1.
The clinical impact of pharmacogenetics on the treatment of epilepsy.
Löscher, W, Klotz, U, Zimprich, F, Schmidt, D
Epilepsia. 2009;(1):1-23
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Abstract
Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA-B*1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy.
2.
Inherited conduction system abnormalities--one group of diseases, many genes.
Wolf, CM, Berul, CI
Journal of cardiovascular electrophysiology. 2006;(4):446-55
Abstract
The cardiac conduction system can be anatomically, developmentally, and molecularly distinguished from the working myocardium. Abnormalities in cardiac conduction can occur due to a variety of factors, including developmental and congenital defects, acquired injury or ischemia of portions of the conduction system, or less commonly due to inherited diseases that alter cardiac conduction system function. So called "idiopathic" conduction system degeneration may have familial clustering, and therefore is consistent with a hereditary basis. This "Molecular Perspectives" will highlight several diverse mechanisms of isolated conduction system disease as well as conduction system degeneration associated with other cardiac and non-cardiac disorders. The first part of this review focuses on channelopathies associated with conduction system disease. Human genetic studies have identified mutations in the sodium channel SCN5A gene causing tachyarrhythmia disorders, as well as progressive cardiac conduction system diseases, or overlapping syndromes. Next, the importance of embryonic developmental genes such as homeobox and T-box transcription factors are highlighted in conduction system development and function. Conduction system diseases associated with multisystem disorders, such as muscular and myotonic dystrophies, will be described. Last, a new glycogen storage cardiomyopathy associated with ventricular preexcitation and progressive conduction system degeneration will be reviewed. There are a myriad of mutations identified in genes encoding cardiac transcription factors, ion channels, gap junctions, energy metabolism regulators, lamins and other structural proteins. Understanding of the molecular and ionic mechanisms underlying cardiac conduction is essential for the appreciation of the pathogenesis of conduction abnormalities in structurally normal and altered hearts.
3.
Inherited sodium avid states.
Achard, JM, Hadchouel, J, Faure, S, Jeunemaitre, X
Advances in chronic kidney disease. 2006;(2):118-23
Abstract
Several familial forms of hypertension have been identified, in which the mendelian pattern of inheritance indicated that hypertension results from the alteration of a single gene. This short review focuses on those rare monogenic disorders characterized by a low-renin profile. This common feature reflects that the causative mutations responsible for these disorders all result in an excessive sodium reabsorption in the aldosterone-dependent nephron. Low-renin familial hypertensions with hypokalemia encompass familial hyperaldosteronisms, in which aldosterone levels are elevated, and familial pseudohyperaldosteronisms, mimicking aldosteronism despite appropriately suppressed aldosterone levels. In these disorders, the avidity of the kidney for sodium is because of dysregulated sodium reabsorption through the epithelial sodium channel ENaC and results in potassium wasting and metabolic alcalosis. Familial hypertension with hyperkalemia is a specific syndrome resulting from mutations in at least 3 different genes, among which 2 have been recently identified. These genes encode members of a new family of kinase, the WNK kinases, involved in the regulation of sodium and potassium excretion by the kidney.
4.
Clinical and molecular genetics of myoclonic-astatic epilepsy and severe myoclonic epilepsy in infancy (Dravet syndrome).
Scheffer, IE, Wallace, R, Mulley, JC, Berkovic, SF
Brain & development. 2001;(7):732-5
Abstract
The majority of severe epileptic encephalopathies of early childhood are symptomatic where a clear etiology is apparent. There is a small subgroup, however, where no etiology is found on imaging and metabolic studies, and genetic factors are important. Myoclonic-astatic epilepsy (MAE) and severe myoclonic epilepsy in infancy (SMEI), also known as Dravet syndrome, are epileptic encephalopathies where multiple seizure types begin in the first few years of life associated with developmental slowing. Clinical and molecular genetic studies of the families of probands with MAE and SMEI suggest a genetic basis. MAE was originally identified as part of the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus (GEFS(+)). Recent clinical genetic studies suggest that SMEI forms the most severe end of the spectrum of the GEFS(+). GEFS(+) has now been associated with molecular defects in three sodium channel subunit genes and a GABA subunit gene. Molecular defects of these genes have been identified in patients with MAE and SMEI. Interestingly, the molecular defects in MAE have been found in the setting of large GEFS(+) pedigrees, whereas, more severe truncation mutations arising de novo have been identified in patients with SMEI. It is likely that future molecular studies will shed light on the interaction of a number of genes, possibly related to the same or different ion channels, which result in a severe phenotype such as MAE and SMEI.