CHAPTER 1
Clinical Heterogeneity of ALS - Implications for Models and Therapeutic Development

Serena Lattante1,2 and Mario Sabatelli3,4

1 Unità Operativa Complessa di Genetica Medica, Dipartimento di Scienze di Laboratorio e Infettivologico, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

2 Sezione di Medicina Genomica, Dipartimento Scienze della Vita e Sanità Pubblica, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy

3 Centro Clinico NEMO adulti, U.O.C. Neurologia, Dipartimento di Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo Fondazione

4 Sezione di Neurologia, Dipartimento di Neuroscienze, Facoltà di Medicina e Chirurgia, Università Cattolica Sacro Cuore, Rome, Italy

INTRODUCTION

Amyotrophic lateral sclerosis (ALS) was first described in 1874 as a specific neurological disease by the French neurologist Jean-Martin Charcot, who chose this term to reflect both clinical observations and post-mortem pathological findings. Amyotrophic refers to clinical evidence of muscle atrophy as a consequence of the loss of lower motor neurons (LMNs). Lateral sclerosis refers to the pathological observation of hardness of the lateral columns of the spinal cord, following upper motor neuron (UMN) degeneration [1]. UMN degeneration is followed by the formation of a sort of scar. The disease leads to progressive paralysis, with death occurring due to respiratory failure within three to five years after symptom onset.

The classical form is characterized by the concomitant involvement of UMNs in the cerebral cortex and LMNs located in the brainstem and the spinal cord. Clinical manifestations of UMN damage are loss of dexterity of the hands and spastic gait associated with overactive tendon reflexes. These signs are frequently associated with pathological reflexes, including Chaddock and Babinski signs (extension of the big toe after rubbing the lateral malleolus and the sole of the foot, respectively) and Hoffmann sign (flexion and adduction of index finger and thumb when flicking the nail of the middle finger downward). Corticobulbar involvement leads to slurred speech and difficulty swallowing, often with pathological crying and laughing. The consequence of LMN degeneration is weakness, which may involve any muscle of the body including those of the tongue, pharynx, or larynx (innervated by bulbar motor neurons); those of upper and lower limbs; and the respiratory muscles. Oculomotor and Onuf's motor neurons are usually spared. Muscular atrophy, reduced reflexes, and signs of hyperexcitability in motor neurons, such as fasciculation and cramps, are additional features of LMN degeneration.

The combination of the these symptoms and signs of UMN and LMN dysfunction results in a peculiar and stereotypical picture, which in most cases is easy for expert clinicians to identify. However, there is an evident clinical heterogeneity among ALS patients, which is determined by several independent elements. The age of onset and survival, two major phenotype features, show a marked variability among patients. Furthermore, the relative number of UMN and LMN signs may show substantial differences. An additional contributor to this heterogeneity is the evidence that the types of cells impaired in ALS may extend beyond UMNs and LMNs to include the frontal and temporal cortex, extrapyramidal system, peripheral nerves, and skeletal muscles, giving rise to variable and sometimes overlapping phenotypes.

Finally, genetic research has revealed that ALS is linked with several causative genes - a list that will probably increase in the coming years due to the rapid improvement of next-generation sequencing technologies. ALS-related genes are implicated in various cellular functions, including RNA metabolism, autophagy, and axonal transport, suggesting significant heterogeneity in disease mechanisms as well.

Thus, it appears that ALS is used as an umbrella term referring to a spectrum of disorders with diverse clinical manifestations, heterogeneous disease mechanisms, and (probably) different responses to therapies. On the other hand, all ALS patients, except carriers of superoxide dismutase 1 (SOD1) and fused in sarcoma (FUS) variants, appear to be unified by a single pathological signature: the presence of abnormal accumulation of the transactivation response DNA binding protein (TDP-43) in the cytoplasm of neuronal and glial cells [2].

CLINICAL HETEROGENEITY OF ALS

Familial and Sporadic ALS

The disease occurs sporadically in the majority of cases (sporadic amyotrophic lateral sclerosis [sALS]), and nearly 10% of patients have a positive family history (familial amyotrophic lateral sclerosis [fALS]) [3]. However, the dichotomy between fALS and sALS is less clear than previously assumed, since several clinical, pathological, and genetic observations support the view that they are linked with each other over a continuum. From a clinical point of view, patients with sALS are indistinguishable from those with fALS. Both conditions show similar pathological patterns - the presence of ubiquitinated TDP-43 positive inclusions in neuronal cells - with the only exception being patients with SOD1 and FUS mutations in which the SOD1 and FUS proteins are detected, respectively [4]. Importantly, fewer than 50% of fALS patients show a clear Mendelian inheritance, usually autosomal-dominant (definite fALS). In the remaining fALS cases, the genetic architecture is less clear as familiarity is assumed by the presence of a single relative with ALS beyond the propositus. These cases are defined as probable fALS when the affected subject is a first- or second-degree relative and possible fALS when the subject is more distant than second-degree. Finally, the most consistent link between sALS and fALS is the observation that all genes involved in fALS are invariably found to be mutated in patients with apparently sporadic disease [3]. Genetic variants in major ALS genes have been detected in about 15% of sporadic forms [5, 6].

Age of Onset

ALS affects people of all ages, with a peak between ages 60 and 79. Recent population-based studies reported a prevalence of ALS between 4.1 and 8.4 per 100?000 [7]. Patients with onset in the first two decades are extremely rare; such cases are termed juvenile ALS. This appears to be a different condition than classic ALS as it is familial in most cases, generally has autosomal recessive inheritance, and shows a very prolonged course. Patients with onset between 20 and 40?years are said to have young-adult ALS; this is otherwise classic ALS, although it has peculiar clinical features including predominant UMN signs, male prevalence, and more prolonged survival (usually greater than five years). It remains unclear whether distinctive clinical features of young-adult ALS are related to a different disease mechanism. Finally, very rare patients with onset before 20?years show an otherwise classic ALS with sporadic occurrence and an aggressive course. Most of the reported cases harbor a de novo mutation in the FUS gene.

Survival

The median survival of ALS is approximately three?years from the onset, and about 70% of patients die within five?years from onset. However, the duration of the disease differs widely in individual patients, ranging from a few months to over 10?years. Such remarkable variability is a major factor in favor of the hypothesis of ALS as a syndrome rather than a single disease. Median survival is worse in patients with bulbar onset ALS than with the spinal onset. Patients with disease onset before the age of 40 and patients with predominant UMN signs show a better prognosis. In most ALS patients, the cause of death is respiratory failure due to the degeneration of motor neurons controlling thoracic and diaphragmatic muscles. Of note, both the temporal and spatial patterns of the disease spread are important determinants of survival. Regarding the temporal pattern, the spreading rate of the degenerative process may vary among patients, with some patients showing a very rapid, aggressive course and others a slow progression. The spatial pattern is also important, since the sequence in which various body regions are involved is extremely variable and the survival changes if respiratory muscles are among the first or last to be affected.

Classic ALS, LMN Form, and UMN Form

By definition, ALS is characterized by a combination of LMN and UMN clinical and electrophysiological signs. However, the relative mix of UMN and LMN impairment is highly variable among patients, and clinical manifestations of ALS exist on a continuum whose extremes are represented by cases showing pure LMN dysfunction on one side and cases with pure UMN signs on the other side. Classic ALS (Charcot type) is the most frequent form, accounting for about 70-90% of cases, and is characterized by predominant LMN signs combined with slight to moderate pyramidal signs. Patients with pure LMN signs without any accompanying clinical or electrophysiological UMN signs are labeled as having progressive...