Stroke is an important clinical problem because of its large contribution to mortality. The main causal and treatable risk factors for stroke include hypertension, diabetes mellitus, dyslipidemia, and smoking. In addition to these risk factors, recent studies have shown the importance of genetic factors and interactions between multiple genes and environmental factors. Genetic linkage analyses of families and sib-pairs as well as candidate gene association studies have implicated several loci and many candidate genes in predisposition to ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Recent genome-wide association studies identified various loci and genes that confer susceptibility to ischemic stroke or intracranial aneurysm. Such studies may provide insight into the function of implicated genes as well as into the role of genetic factors in the development of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage.

Sudden cardiac death is the leading cause of non-traumatic mortality in young (<35 years old) athletes, with recent data suggesting the incidence to be higher than what was previously estimated. The vast majority of deaths are caused by silent hereditary or congenital cardiac disorders. Over the last decade, advances in our understanding of both the genetic and clinical mechanisms underlying these conditions, particularly those associated with a structurally normal heart, have led to advances in diagnosis and management including interventions and lifestyle modifications that aim to minimize the risk of sudden cardiac death (SCD). Coupled with effective screening programs, other strategies such as emergency response planning and the use of automated external defibrillators have also emerged as strategies in preventing and treating sudden cardiac arrest.

This book aims to provide an overview of the genetic and clinical aspects of SCD in young athletes, with particular emphasis on the specific issues related to diagnosis and management that these unique group of individuals pose to a physician. Specific diagnostic and management dilemmas will be illustrated through clinical cases and the most up-to-date guidelines regarding participation in sport outlined.

The clinical syndrome of chronic heart failure (CHF) is the hallmark of progressive cardiac decompensation, one of the most common chronic medical conditions that affect around 2% of the adult population worldwide irrespective of ethnic and geographic origin (Anonymous). Apart from ischemic heart disease, hypertension, infection, and inflammation, several other etiologic factors account for irreparable and irreversible myocardial damage leading to heart failure (HF). Genetic and genomic factors are now increasingly identified as one of the leading underlying factors (Arab and Liu 2005). These factors may be related to pathogenic alterations (mutation or polymorphism) within specific cardiac genes, mutations in genes incorporating single or multiple molecular pathways (protein families) relevant to cardiac structure and/or function, genetic or genomic polymorphisms of uncertain significance (gene variants, single-nucleotide polymorphisms (SNPs), and copy number variations (CNVs)), and epigenetic or epigenomic changes that influence cardiac gene functions scattered across the human genome. Recent genetic and genomic studies in both systolic and diastolic ventricular dysfunction, the hallmark of CHF, have revealed a number of mutations in genes belonging to specific cardiac protein families. For example, around 200 mutations are now known to exist in around 15 genes coding for several different types of sarcomere proteins (Liew and Dzau 2004). The sarcomere protein family, alone, accounts for the bulk of inherited cardiomyopathies including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), and left ventricular (LV) non-compaction (LVNC). In addition, there are several other potentially relevant factors involving different genes and genome-level elements. This article presents a systematic account on the available factual information and interpretations based on genetic and genomic studies in CHF (Liew and Dzau 2004). Genomic and molecular approaches have opened the way for a renewed debate for taxonomy of CHF (Ashrafian and Watkins 2007). The review draws attention to the potential diagnostic and therapeutic implications of genomic and transcriptional profiling in HF and translational genomics research that is likely to permit greater personalization of prevention and treatment strategies to address the complexities of managing clinical HF (Creemers, Wilde et al. 2011).

In this e-book, motor neuron disease (MND) shall refer to amyotrophic lateral sclerosis (ALS), the most common neurodegenerative disorder affecting both the upper and lower motor neurons. With the discovery of C9ORF72 expansions in approximately 10% of all MND cases, in certain populations, we stand at the brink of a new era of MND research and hopefully treatment facilitated by the ability to associate a relatively large group of patients with a similar disease mechanism. This review will summarise both current clinical management of MND and our present understanding of the molecular pathogenesis of MND. Study of C9ORF72-MND has the potential to rapidly advance both of these aspects in the coming years.

In the first section, we will discuss the clinical features of MND and describe how patients with this devastating condition present, are investigated, and managed in the 21st century. Although, currently, management is limited by an incomplete understanding of disease pathophysiology, there is much which can be done to assist and support patients with MND. In the following sections, we will discuss molecular mechanisms implicated in MND, highlighting observations which unify different theories. Particular attention will be given to placing proposed mechanisms within the clinical course of MND. Furthermore, novel therapeutic targets will be discussed.

Neurofibromatosis type 1 (NF1) is a common autosomal dominantly inherited, tumour predisposition syndrome affecting 1/3,000-4,000 individuals worldwide. This inherited disorder results from the mutational inactivation of the NF1 gene on human chromosome 17. The NF1 gene contains 61 exons that give rise to 12kb mRNA encoding neurofibromin. The 327kDa (2,818 amino acid) neurofibromin protein is expressed in most tissues and has a number of alternative isoforms. Neurofibromin is a tumour suppressor protein and down-regulates cellular Ras. Increased active Ras-GTP levels also stimulate the important PI3K/AKT/mTOR signalling pathway that protects cells from apoptosis.

The major clinical featues of NF1 include multiple café-au-lait macules, skinfold freckles, iris Lisch nodules, and neurofibromas. The diagnostic criteria for clinical diagnosis have been well established. However, there are a small number of cases in which the diagnosis is not certain. The germline mutation rate for the NF1 gene is 10-fold higher than that observed for most other inherited diseases. Using a combination of different techniques, almost 95% of germline mutations can be detected. To date, only two firm genotype phenotype correlations have been reported. NF1 phenotype exhibits large variations within a family, evidence for modifying loci regulating the expression of an NF1 gene is beginning to emerge. We also are gaining knowledge on the molecular mechanisms associated with the development of different types of tumours. It is encouraging that the results of recent laboratory and clinical research are finally being translated into clinical trials. With the availability of high-throughput technologies, sophisticated animal models, and multi-centre clinical trials, the future for NF1 sufferers is looking optimistic.

This book aims to provide an overview of the genetic and clinical aspects of NF1 and its role in both NF1-associated and sporadic tumour development. It emphasizes the recent developments in this field and some of the promising on-going clinical trials.

Current knowledge of the etiology of congenital malformations of the human gastrointestinal tract is covered in this book, prefaced by some introductory notes on embryological development. Malformations involving the esophagus, stomach, small and large intestine, anus and rectum, pancreas, and hepato-billiary system are covered. There is a focus on covering those malformations for which a molecular genetic etiology is understood, but other causations, including environmental exposures, twinning, and unknown etiology are also included. For completeness, some disorders are included which are not, strictly, malformations, or which do not, strictly, involve the gastrointestinal tract. Such disorders include Hirschsprung disease, congenital diaphragmatic hernia, omphalocele, and gastroschisis. Suggested approaches to clinical evaluation of individuals with gastrointestinal malformations are included.

This book reviews the molecular genetics of the thalassemia syndromes, inherited hemoglobin disorders that comprise the commonest monogenic disorders globally. Thalassemias are found in high frequencies in tropical regions corresponding to the malaria belt. Beta thalassemia traits show high HbA2 by HPLC, and β-globin mutations (commonly point mutations) are detected by using ARMS-PCR, reverse dot-blot analysis and β-globin gene sequencing. Globally >300 β globin gene mutations exist, however regional mutations are limited to 5-6 common ones. Alpha globin gene defects can only be identified by molecular tests, the exception being HbH disease that shows “golf ball” appearance in HbH preparation, pre-integration peaks on HPLC and a fast-moving band on hemoglobin electrophoresis. Multiplex Gap-PCR identifies common α-globin gene deletions. Specific PCR across the junction caused by the unequal crossing over can detect α-gene triplication. However, heterozygosity or homozygous triplication cannot be resolved by this technique. Non-deletional α-thalassemia can be characterized by specific α-globin gene sequencing. Identification of unusual deletions requires Multiplex Ligation-dependent Probe Amplification. In conclusion, the molecular characterization of human globin gene disorders is required to resolve the phenotypically heterogeneous thalassemia syndromes. Molecular analysis is also an important tool to prevent these disorders by offering prenatal screening in regions with a high disease burden.

Osteogenesis imperfecta (OI) is a disease encompassing a group of disorders mainly characterized by bone fragility and is the commonest form of heritable bone fragility. In this book, the clinical presentations with particular emphasis on rare phenotypes associated with OI are discussed together with molecular advances in diagnosis and treatment of OI. There is a broad spectrum of clinical severity in OI, ranging from multiple fractures in utero and perinatal death, to near-normal adult stature and low fracture incidence. Facial dysmorphism has been noted, but is not well described, nor is it an invariable feature. Sillence et al., in 1979, provided the clinical classification, which has been further expanded. Genetic defects in type 1 collagen can be identified in 85% of patients with a clinical diagnosis of OI, that is, mutations in COL1A1/COL1A2, which follows an autosomal dominant pattern of inheritance. Several genes have now been implicated in autosomal recessive forms of OI and X-linked osteoporosis. Given the possible antenatal presentation and prognosis associated with OI, it is important to make this diagnosis early and be able to distinguish this from other lethal skeletal dysplasias. It is also important to distinguish nonaccidental injury from a pathological cause of fractures, such as OI, and diagnose this promptly in these situations. However, this is not always possible due to variability in presentation and inability to pinpoint the precise genetic etiology despite extensive genetic testing. OI is one such rare genetic condition where treatment is available in the form of bisphosphonates, which has a huge impact on quality of life. Despite advances in medical therapy, multidisciplinary management including physiotherapy remains the mainstay of treatment and improved outcomes in OI.