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Affected Individuals (affected + individual)
Selected AbstractsCandidate genes and the behavioral phenotype in 22q11.2 deletion syndromeDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2008Sarah E. Prasad Abstract There is an overwhelming evidence that children and adults with 22q11.2 deletion syndrome (22q11.2DS) have a characteristic behavioral phenotype. In particular, there is a growing body of evidence that indicates an unequivocal association between 22q11.2DS and schizophrenia, especially in adulthood. Deletion of 22q11.2 is the third highest risk for the development of schizophrenia, with only a greater risk conferred by being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual. Both linkage and association studies of people with schizophrenia have implicated several susceptibility genes, of which three are in the 22q11.2 region; catechol- o -methyltransferase (COMT), proline dehydrogenase (PRODH), and Gnb1L. In addition, variation in Gnb1L is associated with the presence of psychosis in males with 22q11.2DS. In mouse models of 22q11.2DS, haploinsufficiency of Tbx1 and Gnb1L is associated with reduced prepulse inhibition, a schizophrenia endophenotype. The study of 22q11.2DS provides an attractive model to increase our understanding of the development and pathogenesis of schizophrenia and other psychiatric disorders in 22q11.2DS and in wider population. © 2008 Wiley-Liss, Inc. Dev Disabil Res Rev 2008;14:26,34. [source] How best to fight that nasty itch , from new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus to novel therapeutic approachesEXPERIMENTAL DERMATOLOGY, Issue 3 2005T. Biró While the enormous clinical and psychosocial importance of pruritus in many areas of medicine and the detrimental effects of chronic ,itch' on the quality of life of an affected individual are widely appreciated, the complexity of this sensation is still often grossly underestimated. The current Controversies feature highlights this complexity by portraying pruritus as a truly interdisciplinary problem at the crossroads of neurophysiology, neuroimmunology, neuropharmacology, protease research, internal medicine, and dermatology, which is combated most successfully if one keeps the multilayered nature of ,itch' in mind and adopts a holistic treatment approach , beyond the customary, frequently frustrane monotherapy with histamine receptor antagonists. In view of the often unsatisfactory, unidimensional, and altogether rather crude standard instruments for pruritus management that we still tend to use in clinical practice today, an interdisciplinary team of pruritus experts here critically examines recent progress in pruritus research that future itch management must take into consideration. Focusing on new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus, and discussing available neuropharmacological tools, specific research avenues are highlighted, whose pursuit promises to lead to novel, and hopefully more effective, forms of pruritus management. [source] Outcomes research: what is it and why does it matter?INTERNAL MEDICINE JOURNAL, Issue 3 2003M. Jefford Abstract Outcomes research is a broad umbrella term without a consistent definition. However it tends to describe research that is concerned with the effectiveness of public-health interventions and health services; that is, the outcomes of these services. Attention is frequently focused on the affected individual , with measures such as quality of life and preferences , but outcomes research may also refer to effectiveness of health-care delivery, with measures such as cost-effectiveness, health status and disease burden. The present review details the historical background of outcomes research to reveal the origins of its diversity. The value and relevance of outcomes research, commonly employed research techniques and examples of recent publications in the area are also discussed. (Intern Med J 2003; 33: 110,118) [source] The treatment of leprosy in 19th-century London: a case study from St Marylebone cemeteryINTERNATIONAL JOURNAL OF OSTEOARCHAEOLOGY, Issue 3 2009D. WalkerArticle first published online: 19 MAY 200 Abstract A young adult male, context [825], exhibiting a suite of proliferative and erosive skeletal changes, was excavated from the old burial ground of St Marylebone, London, in 2005 by the Museum of London Archaeology Service (MoLAS). Although pathognomonic rhinomaxillary changes were absent, a number of lesions were of a type previously recorded in individuals suffering from lepromatous leprosy, including resorption of the alveolar process of the maxillae and the digits of the right hand, osteomyelitis in the left ulna and collapse of the left ankle. Whilst this infectious disease was widespread in medieval Britain, it had declined by the 19th century, and has been identified in only one other post-medieval archaeological context. The right leg of [825] had been surgically amputated. This form of intervention was a recognised treatment for the complications of the disease, where neuropathic damage of limbs led to life-threatening infection. The healing of the amputation demonstrates the success of the operation, and the skill of the surgeon. Although the identity of the affected individual is unknown, burial within St Marylebone cemetery implies a level of status not frequently associated with leprosy sufferers in the past. Copyright © 2008 John Wiley & Sons, Ltd. [source] Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with inadvertent caries in infantsINTERNATIONAL JOURNAL OF PAEDIATRIC DENTISTRY, Issue 1 2007FELIX BLAKE Background., Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare systemic disease that is associated with early tooth decay. Case report., This report describes the case of a 3-year-old boy suffering from LCHADD. At the time of referral, extensive carious lesions of the subject's maxillary dentition necessitated the surgical removal of eight teeth. Preventive treatment for LCHADD involves a regular oral intake of glucose that is vital for the survival of the affected individual. In young infants, the glucose solution needs to be administered as often as every 3 h in order to prevent hypoglycaemia, leading to a local environment similar to that experienced in nursing bottle syndrome. While nursing bottle syndrome can be resolved by eliminating the sugar substrate and curtailing the feeding sessions, these alternatives are not available in cases of LCHADD. Conclusion., This report highlights this rare disease and emphasizes its dire consequences for the dentition. Prophylactic recommendations for high-risk children are reviewed. Familiarity with LCHADD allows this high-risk group of patients to be identified, and thus, ensures diligent prophylactic action. [source] Economic evaluation of neonatal screening for phenylketonuria and congenital hypothyroidismJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 11 2005EA Geelhoed Objective: To evaluate the costs and benefits of neonatal screening for phenylketonuria (PKU) and congenital hypothyroidism (CH). Neonatal screening for PKU and CH is common throughout the developed world. It represents a model of preventive care in that the screening procedure is simple and intellectual disability is otherwise irreversible. Changes in treatment and care, and in particular the advent of maternal PKU, require regular evaluation of a programme that also impacts on a large healthy population. Method: Costs of screening were based on the programme provided within Western Australia. Costs averted were derived using patterns of care currently adopted in Western Australia and applied according to historical patterns of intellectual disability for each condition. Results: A net saving of $A2.9 million is attributable to the programme annually. The economic benefits derive from the prevention of intellectual disability which otherwise incurs costs throughout the life of the affected individual. Maternal PKU represented a minor proportion of overall costs. Sensitivity analysis showed that the cost savings were robust, given changes in the levels of intellectual disability, but varied according to the discount rate. The result of a net saving was evident under all assumptions. Conclusion: Neonatal screening for PKU and CH is a cost saving use of resources and the emergence of maternal PKU has not had a significant effect on the economic outcomes. [source] Congenital central hypoventilation syndrome from past to future: Model for translational and transitional autonomic medicine,PEDIATRIC PULMONOLOGY, Issue 6 2009Debra E. Weese-Mayer Abstract The modern story of CCHS began in 1970 with the first description by Mellins et al., came most visibly to the public eye with the ATS Statement in 1999, and continues with increasingly fast paced advances in genetics. Affected individuals have diffuse autonomic nervous system dysregulation (ANSD). The paired-like homeobox gene PHOX2B is the disease-defining gene for CCHS; a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS. Approximately 90% of individuals with the CCHS phenotype will be heterozygous for a polyalanine repeat expansion mutation (PARM); the normal allele will have 20 alanines and the affected allele will have 24,33 alanines (genotypes 20/24,20/33). The remaining ,10% of individuals with CCHS will have a non-PARM (NPARM), in the PHOX2B gene; these will be missense, nonsense, or frameshift. CCHS and PHOX2B are inherited in an autosomal dominant manner with a stable mutation. Approximately 8% of parents of a CCHS proband will be mosaic for the PHOX2B mutation. A growing number of cases of CCHS are identified after the newborn period, with presentation from infancy into adulthood. An improved understanding of the molecular basis of the PHOX2B mutations and of the PHOX2B genotype/CCHS phenotype relationship will allow physicians to anticipate the clinical phenotype for each affected individual. To best convey the remarkable history of CCHS, and to describe the value of recognizing CCHS as a model for translational and transitional autonomic medicine, we present this review article in the format of a chronological story, from 1970 to the present day. Pediatr Pulmonol. 2009; 44:521,535. © 2009 Wiley-Liss, Inc. [source] Towards characterization of palmoplantar keratoderma caused by gain-of-function mutation in loricrin: analysis of a family and review of the literatureBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2006M.M. Gedicke Summary Loricrin keratoderma is an autosomal dominant palmoplantar keratoderma heterogeneous in clinical appearance. We report a family with diffuse ichthyosis and honeycomb palmoplantar keratoderma but no occurrence of pseudoainhums or autoamputations. All patients were born as collodion babies and displayed prominent knuckle pads. We identified the previously reported mutation 730insG in LOR, which elongates loricrin by 22 amino acids because of delayed termination. As pseudoainhums are missing in all patients of the family reported, we propose two compulsory features of loricrin keratoderma: (i) honeycomb palmoplantar keratoderma and (ii) diffuse ichthyosiform dermatosis. Therefore we suggest that the condition should be described clinically as ,honeycomb palmoplantar keratoderma with ichthyosis'. Furthermore, we have assessed the amounts of transcript of LOR using pyrosequencing. This revealed an equal expression of mutant and wild-type alleles of LOR in an affected individual. These findings further underline the gain-of-function theory for mutant LOR in loricrin keratoderma. [source] The neuroanatomy and neuroendocrinology of fragile X syndromeDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2004David Hessl Abstract Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene,brain,behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical features that are unique to this syndrome. In this article, we summarize studies focused on the neuroanatomy and neuroendocrinology of FXS. A review of structural imaging studies of individuals with the full mutation shows that several brain regions are enlarged, including the hippocampus, amygdala, caudate nucleus, and thalamus, even after controlling for overall brain volume. These regions mediate several cognitive and behavioral functions known to be aberrant in FXS such as memory and learning, information and sensory processing, and social and emotional behavior. Two regions, the cerebellar vermis, important for a variety of cognitive tasks and regulation of motor behavior, and the superior temporal gyrus, involved in processing complex auditory stimuli, are reported to be reduced in size relative to controls. Functional imaging, typically limited to females, has emphasized that individuals with FXS do not adequately recruit brain regions that are normally utilized by unaffected individuals to carry out various cognitive tasks, such as arithmetic processing or visual memory tasks. Finally, we review a number of neuroendocrine studies implicating hypothalamic dysfunction in FXS, including abnormal activation of the hypothalamic,pituitary,adrenal (HPA) axis. These studies may help to explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. In the future, innovative longitudinal studies to investigate development of neurobiologic and behavioral features over time, and ultimately empirical testing of pharmacological, behavioral, and even molecular genetic interventions using MRI are likely to yield significant positive changes in the lives of persons with FXS, as well as increase our understanding of the development of psychiatric and learning problems in the general population. MRDD Research Reviews 2004;10:17,24. © 2004 Wiley-Liss, Inc. [source] Familial paroxysmal exercise-induced dystonia: atypical presentation of autosomal dominant GTP-cyclohydrolase 1 deficiencyDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 6 2010RUSSELL C DALE Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced after many minutes of exercise, and was never present at rest, or on initiation of movements. In addition, family members suffered restless legs syndrome (RLS), depression, and adult-onset Parkinsonism. The index case had low cerebrospinal fluid neurotransmitters and pterins. The PED and RLS stopped on initiation of l -Dopa therapy. Both live family members were found to have a nonsense mutation (p.E84X) in exon 1 of the GTP-cyclohydrolase 1 (GCH-1) gene. We propose that GCH-1 mutations should be considered a genetic cause of familial PED, especially if additional clinical features of monoaminergic deficiency are present in affected individuals. [source] Internet forums: a self-help approach for individuals with schizophrenia?ACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2005H. Haker Objective:, To study if and how online self-help forums for individuals with schizophrenia are used. Method:, We analysed 1200 postings of 576 users in 12 international schizophrenia forums regarding communicative skills [fields of interest and self-help mechanisms (SHM)]. Results:, The forums were predominantly used by affected individuals, few relatives or friends. The fields of interest of the users concern daily problems of the illness like symptoms and emotional involvement with the illness. Self-help mechanisms mostly used are disclosure and providing information. Emotional interaction e.g. empathy or gratitude were comparatively rare. Conclusion:, Individuals suffering from schizophrenia participate in online self-help forums using the same SHM, discussing similar topics as do individuals with other psychiatric disorders as well as not affected relatives and caregivers. Therefore, this tool seems to be a useful approach to cope with alienation and isolation, albeit only a small number of schizophrenia forums are found in the Internet. [source] Understanding the impact of painful diabetic neuropathyDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S1 2003Cristian Quattrini Abstract Painful neuropathy is a common and often distressing complication of diabetes. It has considerable impact on the social and psychological well-being of affected individuals. There are two distinct forms of painful neuropathy: an acute and self-limiting form that resolves within a year or a chronic form that can go on for years. There are now a number of drugs available for the treatment of neuropathic pain. However, some may fail to respond to these drugs or may have unacceptable adverse side effects. When this is the case, the patient's quality of life can be severely affected. Health care professionals need to assess the full impact of painful neuropathy. In this article we review a number of instruments that are used to assess the severity of painful neuropathy and its impact on the quality of life. Copyright © 2003 John Wiley & Sons, Ltd. [source] Familial partial epilepsy with variable foci: A new family with suggestion of linkage to chromosome 22q12EPILEPSIA, Issue 9 2010José Morales-Corraliza Summary Familial partial epilepsy with variable foci (FPEVF) is an autosomal dominant form of partial epilepsy characterized by the presence of epileptic seizures originating from different cerebral lobes in different members of the same family. Linkage to chromosomes 22q12 and 2q36 has been reported, although only six families have been published. We studied a new FPEVF family including nine affected individuals. The phenotype in this family was similar to that previously described and consisted of nocturnal and daytime seizures with semiology suggesting a frontal lobe origin. A video-EEG (electroencephalography) recording of the proband's seizures is presented and revealed hyperkinetic seizures of frontal lobe origin preceded by left frontal spikes. We excluded linkage to chromosome 2q36 and found a suggestion of linkage to chromosome 22q12 with a lod score of 2.64 (, = 0) for marker D22S689. [source] Validation of a brief screening instrument for the ascertainment of epilepsyEPILEPSIA, Issue 2 2010Ruth Ottman Summary Purpose:, To validate a brief screening instrument for identifying people with epilepsy in epidemiologic or genetic studies. Methods:, We designed a nine-question screening instrument for epilepsy and administered it by telephone to individuals with medical record,documented epilepsy (lifetime history of ,2 unprovoked seizures, n = 168) or isolated unprovoked seizure (n = 54), and individuals who were seizure-free on medical record review (n = 120), from a population-based study using Rochester Epidemiology Project resources. Interviewers were blinded to record-review findings. Results:, Sensitivity (the proportion of individuals who screened positive among affected individuals) was 96% for epilepsy and 87% for isolated unprovoked seizure. The false positive rate (FPR, the proportion who screened positive among seizure-free individuals) was 7%. The estimated positive predictive value (PPV) for epilepsy was 23%, assuming a lifetime prevalence of 2% in the population. Use of only a single question asking whether the subject had ever had epilepsy or a seizure disorder resulted in sensitivity 76%, FPR 0.8%, and estimated PPV 66%. Subjects with epilepsy were more likely to screen positive with this question if they were diagnosed after 1964 or continued to have seizures for at least 5 years after diagnosis. Discussion:, Given its high sensitivity, our instrument may be useful for the first stage of screening for epilepsy; however, the PPV of 23% suggests that only about one in four screen-positive individuals will be truly affected. Screening with a single question asking about epilepsy yields a higher PPV but lower sensitivity, and screen-positive subjects may be biased toward more severe epilepsy. [source] Quantitative EEG Asymmetry Correlates with Clinical Severity in Unilateral Sturge-Weber SyndromeEPILEPSIA, Issue 1 2007Laura A. Hatfield Summary:,Purpose: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder with vascular malformations of the skin, brain, and eye. SWS results in ischemic brain injury, seizures, and neurologic deficits. We hypothesized that a decrease in quantitative EEG (qEEG) power, on the affected side, correlates with clinical severity in subjects with SWS. Methods: Fourteen subjects had 16-channel scalp EEG recordings. Data were analyzed using fast Fourier transform and calculation of power asymmetry. Blinded investigators assigned scores for clinical neurological status and qualitative assessment of MRI and EEG asymmetry. Results: The majority of subjects demonstrated lower total power on the affected side, usually involving all four frequency bands (delta, theta, alpha, and beta). qEEG asymmetry correlated strongly with neurologic clinical severity scores and MRI asymmetry scores. qEEG data generally agreed with the MRI evidence of regional brain involvement. In MRI-qEEG comparisons that did not agree, decreased power on qEEG in a brain region not affected on MRI was more likely to occur in subjects with more severe neurologic deficits. Conclusions: qEEG provides an objective measure of EEG asymmetry that correlates with clinical status and brain asymmetry seen on MRI. These findings support the conclusion that qEEG reflects the degree and extent of brain involvement and dysfunction in SWS. qEEG may potentially be a useful tool for early diagnosis and monitoring of disease progression in SWS. qEEG may prove useful, in severely affected individuals with SWS, for determining regions of brain dysfunction. [source] Autosomal Dominant Early-onset Cortical Myoclonus, Photic-induced Myoclonus, and Epilepsy in a Large PedigreeEPILEPSIA, Issue 10 2006Elena Gardella Summary:,Purpose: Cortical tremor, a form of rhythmic cortical myoclonus (rhythmic CM), and epilepsy have been described in families with autosomal dominant inheritance. Linkage analyses revealed two putative loci on chromosome 2p and 8q. Clinical photosensitivity was not a prominent feature in such families. We describe a large Italian family with rhythmic CM, photosensitivity, and epilepsy. Methods: Twenty-three individuals of a five-generation family were studied. Linkage analyses for the loci on chromosome 2p11.1 and 8q23.3 were performed. Results: Of the 23 studied family members, 16 were affected. Rhythmic CM of childhood onset was present in all 16 individuals (onset ranging from 3 to 12 years), was associated with photic-induced myoclonic jerks in seven, and with epileptic seizures in six (onset ranging from 23 to 34 years). Five children of the V generation manifested also episodes of arousal with generalized tremor in early infancy ("tremulous arousals"). Jerk-locked back-averaging of rhythmic CM of six affected individuals, documented a premyoclonic EEG correlate. C-reflex at rest was present in two affected adults. Linkage analyses excluded mapping to the 2p11.1 and 8q23.3 loci. Conclusions: Clinical variability and severity of the phenotypes in this family are in line with those of previously described pedigrees with autosomal dominant cortical myoclonus and epilepsy. In this family, a progression of symptoms was found: rhythmic CM and tremulous arousals occurred in childhood, whereas visually induced manifestations and epileptic seizures occurred during adolescence,adulthood. Exclusion of linkage to the two known loci is consistent with genetic heterogeneity of such familial clustering of symptoms. [source] Lymphoscintigraphy of draught horses with chronic progressive lymphoedemaEQUINE VETERINARY JOURNAL, Issue 2 2006H. E. V. De Cock Summary Reasons for performing study: Early diagnosis of chronic progressive lymphoedema (CPL) may result in more effective interventions and provide a basis for further investigation of whether early diagnosis could be used as a means of eliminating potential genetic influences by cessation of breeding from affected individuals. Hypothesis: Lymphoscintigraphy may be useful in draught horses to differentiate early lesions of CPL from other conditions in the pastern region. Methods: Forelimbs of 2 normal and 5 CPL-affected draught horses were evaluated with lymphoscintigraphy. Results: Lymphoscintigraphy showed clearly the presence of interstitial fluid stasis and delayed lymphatic drainage in the affected extremities of diseased animals in contrast to normal animals of these breeds. The rate of decreased clearance of a particulate radiopharmaceutical from the tissues was related positively to the severity of clinical signs. Conclusions and potential relevance: Our findings support the hypothesis that lymph stasis is probably responsible for the progressive swelling and concurrent skin lesions observed in association with CPL in draught horses. Lymphoscintigraphy should also prove useful in diagnosis of CPL in draught horses, even in the mild stages of the disease; such early diagnosis may result in more effective intervention. [source] Genetic aspects of the Paget's disease of bone: concerns on the introduction of DNA-based tests in the clinical practice.EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2010Advantages, disadvantages of its application Eur J Clin Invest 2010; 40 (7): 655,667 Abstract Background, A large amount of genetic studies have clearly demonstrated the existence of a genetic susceptibility to Paget's disease of bone (PDB). Although the disease is genetically heterogeneous, the SQSTM1/p62 gene, encoding a protein with a pathophysiological role in both osteoclast differentiation and activity, has been found worldwide to harbour germline mutations in most of the PDB patients from geographically distant populations originating from different areas of Europe, both in sporadic and familial cases. Materials and Methods, Thus, SQSTM1/p62 gene mutations may confer an increased lifetime risk of developing PDB. Results, Several different genotype-phenotype analyses have shown a high penetrance for such mutations. These results suggest the opportunity to perform genetic testing in affected individuals and then, after the identification of a SQSTM1/p62 gene germline mutation, in their relatives as a real and concrete strategy to increase the diagnostic sensitivity in most of the asymptomatic mutant carriers. However, it is of note to underlie that an incomplete penetrance for SQSTM1/p62 gene mutations has also been reported. Conclusions, In light of all these contradictory evidences, a review on whether, when and why apply the DNA test to those subjects, its interpretation and clinical application is necessary. In fact, a growing number of preventive care options are now available to affected patients and families and the process of systematically assessing risk is becoming increasingly important for both patients and physicians. [source] The science of endothelin-1 and endothelin receptor antagonists in the management of pulmonary arterial hypertension: current understanding and future studiesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2009N. J. Davie Abstract Pathological vascular remodelling is a key contributor to the symptomatology of pulmonary arterial hypertension (PAH), and reversing this process may offer the best hope for improving this debilitating condition. The vascular remodelling process is believed to be due to endothelial cell dysfunction and to involve altered production of endothelial cell-derived vasoactive mediators. The observation that circulating plasma levels of the vasoactive peptide endothelin (ET)-1 are raised in patients with PAH, and that ET-1 production is increased in the pulmonary tissue of affected individuals, makes it a particularly interesting target for a therapeutic intervention in PAH. Clinical trials with ET receptor antagonists (ETRAs) show that they provide symptomatic benefit in patients with PAH, thereby proving the clinical relevance of the ET system as a therapeutic target. In this paper, we review the role of ET-1 together with the available data on the roles of the specific ET receptors and ETRAs in PAH. In particular, we discuss the possible role of ET receptor selectivity in the vascular remodelling process in PAH and whether selective ETA or nonselective ETA/ETB blockade offers the greatest potential to improve symptoms and alter the clinical course of the disease. [source] Mineral metabolism disturbances in patients with chronic kidney diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 8 2007B. Kestenbaum Abstract Background Kidney disease, especially chronic kidney disease (CKD), is a worldwide public health problem with serious adverse health consequences for affected individuals. Secondary hyperparathyroidism, a disorder characterized by elevated serum parathyroid hormone levels, and alteration of calcium and phosphorus homeostasis are common metabolic complications of CKD that may impact cardiovascular health. Materials and methods Here, we systematically review published reports from recent observational studies and clinical trials that examine markers of altered mineral metabolism and clinical outcomes in patients with CKD. Results Mineral metabolism disturbances begin early during the course of chronic kidney disease, and are associated with cardiovascular disease and mortality in observational studies. Vascular calcification is one plausible mechanism connecting renal-related mineral metabolism with cardiovascular risk. Individual therapies to correct mineral metabolism disturbances have been associated with clinical benefit in some observational studies; clinical trials directed at more comprehensive control of this problem are warranted. Conclusions There exists a potential to improve outcomes for patients with CKD through increased awareness of the Bone Metabolism and Disease guidelines set forth by the National Kidney Foundation,Kidney Disease Outcomes Quality Initiative. Future studies may include more aggressive therapy with a combination of agents that address vitamin D deficiency, parathyroid hormone and phosphorus excess, as well as novel agents that modulate circulating promoters and inhibitors of calcification. [source] Novel SDHD germ-line mutations in pheochromocytoma patientsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2007C. Neumayer Abstract Background,SDHD germ-line mutations predispose to pheochromocytoma (PCC) and paraganglioma (PGL). Material and methods, The incidence and types of SDHD germ-line mutations are determined in 70 patients with apparently sporadic adrenal and extra-adrenal PCC. Results,SDHD sequence variants were identified in the germ line of five patients. Two of three novel mutations were in exon 1 and one in exon 3. One patient had a codon 1 missense mutation (M1K) and a concurrent 3-bp deletion in intron 1. Three of 10 family members had only the exon 1 mutation, whereas one had only the intron 1 mutation. The other exon 1 mutation resulted from a deletion of nucleotides 28,33 with a 12-bp in-frame insertion (c.28_33 del ins TAGGAGGCCCTA). This mutation generated a premature stop codon after codon 9 and was also present in the brother who had a bilateral PCC. The third patient with a carotid body tumour, with an abdominal and a thoracic PGL had a 12-bp deletion in exon 3 (codons 91,94, c.271_282 del). Her father carried the same mutation and had bilateral carotid body tumours. Two further patients, one with six PGL, carried a previously described H50R polymorphism, whose disease-specific relevance is currently unclear. The three patients with bona fide SDHD mutations were younger than those without germ-line mutations. Conclusion,SDHD germ-line mutations are rare in patients with PCC, but their identification is an important prerequisite for the clinical care and appropriate management of affected individuals and their families. [source] Ultimate success in epilepsy , the patient's perspectiveEUROPEAN JOURNAL OF NEUROLOGY, Issue 2005J. W. Sander Most people with epilepsy can live outwardly normal lives, but fear about impending seizures, driving restrictions, lack of independence, employment and social problems, medication-related adverse effects and the presence of cognitive or psychiatric complications are all concerns readily identified by affected individuals. While seizure control is the overriding goal of treatment, it is essential to realize the importance that patients place on other aspects of daily functioning. While many of the concerns identified by patients can only be managed by improved social support, others (e.g. neuropsychological impairment, medication-related adverse events, cognitive impairment, sleep disturbance) may be amenable to therapy (if available) or to the selection of a more appropriate antiepileptic drug. Each antiepileptic drug has a unique pharmacodynamic and tolerability profile. Awareness by the treating clinician of the pharmacological profile of each drug may help to minimize unwanted treatment-related effects and possibly improve the outcome of treatment from an epilepsy patient's perspective. Therefore, in order to achieve true treatment success, clinicians need to understand how individuals perceive their disorder and, where possible, address those factors that adversely affect patient quality of life. For the person with epilepsy, successful treatment involves beneficial effects on social, vocational and psychological function. This extends beyond seizure control to freedom from the fear associated with seizures, confidence in pharmacological therapy and improvements in health-related quality of life. [source] A genome-wide quantitative trait loci scan of neurocognitive performances in families with schizophreniaGENES, BRAIN AND BEHAVIOR, Issue 7 2010Y.-J. Lien Patients with schizophrenia frequently display neurocognitive dysfunction, and genetic studies suggest it to be an endophenotype for schizophrenia. Genetic studies of such traits may thus help elucidate the biological pathways underlying genetic susceptibility to schizophrenia. This study aimed to identify loci influencing neurocognitive performance in schizophrenia. The sample comprised of 1207 affected individuals and 1035 unaffected individuals of Han Chinese ethnicity from 557 sib-pair families co-affected with DSM-IV (Diagnostic and Statistical Manual, Fourth Edition) schizophrenia. Subjects completed a face-to-face semi-structured interview, the continuous performance test (CPT) and the Wisconsin card sorting test (WCST), and were genotyped with 386 microsatellite markers across the genome. A series of autosomal genome-wide multipoint nonparametric quantitative trait loci (QTL) linkage analysis were performed in affected individuals only. Determination of genome-wide empirical significance was performed using 1000 simulated genome scans. One linkage peak attaining genome-wide significance was identified: 12q24.32 for undegraded CPT hit rate [nonparametric linkage z (NPL-Z) scores = 3.32, genome-wide empirical P = 0.03]. This result was higher than the peak linkage signal obtained in the previous genome-wide scan using a dichotomous diagnosis of schizophrenia. The identification of 12q24.32 as a QTL has not been consistently implicated in previous linkage studies on schizophrenia, which suggests that the analysis of endophenotypes provides additional information from what is seen in analyses that rely on diagnoses. This region with linkage to a particular neurocognitive feature may inform functional hypotheses for further genetic studies for schizophrenia. [source] Association evidence of schizophrenia with distal genomic region of NOTCH4 in Taiwanese familiesGENES, BRAIN AND BEHAVIOR, Issue 6 2007C.-M. Liu Evidence for association with schizophrenia has been reported for NOTCH4, although results have been inconsistent. Previous studies have focused on polymorphisms in the 5, promoter region and first exon of NOTCH4. Our aim was to test the association of the entire genomic region of NOTCH4 in 218 families with at least two siblings affected by schizophrenia in Taiwan. We genotyped seven single nucleotide polymorphisms (SNPs) of this gene, with average intermarker distances of 5.3 kb. Intermarker linkage disequilibrium (LD) was calculated using gold software, and single-locus and haplotype association analyses were performed using transmit software. We found that the T allele of SNP rs2071285 (P= 0.035) and the G allele of SNP rs204993 (P= 0.0097) were significantly preferentially transmitted to the affected individuals in the single-locus association analysis. The two SNPs were in high LD (D, > 0.8). Trend for overtransmission was shown for the T-G haplotype of the two SNPs to affected individuals (P= 0.053), with the A-A haplotype significantly undertransmitted (P= 0.034). The associated region distributed across the distal portion of the NOTCH4 gene and overlapped with the genomic region of the G-protein signaling modulator 3 and pre-B-cell leukemia transcription factor 2. In summary, we found modest association evidence between schizophrenia and the distal genomic region of NOTCH4 in this Taiwanese family sample. Further replication for association with the distal genomic region of NOTCH4 is warranted. [source] PEL: an unbiased method for estimating age-dependent genetic disease risk from pedigree data unselected for family historyGENETIC EPIDEMIOLOGY, Issue 5 2009F. Alarcon Abstract Providing valid risk estimates of a genetic disease with variable age of onset is a major challenge for prevention strategies. When data are obtained from pedigrees ascertained through affected individuals, an adjustment for ascertainment bias is necessary. This article focuses on ascertainment through at least one affected and presents an estimation method based on maximum likelihood, called the Proband's phenotype exclusion likelihood or PEL for estimating age-dependent penetrance using disease status and genotypic information of family members in pedigrees unselected for family history. We studied the properties of the PEL and compared with another method, the prospective likelihood, in terms of bias and efficiency in risk estimate. For that purpose, family samples were simulated under various disease risk models and under various ascertainment patterns. We showed that, whatever the genetic model and the ascertainment scheme, the PEL provided unbiased estimates, whereas the prospective likelihood exhibited some bias in a number of situations. As an illustration, we estimated the disease risk for transthyretin amyloid neuropathy from a French sample and a Portuguese sample and for BRCA1/2 associated breast cancer from a sample ascertained on early-onset breast cancer cases. Genet. Epidemiol. 33:379,385, 2009. © 2008 Wiley-Liss, Inc. [source] Interpreting analyses of continuous covariates in affected sibling pair linkage studiesGENETIC EPIDEMIOLOGY, Issue 6 2007Silke Schmidt Abstract Datasets collected for linkage analyses of complex human diseases often include a number of clinical or environmental covariates. In this study, we evaluated the performance of three linkage analysis methods when the relationship between continuous covariates and disease risk or linkage heterogeneity was modeled in three different ways: (1) The covariate distribution is determined by a quantitative trait locus (QTL), which contributes indirectly to the disease risk; (2) the covariate is not genetically determined, but influences the disease risk through statistical interaction with a disease susceptibility locus; (3) the covariate distribution differs in families linked or unlinked to a particular disease susceptibility locus. We analyzed simulated datasets with a regression-based QTL analysis, a nonparametric analysis of the binary affection status, and the ordered subset analysis (OSA). We found that a significant OSA result may be due to a gene that influences variability in the population distribution of a continuous disease risk factor. Conversely, a regression-based QTL analysis may detect the presence of gene-environment (G × E) interaction in a sample of primarily affected individuals. The contribution of unaffected siblings and the size of baseline lod scores may help distinguish between QTL and G × E models. As illustrated by a linkage study of multiplex families with age-related macular degeneration, our findings assist in the interpretation of analysis results in real datasets. They suggest that the side-by-side evaluation of OSA and QTL results may provide important information about the relationship of measured covariates with either disease risk or linkage heterogeneity. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc. [source] Exploring the "two-hit hypothesis" in NF2: Tests of two-hit and three-hit models of vestibular schwannoma developmentGENETIC EPIDEMIOLOGY, Issue 4 2003Ryan Woods Abstract Neurofibromatosis 2 (NF2) is a genetic disease that occurs in approximately 1 in 40,000 live births. Almost all affected individuals develop bilateral tumors of Schwann cells that surround the vestibular nerves; these tumors are known as vestibular schwannomas (VS). Evidence from molecular genetic studies suggests that at least two mutations are involved in formation of VS in patients with NF2. Several authors proposed probabilistic models for this process in other tumors, and showed that such models are consistent with incidence data. We evaluated two different probabilistic models for a "2-hit" hypothesis for VS development in NF2 patients, and we present results from fitting these models to incidence data. Molecular evidence does not exclude the possibility that additional hits are necessary for the development of VS, and we also assessed a "3-hit" model for tumor formation. The "3-hit" model fits the data marginally better than one of the "2-hit" models and much better than the other "2-hit" model. Our findings suggest that more than two mutations may be necessary for VS development in NF2 patients. Genet Epidemiol 24:265,272, 2003. © 2003 Wiley-Liss, Inc. [source] Optimal designs for estimating penetrance of rare mutations of a disease-susceptibility geneGENETIC EPIDEMIOLOGY, Issue 3 2003Gail Gong Abstract Many clinical decisions require accurate estimates of disease risks associated with mutations of known disease-susceptibility genes. Such risk estimation is difficult when the mutations are rare. We used computer simulations to compare the performance of estimates obtained from two types of designs based on family data. In the first (clinic-based designs), families are ascertained because they meet certain criteria concerning multiple disease occurrences among family members. In the second (population-based designs), families are sampled through a population-based registry of affected individuals called probands, with oversampling of probands whose families are more likely to segregate mutations. We generated family structures, genotypes, and phenotypes using models that reflect the frequencies and penetrances of mutations of the BRCA1/2 genes. We studied the effects of risk heterogeneity due to unmeasured, shared risk factors by including risk variation due to unmeasured genotypes of another gene. The simulations were chosen to mimic the ascertainment and selection processes commonly used in the two types of designs. We found that penetrance estimates from both designs are nearly unbiased in the absence of unmeasured shared risk factors, but are biased upward in the presence of such factors. The bias increases with increasing variation in risks across genotypes of the second gene. However, it is small compared to the standard error of the estimates. Standard errors from population-based designs are roughly twice those from clinic-based designs with the same number of families. Using the root-mean-square error as a measure of performance, we found that in all instances, the clinic-based designs gave more accurate estimates than did the population-based designs with the same numbers of families. Rough variance calculations suggest that clinic-based designs give more accurate estimates because they include more identified mutation carriers. Genet Epidemiol 24:173,180, 2003. © 2003 Wiley-Liss, Inc. [source] True and false positive peaks in genomewide scans: The long and the short of itGENETIC EPIDEMIOLOGY, Issue 4 2001Peter Visscher Abstract When performing a genome scan in linkage or linkage disequilibrium studies to detect loci underlying complex or quantitative traits, it is important to attempt to distinguish between true and false positives using the appropriate statistical methods. There has been some controversy in the literature regarding the use of the length of a positive peak, i.e., the length of a chromosome region displaying identity-by-descent in linkage studies among affected individuals or the length of a continuous chromosome region for which the test statistic is above a certain threshold. We show in this study, by reasoning and by simulation studies, that conditional on the strength of evidence for a locus affecting a trait of interest, i.e., conditional on the peak height of a test statistic, there is no information in the length of the peak. Our finding has implications for linkage and association studies. Genet. Epidemiol. 20:409,414, 2001. © 2001 Wiley-Liss, Inc. [source] Role of the Rap1 GTPase in astrocyte growth regulationGLIA, Issue 3 2003Anthony J. Apicelli Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome in which affected individuals develop nervous system abnormalities that might reflect astrocyte dysfunction. The TSC2 gene product, tuberin, encodes a GTPase-activating protein (GAP) domain, which regulates the activity of Rap1 in vitro. To determine whether dysregulated Rap1, resulting from TSC2 inactivation, leads to increased astrocyte proliferation in vivo, we generated transgenic mice expressing activated Rap1G12V specifically in astrocytes. We observed no statistically significant difference in the number of astrocytes between wild-type and GFAP-Rap1G12V littermates in vivo; however, during log-phase growth, we observed a 25% increase in GFAP-Rap1G12V astrocyte doubling times compared to wild-type controls. This decreased proliferation was associated with delayed MAP kinase, but not AKT, activation. Lastly, to determine whether constitutive Rap1 activation could reverse the increased astrocyte proliferation observed in transgenic mice expressing oncogenic RasG12V, we generated transgenic mice expressing both RasG12V and Rap1G12V in astrocytes. These double transgenic mice showed a striking reversion of the RasG12V astrocyte growth phenotype. Collectively, these results argue that the tumor suppressor properties of tuberin are unlikely to be related to Rap1 inactivation and that Rap1 inhibits mitogenic Ras pathway signaling in astrocytes. GLIA 42:225,234, 2003. © 2003 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||||||||