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Molecular Diagnosis of Autosomal Dominant Polycystic Kidney Disease
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Matthew Lanktree, Amirreza Haghighi, Xueweng Song, York Pei
Ultrasound examination of the kidney is the modality employed for initial screening. Understanding the progressive nature of ADPKD is important for diagnosis, leading to age-dependent imaging criteria. In the context of a positive family history of polycystic kidney disease, between age 18 and 39, the presence of at least three visible cysts is diagnostic of ADPKD.8 Due to the increasing prevalence of simple cysts with age, in a patient over age 60, four cysts must be visible in each kidney. Genetic testing can be useful to provide diagnostic certainty, often in the context of no apparent family history or equivocal imaging findings. A requirement for disease exclusion at a young age, such as in living donor transplant assessments or prenatal or preimplantation diagnostics, are additional indications for genetic testing. Scenarios for which genetic testing is being increasingly used in a clinical context include early and severe disease, risk stratification to identify “high-risk” patients for treatment with therapies associated with a therapeutic burden, marked intrafamilial discordance in disease severity, atypical imaging findings and discrepancy between imaging findings and decline in renal function, and suspicion of a phenocopy (i.e., autosomal dominant tubulointerstitial kidney disease) or syndromic (i.e., nephronophthisis) form of polycystic kidney disease.9,10
Medicinal poisons
Published in Jason Payne-James, Richard Jones, Simpson's Forensic Medicine, 2019
Jason Payne-James, Richard Jones
Since the 1990s, the concept of primary ‘inherited’ arrhythmia syndromes, or ion channelopathies, has developed from advances in molecular genetics. Alterations in genes coding for membrane proteins, such as ion channels or their associated proteins responsible for the generation of cardiac action potentials (AP), cause specific malfunctions which eventually lead to cardiac arrhythmias. These arrhythmic disorders include a wide variety of conditions. Among these, long QT, and Brugada, syndromes are the most extensively studied, and drugs cause a phenocopy of these two diseases. More than 10 different genes have been reported to be responsible for each syndrome. Individuals with long QT syndrome (LQTS) experience abnormal prolongation of the QT interval – the portion of the electrocardiogram (ECG) that represents repolarisation of cardiomyocytes (Figure 25.1). The QT interval extends from the onset of the Q wave to the end of the T wave. The normal rate-adjusted length for the QT interval is less than 440 milliseconds. A prolonged QT interval favours the occurrence of a lethal form of ventricular tachycardia known as torsades des pointes. The QT prolongation may be caused by genetic aberration or it may be acquired. Even those with the genetic form of the disease may have a perfectly normal-appearing electrocardiogram until some event causes the QT interval to lengthen, become pathologically long and produce an arrhythmia. The diagnosis is made by DNA resequencing.
Disorders of bone and connective tissue
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Stippled bone epiphyses may be seen in early life on bone X-rays in a variety of conditions, so care must be taken before accepting the specific diagnosis of Conradi syndrome. In this, cataract, mental retardation and ichthyosis may all occur. Both autosomal dominant and recessive forms exist (the latter more severe and due to a peroxisomal defect); X-linked inheritance, both dominant and recessive, occurs occasionally. A phenocopy is also produced by maternal warfarin ingestion in early pregnancy and must be excluded before a genetic basis is assumed.
Advances in genetic testing and optimization of clinical management in children and adults with epilepsy
Published in Expert Review of Neurotherapeutics, 2020
Marcello Scala, Amedeo Bianchi, Francesca Bisulli, Antonietta Coppola, Maurizio Elia, Marina Trivisano, Dario Pruna, Tommaso Pippucci, Laura Canafoglia, Simona Lattanzi, Silvana Franceschetti, Carlo Nobile, Antonio Gambardella, Roberto Michelucci, Federico Zara, Pasquale Striano
Focused history taking should start from a classic three-generation pedigree, which can be extended to further generations if more information becomes available. Standardized human pedigree nomenclature according to the recommendations of the National Society of Genetic Counselors (NSGC) should be used [16]. Particular attention should be paid to possible parental consanguinity, twin pregnancies, abortions or miscarriages, and infantile deaths. Whenever possible, the sex of aborted/miscarried fetuses should be specified, since this data might provide clues toward a specific inheritance pattern (e.g., recurrent miscarriages of male fetuses might suggest a male-lethal X-linked condition). Affected individuals should be characterized according to the type of epilepsy and, ideally, seizure semiology. The occurrence of provoked and febrile seizures (sometimes requiring specific investigation) should also be reported. Neurocognitive comorbidities, including intellectual disability (ID) and ASD, should be indicated as well. When interpreting a pedigree, the occurrence of distinct epileptic syndromes in different family members (phenotypic variability) and non-genetic conditions (e.g., post-traumatic epilepsy) mimicking the studied epileptic disorder (phenocopy) should always be considered. Eventually, it is always advisable to update the pedigree at each follow-up evaluation.
N-acetyltransferase: the practical consequences of polymorphic activity in man
Published in Xenobiotica, 2020
It is important to differentiate between polymorphisms at the phenotype and genotype levels. They are not equivalent and must not be assumed to be so. Polymorphism at the phenotype level indicates differences in actual enzyme activity, a functional and measurable response in terms of substrate turnover that influences the proportion of an administered dose of drug moving through the body that undergoes a certain defined metabolic transformation. It provides a reflection of what is actually happening at that time and an overall “whole body” measurement of the examined process. This is what is of importance in the clinical situation. Polymorphisms at the genetic level indicate the possession of certain allelic variants that are known, via transcription and translation, to code for enzymes with certain characteristics. However, it is a long journey from gene to enzyme during which many variable and perhaps unknown epigenetic factors may intercede in an unclear manner, to influence, disrupt and obfuscate any attempt at direct transcendence. Association and interdependence of gene loci (e.g. multilocus haplotype frequencies, linkage disequilibrium and other phenomena) may also play a silent role. Genotype does not necessarily dictate phenotype. Hence, genotyping, although an excellent first approach, cannot replace phenotyping in the clinical situation. The emerging problems of “phenocopy” and “phenoconversion” must also be taken into account (Shah & Smith, 2012, 2015).
Pharmacogenetics and drug metabolism: historical perspective and appraisal
Published in Xenobiotica, 2020
Robert L. Smith, Stephen C. Mitchell
The circumstances of individuals also may change from time to time, with various unappreciated factors taking their toll. The existence of certain disease states, comorbidities in a hospital situation, may lead to phenoconversion. Some HIV-positive subjects have been shown to display a CYP2D6 enzyme activity approaching that of a “poor metaboliser" phenotype although possessing an underlying “extensive metaboliser" genotype (O’Neil et al., 2000). Similar situations have arisen in patients with liver disease, undergoing liver transplantations and with certain cancers. The co-medication of prescription drugs, and the ingestion of over-the-counter preparations, may induce phenocopy, converting an “extensive metaboliser" genotype into a phenotypic “poor metaboliser". This latter phenomenon may last for a few hours to several days (Preskorn et al., 2013; Shah & Smith, 2012, 2015). Such confounding factors are not unsubstantial and must be taken into consideration.