PRIMEVIEW AMYOTROPHIC LATERAL SCLEROSIS

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EPIDEMIOLOGY Amyotrophic lateral sclerosis (ALS; DIAGNOSIS also known as motor neuron disease) is a rare, neurodegenerative disease that is Up to 50% of patients develop In Europe, incidence is in the range of 2–3 cases characterized by the degeneration of cognitive and/or behavioural UPPER LOWER per 100,000 individuals; incidence is lower in upper and lower motor neurons, leading impairments during the course MOTOR MOTOR east Asia (0.8 cases per 100,000 individuals) to muscle weakness and paralysis. Diagnosis NEURON NEURON of the disease includes and south Asia (0.7 cases per 100,000 clinical investigation individuals). The phenotype of ALS varies between populations. For example, MECHANISMS to rule out other causes of the symptoms and the age at onset of symptoms to identify evidence of and diagnosis is higher in Europe ALS can be classified as either sporadic or familial. disease progression than in Asia or South America. Familial ALS has been associated with mutations In addition, the proportion of in >30 genes, but mutations in four genes — individuals with bulbar-onset C9orf72, TARDBP, SOD1 and FUS — account Some disease is much lower in Asia for >70% of cases. Proteins encoded by these forms of ALS than in Europe and patient genes are involved in several aspects of motor share a genetic overlap survival is lower in Europe neuron function, including protein homeostasis, with neuropsychiatric (24 months from the DNA repair, RNA metabolism, vesicle transport, conditions, such as onset of disease) than mitochondrial function and glial cell function. schizophrenia in central Asia Several of these mechanisms probably interact to Symptoms of upper (48 months). contribute to the degeneration of motor neurons motor neuron in ALS. In general, the proteins encoded by these degeneration genes are ubiquitously expressed, so why these include spasticity mutations lead to the selective degeneration and muscle of motor neurons, and not other cell types, weakness, whereas MANAGEMENT is unknown. The pathological hallmark of ALS fasciculations is the accumulation of intraneuronal protein (twitching), muscle Few randomized controlled trials assessing aggregates, which, in most individuals, contain cramps and wasting One‑third symptomatic therapies in patients with ALS have TAR DNA‑binding protein 43. are indicative of of patients been conducted; accordingly, many therapies are However, other proteins can form lower motor neuron present with bulbar- based on the management of other diseases. For aggregates, including superoxide degeneration onset disease, which is example, anticholinergic drugs can be used to dismutase 1 and characterized by dysarthria treat sialorrhoea (hypersalivation), baclofen can neurofilament. (difficulty speaking) and be used to treat spasticity and muscle relaxants Whether these protein dysphagia (difficulty can be used to treat cramps. The management of aggregates or the swallowing); the rest present dysphagia includes dietary changes, swallowing protein complexes that with spinal-onset disease, manoeuvres and exercise and, if severe, use of a The gross precede their formation which is characterized gastrostomy tube. Other available symptomatic macroscopic are toxic to by limb muscle treatments include speech therapy for dysarthria features of ALS OUTLOOK weakness neurons is poorly include atrophy of and noninvasive ventilation for respiratory failure. understood. skeletal muscle and the motor cortex, One barrier to the development the overall integrity and function in humans will enhance our and sclerosis of the of effective treatments for ALS of brain networks. Improvements understanding of ALS and enable Two disease-modifying therapies — pyramidal tracts is the poor understanding of how in model systems to study ALS and us to target therapies to specific riluzole and edaravone — have been the pathology of disease affects better ways to study the disease aspects of the pathophysiology. approved by the US FDA

Written by Louise Adams; designed by Laura Marshall Article number: 17072; doi:10.1038/nrdp.2017.72; published online 5 Oct 2017 ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved.