In the majority of cases, the onset of the disease takes the form of muscle weakness. This reduction in strength can appear in completely different ways, depending on the group of muscles affected. The disease may first be noticed as clumsiness of the hands, e.g. when shaving, writing or doing fine manual work. This is the case in about 40% of patients. If the disease starts in the lower limbs (in a further 40% of cases), an unsteady gait or weakness of the legs is usually noticed. The onset of the disease may also be apparent as muscle wasting (atrophy) or stiffness (spasticity).

Typical symptoms at the start of the disease also include muscle cramps, especially in the calf muscles. A basic distinction must be made between disease onset in the limbs (spinal disease onset) and the less frequent form that begins with disorders of speech or swallowing (bulbar disease onset). About 20 to 30% of patients suffer from the bulbar form at the start. The slight change in speech may be noticed first by other people before the patients themselves become aware of the gradual alteration in their speech. What is important is that the spinal and bulbar forms are due to the same cause, no matter how different the patients' symptoms. Body perception, sensory functions, control of urine and faeces and also memory are usually spared by the disease process.