SLCO1B1 haplotypes are not associated with atorvastatin-induced myalgia in Brazilian patients with familial hypercholesterolemia

Purpose Recent studies reported the association of SLCO1B1 haplotypes with the development of musculoskeletal side effects during simvastatin use. The aim was to evaluate the pharmacogenetic association of SLCO1B1 haplotypes with atorvastatin-induced myalgia in a sample of individuals on high-dose atorvastatin regimens. Methods One hundred and forty-three patients with familial hypercholesterolemia were followed for at least 12 months while receiving atorvastatin. Genotypes for the rs2306283 (c.A388G) and rs4149056 (c.T521C) polymorphisms were detected by high-resolution melting analysis. These markers form four distinct haplotypes (*1A, *1B, *5 and *15). Results During the follow-up period, 14 (9.8%) patients developed myalgia and 16 (11.2%) presented CK levels more than 3 times the upper limit of the normal range. No association of the SLCO1B1 rs2306283 and rs4149056 genotypes or haplotypes with the presence of myalgia or creatine kinase (CK) values was found. Presence of rs2306283 AG+GG genotypes was not associated with increased risks of myalgia or abnormal CK values (OR 2.08, 95% CI 0.62-7.00, p=0.24 and OR 0.51, 95% CI 0.21-1.26, p=0.15 respectively). The presence of rs4149056 TC+CC genotypes was also not associated with increased risk of myalgia or abnormal CK values (OR 2.24, 95% CI 0.47-10.72, p=0.31 and OR 1.51, 95% CI 0.57-3.96, p=0.41 respectively). Conclusions Our findings reaffirm that the SLCO1B1 genetic risk appears to be greater in those patients receiving simvastatin compared with those receiving atorvastatin. This suggests that the importance of SLCO1B1 haplotypes depends on the specific statin that has been used.

Activation of cytokines corroborate with development of inflammation and autoimmunity in thromboangiitis obliterans patients

Thromboangiitis obliterans (TAO) is a segmental inflammatory occlusive disorder that affects the arm and leg arteries of young smokers. The immune system seems to play a critical role in the aetiology of TAO; however, knowledge of the aspects involved in the progression of vascular tissue inflammation and, consequently, the evolution of this disease is still limited. This study was carried out to investigate the cytokine levels of tumour necrosis factor (TNF)-a, interleukin (IL)-1 beta, IL-4, IL-17 and IL-23 in the plasma of TAO patients presenting with acute clinical manifestations. The study included 20 TAO patients (n = 10 women; n = 10 men) aged 3859 years under clinical follow-up, classified into two groups: (i) TAO former smokers (n = 11) and (ii) TAO active smokers (n = 9); the control groups included normal volunteer non-smokers (n = 10, active smokers (n = 10) and former smokers (n = 10). Patients' plasma samples were measured using the sandwich enzyme-linked immunosorbent assay. Statistical analyses were performed using the non-parametric MannWhitney U-test, with parameters significant at P < 0.05. The activities of all cytokines were different in groups of TAO patients when compared with normal controls, and decreased for control smokers. Increased levels of TNF-a, IL-1 beta, IL-4, IL-17 and IL-23 were significant in patients with TAO when compared to the controls (P < 0.005, all parameters). The results presented here indicate an increased production of cytokines in TAO, possibly contributing to the inflammatory response observed in the patients' vascular levels. In addition, the increased levels of IL-17 and IL-23 suggest that the disturbance of TAO is involved with mechanisms of autoimmunity. Thus, the discovery of IL-17 and its association with inflammation and autoimmune pathology has reshaped our viewpoint regarding the pathogenesis of TAO, which was based previously on the T helper type 1 (Th1)Th2 paradigm.

A familial case with interstitial 2q36 deletion: Variable phenotypic expression in full and mosaic state

Submicroscopic chromosomal anomalies play an important role in the etiology of craniofacial malformations, including midline facial defects with hypertelorism (MFDH). MFDH is a common feature combination in several conditions, of which Frontonasal Dysplasia is the most frequently encountered manifestation; in most cases the etiology remains unknown. We identified a parent to child transmission of a 6.2 Mb interstitial deletion of chromosome region 2q36.1q36.3 by array-CGH and confirmed by FISH and microsatellite analysis. The patient and her mother both presented an MFDH phenotype although the phenotype in the mother was much milder than her daughter. Inspection of haplotype segregation within the family of 2q36.1 region suggests that the deletion arose on a chromosome derived from the maternal grandfather. Evidences based on FISH, microsatellite and array-CGH analysis point to a high frequency mosaicism for presence of a deleted region 2q36 occurring in blood of the mother. The frequency of mosaicism in other tissues could not be determined. We here suggest that the milder phenotype observed in the proband's mother can be explained by the mosaic state of the deletion. This most likely arose by an early embryonic deletion in the maternal embryo resulting in both gonadal and somatic mosaicism of two cell lines, with and without the deleted chromosome. The occurrence of gonadal mosaicism increases the recurrence risk significantly and is often either underestimated or not even taken into account in genetic counseling where new mutation is suspected. (C) 2012 Elsevier Masson SAS. All rights reserved.

Longitudinal familial analysis of blood pressure involving parametric (co)variance functions

Abstract Background For analyzing longitudinal familial data we adopted a log-linear form to incorporate heterogeneity in genetic variance components over the time, and additionally a serial correlation term in the genetic effects at different levels of ages. Due to the availability of multiple measures on the same individual, we permitted environmental correlations that may change across time. Results Systolic blood pressure from family members from the first and second cohort was used in the current analysis. Measures of subjects receiving hypertension treatment were set as censored values and they were corrected. An initial check of the variance and covariance functions proposed for analyzing longitudinal familial data, using empirical semi-variogram plots, indicated that the observed trait dispersion pattern follows the assumptions adopted. Conclusion The corrections for censored phenotypes based on ordinary linear models may be an appropriate simple model to correct the data, ensuring that the original variability in the data was retained. In addition, empirical semi-variogram plots are useful for diagnosis of the (co)variance model adopted.

1031-1034delTAAC (Leu125Stop): a novel familial UBE3A mutation causing Angelman syndrome in two siblings showing distinct phenotypes

Background More than 50 mutations in the UBE3A gene (E6-AP ubiquitin protein ligase gene) have been found in Angelman syndrome patients with no deletion, no uniparental disomy, and no imprinting defect. Case Presentation We here describe a novel UBE3A frameshift mutation in two siblings who have inherited it from their asymptomatic mother. Despite carrying the same UBE3A mutation, the proband shows a more severe phenotype whereas his sister shows a milder phenotype presenting the typical AS features. Conclusions We hypothesized that the mutation Leu125Stop causes both severe and milder phenotypes. Potential mechanisms include: i) maybe the proband has an additional problem (genetic or environmental) besides the UBE3A mutation; ii) since the two siblings have different fathers, the UBE3A mutation is interacting with a different genetic variant in the proband that, by itself, does not cause problems but in combination with the UBE3A mutation causes the severe phenotype; iii) this UBE3A mutation alone can cause either typical AS or the severe clinical picture seen in the proband.

Gagueira desenvolvimental persistente familial: perspectivas genéticas

A gagueira é uma desordem da comunicação oral que tem uma característica multidimensional. A predisposição biológica no desenvolvimento da gagueira ainda não é bem compreendida, mas contribuições genéticas para esta predisposição são reforçadas tanto por referências à agregação familial da gagueira, quanto à gagueira familial, que têm aparecido na literatura há mais de 70 anos. Assim, procuramos estabelecer uma revisão quanto aos prováveis fatores genéticos envolvidos com a manifestação da gagueira desenvolvimental persistente familial. A identificação de genes relacionados à gagueira, bem como de alterações em suas estruturas (por exemplo, mutações), contribuem significativamente para sua compreensão. O modelo exato de transmissão da herança genética para a gagueira ainda não está claramente definida e, provavelmente pode ser diferente entre diferentes famílias e populações. As análises genômicas demonstram, concomitantemente, a relevância dos componentes genéticos envolvidos e sua complexidade, sugerindo assim tratar-se de uma doença poligênica, na qual diversos genes de efeitos variados podem estar envolvidos com o aumento da susceptibilidade de ocorrência da gagueira. O clínico deverá estar alerta ao fato de que uma criança com histórico familial positivo para gagueira poderá ter uma forte tendência a desenvolver o distúrbio de forma crônica. É importante que o clínico esteja atento, de modo a fornecer às famílias orientações precisas sobre o distúrbio. As avaliações objetivas e os tratamentos controlados têm um papel muito importante para o domínio da evolução do distúrbio.

Proctocolectomy and ileal J-pouch anal anastomosis on the surgical treatment of familial adenomatous polyposis and ulcerative colitis: analysis of 49 cases

OBJECTIVE: To evaluate the results of ileal J-pouch anal anastomosis in ulcerative colitis and familial adenomatous polyposis. METHOD: Retrospective analysis of medical records of 49 patients submitted to ileal J-pouch anal anastomosis. RESULTS: Ulcerative colitis was diagnosed in 65% and familial adenomatous polyposis in 34%. Mean age was 39.5 years. 43% were male. Among familial adenomatous polyposis, 61% were diagnosed with colorectal cancer. Thirty-one percent of patients with ulcerative colitis was submitted to a previous surgical approach and 21% of these had toxic megacolon. Average hospital stay was 10 days. Post-operative complications occurred in 50% of patients with ulcerative colitis and 29.4% with familial adenomatous polyposis. Intestinal diversion was performed in 100% of ulcerative colitis and 88% of familial adenomatous polyposis. Pouchitis occurred in eight cases (seven ulcerative colitis and one FAP), requiring excision of the pouch in three ulcerative colitis. Mortality rate was 7.6%: two cases of carcinoma on the pouch and two post-operative complications. Late post-operative complications occurred in 22.4%: six familial adenomatous polyposis and five ulcerative colitis). Two patients had erectile dysfunction, and one retrograde ejaculation. One patient with severe perineal dermatitis was submitted to excision of the pouch. Incontinence occurred in four patients and two reported soil. Mean bowel movement was five times a day. CONCLUSION: Ileal J-pouch anal anastomosis is a safe surgery with acceptable morbidity and good functional results, if well indicated and performed in referral centers.

Mercury-induced autoimmunity : Genetics and immunoregulation

The existence of immune self-tolerance allows the immune system to mount responses against infectious agents, but not against self-molecular constitutes. Although self-tolerance is a robust phenomenon, in some individuals as well as in experimental models, the self-tolerance breaks down and as a result, a self-destructive autoimmune disease emerges. The underlying mechanisms for the development of autoimmune diseases are not known, but genetic, environmental and immunological factors are suggested to be involved. In this thesis, we used murine mercury-induced autoimmunity to test this suggestion. In susceptible mice mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of IgG1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. In contrast, in resistant DBA/2 (H-2d) mice, none of these characteristics develop after exposure to mercury. By crossing and backcrossing mercury-resistant DBA/2 mice to mercury susceptible strains, we found that the resistance was inherited as a dominant trait in F1 hybrids and that one gene or a cluster of genes located in the H-2 loci determined the resistance to ANolA production, whereas resistance to the other characteristics was found to be controlled by two or three non-H-2 genes. We further put forward the “cryptic peptide hypothesis” to investigate whether mercury and another xenobiotic metal use similar pathway(s) to induce the H-2 linked production of ANolA. We found that while mercury stimulated ANolA synthesis in all H-2 susceptible (H-2s, H-2q and H-2f) mouse strains, silver induced only ANolA responses in H-2s and H-2q mice, but not in H-2f mice. Further studies showed that the resistance to silver-induced ANolA production in H-2f mice was inherited as a dominant trait. We next tested the proposition that mercury induces more adverse immunological effects in mouse strains, which are genetically prone to develop autoimmune diseases, using tight-skin 1 mice, an animal model for human Scleroderma. It was found that in this strain, mercury induced a strong immune activation with autoimmune characteristics, but did not accelerate the development of dermal fibrosis, a characteristic in Tsk/1 mice. Finally we addressed the Th1/Th2 cross-regulation paradigm by examining if a Th1-type of response could interact with a Th2-type of response if simultaneous induced in susceptible mice. Our findings demonstrated that mercury-induced autoimmunity (Th2-type) and collagen-induced arthritis (CIA) (Th1-type) can interact in a synergistic, antagonistic or additive fashion, depending on at which stage of CIA mercury is administered.

The KIT gene in familial mastocytosis

Familial cutaneous mastocytosis is an exceptional condition of unknown etiology. In this study we report the largest series of patients with familial cutaneous mastocytosis without other manifestations (18 affected subjects from seven unrelated families), and we investigate the role of germ-line KIT mutations in the pathogenesis of the disease. The mean age at onset was 5.4 years (range from birth to 22 years), and the clinical behavior was variable over a mean follow up period of 15.1 years (range 2-36): improvement in seven, stability in eight and worsening in the remaining three patients. The pattern of inheritance was compatible with an autosomal dominant trait with incomplete penetrance; a female preponderance (14 females vs 4 males, ratio 3.5:1) was noted; among the six women who have been pregnant at least once, three experienced important clinical changes during pregnancy. No germ-line mutation was found in the exons 10, 11, and 17 of the KIT proto-oncogene, which are the most commonly mutated exons in sporadic mastocytosis. However, in the majority of affected subjects we found the Met541Leu polymorphic variant of the KIT gene, which seems to confer a growth advantage to mast cells in vitro. This observation further suggests that the Met541Leu may be a predisposing factor of cutaneous mastocytosis, although it seems to be neither necessary nor sufficient for the development of the disease.

Narcolepsy: autoimmunity, effector T cell activation due to infection, or T cell independent, major histocompatibility complex class II induced neuronal loss?

Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of narcolepsy being an immune-mediated disease. Narcolepsy is associated with polymorphisms of the genes encoding T cell receptor alpha chain, tumour necrosis factor alpha and tumour necrosis factor receptor II. Moreover the rate of streptococcal infection is increased at onset of narcolepsy. The hallmarks of anti-self reactions in the tissue--namely upregulation of major histocompatibility antigens and lymphocyte infiltrates--are missing in the hypothalamus. These findings are questionable because they were obtained by analyses performed many years after onset of disease. In some patients with narcolepsy autoantibodies to Tribbles homolog 2, which is expressed by hypocretin neurons, have been detected recently. Immune-mediated destruction of hypocretin producing neurons may be mediated by microglia/macrophages that become activated either by autoantigen specific CD4(+) T cells or superantigen stimulated CD8(+) T cells, or independent of T cells by activation of DQB1*0602 signalling. Activation of microglia and macrophages may lead to the release of neurotoxic molecules such as quinolinic acid, which has been shown to cause selective destruction of hypocretin neurons in the hypothalamus.

Multiple small "imaging" branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?

Most screening programs for familial pancreatic cancer are currently based on endoscopic ultrasonography and/or magnetic resonance imaging (MRI). Cystic lesions, especially those suspicious for small intraductal pancreatic mucinous neoplasms (IPMNs) of the branch ducts, can be visualized in up to 40 % of individuals at risk, but their pathological importance in the setting of FPC is yet not well established. Individuals at risk from a prospective screening program for familial pancreatic cancer with small "imaging" IPMNs of the branch-duct type (BD-IPMN) who underwent pancreatic resection were analysed regarding clinico-pathological data and the locations of pancreatic lesions. Five of 125 individuals at risk who underwent screening had multiple small (size 2-10 mm) unicystic lesions and/or multicystic single lesions in the pancreatic body and tail suspicious for BD-IPMNs upon MRI imaging and decided to undergo surgical resection after interdisciplinary counselling, although none fulfilled the consensus criteria for IPMN resection. Histological examination revealed BD-IPMNs with low or moderate dysplasia of the gastric type in combination with multifocal PanIN2 and PanIN3 lesions in 4 individuals. The remaining patient had only tiny ductectasias in the pancreatic tail with multifocal PanIN 2 lesions in the entire gland and one PanIN3 lesion in the pancreatic head. Intriguingly, the location of the most dysplastic histological lesions (PanIN3) did not correspond to the preoperatively detected lesions and were not visible in preoperative imaging. In the setting of FPC, the presence of multiple small "imaging" BD-IPMNs may indicate the presence of high-grade PanIN lesions elsewhere in the pancreas.

Fatal myocardial infarction at 4.5 years in a case of homozygous familial hypercholesterolaemia

Management of homozygous familial hypercholesterolaemia is notoriously difficult. For these patients, LDL apheresis is considered the treatment of choice. Treatment initiation is advocated generally from the age of seven years onwards (Thompson et al., Atherosclerosis 198:247-255, 2008). Here, we present the case of a young girl from a large inbred family of Turkish descent with homozygous familial hypercholesterolaemia and fatal outcome at the early age of 4(1/2) years.In conclusion, this case suggests that management of homozygous familial hypercholesterolaemia may require earlier and more aggressive treatment, including LDL apheresis before the age of seven years.

Recurrent acute and chronic pancreatitis in two brothers with familial chylomicronemia syndrome

The chylomicronemia syndrome is well recognized as a rare etiologic factor of acute pancreatitis; however, whether hypertriglyceridemia can cause chronic pancreatitis (CP) remains unclear. We describe the long-time course of 2 brothers with the familial chylomicronemia syndrome caused by identical compound heterozygous mutations in the lipoprotein lipase (LPL) gene with markedly reduced LPL activity. Other etiologic factors were excluded, including mutations in the PRSS1, SPINK1, and CFTR gene. Although both brothers had recurrent acute pancreatitis and the same LPL genotype, CP became evident in only one patient. Progression to CP was associated with a more severe disease course. Thus, the chylomicronemia syndrome may cause CP in the absence of other known causative factors, and similar to alcoholic and hereditary CP, a more severe disease course is associated with disease progression.