Preface

Motor neuron diseases (MNDs) are a clinically and pathologically heterogenous group of neurodegenerative disorders, which are associated with progressive damage of the upper (UMN) or lower motor neurons (LMN) or both. MNDs encompass disorders such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinobulbar muscular atrophy (SBMA), and hereditary spastic paraparesis (HSP). The involvement of the LMN manifests with muscle weakness, atrophy, and fasciculations. On the other hand, the degradation of the UMN leads to spastic paresis, hyperreflexia, clonus, and positive Babinski sign. Due to a wide variety of clinical phenotypes, complex genetical background, as well as the absence of reliable biomarkers, some MNDs still pose a diagnostic challenge for clinicians. Regarding SMA, the unraveling of the underlying genetical pathology led to the discovery of three efficacious and safe therapeutic interventions. These therapies, however, are not curative. Concerning ALS, the most common form of ALS has been identified in the course of intense research over 50 potentially causative or disease-modifying genes. Sadly, despite these advances, treatment options remain limited for the majority of ALS patients. In this book, we address the latest scientific updates in the genetics, pathophysiology, diagnostics, and treatment of MNDs.

#### **Natalia Szejko**

Department of Clinical Neurosciences, University of Calgary, Alberta, Canada

> Department of Bioethics, Medical University of Warsaw, Warsaw, Poland

#### **Kamila Saramak**

Department of Neurology, Hochzirl Hospital, Zirl, Austria

**1**

**Chapter 1**

**1. Introduction**

Introductory Chapter:

*Kamila Saramak and Natalia Szejko*

(SBMA), and hereditary spastic paraparesis (HSP) [2].

**2. Lower motor neuron (LMN) syndromes**

described together with ALS [5].

**2.1 Spinal muscular atrophy (SMA)**

Motor Neurons – New Insights

Motor neuron diseases (MNDs) are a group of progressive neurodegenerative disorders associated with the degradation of the upper (UMN) and lower motor neurons (LMN), without affecting sensory and autonomic systems [1]. MNDs can be classified based on the pattern of motor neuron involvement; they encompass pure LMN syndromes, mixed upper and lower motor neuron diseases, and pure UMN syndromes [2]. MNDs patients display a large heterogeneity of clinical symptoms, including muscular weakness, atrophy, and corticospinal tract signs in varying combinations and severities, presenting a unique diagnostic challenge to clinicians [3]. In this chapter, we provide an overview of MNDs, in particular amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinobulbar muscular atrophy

The pure LMN syndromes are characterized by a selective degeneration of the anterior horn cells in the spinal cord and the motor nuclei in the brain stem, which inevitably leads to muscle weakness, atrophy, and fasciculations. They encompass spinal muscular atrophy (SMA) and spinobulbar muscular atrophy (SBMA), which is also known as Kennedy's disease [4]. Progressive muscular atrophy (PMA) will be

SMA is an autosomal recessive disease with a prevalence of 1 per 10,000 live born infants. It is most often related to mutations in the *Survival Motor Neuron 1 (SMN1)* gene, which encodes SMN, a protein essential for the development and survival of motor neurons. A paralogous gene, *SMN2*, also encodes the SMN protein but produces considerably less of it. SMA is associated with the degradation of anterior horn cells in the spinal cord and motor nuclei in the brain stem, producing weakness of limb, trunk, bulbar, and respiratory muscles [6]. SMA can be classified into five types (SMA 0–IV) according to age of onset and its clinical course. The beginning of symptoms varies from before birth (type 0) to adulthood (type IV) [7]. SMA type 0 is the rarest and the most severe form of SMA, usually resulting in death due to respiratory failure and bulbar deterioration within the first month of life. SMA type I is the

**Chapter 1**
