Introduction

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder in adults. The disease is characterized by the progressive loss of both upper and lower motoneurons, and is invariably fatal. Symptoms at the beginning of the disease include fatigue, cramps, muscular atrophy, weakness and wasting of one or more limbs or fasciculation of the tongue. As the disease progresses, patients become paralyzed and ultimately die from respiratory failure, typically within 1–3 years after diagnosis. The only medication approved for treatment of ALS is Rilutec® (Riluzole, a glutamate antagonist). However, ALS can currently not be cured and the available therapy offers only limited success, with a life extension of 3–4 months depending on the initiation of treatment. Famous ALS patients, such as the British physicist Stephen Hawking, the US baseball player Lou Gehrig (after whom the disease is named in the US), as well as the recent high incidence of ALS in soccer players especially in Italy have generated an increased public interest into this disease.

The emotional, social, and physical burdens of ALS are evident. Disease management requires sustained effort by patients, their families, caregivers, and healthcare professionals. Further, the economic impact of this disease is enormous. As the diagnosis of ALS is usually reached by exclusion, patients at the beginning of their disease generally undergo a series of arduous tests (magnetic resonance imaging (MRI), electrophysiologic studies, muscle biopsies, and blood studies).

Introduction

Prion diseases represent a disease complex that is clinically rare. However, they are epidemiologically important severe diseases, and very likely to be important for our basic understanding of neurodegeneration in principle. This is reflected in this introductory clinical overview, which presents the clinical diagnostic and differential diagnostic approach to the patient; then a review follows which focuses on the current status of the field of basic sciences of prion diseases.

The history of prion diseases started in the year 1920 when Hans Gerhard Creutzfeldt described a mysterious focal disease of the central nervous system of a 22-year-old female patient, which clinically was characterized by progressive psychomotor disturbances and cortical symptoms (Creutzfeldt, 1920). In his autopsy he observed a pronounced gliosis which accompanied non-inflammatory focal lesions of the cortex. One year later, Alfons Jakob saw three similar cases which he also considered a new entity – he described a spastic pseudosclerosis and encephalomyelitis with disseminated focal degeneration (Jakob, 1921). Based on the similarity of the reported cases, Walter Spielmeyer suggested the name Creutzfeldt–Jakob disease (CJD). In 1936, the Gerstmann–Sträussler–Schenker (GSS) syndrome was first described and in 1957 fatal familial insomnia (FFI) (Gerstmann & Sträussler 1936; Lugaresi et al., 1986). In the 1960s, interest in the epidemiology of prion diseases increased when Gajdusek and Gibbs showed that Kuru – a disease first observed by the German Walter Zigas and Carleton Gajdusek among the Fore in Papua New Guinea and thought to be associated with cannibalism – could be transmitted to non-human primates and had similarities with the spongiform encephalopathy of sheep-scrapie (Zigas & Gajdusek, 1957; Hadlow, 1959; Gajdusek & Gibbs, 1966).

Neurodegenerative diseases are becoming increasingly prevalent with the aging of the general population. The twentieth century witnessed a significant demographic change in the human population of the industrialized world that is currently followed by a similar shift of life expectancy to upper age ranges in Asia, Africa, and Middle and South America. Quality of life of the aging population of the world is, to a great extent, determined by the normal aging process of neurons in the central nervous system and especially by the occurrence of diseases characterized by accelerated neuronal loss: diseases which are traditionally designated as being neurodegenerative. They are presently amongst the major contributors to disability and disease in human populations.

Alzheimer's disease is the most prevalent of the neurodegenerative diseases followed by Parkinson's disease. Amyotrophic lateral sclerosis and Huntington's disease affect smaller numbers of patients but have devastating consequences. A large number of other rarer neurodegenerative diseases have similar profound effects on the patients and families who are afflicted by these illnesses. Research into the pathogenesis and treatment for these disorders is exploding exponentially. To a great extent this has been fostered by major advances in genetics, since we now know mutations that are associated with a large number of these illnesses. This includes familial forms of Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, ALS, Huntington's disease and a variety of ataxias.