Beyond Motor Neuron Degeneration: Non-Motor Manifestations and Multisystem Involvement in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects the motor system through the degeneration of motor neurons in the motor cortex, brainstem nuclei, and anterior horn of the spinal cord. ALS typically has a focal onset characterized by muscle weakness, followed by progressive spreading to other body regions, with respiratory muscle failure representing the main life-limiting complication. Median survival is approximately 2–5 years after disease onset. In addition to the well-established motor manifestations, non-motor symptoms are increasingly recognized and may occur in approximately 50% of patients. These include behavioral and neuropsychiatric disturbances, sleep disorders, sensory abnormalities, autonomic dysfunction involving the cardiovascular, gastrointestinal, and genitourinary systems, as well as metabolic and endocrine alterations. Recent evidence supports the concept of ALS as a multisystem disorder characterized by substantial clinical, genetic, and neuropathological heterogeneity. Nevertheless, non-motor manifestations remain less extensively characterized than motor symptoms and are frequently underestimated in clinical practice. This narrative review summarizes the current evidence on non-motor manifestations in ALS, discusses their potential underlying mechanisms and impact on quality of life, and highlights areas requiring further investigation. A better understanding and systematic assessment of these manifestations may contribute to a more comprehensive and patient-centered approach to ALS care.