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1
Miller-Hodges, Eve, et Christopher Mitchell. The patient with Wilms tumour. Sous la direction de Giuseppe Remuzzi. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0173_update_001.
Texte intégralRésumé :
Wilms tumour is the most common renal tumour in childhood. It is most commonly identified as a large abdominal mass. Treatment by surgical removal and chemotherapy, and radiotherapy in more advanced stages, is curative in most patients. Five year survival is over 90%. Survivors may be at some risk from long term complications including the effects of radiotherapy on the remaining kidney.A small minority of Wilms tumours occur in individuals with an underlying mutation in the WT1 gene. WT1 mutations may also cause developmental abnormalities of the genitourinary system, and renal disease including steroid-resistant nephrotic syndrome / focal segmental glomerulosclerosis.
2
Mammoser, Aaron. Infiltrative Astrocytomas. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0126.
Texte intégralRésumé :
Diffuse astrocytomas are WHO grade II astrocytomas that are distinguished from other WHO grade I and II astrocytomas because they are infiltrative, incurable, and have an intrinsic tendency to undergo malignant transformation to an anaplastic astrocytoma or a secondary glioblastoma. They are most often diagnosed in young adults in their 30s and 40s, and have a genetic profile that is different than primary glioblastoma. Anaplastic astrocytomas frequently arise from diffuse astroctyomas and share many of the same molecular abnormalities but tend to acquire more as they inevitably progress to glioblastoma. Recent studies identified mutations associated with WHO grade II and III tumors that predict a progression to a secondary glioblastoma with a better overall prognosis than primary glioblastoma. WHO grade II and III tumors that do not exhibit this typical mutation pattern often behave more aggressively than their counterparts, with a worse prognosis than higher grade tumors with a more favorable genotype.
3
Syrris, Petros, et Alexandros Protonotarios. Arrhythmogenic right ventricular cardiomyopathy : genetics. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0359.
Texte intégralRésumé :
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder of the heart muscle which is typically inherited in an autosomal dominant manner. It is believed to be familial in over 50% of cases. A recessive mode of inheritance has also been reported in syndromic cases with cardiocutaneous features. The classic form of the disorder is considered to be ‘a disease of the desmosome’ as pathogenic variants have been identified in five genes encoding key desmosomal proteins: plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. Mutations in these genes account for 30–50% of ARVC cases. A further eight non-desmosomal genes have also been implicated in the pathogenesis of the disorder but only account for rare cases. Studies of patients with ARVC-associated gene mutations have revealed marked genetic heterogeneity and very limited genotype–phenotype correlation. Disease expression often varies significantly amongst individuals carrying the same mutation. It has been proposed that the presence of more than one sequence variant is required to determine overt clinical disease and patients with multiple variants have a more severe phenotype compared to single variant carriers. Identification of a potentially pathogenic variant comprises a major criterion in the diagnosis of ARVC but informative integration of genetic testing into clinical practice remains challenging. Gene testing should be used to identify asymptomatic family members at risk and only aids diagnosis in cases of high suspicion for ARVC, along with other evident features of the disease already present. However, genetic findings should be used with caution in clinical practice and their interpretation must be performed in expert centres.
4
Walsh, Richard A. Parkinson’s Disease or Essential Tremor ? Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780190607555.003.0016.
Texte intégralRésumé :
Fragile X-associated tremor ataxia syndrome is a heredodegenerative syndrome that presents in older men as a tremor syndrome with less prominent ataxia and cognitive impairment initially. The underlying genetic cause, a premutation in the FMR1 gene, results in a toxic accumulation of mRNA. The full mutation, a triple-repeat expansion of more than 200 CGG repeats, gives rise to a reduction in FMR1 protein expression and fragile X, a neurodevelopmental disorder that may be identified in successive male generations. The prevalence of carrier status is high in the general population, and it is likely that most movement disorders clinics will have one or more patients with this syndrome, potentially carrying a label of essential tremor.
5
Quain, Angela, et Anne M. Comi. Sturge-Weber Syndrome and Related Cerebrovascular Malformation Syndromes. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0112.
Texte intégralRésumé :
Sturge-Weber syndrome is a rare disorder presenting with a capillary malformation, better known as a port-wine birthmark, on the upper face, glaucoma, and a leptomeningeal angioma. Most children develop seizures and strokes, with variable degrees of neurodevelopmental impairments including hemiparesis, visual field deficits, cognitive deficits, epilepsy, and migraines. In 2013, a somatic activating mutation in GNAQ was identified in the capillary malformations and leptomeningeal angiomas of Sturge-Weber patients. In the diagnosis of Sturge-Weber syndrome, contrast-enhanced imaging is essential to the diagnosis of brain involvement. Functional imaging has demonstrated impaired venous drainage and a role for seizures in exacerbating perfusion deficits. Aggressive seizure management is fundamental to treatment. Some data supports the use of low-dose aspirin to reduce the occurrence of strokelike episodes and seizures.
6
Mammoser, Aaron. Primary and Secondary Glioblastoma. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0127.
Texte intégralRésumé :
Glioblastoma, formerly glioblastoma multiforme, is synonymous with WHO grade IV astrocytoma and is the most commonly diagnosed astrocytoma; it carries with it significant clinical, histologic, and molecular heterogeneity, with subtypes of the tumor and important new mutations associated with it characterized over the previous decade. Gene expression profiling has identified four tumor subgroups associated with specific mutational patterns, age of onset, and prognosis. The discovery of isocitrate dehydrogenase (IDH) mutations has led to further delineation between primary and secondary glioblastoma. Despite promising new investigational treatments, glioblastoma remains an incurable and fatal tumor.
7
Schwartz, Peter J., et Lia Crotti. Monogenic and oligogenic cardiovascular diseases : genetics of arrhythmias—catecholaminergic polymorphic ventricular tachycardia. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0152.
Texte intégralRésumé :
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited disorder associated with syncope and sudden death manifesting in the young during sympathetic activation. The electrocardiogram is normal and the heart is structurally normal. The diagnosis is usually made with an exercise stress test that shows a typical pattern of onset and offset of adrenergically induced ventricular arrhythmias. Molecular screening of RyR2, the major CPVT gene, is recommended whenever the suspicion of CPVT is high. If a disease-causing mutation is identified, cascade screening allows pre-symptomatic diagnosis among family members. All affected subjects should be treated with beta blockers (nadolol or propranolol). Preliminary data support the association of beta blockers with flecainide. After a cardiac arrest, an implantable cardioverter defibrillator (ICD) should be implanted, but it is accompanied by a disquietingly high incidence of adverse effects. After syncope on beta blocker therapy, left cardiac sympathetic denervation is most effective, preserves quality of life, and does not preclude a subsequent ICD implantation.
8
Hall, Andrew, et Shamima Rahman. Mitochondrial diseases and the kidney. Sous la direction de Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0340.
Texte intégralRésumé :
Mitochondrial disease can affect any organ in the body including the kidney. As increasing numbers of patients with mitochondrial disease are either surviving beyond childhood or being diagnosed in adulthood, it is important for all nephrologists to have some understanding of the common renal complications that can occur in these individuals. Mitochondrial proteins are encoded by either mitochondrial or nuclear DNA (mtDNA and nDNA, respectively); therefore, disease causing mutations may be inherited maternally (mtDNA) or autosomally (nDNA), or can arise spontaneously. The commonest renal phenotype in mitochondrial disease is proximal tubulopathy (Fanconi syndrome in the severest cases); however, as all regions of the nephron can be affected, from the glomerulus to the collecting duct, patients may also present with proteinuria, decreased glomerular filtration rate, nephrotic syndrome, water and electrolyte disorders, and renal tubular acidosis. Understanding of the relationship between underlying genotype and clinical phenotype remains incomplete in mitochondrial disease. Proximal tubulopathy typically occurs in children with severe multisystem disease due to mtDNA deletion or mutations in nDNA affecting mitochondrial function. In contrast, glomerular disease (focal segmental glomerulosclerosis) has been reported more commonly in adults, mainly in association with the m.3243A<G point mutation. Co-enzyme Q10 (CoQ10) deficiency has been particularly associated with podocyte dysfunction and nephrotic syndrome in children. Underlying mitochondrial disease should be considered as a potential cause of unexplained renal dysfunction; clinical clues include lack of response to conventional therapy, abnormal mitochondrial morphology on kidney biopsy, involvement of other organs (e.g. diabetes, cardiomyopathy, and deafness) and a maternal family history, although none of these features are specific. The diagnostic approach involves acquiring tissue (typically skeletal muscle) for histological analysis, mtDNA screening and oxidative phosphorylation (OXPHOS) complex function tests. A number of nDNA mutations causing mitochondrial disease have now been identified and can also be screened for if clinically indicated. Management of mitochondrial disease requires a multidisciplinary approach, and treatment is largely supportive as there are currently very few evidence-based interventions. Electrolyte deficiencies should be corrected in patients with urinary wasting due to tubulopathy, and CoQ10 supplementation may be of benefit in individuals with CoQ10 deficiency. Nephrotic syndrome in mitochondrial disease is not typically responsive to steroid therapy. Transplantation has been performed in patients with end-stage kidney disease; however, immunosuppressive agents such as steroids and tacrolimus should be used with care given the high incidence of diabetes in mitochondrial disease.
9
Elliott, Perry, et Alexandros Protonotarios. Arrhythmogenic right ventricular cardiomyopathy : management of symptoms and prevention of sudden cardiac death. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0361.
Texte intégralRésumé :
Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) have arrhythmia-related symptoms or are identified during screening of an affected family. Heart failure symptoms occur late in the disease’s natural history. As strenuous exercise has been associated with disease acceleration and worsening of ventricular arrhythmias, lifestyle modification with restricted athletic activities is recommended upon disease diagnosis or even identification of mutation carrier status. An episode of an haemodynamically unstable, sustained ventricular tachycardia or ventricular fibrillation as well as severe systolic ventricular dysfunction constitute definitive indications for implantable cardioverter defibrillator (ICD) implantation, which should also be considered following tolerated sustained or non-sustained ventricular tachycardia episodes, syncope, or in the presence of moderate ventricular dysfunction. Antiarrhythmic medications are used as an adjunct to device therapy. Catheter ablation is recommended for incessant ventricular tachycardia or frequent appropriate ICD interventions despite maximal pharmacological therapy. Amiodarone alone or in combination with beta blockers is most effective for symptomatic ventricular arrhythmias. Beta blockers are considered for use in all patients with a definite diagnosis but evidence for their prognostic benefit is sparse. Heart failure symptoms are managed using standard protocols and heart transplantation is considered for severe ventricular dysfunction or much less commonly uncontrollable ventricular arrhythmias.
10
Sadleir, Lynette G., Jozef Gecz et Ingrid E. Scheffer. Epilepsies That Occur Predominantly in Girls. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0041.
Texte intégralRésumé :
Availability of DNA sequencing has led to an increase in the number of children being identified with mutations in specific genes in specific epilepsy phenotypes. The presence of mutations that cause epilepsy only in females is one of the discoveries revealed in the sequencing era. Mutations in PCDH19 and CDKL5 are distinctive and identifiable forms of female-only epilepsy, and clinicians should consider PCDH19 in normal girls presenting with clusters of afebrile or febrile seizures in the first 3 years of life, and CDKL5 in girls or boys presenting with severe developmental delay within the first 6 months of life followed by intractable seizures including spasms within the first 2 years.
11
O’Reilly, Éilis J. Epidemiology of Amyotrophic Lateral Sclerosis. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0025.
Texte intégralRésumé :
The epidemiology of ALS is an emerging field and, like the epidemiology of cardiovascular disease and cancer in the mid last century, requires time for convergence of findings. There appears to be a genetic influence, and one study of twins found that heritability of sporadic ALS is 60%. At present it is thought that 60$ to 70% of genetic mutations responsible for fALS in populations of European ancestry are known. SOD1 mutations were the earliest discoveries in fALS. Subsequently, mutations were identified in TARDBP, which encodes TDP-43 protein found in neuronal inclusions in fALS and frontotemporal dementia (FTD). High rates of ALS have also been reported in military personnel and in certain groups of elite athletes such as soccer players.
12
Vester, Udo, et Stefanie Weber. Townes–Brocks syndrome. Sous la direction de Adrian Woolf. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0359.
Texte intégralRésumé :
Townes–Brocks syndrome (TBS) is an autosomal dominant disease with variable expression. Classical features are imperforate anus, dysplastic ears with congenital hearing deficit, and triphalangeal thumbs in most cases. A variety of other malformations (renal, genitourinary, heart, central nervous system, eyes) or hypothyroidism has been described. Mutations in SALL1 have been identified in patients with TBS and genetic testing allows confirmation of the diagnosis. Familiar and sporadic forms (caused by de novo mutations) seem to be equally distributed. Renal involvement in TBS is not uncommon and includes renal agenesis, hypo-/dysplasia, and renal cysts and may eventually lead to chronic renal failure. As renal function may not deteriorate before adulthood, renal function should be monitored in all patients. As cases with TBS can be oligosymptomatic, TBS should be suspected in every case with unexplained renal failure, minor abnormalities, or indicative family history. Genetic counselling is mandatory in identified cases.
13
Smith-Hicks, C. L., et S. Naidu. Rett Syndrome. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0054.
Texte intégralRésumé :
Rett Syndrome (RTT) is a neurodevelopmental disorder that predominantly affects females but males with RTT have been identified. RTT was first described by an Austrian pediatrician, Andreas Rett. Rett syndrome was mapped to chromosome Xq28 in 1998 and a year later it was determined to be due to mutations in the MeCP2 gene at this locus. Identification of the gene led to the broadening of the clinical phenotype and further characterization into classic and atypical forms of the disease that overlap with Autism spectrum disorders during the period of regression. More than 95% of individuals with classic RTT have mutations in the MeCP2 gene.
14
Wordsworth, Paul. Metabolic disease of skeleton and inherited disorders. Oxford University Press, 2011. http://dx.doi.org/10.1093/med/9780199550647.003.010001.
Texte intégralRésumé :
♦ Classic metabolic bone diseases include osteoporosis, osteomalacia, Paget’s disease, and parathyroid bone disease♦ Heritable disorders of the skeleton include numerous osteochrondrodysplasias, Marfan syndrome, and Ehlers-Danlos syndrome♦ Investigation of short stature is indicated for those below 0.4 percentile, with skeletal disproportion and/or progressive shortness♦ Genetic mutations for most of these conditions have been identified but clinical/radiographic features are usually diagnostic.
15
Harold, Denise, et Julie Williams. Molecular genetics and biology of dementia. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199644957.003.0008.
Texte intégralRésumé :
Considerable progress has been made in our understanding of the genetics and molecular biology of dementia. In this chapter we focus predominantly on the most common form of dementia, Alzheimer’s disease (AD), but also discuss vascular dementia and frontotemporal dementia. Genetic mutations have been identified that cause Mendelian subtypes of each disorder, and in recent years genome-wide association studies have greatly aided the identification of risk genes for more common forms of disease. For example, 9 susceptibility genes have been identified in AD in the past 3 years as a result of genome-wide association studies, the first robust risk loci to be identified since APOE in 1993. This progress in genetic research is having a dramatic effect on our understanding of disease pathogenesis, by refining previous ideas and defining new primary disease mechanisms.
16
Tülümen, Erol, et Martin Borggrefe. Monogenic and oligogenic cardiovascular diseases : genetics of arrhythmias—short QT syndrome. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0150.
Texte intégralRésumé :
Short QT syndrome (SQTS) is a very rare, sporadic or autosomal dominant inherited channelopathy characterized by abnormally short QT intervals on the electrocardiogram and increased propensity to atrial and ventricular tachyarrhythmias and/or sudden cardiac death. Since its recognition as a distinct clinical entity in 2000, significant progress has been made in defining the clinical, molecular, and genetic basis of SQTS. To date, several causative gain-of-function mutations in potassium channel genes and loss-of-function mutations in calcium channel genes have been identified. The physiological consequence of these mutations is an accelerated repolarization, thus abbreviated action potentials and shortened QT interval with an increased inhomogeneity and dispersion of repolarization. Regarding other rare monogenetic arrhythmias, a genetic basis of atrial fibrillation was considered very unlikely until very recently. However, in the last decade the heritability of atrial fibrillation in the general population has been well described in several epidemiological studies. So far, more than 30 genes have been implicated in atrial fibrillation through candidate gene approach studies, and 14 loci were found to be associated with atrial fibrillation through genome-wide association studies. This genetic heterogeneity and the low prevalence of mutations in any single gene restrict the clinical utility of genetic screening in atrial fibrillation.
17
Knott, Andrew B., et Ella Bossy-Wetzel. Mitochondrial Changes and Bioenergetics in Neurodegenerative Diseases. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780190233563.003.0012.
Texte intégralRésumé :
Mitochondria are dynamic organelles that are of critical importance for cellular survival and health. Because mitochondria play central roles in energy production and synaptic maintenance, neurons are believed to be particularly vulnerable to mitochondrial dysfunction. The discovery that genetic mutations in genes coding for mitochondrial proteins cause neurodegenerative conditions further hinted at the likelihood that mitochondrial dysfunction is a key pathway of neurodegeneration. Indeed, a wealth of research has identified mitochondrial dysfunction as an early and shared event of all common neurodegenerative diseases, both genetic and sporadic in origin. Specific types of mitochondrial dysfunction that have been observed in most neurodegenerative diseases include bioenergetic failure, increased oxidative stress, mitochondrial DNA mutations, defective calcium handling, impaired mitochondrial dynamics, defective mitophagy, and decreased mitochondrial biogenesis. The search for drugs that successfully target these pathways of mitochondrial dysfunction in neurodegeneration is ongoing.
18
Cunningham, Steve. Diagnosis and process of care. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780198702948.003.0002.
Texte intégralRésumé :
Children with CF are now identified by newborn screening programmes, but not in every country, nor is every case is identified by newborn screening. Methods of diagnosis have become more complex as the CF gene has been mapped and more mutations identified, some of which may not be associated with disease. The sweat test remains the primary method of diagnosis, along with clinical symptoms. Clinical care is increasingly orientated to reduce the risk of cross-infection between patients. The range of organisms for which cross-infection measures are put in place is increasing. Routine clinic review is outlined and recommendations made. Annual review is described in detail. Transition is a pivotal period in patient management requiring structure and support. Patients (and parents) should be informed about the transition plan early and the delivery standard across all patients, but delivered at an age and pace commensurate with the adolescent’s clinical and psychological needs.
19
Garcia-Pavia, Pablo, et Fernando Dominguez. Left ventricular non-compaction : genetics and embryology. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0362.
Texte intégralRésumé :
Left ventricular non-compaction (LVNC) is a rare disorder that is considered an ‘unclassified cardiomyopathy’ by the European Society of Cardiology. Several different gene mutations related to LVNC have been identified, involving sarcomeric, cytoskeletal, Z-line, ion channel, mitochondrial, and signalling proteins. However, there is broad genetic overlap between LVNC and other inherited cardiac diseases such as dilated cardiomyopathy and hypertrophic cardiomyopathy. LVNC could also be part of multisystemic genetic entities such as Barth syndrome, or accompany congenital heart defects.
20
Trocello, Jean-Marc, et France Woimant. Disorders of Copper and Iron Metabolism. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0044.
Texte intégralRésumé :
Both copper and iron are essential metals that have a critical function in a series of biochemical pathways. This chapter describes the disorders associated with genetic abnormalities in copper and iron metabolic pathways and their manifestations in adult patients. Mutations in the genes of the copper transporting P-type ATPases, ATP7A and ATP7B are associated with Wilson disease, Menkes disease, occipital horn syndrome and ATP7A-related distal motor neuropathy. Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by excess iron deposition in globus pallidus, substantia nigra pars reticulata, striata and cerebellar dentate nuclei. Several genes associated with NBIA have been identified.
21
Jadon, Deepak R., Tehseen Ahmed et Ashok K. Bhalla. Disorders of bone mineralization—osteomalacia. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0146.
Texte intégralRésumé :
Disorders of bone mineralization cause rickets in children and osteomalacia in adults. Both remain common in developing countries. Incidence in Western countries had declined since the fortification of foodstuffs, but appears to be increasing again. Calcium and inorganic phosphate are the key precursors for bone mineralization and growth. The commonest aetiology of osteomalacia is vitamin D deficiency, primarily due to low dietary intake and inadequate sun exposure. In the last decade gene mutations have been identified that are responsible for inherited rickets and osteomalacia, particularly those that result in phosphate deficiency, hypophosphatasia, and vitamin D receptor or metabolizing enzyme mutations. Additionally, the pathogenesis of tumour-induced osteomalacia is becoming better understood. Osteomalacia may present as bone pain and tenderness, muscle pain and weakness, and skeletal deformity or fracture. Key investigations include biochemical assessment and plain radiographs. Radioisotope bone scans and bone biopsy may be considered in selected cases. Differential diagnoses include osteoporosis, seronegative arthritides, and localized soft tissue disorders. Treatment, guided by the underlying aetiology, aims to reduce symptoms, fracture risk, bone deformity and sequelae. Vitamin D deficient patients require vitamin D and calcium replacement.
22
Jadon, Deepak R., Tehseen Ahmed et Ashok K. Bhalla. Disorders of bone mineralization—osteomalacia. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199642489.003.0146_update_001.
Texte intégralRésumé :
Disorders of bone mineralization cause rickets in children and osteomalacia in adults. Both remain common in developing countries. Incidence in Western countries had declined since the fortification of foodstuffs, but appears to be increasing again. Calcium and inorganic phosphate are the key precursors for bone mineralization and growth. The commonest aetiology of osteomalacia is vitamin D deficiency, primarily due to low dietary intake and inadequate sun exposure. In the last decade gene mutations have been identified that are responsible for inherited rickets and osteomalacia, particularly those that result in phosphate deficiency, hypophosphatasia, and vitamin D receptor or metabolizing enzyme mutations. Additionally, the pathogenesis of tumour-induced osteomalacia is becoming better understood. Osteomalacia may present as bone pain and tenderness, muscle pain and weakness, and skeletal deformity or fracture. Key investigations include biochemical assessment and plain radiographs. Radioisotope bone scans and bone biopsy may be considered in selected cases. Differential diagnoses include osteoporosis, seronegative arthritides, and localized soft tissue disorders. Treatment, guided by the underlying aetiology, aims to reduce symptoms, fracture risk, bone deformity and sequelae. Vitamin D deficient patients require vitamin D and calcium replacement.
23
Sayer, John A., et Roslyn J. Simms. Nephronophthisis. Sous la direction de Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0317_update_001.
Texte intégralRésumé :
Nephronophthisis (NPHP) is a clinically heterogeneous autosomal recessive cystic kidney disease and the leading genetic cause of end-stage renal failure in children and young adults. Whilst enlarged dysplastic cystic kidneys are associated with infantile NPHP, more typically renal ultrasound reveals normal kidney size and corticomedullary cysts in a child with polyuria and secondary enuresis. Extrarenal manifestations occur in 10–15% including retinal degeneration, cerebellar vermis hypoplasia and liver fibrosis, requiring referral to other specialists. Mutations in 18 genes have been identified to cause NPHP, but a genetic diagnosis still cannot be found in many patients. NPHP is classified as a ciliopathy because of the localization of the protein products of the associated genes. Currently there is no specific therapy for NPHP.
24
Medjeral-Thomas, Nicholas, Anna Richards et Matthew C. Pickering. Molecular basis of complement-mediated renal disease. Sous la direction de Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0333.
Texte intégralRésumé :
Abnormal regulation of complement is intimately associated with C3 glomerulopathy and atypical haemolytic uraemic syndrome. Atypical haemolytic uraemic syndrome is characterized by renal thrombotic microangiopathy due to an inability to regulate complement activation along the renal endothelium. The development of thrombosis is critically dependent on the ability to activate C5. Eculizumab, a monoclonal anti-C5 antibody, is an effective therapy for this condition. C3 glomerulopathy refers to glomerular lesions characterized by accumulation of C3 in the absence of immunoglobulin. The prototypic example is dense deposit disease. This condition is associated with impaired regulation of the alternative pathway in plasma. In other subtypes of C3 glomerulopathy, familial studies have identified mutations within the complement factor H-related protein family. Polymorphic variation within this protein family also influences susceptibility to IgA nephropathy. The mechanism underlying these associations remains unknown and is the subject of ongoing research efforts.
25
Abnet, Christian C., Olof Nyrén et Hans-Olov Adami. Esophageal Cancer. Oxford University Press, 2018. http://dx.doi.org/10.1093/oso/9780190676827.003.0009.
Texte intégralRésumé :
Esophageal cancer shows distinct geographic distributions, changing incidence rates, and primary risk factors when examined separately as squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma remains the dominant histologic type in many low- and middle-income countries and occurs frequently, while adenocarcinoma is classified as rare but predominates in Western countries. Tobacco and alcohol are the dominant risk factors for squamous cell carcinoma in Western countries, but not in high-incidence Asian populations, where hot beverages and specific nutritional deficiencies may be important. For adenocarcinoma, tobacco use is causal while alcoholic beverages are not. Rather, obesity and gastroesophageal reflux disease are the other dominant identified risk factors. Genetic predisposing factors and somatic mutations are also cell type specific. The differences in esophageal cancer incidence within and between countries, by sex and race, and in known risk factors suggest major strides in understanding the etiology of esophageal cancer is within reach.
26
Tangen, Catherine M., Marian L. Neuhouser et Janet L. Stanford. Prostate Cancer. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780190238667.003.0053.
Texte intégralRésumé :
Prostate cancer is the most common solid tumor and the second leading cause of cancer-related mortality in American men. Worldwide, prostate cancer ranks second and fifth as a cause of cancer and cancer deaths, respectively. Despite the international burden of disease due to prostate cancer, its etiology is unclear in most cases. Established risk factors include age, race/ancestry, and family history of the disease. Prostate cancer has a strong heritable component, and genome-wide association studies have identified over 110 common risk-associated genetic variants. Family-based sequencing studies have also found rare mutations (e.g., HOXB13) that contribute to prostate cancer susceptibility. Numerous environmental and lifestyle factors (e.g., obesity, diet) have been examined in relation to prostate cancer incidence, but few modifiable exposures have been consistently associated with risk. Some of the variability in results may be related to etiological heterogeneity, with different causes underlying the development of distinct disease subgroups.
27
Hope, James, et Mark P. Dagleish. Prion-protein-related diseases of animals and man. Oxford University Press, 2011. http://dx.doi.org/10.1093/med/9780198570028.003.0041.
Texte intégralRésumé :
Scrapie, bovine spongiform encephalopathy (BSE), Creutzfeldt–Jakob disease (CJD), and related diseases of mink (transmissible mink encephalopathy), mule deer and elk (chronic wasting disease) are the founder members of a group of diseases called the transmissible degenerative (or spongiform) encephalopathies (TSE). These diseases can be transmitted by prions from affected to healthy animals by inoculation or by feeding diseased tissues. Prions are cellular proteins that can transfer metabolic and pathological phenotypes vertically from parent to progeny or horizontally between cells and animals. TSEs are characterised by the accumulation of the prion form of the mammalian prion protein (PrPC) in the central nervous system or peripheral tissues of animals and humans. Mutations of the human PrP gene are linked to rare, familial forms of disease and prion-protein gene polymorphisms in humans and other species are linked to survival time and disease characteristics in affected individuals. Iatrogenic transmission of CJD in man has occurred, and a variant form of CJD (vCJD) is due to cross-species transmission of BSE from cattle to humans. Atypical forms of scrapie and BSE have been identified during large-scale monitoring for TSEs worldwide. This chapter outlines our current understanding of scrapie, BSE, CJD and other TSEs and highlights recent progress in defining the role in disease of the prion protein, PrP.
28
Holliday, Kate L., Wendy Thomson et John McBeth. Genetics of chronic musculoskeletal pain. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0045.
Texte intégralRésumé :
Chronic pain disorders are prevalent and a large burden on health care resources. Around 10% of the general population report chronic widespread pain, which is the defining feature of fibromyalgia. Fibromyalgia is a poorly understood idiopathic disorder which is also characterized by widespread tenderness and commonly occurs with comorbid mood disorders, fatigue, sleep disturbance, and cognitive dysfunction. A role for genetics in chronic pain disorders has been identified by twin studies, with heritability estimates of around 50%. Susceptibility genes for chronic pain are likely to be involved in pain processing or the psychological component of these disorders. A number of genes have been implicated in influencing how pain is perceived due to mutations causing monogenic pain disorders or an insensitivity to pain from birth. The role of common variation, however, is less well known. The findings from human candidate gene studies of musculoskeletal pain to date are discussed. However, the scope of these studies has been relatively limited in comparison to other complex conditions. Identifying susceptibility loci will help to determine the biological mechanisms involved and potentially new therapeutic targets; however, this is a challenging research area due to the subjective nature of pain and heterogeneity in the phenotype. Using more quantitative phenotypes such as experimental pain measures may prove to be a more fruitful strategy to identify susceptibility loci. Findings from these studies and other potential approaches are discussed.
29
Holliday, Kate L., Wendy Thomson, John McBeth et Nisha Nair. Genetics of chronic musculoskeletal pain. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199642489.003.0045_update_001.
Texte intégralRésumé :
Chronic pain disorders are prevalent and a large burden on health care resources. Around 10% of the general population report chronic widespread pain, which is the defining feature of fibromyalgia. Fibromyalgia is a poorly understood idiopathic disorder which is also characterized by widespread tenderness and commonly occurs with comorbid mood disorders, fatigue, sleep disturbance, and cognitive dysfunction. A role for genetics in chronic pain disorders has been identified by twin studies, with heritability estimates of around 50%. Susceptibility genes for chronic pain are likely to be involved in pain processing or the psychological component of these disorders. A number of genes have been implicated in influencing how pain is perceived due to mutations causing monogenic pain disorders or an insensitivity to pain from birth. The role of common variation, however, is less well known. The findings from human candidate gene studies of musculoskeletal pain to date are discussed. However, the scope of these studies has been relatively limited in comparison to other complex conditions. Identifying susceptibility loci will help to determine the biological mechanisms involved and potentially new therapeutic targets; however, this is a challenging research area due to the subjective nature of pain and heterogeneity in the phenotype. Using more quantitative phenotypes such as experimental pain measures may prove to be a more fruitful strategy to identify susceptibility loci. Findings from these studies and other potential approaches are discussed.
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Cui, Zhao, Neil Turner et Ming-hui Zhao. Alport post-transplant antiglomerular basement membrane disease. Sous la direction de Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0075.
Texte intégralRésumé :
Alport antiglomerular basement membrane (anti-GBM) disease is a rare example of disease caused by allo-sensitization after renal transplantation, first described in 1992. Because the recipient lacks a specific glomerular basement membrane (GBM) protein, they can become sensitized to the normal molecule present in the GBM of the donor kidney. The disease is restricted to the allograft. Interestingly severe disease arises from this only arises rarely, certainly less than 1 in 20, probably closer to 1 in 50. It characteristically causes late graft loss in a first transplant with accelerated tempo in later allografts, and in its most extreme form recurs within days. However, inexplicably some subsequent transplants do not provoke aggressive recurrence. Treatment of the most aggressive disease is difficult and in most cases has been ultimately unsuccessful. Lower levels of immune response, marked by linear binding of immunoglobulin-G to GBM without glomerular disease, are not uncommon in Alport patients after transplantation and should not lead to altered treatment. Immunoassays for anti-GBM antibodies can be misleading as in most cases the target of antibodies is the α5 chain of type IV collagen, rather than the α3 chain which is the target in spontaneous anti-GBM disease. Overall the outcome of transplantation in Alport syndrome is better than average. This complication is more likely in patients with partial or total gene deletion rather than point mutations, but no other predictive features have been identified.