and clinical data from patients who underwent targeted multigene panel testing of up to 19 genes associated with hereditary kidney cancer from 2013 to 2016. The frequency of positive (mutation/variant likely pathogenic), inconclusive (variant of unknown significance), and negative results was evaluated. A logistic regression analysis evaluated predictive factors for a positive test. Patients (n = 1235) had a median age at diagnosis of 46 years, which was significantly younger than the US population of individuals with kidney cancer (P < .0001). Overall, 6.1%, 75.5%, and 18.4% of individuals had positive, negative, and inconclusive results, respectively. The most commonly altered genes included folliculin (FLCN) and fumarate hydratase (FH), which were altered in 1.8% and 1.3% of patients, respectively. Tuberous Sclerosis Complex 2 (TSC2), mesenchymal epithelial transition factor proto-oncogene (MET), and PMS1 homolog 2 (PMS2) had the highest rates of variants of unknown significance, which were identified in 2.7%, 2.2%, and 1.7% of patients, respectively. Early age of onset was the only factor that was identified as predictive of a positive test on multivariate analysis (odds ratio, 0.975; P = .0052) and may be the only identifying characteristic of low-penetrant syndromes, such as those associated with MITF (melanogenesis-associated transcription factor) mutations, which do not have singular histology or a family history of kidney cancer. Panel tests may be particularly useful for patients who lack distinguishing clinical characteristics of known hereditary kidney cancer syndromes. The current results support the use of early age of onset for genetic counseling and/or testing. Cancer 2017;123:4363-71. © 2017 American Cancer Society. © 2017 American

Illness representations, knowledge and motivation to perform presymptomatic testing for late-onset genetic diseases.

PubMed

Leite, Ângela; Dinis, Maria Alzira P; Sequeiros, Jorge; Paúl, Constança

2017-02-01

This study addresses the relation between illness representations, knowledge and motivation to perform the presymptomatic testing (PST) of subjects at-risk for Familial Amyloydotic Polyneuropathy (FAP), Huntington's disease (HD) and Machado-Joseph disease (MJD), compared with subjects at-risk for Hereditary Hemochromatosis (HH). The sample comprised a clinical group of 213 subjects at genetic risk for FAP, HD and MJD, and a comparison group of 31 subjects at genetic risk for HH, that answered three open-ended questions relating illness representations, knowledge about the disease, and motivation to perform PST. People at-risk for FAP, HD and MJD use more metaphors, make more references to the family, are more concerned with the future and feel more out of curiosity and to learn, than for HH. These subjects at-risk correspond to the profile of somatic individual or personhood, wherein the unsubjectivation of the disease can function as a coping mechanism.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernstein, S.E.

Hereditary anemias of mice are the chief objects of investigation, specificially four macrocytic anemias, 3 types of hemolytic anemia, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, the autoimmune hemolytic anemia of NZB mice, an ..cap alpha..-thalassemia and a new hypochromic anemia with hemochromatosis. New types of anemia may be analyzed as new mutations appear. Three new mutations have been identified during the past 18 months. These anemias are studied through characterization of peripheral blood values, determinations of radiosensitivity under a variety of conditions, measurements of iron metabolism and heme synthesis, study of normal and abnormal erythrocyte membrane proteins,more » histological and biochemical characterization of blood-forming tissue, functional tests of the stem-cell component, examination of responses to erythroid stimuli, and transplantation of tissue and parabiosis between individuals of differently affected genotypes. 31 refs.« less

Neuroendocrine Differentiation in Sporadic CRC and Hereditary Nonpolyosis Colorectal Cancer

PubMed Central

Sun, M. H.

2004-01-01

Extent neuroendocrine differentiation can be encountered in many human neoplasm derived from different organs and systems using immunohistochemistry and ultrastructural techniques. The tumor cells' behaviors resemble those of neurons and neuroendocrine cells. The presence of neuroendocrine differentiation reputedly appears to be associated with a poorer prognosis than the adenocarcinoma counterparts in sporadic human neoplasm. In this review the neuroendocrine carcinoma and the adenocarcinoma with neuroendocrine differentiation of colon and rectum both in sporadic colorectal carcinoma and the hereditary nonpolyposis colorectal cancer, the relationship of neuroendocrine differentiation and some possible molecular pathways in tumorogenesis of colorectal cancer will be discussed. Possible treatment strategy will also be addressed. PMID:15528794

In Situ Proximity Ligation Assays Indicate That Hemochromatosis Proteins Hfe and Transferrin Receptor 2 (Tfr2) Do Not Interact

PubMed Central

Rishi, Gautam; Crampton, Emily M.; Wallace, Daniel F.; Subramaniam, V. Nathan

2013-01-01

The hemochromatosis associated proteins HFE and Transferrin Receptor 2 (TFR2) have been shown to be important for the proper regulation of hepcidin. A number of in vitro studies using transient overexpression systems have suggested that an interaction between HFE and TFR2 is required for the regulation of hepcidin. This model of iron sensing which centers upon the requirement for an interaction between HFE and TFR2 has recently been questioned with in vivo studies in mice from our laboratory and others which suggest that Hfe and Tfr2 can regulate hepcidin independently of each other. To re-examine the postulated interaction between Hfe and Tfr2 we developed a novel expression system in which both proteins are stably co-expressed and used the proximity ligation assay to examine the interactions between Hfe, Tfr1 and Tfr2 at a cellular level. We were able to detect the previously described interaction between Hfe and Tfr1, and heterodimers between Tfr1 and Tfr2; however no interaction between Hfe and Tfr2 was observed in our system. The results from this study indicate that Hfe and Tfr2 do not interact with each other when they are stably expressed at similar levels. Furthermore, these results support in vivo studies which suggest that Hfe and Tfr2 can independently regulate hepcidin. PMID:24155934

Ultimate boundedness stability and controllability of hereditary systems

NASA Technical Reports Server (NTRS)

Chukwu, E. N.

1979-01-01

By generalizing the Liapunov-Yoshizawa techniques, necessary and sufficient conditions are given for uniform boundedness and uniform ultimate boundedness of a rather general class of nonlinear differential equations of neutral type. Among the applications treated by the methods are the Lienard equation of neutral type and hereditary systems of Lurie type. The absolute stability of this later equation is also investigated. A certain existence result of a solution of a neutral functional differential inclusion with two point boundary values is applied to study the exact function space controllability of a nonlinear neutral functional differential control system. A geometric growth condition is used to characterize both the function space and Euclidean controllability of another nonlinear delay system which has a compact and convex control set. This yields conditions under which perturbed nonlinear delay controllable systems are controllable.

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.

PubMed

Li, Junyan; Jing, Ruilin; Wei, Hongyi; Wang, Minghao; Qi, Xiaowei; Liu, Haoxi; Liu, Jian; Ou, Jianghua; Jiang, Weihua; Tian, Fuguo; Sheng, Yuan; Li, Hengyu; Xu, Hong; Zhang, Ruishan; Guan, Aihua; Liu, Ke; Jiang, Hongchuan; Ren, Yu; He, Jianjun; Huang, Weiwei; Liao, Ning; Cai, Xiangjun; Ming, Jia; Ling, Rui; Xu, Yan; Hu, Chunyan; Zhang, Jianguo; Guo, Baoliang; Ouyang, Lizhi; Shuai, Ping; Liu, Zhenzhen; Zhong, Ling; Zeng, Zhen; Zhang, Ting; Xuan, Zhaoling; Tan, Xuanni; Liang, Junbin; Pan, Qinwen; Chen, Li; Zhang, Fan; Fan, Linjun; Zhang, Yi; Yang, Xinhua; Li, Jingbo; Chen, Chongjian; Jiang, Jun

2018-05-12

Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n=937). Clinical information was collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non-BRCA1/2 gene. Major mutant non-BRCA1/2 genes were TP53 (n=18), PALB2 (n=11), CHEK2 (n=6), ATM (n=6), and BARD1 (n=5). No factors predicted pathologic mutations in non-BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER-2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non-BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rates (1.9% and 1.2%). Although no factors predicted for detrimental mutations in non-BRCA1/2 genes, some clinical features were associated with mutations of several particular genes. This article is protected by copyright. All rights reserved. © 2018 UICC.

A case of concomitant Gilbert's syndrome and hereditary spherocytosis

PubMed Central

Lee, Hee Jung; Moon, Hee Seok; Lee, Eaum Seok; Kim, Seok Hyun; Sung, Jae Kyu; Lee, Byung Seok; Jeong, Hyun Yong; Eu, Young Jae

2010-01-01

We describe moderate hyperbilirubinemia in a 28-year-old man who suffered from gallstones and splenomegaly, with combined disorders of hereditary spherocytosis (HS) and Gilbert's syndrome (GS). Since it is difficult to diagnose HS in the absence of signs of anemia, we evaluated both the genetic mutation in the UGT1A1 gene and abnormalities in the erythrocyte membrane protein; the former was heterozygous for a UGT1A1 allele with three mutations and the latter was partially deficient in ankyrin expression. This is the first report of the concomitance of HS and GS with three heterozygous mutations [T-3279G, A (TA)7TAA, and G211A] in the UGT1A1 gene. PMID:20924216

In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11

PubMed Central

Varga, Rita-Eva; Khundadze, Mukhran; Damme, Markus; Nietzsche, Sandor; Hoffmann, Birgit; Stauber, Tobias; Koch, Nicole; Hennings, J. Christopher; Franzka, Patricia; Huebner, Antje K.; Kessels, Michael M.; Biskup, Christoph; Jentsch, Thomas J.; Qualmann, Britta; Braulke, Thomas; Kurth, Ingo; Beetz, Christian; Hübner, Christian A.

2015-01-01

Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice. PMID:26284655

In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11.

PubMed

Varga, Rita-Eva; Khundadze, Mukhran; Damme, Markus; Nietzsche, Sandor; Hoffmann, Birgit; Stauber, Tobias; Koch, Nicole; Hennings, J Christopher; Franzka, Patricia; Huebner, Antje K; Kessels, Michael M; Biskup, Christoph; Jentsch, Thomas J; Qualmann, Britta; Braulke, Thomas; Kurth, Ingo; Beetz, Christian; Hübner, Christian A

2015-08-01

Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice.

Red blood cell aquaporin-1 expression is decreased in hereditary spherocytosis.

PubMed

Crisp, Renée L; Maltaneri, Romina E; Vittori, Daniela C; Solari, Liliana; Gammella, Daniel; Schvartzman, Gabriel; García, Eliana; Rapetti, María C; Donato, Hugo; Nesse, Alcira

2016-10-01

Aquaporin-1 (AQP1) is the membrane water channel responsible for changes in erythrocyte volume in response to the tonicity of the medium. As the aberrant distribution of proteins in hereditary spherocytosis (HS) generates deficiencies of proteins other than those codified by the mutated gene, we postulated that AQP1 expression might be impaired in spherocytes. AQP1 expression was evaluated through flow cytometry in 5 normal controls, 1 autoimmune hemolytic anemia, 10 HS (2 mild, 3 moderate, 2 severe, and 3 splenectomized), and 3 silent carriers. The effect of AQP1 inhibitors was evaluated through water flow-based tests: osmotic fragility and hypertonic cryohemolysis. Serum osmolality was measured in 20 normal controls and 13 HS. The effect of erythropoietin (Epo) on AQP1 expression was determined in cultures of erythroleukemia UT-7 cells, dependent on Epo to survive. Independent of erythrocyte size, HS patients showed a lower content of AQP1 in erythrocyte membranes which correlated with the severity of the disease. Accordingly, red blood cells from HS subjects were less sensitive to cryohemolysis than normal erythrocytes after inhibition of the AQP1 water channel. A lower serum osmolality in HS with respect to normal controls suggests alterations during reticulocyte remodeling. The decreased AQP1 expression could contribute to explain variable degrees of anemia in hereditary spherocytosis. The finding of AQP1 expression induced by Epo in a model of erythroid cells may be interpreted as a mechanism to restore the balance of red cell water fluxes.

[Hereditary heterozygous factor VII deficiency in patients undergoing surgery : Clinical relevance].

PubMed

Woehrle, D; Martinez, M; Bolliger, D

2016-10-01

A hereditary deficiency in coagulation factor VII (FVII) may affect the international normalized ratio (INR) value. However, FVII deficiency is occasionally associated with a tendency to bleed spontaneously. We hypothesized that perioperative substitution with coagulation factor concentrates might not be indicated in most patients. In this retrospective data analysis, we included all patients with hereditary heterozygous FVII deficiency who underwent surgical procedures at the University Hospital Basel between December 2010 and November 2015. In addition, by searching the literature, we identified publications reporting patients with FVII deficiency undergoing surgical procedures without perioperative substitution. We identified 22 patients undergoing 46 surgical procedures, resulting in a prevalence of 1:1500-2000. Coagulation factor concentrates were administered during the perioperative period in 15 procedures (33 %), whereas in the other 31 procedures (66 %), FVII deficiency was not substituted. No postoperative bleeding or thromboembolic events were reported. In addition, we found no differences in pre- and postoperative hemoglobin and coagulation parameters, with the exception of an improved postoperative INR value in the substituted group. In the literature review, we identified five publications, including 125 patients with FVII deficiency, undergoing 213 surgical procedures with no perioperative substitution. Preoperative substitution using coagulation factor concentrates does not seem to be mandatory in patients with an FVII level ≥15 %. For decision-making on preoperative substitution, patient history of an increased tendency to bleed may be more important than the FVII level or increased INR value.

Hereditary paraganglioma due to the SDHD M1I mutation in a second Chinese family: a founder effect?

PubMed

Lee, Soo-Chin; Chionh, Siok-Bee; Chong, Siew-Meng; Taschner, Peter E M

2003-06-01

Hereditary paraganglioma is a rare condition that is inherited in an autosomal-dominant fashion. Four distinct loci have been associated with hereditary paraganglioma, including the SDHD, SDHC, and SDHB genes and a locus at 11q13. The SDHD, SDHC, and SDHB genes code for subunits of succinate dehydrogenase, which forms part of the mitochondrial respiratory chain. SDHD mutations are widely distributed along the gene with no apparent hot spots, although a founder effect has been described in the Dutch population. Following a prior report of the SDHD M1I mutation in an Australian Chinese family, a second Chinese family with the same mutation is reported. The proband developed bilateral head and neck paragangliomas at age 34 years and a functioning adrenal pheochromocytoma and two extra-adrenal abdominal paragangliomas 7 years later. His brother had unilateral head and neck paraganglioma at age 39 years. Given the multicentricity of the proband's tumor and the familial clustering of paragangliomas, a clinical diagnosis of hereditary paraganglioma was made, and the proband was tested for a mutation in the SDHD gene. The proband was found to be heterozygous for the SDHD MII mutation that removes the start codon, and his brother subsequently tested positive for the same mutation. The family is not related to the Australian Chinese family. The finding suggests the possibility of a founder effect in the Chinese population and warrants further investigation.

HFE gene variants affect iron in the brain.

PubMed

Nandar, Wint; Connor, James R

2011-04-01

Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.

Clinical and neurophysiologic characterization of an European family with hereditary sensory neuropathy, paroxysmal cough and gastroesophageal reflux.

PubMed

Barros, Pedro; Morais, Hugo; Santos, Catarina; Roriz, José; Coutinho, Paula

2014-04-01

In 2002, Spring et al reported a family with an autosomal dominant form of hereditary sensory neuropathy; patients also presented adult onset of gastroesophageal reflux and cough. Since then, no further families have been described. To study a new Portuguese family with these characteristics. To describe the clinical and neurophysiologic characteristics of one family with features of sensory neuropathy associated with cough and gastroesophageal erflux. Three of five siblings presented a similar history of paroxysmal cough (5th decade). About a decade later they experienced numbness and paraesthesia in the feet and in all cases there was evidence of an axonal sensory neuropathy. A history of gastroesophageal reflux of variable severity and age of onset was also present. Molecular genetic studies have demonstrated genetic heterogeneity between the hereditary sensory neuropathy type 1 subtypes. The identification of these families is of major importance because further work is required to identify the underlying genetic defect.

Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer.

PubMed

Trujillano, Daniel; Weiss, Maximilian E R; Schneider, Juliane; Köster, Julia; Papachristos, Efstathios B; Saviouk, Viatcheslav; Zakharkina, Tetyana; Nahavandi, Nahid; Kovacevic, Lejla; Rolfs, Arndt

2015-03-01

Genetic testing for hereditary breast and/or ovarian cancer mostly relies on laborious molecular tools that use Sanger sequencing to scan for mutations in the BRCA1 and BRCA2 genes. We explored a more efficient genetic screening strategy based on next-generation sequencing of the BRCA1 and BRCA2 genes in 210 hereditary breast and/or ovarian cancer patients. We first validated this approach in a cohort of 115 samples with previously known BRCA1 and BRCA2 mutations and polymorphisms. Genomic DNA was amplified using the Ion AmpliSeq BRCA1 and BRCA2 panel. The DNA Libraries were pooled, barcoded, and sequenced using an Ion Torrent Personal Genome Machine sequencer. The combination of different robust bioinformatics tools allowed detection of all previously known pathogenic mutations and polymorphisms in the 115 samples, without detecting spurious pathogenic calls. We then used the same assay in a discovery cohort of 95 uncharacterized hereditary breast and/or ovarian cancer patients for BRCA1 and BRCA2. In addition, we describe the allelic frequencies across 210 hereditary breast and/or ovarian cancer patients of 74 unique definitely and likely pathogenic and uncertain BRCA1 and BRCA2 variants, some of which have not been previously annotated in the public databases. Targeted next-generation sequencing is ready to substitute classic molecular methods to perform genetic testing on the BRCA1 and BRCA2 genes and provides a greater opportunity for more comprehensive testing of at-risk patients. Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P).

PubMed

Campellone, Joseph V

2013-06-01

Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a rare disorder inherited in an autosomal dominant fashion. Patients present with slowly progressive proximal-predominant weakness, painful muscle cramps, fasciculations, large-fiber sensory loss, and areflexia. Electrodiagnostic (EDX) studies typically reveal abnormalities consistent with a sensorimotor neuronopathy. A patient with HMSN-P underwent EDX studies, revealing ongoing and chronic neurogenic denervation, motor unit instability, and neuromyotonic discharges, further defining the spectrum of EDX findings in HMSN-P. The clinical, pathological, and genetic features are also reviewed. The appearance of HMSN-P in the United States and elsewhere calls for clinicians in nonendemic regions to be familiar with this rare disorder, which has typically been geographically confined.

Hereditary internal anal sphincter myopathy causing proctalgia fugax and constipation: further clinical and histological characterization in a patient.

PubMed

König, P; Ambrose, N S; Scott, N

2000-01-01

Hereditary internal anal sphincter myopathy is a very rare condition, only three families have so far been described in the literature. In this case report further clinical and histological findings of one affected member of one of the above families are presented.

Molecular Analysis of BMPR2, TBX4, and KCNK3 and Genotype-Phenotype Correlations in Spanish Patients and Families With Idiopathic and Hereditary Pulmonary Arterial Hypertension.

PubMed

Navas, Paula; Tenorio, Jair; Quezada, Carlos Andrés; Barrios, Elvira; Gordo, Gema; Arias, Pedro; López Meseguer, Manuel; Santos-Lozano, Alejandro; Palomino Doza, Julian; Lapunzina, Pablo; Escribano Subías, Pilar

2016-11-01

Recent advances in genetics have led to the discovery of new genes associated with pulmonary arterial hypertension, such as TBX4 and KCNK3. The phenotype and prognosis associated with these new genes have been scarcely described and their role in the Spanish population is unknown. The aim of this study was to characterize the genetics of a Spanish cohort of patients with idiopathic and hereditary pulmonary arterial hypertension and to describe the phenotype and prognostic factors associated with BMPR2 and the new genes (KCNK3 and TBX4). A total of 165 adult patients were screened for BMPR2, KCNK3, and TBX4 mutations, 143 with idiopathic pulmonary arterial hypertension and 22 with hereditary pulmonary arterial hypertension. Baseline characteristics and survival were compared among the different subgroups and predictors of poor outcomes were analyzed. We also performed family screening. The genetic study identified a possibly associated mutation in 11.10% of the idiopathic cases (n = 16) and in 68.18% of the hereditary cases (n = 15). There were 19 mutations in BMPR2, 4 in TBX4, and 3 in KCNK3. The forms associated with TBX4 showed the highest survival rate (P < .01). Advanced functional class at diagnosis was the only factor associated with poor outcomes in the hereditary forms. In the family screening, 37.5% of relatives tested positive. The genetics of pulmonary arterial hypertension in the Spanish population may differ from other populations, with a lower proportion of BMPR2 causative mutations. In our cohort, TBX4-related forms of pulmonary arterial hypertension showed a more benign course and late diagnosis was the only predictor of adverse outcomes in the hereditary forms of the disease. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Different foveal schisis patterns in each retinal layer in eyes with hereditary juvenile retinoschisis evaluated by en-face optical coherence tomography.

PubMed

Yoshida-Uemura, Tomoyo; Katagiri, Satoshi; Yokoi, Tadashi; Nishina, Sachiko; Azuma, Noriyuki

2017-04-01

To analyze the structures of schisis in eyes with hereditary juvenile retinoschisis using en-face optical coherence tomography (OCT) imaging. In this retrospective observational study, we reviewed the medical records of patients with hereditary juvenile retinoschisis who underwent comprehensive ophthalmic examinations including swept-source OCT. OCT images were obtained from 16 eyes of nine boys (mean age ± standard deviation, 10.6 ± 4.0 years). The horizontal OCT images at the fovea showed inner nuclear layer (INL) schisis in one eye (6.3 %), ganglion cell layer (GCL) and INL schisis in 12 eyes (75.0 %), INL and outer plexiform layer (OPL) schisis in two eyes (12.5 %), and GCL, INL, and OPL schisis in one eye (6.3 %). En-face OCT images showed characteristic schisis patterns in each retinal layer, which were represented by multiple hyporeflective holes in the parafoveal region in the GCL, a spoke-like pattern in the foveal region, a reticular pattern in the parafoveal region in the INL, and multiple hyporeflective polygonal cavities with partitions in the OPL. Our results using en-face OCT imaging clarified different patterns of schisis formation among the GCL, INL, and OPL, which lead to further recognition of structure in hereditary juvenile retinoschisis.

Initial Results of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome.

PubMed

Howarth, Dt R; Lum, Sharon S; Esquivel, Pamela; Garberoglio, Carlos A; Senthil, Maheswari; Solomon, Naveenraj L

2015-10-01

Multigene panel testing for hereditary cancer risk has recently become commercially available; however, the impact of its use on patient care is undefined. We sought to evaluate results from implementation of panel testing in a multidisciplinary cancer center. We performed a retrospective review of consecutive patients undergoing genetic testing after initiating use of multigene panel testing at Loma Linda University Medical Center. From February 13 to August 25, 2014, 92 patients were referred for genetic testing based on National Comprehensive Cancer Network guidelines. Testing was completed in 90 patients. Overall, nine (10%) pathogenic mutations were identified: five BRCA1/2, and four in non-BRCA loci. Single-site testing identified one BRCA1 and one BRCA2 mutation. The remaining mutations were identified by use of panel testing for hereditary breast and ovarian cancer. There were 40 variants of uncertain significance identified in 34 patients. The use of panel testing more than doubled the identification rate of clinically significant pathogenic mutations that would have been missed with BRCA testing alone. The large number of variants of uncertain significance identified will require long-term follow-up for potential reclassification. Multigene panel testing provides additional information that may improve patient outcomes.

Hereditary Melanoma: Update on Syndromes and Management - Genetics of familial atypical multiple mole melanoma syndrome

PubMed Central

Soura, E.; Eliades, P.; Shannon, K.; Stratigos, A.; Tsao, H.

2015-01-01

Malignant melanoma is considered the most lethal skin cancer if not detected and treated at its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (i.e. unilateral lineage, multi-generational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. Such patients have a high risk of developing multiple primary melanomas and internal organ malignancies especially pancreatic cancer; thus, a multidisciplinary approach is necessary in many cases. The value of dermoscopy examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. But, this must be performed with care and only by qualified individuals trained in cancer risk analysis. PMID:26892650

Genetics of hereditary neurological disorders in children.

PubMed

Huang, Yue; Yu, Sui; Wu, Zhanhe; Tang, Beisha

2014-04-01

Hereditary neurological disorders (HNDs) are relatively common in children compared to those occurring in adulthood. Recognising clinical manifestations of HNDs is important for the selection of genetic testing, genetic testing results interpretation, and genetic consultation. Meanwhile, advances in next generation sequencing (NGS) technologies have significantly enabled the discovery of genetic causes of HNDs and also challenge paediatricians on applying genetic investigation. Combination of both clinical information and advanced technologies will enhance the genetic test yields in clinical setting. This review summarises the clinical presentations as well as genetic causes of paediatric neurological disorders in four major areas including movement disorders, neuropsychiatric disorders, neuron peripheral disorders and epilepsy. The aim of this review is to help paediatric neurologists not only to see the clinical features but also the complex genetic aspect of HNDs in order to utilise genetic investigation confidently in their clinical practice. A smooth transition from research based to clinical use of comprehensive genetic testing in HNDs in children could be foreseen in the near future while genetic testing, genetic counselling and genetic data interpretation are in place appropriately.

Overlapping molecular pathological themes link Charcot-Marie-Tooth neuropathies and hereditary spastic paraplegias.

PubMed

Timmerman, Vincent; Clowes, Virginia E; Reid, Evan

2013-08-01

In this review we focus on Charcot-Marie-Tooth (CMT) neuropathies and hereditary spastic paraplegias (HSPs). Although these diseases differ in whether they primarily affect the peripheral or central nervous system, both are genetically determined, progressive, long axonopathies that affect motor and sensory pathways. This commonality suggests that there might be similarities in the molecular pathology underlying these conditions, and here we compare the molecular genetics and cellular pathology of the two groups. Copyright © 2012 Elsevier Inc. All rights reserved.

Understanding childhood asthma in focus groups: perspectives from mothers of different ethnic backgrounds

PubMed Central

Cane, Rachel; Pao, Caroline; McKenzie, Sheila

2001-01-01

Background Diagnosing childhood asthma is dependent upon parental symptom reporting but there are problems in the use of words and terms. The purpose of this study was to describe and compare understandings of childhood 'asthma' by mothers from three different ethnic backgrounds who have no personal experience of diagnosing asthma. A better understanding of parents' perceptions of an illness by clinicians should improve communication and management of the illness. Method Sixty-six mothers living in east London describing their ethnic backgrounds as Bangladeshi, white English and black Caribbean were recruited to 9 focus groups. Discussion was semi-structured. Three sessions were conducted with each ethnic group. Mothers were shown a video clip of a boy with audible wheeze and cough and then addressed 6 questions. Sessions were recorded and transcribed verbatim. Responses were compared within and between ethnic groups. Results Each session, and ethnic group overall, developed a particular orientation to the discussion. Some mothers described the problem using single signs, while others imitated the sound or made comparisons to other illnesses. Hereditary factors were recognised by some, although all groups were concerned with environmental triggers. Responses about what to do included 'normal illness' strategies, use of health services and calls for complementary treatment. All groups were concerned about using medication every day. Expectations about the quality of life were varied, with recognition that restrictions may be based on parental beliefs about asthma, rather than asthma itself. Conclusion Information from these focus groups suggests mothers know a great deal about childhood asthma even though they have no personal experience of it. Knowledge of how mothers from these ethnic backgrounds perceive asthma may facilitate doctor – patient communication with parents of children experiencing breathing difficulties. PMID:11667951

Iron storage disease in tapirs.

PubMed

Bonar, Christopher J; Trupkiewicz, John G; Toddes, Barbara; Lewandowski, Albert H

2006-03-01

Recent studies of serum iron and iron binding capacity have indicated that tapirs could be at risk of developing hemochromatosis. However, in recent surveys of pathologic findings in tapirs, hemochromatosis was not reported as a cause of death. This study reviews necropsy reports from three species of tapir (Baird's tapir [Tapirus bairdii], Malayan tapir [Tapirus indicus], and Brazilian tapir [Tapirus terrestris]) at the Philadelphia Zoological Garden between 1902 and 1994. Twelve cases of hemosiderosis, including fatal hemochromatosis in two Baird's tapirs, were found among 19 cases examined histologically. Hemochromatosis has previously been reported in the horse, rhinoceros, and in one Brazilian tapir. Dietary factors were investigated but could not be confirmed to have contributed to the incidence of hemosiderosis and hemochromatosis in the three species of tapir in the Philadelphia Zoological Garden collection.

Molecular pathogenesis and clinical consequences of iron overload in liver cirrhosis.

PubMed

Sikorska, Katarzyna; Bernat, Agnieszka; Wroblewska, Anna

2016-10-01

The liver, as the main iron storage compartment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Excessive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease progression. We have also included literature on adjuvant therapeutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identification of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause significant improvement of liver functions in patients with iron overload. Phlebotomy can have beneficial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and available data suggest that it can be considered as target for adjuvant therapy in this condition.

Hereditary Neuropathy With Liability to Pressure Palsies: Diverse Phenotypes in Childhood.

PubMed

Harada, Yohei; Puwanant, Araya; Herrmann, David N

2016-12-01

Hereditary neuropathy with liability to pressure palsies (HNPP) is a rare autosomal-dominant disorder that most commonly produces recurrent painless focal sensory and motor neuropathies often preceded by minor, mechanical stress, or minor trauma. Herein, we report 2 pediatric cases of HNPP with atypical presentations; isolated muscle cramping and toe walking. Electrophysiologic testing disclosed multifocal sensorimotor polyneuropathy with slowing of sensory conduction velocities in both cases, which prompted PMP 22 gene deletion testing. Multifocal sensorimotor electrophysiologic abnormalities, with slowing of sensory conduction velocities should raise consideration of HNPP in childhood. These case reports emphasize that the diagnosis of HNPP in children requires a high index of suspicion.

Hereditary breast/ovarian cancer--pitfalls in genetic counseling.

PubMed

Dagan, E; Gershoni-Baruch, R

2001-10-01

Genetic counseling and risk assessment, given to women with a family history of breast/ovarian cancer, are regularly based on pedigree analysis. In the Ashkenazi Jewish population, hereditary breast/ovarian cancer is mainly attributed to three founder mutations, namely, 185delAG, 5382insC, and 6174delT, in BRCA1/2 genes. The overall frequency of these mutations, in the Jewish Ashkenazi population, is as high as 2.5%. Based on clinical and family history data, the results of BRCA molecular testing, in Ashkenazi individuals at risk, are appropriately anticipated in most cases. Here we report on five families, in which the segregation of BRCA1/2 mutations, in affected and unaffected family members, was unexpected, emphasizing the need to test, for founder mutations, every Ashkenazi individual at risk, irrespective of the genotype of affected family members. Ultimately, risk assessments and recommendations, in Ashkenazi women, should be invariably based on the results of genetic testing.

Fruit-induced FPIES masquerading as hereditary fructose intolerance.

PubMed

Fiocchi, Alessandro; Dionisi-Vici, Carlo; Cotugno, Giovanna; Koch, Pierluigi; Dahdah, Lamia

2014-08-01

Hereditary fructose intolerance (HFI) symptoms develop at first introduction of fruit during weaning. We report on an infant with suspected HFI who presented with repeated episodes of vomiting and hypotension after ingestion of fruit-containing meals. The first episode occurred at age 4 months. Despite negative genetic testing for HFI, strict avoidance of fruit ingestion resulted in lack of recurrence of symptoms. Oral-fructose-tolerance testing conducted with an apple mousse did not determine hypoglycemia or fructosuria but caused severe hypotension. Allergy evaluations were negative, and the history was diagnostic for fruit-induced food protein-induced enterocolitis syndrome. Because this non-immunoglobulin E-mediated gastrointestinal food hypersensitivity manifests as profuse, repetitive vomiting, often with diarrhea, leading to acute dehydration and lethargy, it may be misinterpreted as HFI. We advise pediatricians to consider food protein-induced enterocolitis syndrome in the differential diagnosis when there is a suspicion of HFI. Copyright © 2014 by the American Academy of Pediatrics.

The effect of the hemochromatosis (HFE) genotype on lead load and iron metabolism among lead smelter workers.

PubMed

Fan, Guangqin; Du, Guihua; Li, Huijun; Lin, Fen; Sun, Ziyong; Yang, Wei; Feng, Chang; Zhu, Gaochun; Li, Yanshu; Chen, Ying; Jiao, Huan; Zhou, Fankun

2014-01-01

Both an excess of toxic lead (Pb) and an essential iron disorder have been implicated in many diseases and public health problems. Iron metabolism genes, such as the hemochromatosis (HFE) gene, have been reported to be modifiers for lead absorption and storage. However, the HFE gene studies among the Asian population with occupationally high lead exposure are lacking. To explore the modifying effects of the HFE genotype (wild-type, H63D variant and C282Y variant) on the Pb load and iron metabolism among Asian Pb-workers with high occupational exposure. Seven hundred and seventy-one employees from a lead smelter manufacturing company were tested to determine their Pb intoxication parameters, iron metabolic indexes and identify the HFE genotype. Descriptive and multivariate analyses were conducted. Forty-five H63D variant carriers and no C282Y variant carrier were found among the 771 subjects. Compared with subjects with the wild-type genotype, H63D variant carriers had higher blood lead levels, even after controlling for factors such as age, sex, marriage, education, smoking and lead exposure levels. Multivariate analyses also showed that the H63D genotype modifies the associations between the blood lead levels and the body iron burden/transferrin. No C282Y variant was found in this Asian population. The H63D genotype modified the association between the lead and iron metabolism such that increased blood lead is associated with a higher body iron content or a lower transferrin in the H63D variant. It is indicated that H63D variant carriers may be a potentially highly vulnerable sub-population if they are exposed to high lead levels occupationally.

Disruption of the Hepcidin/Ferroportin Regulatory System Causes Pulmonary Iron Overload and Restrictive Lung Disease.

PubMed

Neves, Joana; Leitz, Dominik; Kraut, Simone; Brandenberger, Christina; Agrawal, Raman; Weissmann, Norbert; Mühlfeld, Christian; Mall, Marcus A; Altamura, Sandro; Muckenthaler, Martina U

2017-06-01

Emerging evidence suggests that pulmonary iron accumulation is implicated in a spectrum of chronic lung diseases. However, the mechanism(s) involved in pulmonary iron deposition and its role in the in vivo pathogenesis of lung diseases remains unknown. Here we show that a point mutation in the murine ferroportin gene, which causes hereditary hemochromatosis type 4 (Slc40a1 C326S ), increases iron levels in alveolar macrophages, epithelial cells lining the conducting airways and lung parenchyma, and in vascular smooth muscle cells. Pulmonary iron overload is associated with oxidative stress, restrictive lung disease with decreased total lung capacity and reduced blood oxygen saturation in homozygous Slc40a1 C326S/C326S mice compared to wild-type controls. These findings implicate iron in lung pathology, which is so far not considered a classical iron-related disorder. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Leber hereditary optic neuropathy: current perspectives

PubMed Central

Meyerson, Cherise; Van Stavern, Greg; McClelland, Collin

2015-01-01

Leber hereditary optic neuropathy (LHON) is one of the most common inherited optic neuropathies causing bilateral central vision loss. The disorder results from point mutations in mitochondrial DNA and subsequent mitochondrial dysfunction. The primary cell type that is lost in LHON is the retinal ganglion cell, which is highly susceptible to disrupted ATP production and oxidative stress. Inheritance of LHON follows that of mitochondrial genetics, and it has a highly variable clinical phenotype, as other genetic and environmental factors also play a role. Although LHON usually presents with isolated vision loss, some patients suffer other neurological sequelae. For ill-defined reasons, male LHON mutation carriers are more affected than females. Most LHON patients remain legally blind, but a small proportion can experience spontaneous partial recovery, often within the first year of symptom onset. Unfortunately, at this time there are no established curative interventions and treatment is largely supportive. Patients should be offered low vision services and counseled on mitigating risk factors for additional vision loss, such as smoking and consuming alcohol. Encouraging treatments currently undergoing investigation includes ubiquinone analogs, such as idebenone, as well as gene therapy and stem cells to restore ATP synthesis and provide neuroprotection to surviving retinal ganglion cells. PMID:26170609

Depressive symptoms associated with hereditary Alzheimer's disease: a case description.

PubMed

Contreras, Mónica Yicette Sánchez; Vargas, Paula Alejandra Osorio; Ramos, Lucero Rengifo; Velandia, Rafael Alarcón

The authors describe a family group studied by the Centro de Biología Molecular y Biotecnología, and the Clínica de la Memoria, las Demencias y el Envejecimiento (Universidad Tecnológica de Pereira, Colombia), and evaluate the association of depressive symptoms with Alzheimer's disease (AD). This family presented a hereditary pattern for AD characterized by an early onset of dementia symptoms, a long preclinical depressive course, and, once the first symptoms of dementia appeared, a rapid progression to severe cognitive function impairment. The authors found a high prevalence of depressive symptoms in this family and propose that the symptoms could be an important risk factor for developing AD in the presence of other risk factors such as the APOE E4 allele.

The Progress of Gene Therapy for Leber's Optic Hereditary Neuropathy.

PubMed

Zhang, Yong; Tian, Zhen; Yuan, Jiajia; Liu, Chang; Liu, Hong Li; Ma, Si Qi; Li, Bin

2017-01-01

Leber's Optic Hereditary Neuropathy (LHON) is a common cause of teenaged blindness in both eyes for which there is currently no effective treatment. In 1871, the German ophthalmologist Theodor Leber was the first to describe the clinical characteristics of his namesake disease, and through unremitting efforts over the past 100 years, researchers have continued to increase their understanding of LHON. In recent years, using gene therapy, several groups have obtained breakthroughs in the treatment of the disease. In this article, we will review the challenging journey that researchers faced towards our current understanding of LHON, and describe the transition of gene therapy research for LHON from the bench to bedside. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.