Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the upper and lower motor neurons. The degeneration of the lower motor neurons results in the denervation of muscles followed by fasciculation, cramps, muscle wasting, and weakness. The degeneration of the upper motor neurons results in a loss of fine motor control of the lower motor neuron system, causing spastic paresis. The initial presentation varies between patients, depending on the affected motor neurons. Muscle paresis of the limbs is seen in spinal-onset disease (>75% of patients), whereas dysarthria is usually the first symptom in patients with bulbar onset.
Amyotrophic lateral sclerosis typically manifests later in life, with a peak incidence in the 7th decade, with males more frequently affected than females (1.5/1; ). Death typically occurs within 2–3 years of the onset of first symptoms, mainly due to respiratory failure, but overall survival time ranges from a few months to decades. In Europe, the incidence is about 2–3 per 100,000 individuals .
Although defined as a pure motor neuron disease by Charcot in 1869, ALS is now recognized as a multi-systemic disorder that may also affect frontotemporal, oculomotor, cerebellar, and/or sensory systems, and more rarely the basal ganglia and autonomic nervous system . Around 10% of ALS patients fulfill the Neary criteria for frontotemporal dementia (FTD), whereas cognitive impairment with mainly executive dysfunction can be recognized in more than 40% of ALS patients . Initially regarded as distinct diseases, both primary lateral sclerosis (PLS), which affects only upper motor neurons, and progressive muscular atrophy (PMA), which affects only lower motor neurons, are nowadays considered variants of ALS .
According to the revised Escorial criteria, diagnosis relies on the identification of upper and lower motor neuron signs in clinical, electrophysiological, and neuropathological examinations, as well as the progressive spread of signs, whereas differential diagnoses are excluded . Treatable differential diagnoses include spinal stenosis, multifocal motor neuropathy, and myasthenia gravis. To date, there is no definitive diagnostic test for ALS, and the clinical diagnosis instead relies on clinical findings, electrophysiological results, and the exclusion of phenocopies. Although not integrated into standard clinical practice, several biomarkers such as cerebrospinal fluid (CSF) neurofilament levels are useful in supporting the diagnosis, particularly in patients with clinically doubtful signs of upper motor neuron involvement .
Amyotrophic lateral sclerosis patients should be managed by a multidisciplinary team, including neurologists, psychologists, physiotherapists, pulmonologists, speech specialists, and nutritionists . Symptomatic treatment options include pharmacological and nonpharmacological approaches. For instance, spasticity can be addressed by administration of baclofen whereas hypersalivation can be treated with anticholinergic drugs or Botulinum toxin injection into the parotid glands. Pain, as commonly reported by ALS patients, is treated according to the WHO’s pain relief ladder. Dietary changes (e. g., fluid thickeners) can help to improve nutrition and a gastrostomy tube is an option if severe dysphagia is present. Speech therapy is frequently necessary and assisted communication (customized software) can also be used. Non-invasive ventilation is the preferred treatment for respiratory insufficiency. As substantial immobility and loss of speech are the major problems in advanced disease stages, the patients’ individual wishes for life-prolonging therapies (such as tracheostomy) should be addressed at early disease stages in end-of-life discussions, as cognitive or communication difficulties may arise over time.
In most ALS patients the disease cause is unknown. In up to 25% of cases, however, patients have a family history, with close relatives affected by ALS or FTD. Genetic causes have been identified in sporadic as well as familial cases. This review gives an overview of the most frequently as well as newly identified monogenic causes as well as genetic risk factors of ALS and will discuss ALS-specific aspects of genetic counseling of patients and their families.