ALS (amyotrophic lateral sclerosis) is a disease in which the nerve cells that control voluntary movement, called motor neurons, progressively degenerate and die. As these neurons fail, the muscles they control weaken, waste away, and eventually stop working. The process affects everything from hand grip to walking to breathing, typically over a span of months to years.
How Motor Neurons Break Down
The core problem in ALS is that motor neurons become overstimulated and die. Glutamate, the brain’s main excitatory chemical messenger, plays a central role. In a healthy nervous system, glutamate fires a signal and is quickly cleared away. In ALS, that cleanup system fails. Astrocytes, the support cells responsible for absorbing excess glutamate, don’t do their job properly. At the same time, motor neurons ramp up their sensitivity to glutamate by producing more calcium-permeable receptors on their surface. The result is neurons that are constantly overstimulated, a state called excitotoxicity.
This overstimulation triggers a chain of damage inside the cell. Mitochondria, the structures that produce energy for the neuron, change shape and lose function. The cell starts generating harmful molecules called reactive oxygen species, which damage internal structures. The endoplasmic reticulum, responsible for folding and transporting proteins, comes under stress. Together, these processes create a feedback loop: the neuron can’t produce enough energy to cope, toxins build up, and the cell dies. Both upper motor neurons (in the brain) and lower motor neurons (in the spinal cord and brainstem) are affected, which is what distinguishes ALS from other motor neuron conditions.
Where Symptoms Start
ALS typically begins in one of two ways. About two-thirds of people develop limb-onset ALS, meaning weakness starts in the arms or legs. The remaining cases begin with bulbar-onset ALS, which affects the muscles of the tongue, throat, and face first.
Limb-onset ALS often shows up as asymmetric weakness, meaning one hand or foot is noticeably weaker than the other. Someone might start dropping things, struggle to turn a key, or have trouble gripping. If it starts in the shoulders, posture and range of motion suffer. In the legs, it commonly causes foot drop: the ankle weakens so the toe catches the ground during walking, leading to stumbling and falls.
Bulbar-onset ALS is less common but often harder to recognize early. The first signs are slurred speech or difficulty swallowing. Some people also develop pseudobulbar affect, which causes involuntary episodes of laughing or crying that don’t match how they actually feel.
Regardless of where it begins, ALS eventually spreads to other body regions. Someone who starts with hand weakness will, over time, develop trouble with walking, speaking, or breathing as more motor neurons fail.
How ALS Is Diagnosed
There is no single blood test or scan that confirms ALS. Diagnosis relies on the Gold Coast criteria, the current clinical standard, which require three things: progressive motor impairment that followed a period of normal function, evidence of both upper and lower motor neuron dysfunction, and testing that rules out other conditions that could explain the symptoms.
Upper motor neuron damage shows up as exaggerated reflexes, spasticity (a velocity-dependent tightness in the muscles), and slow, poorly coordinated movements. Lower motor neuron damage causes visible muscle wasting and weakness. Electromyography (EMG) is a key diagnostic tool. It looks for two simultaneous patterns: signs that existing motor units have enlarged (because surviving neurons are trying to compensate for dead ones) and evidence that muscle fibers are actively losing their nerve supply, seen as tiny electrical discharges called fibrillation potentials and fasciculation potentials.
This combination of clinical exam and electrical testing, along with MRI and bloodwork to exclude other diseases, is what neurologists piece together to make the diagnosis. The process can take months, partly because early symptoms overlap with many other conditions.
What Drives Some Cases: Genetics
About 5 to 10 percent of ALS cases run in families (familial ALS), while the rest appear without a clear family history (sporadic ALS). More than 40 genes have been linked to the disease, but four account for up to 70 percent of familial cases in European populations.
The most common is C9orf72, responsible for 25 to 40 percent of familial cases and roughly 6 percent of sporadic ones. SOD1 mutations are the second most common, found in 10 to 20 percent of familial cases. TARDBP and FUS mutations are rarer, each accounting for about 4 to 5 percent of familial cases. Notably, about one in ten people with sporadic ALS also carry a known genetic mutation, blurring the line between “inherited” and “random” forms of the disease.
How Breathing Fails
Respiratory failure is the most serious consequence of ALS and the most common cause of death. As motor neurons supplying the diaphragm and other breathing muscles deteriorate, the lungs can no longer inflate fully. Early signs are subtle: fatigue, disrupted sleep, morning headaches from carbon dioxide building up overnight, and shortness of breath when lying flat.
Current guidelines recommend starting non-invasive ventilation (a mask-based breathing device, often used at night first) when forced vital capacity drops below 80 percent of normal and the person has symptoms of developing respiratory failure. Medicare criteria set a stricter threshold: lung capacity below 50 percent or an arterial carbon dioxide level at or above 45 mmHg. In practice, many clinicians begin earlier because non-invasive ventilation has been shown to improve both quality of life and survival.
Tracking the Progression
Clinicians monitor ALS using a tool called the ALSFRS-R, a 12-item scale that scores everyday abilities: speech, salivation, swallowing, handwriting, cutting food, dressing, turning in bed, walking, climbing stairs, and three measures of breathing (shortness of breath, the need for ventilatory support, and difficulty breathing while lying down). Each item is rated from 4 (normal function) to 0 (no ability), giving a total score out of 48. Tracking the rate of decline on this scale helps predict the disease course and guide decisions about assistive devices, feeding tubes, and ventilation.
Median survival from diagnosis has hovered around 18 to 20 months in large studies, though this number reflects the full spectrum, including people diagnosed late. Individual trajectories vary enormously. Some people progress rapidly over months, while others live years or even decades. Bulbar-onset ALS tends to progress faster than limb-onset.
Available Treatments
No treatment cures ALS, but several FDA-approved medications can slow progression or manage symptoms. Riluzole, the first drug approved for ALS, works by blocking excess glutamate release, directly targeting the excitotoxicity process. It’s available as a tablet, a thickened liquid for people with swallowing difficulty, and a dissolvable oral film.
Edaravone (brand name Radicava), approved in 2017, is designed to prevent nerve damage and slow the loss of physical function. It was originally given intravenously but became available as an oral suspension in 2022, making it far more practical for daily use.
For the roughly 1 to 2 percent of people whose ALS is caused by a SOD1 gene mutation, tofersen (Qalsody) was approved in 2023 as the first genetically targeted ALS therapy. It’s delivered by lumbar puncture directly into the spinal fluid.
Nuedexta addresses pseudobulbar affect, those uncontrollable episodes of laughing or crying. Recent evidence suggests it may also improve speech and swallowing function in people with ALS, regardless of whether they have pseudobulbar affect. Beyond medications, the day-to-day management of ALS involves a team approach: physical therapy to maintain mobility as long as possible, speech therapy, nutritional support (sometimes including a feeding tube), and respiratory care as breathing muscles weaken.