Preface

Recent advances in the understanding of the genetics and basic mechanisms of neuromuscular diseases have been both rapid and spectacular. Furthermore, these advances have resulted in an expansion of the methods used for diagnosis—from routine clinical histologic and electrophysiologic tests to more specific techniques, such as biochemical and Western Blot analysis, and, most important, molecular genetic testing. These modern techniques have begun to replace more costly and painful procedures for some patients.

Although the goal of our specialty is to find cures or effective treatments for neuromuscular disorders, the management of symptoms to improve quality of life is still paramount. Ambulation and survival can be prolonged with well-planned rehabilitation programs, orthopaedic surgery, and proper early management of cardiac, respiratory, and gastrointestinal complications, particularly in patients with motor neuron diseases and muscular dystrophy. Prolonged survival has changed the care of these patients. For example, in the past patients with Duchenne muscular dystrophy generally died of respiratory failure before they developed symptomatic cardiac disease; now they are living longer and require aggressive treatment of their cardiac complications to further prolong their lives.

Many excellent textbooks and treatises dedicated to the understanding of the basic mechanisms of clinical and laboratory diagnoses of neuromuscular diseases also include discussions of treatment but this information is not comprehensive. In this text we aim to cover the current treatment and management of these subjects and to discuss promising experimental therapies.

The introductory chapter is a brief overview of the Integrins in the development and pathology of skeletal muscle—information that we hope will be helpful to young clinicians. The next several chapters discuss neuromuscular disorders and their general management, such as rehabilitation, orthopaedic surgery, and cardiac, gastrointestinal, and respiratory care. The balance of the chapters covers specific diseases as well as the basic mechanisms of these disorders.

The information in each chapter is intended to complement that in others, although occasionally there are minor repetitions. When possible, evidence-based treatment

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recommendations are given, particularly for the more common conditions, though we emphasize that the treatment of all patients should be individualized. For less common disorders, for which controlled trials have not yet been published, recommendations are based on published information and the authors' experience.

I am honored and grateful for the collaboration of an excellent group of renowned specialists. They have generously contributed their time and expertise to make what we hope is a textbook that is useful for all physicians who care for patients with neuromuscular disorders.

> **Ashraf Zaher, MD** Lecturer and Consultant of Neurology, University of Mansoura, Mansoura, Egypt

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neuromuscular disorders.

recommendations are given, particularly for the more common conditions, though we emphasize that the treatment of all patients should be individualized. For less common disorders, for which controlled trials have not yet been published, recommendations are based on published information and the authors' experience.

I am honored and grateful for the collaboration of an excellent group of renowned specialists. They have generously contributed their time and expertise to make what we hope is a textbook that is useful for all physicians who care for patients with

**Ashraf Zaher, MD**

Egypt

Lecturer and Consultant of Neurology, University of Mansoura, Mansoura,

**1** 

*1,3UK 2USA* 

**Integrins in the Development** 

*The Scripps Research Institute, CA,* 

*University College London,* 

**and Pathology of Skeletal Muscle** 

*3Dubowitz Neuromuscular Centre, Institute of Child Health,* 

Susan C. Brown1, Ulrich Mueller2 and Francesco J. Conti3,\* *1Veterinary Basic Sciences, The Royal Veterinary College, London, 2Dorris Neuroscience Center and Department of Cell Biology,* 

**1. Introduction** 

function (Campbell and Stull, 2003).

Corresponding Author

 \*

**1.1 Adhesion of muscle fibres to the extracellular matrix** 

Skeletal muscle is composed of many multinucleated myofibres each of which is surrounded by a connective tissue matrix that is essential for the function and the structural integrity of muscle. Apposed to each myofibre is a basement membrane, composed of a mixture of extracellular matrix (ECM) proteins, including collagen, fibronectin, glycoproteins (laminins, perlecan and nidogen) and proteoglycans. The proteins bind to multiple receptors expressed on the surface of muscle fibres: this is most notable at the level of the Z discs where an assembly of cytoskeletal proteins including dystrophin and integrins maintain continuity between the contractile apparatus, cytoskeleton and the ECM. This association of proteins is commonly referred to as the costamere, which is derived from the Latin word *costa,* meaning rib, because they encircle the whole muscle fibre and are arranged at regular intervals, thus conferring the appearance of a rib-like structure (Ervasti, 2003). Costameres are the means by which mechanical stress generated by contraction is diffused laterally across the myofibre. An additional structure where stress is transmitted to the ECM is the myotendinous junction (MTJ), where a connection to the tendon is made at the termini of muscle fibres (Tidball, 1991). This tight association between the muscle fibre and its surrounding matrix not only confers tensile strength to the entire muscle but also plays an important role in development, regeneration and synaptogenesis (Sanes, 2003). Indeed genetic defects in proteins that localise to the costameres and MTJs are a common cause of muscle disease, underscoring their importance in maintaining normal muscle

The two main adhesion systems recognised in striated muscle are the dystrophin-associated protein complex (DPC) and the integrins. Each system is composed of transmembrane
