ALS

• 1. Introduction

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  Stephen Hawking lived for 55 years after doctors diagnosed him with ALS, short for amyotrophic lateral sclerosis. That is longer than any other known person with the condition has survived, and the astrophysicist's case was an unusual one. ALS is also called motor neuron disease, or Lou Gehrig's disease. It is rare and it is terminal. It slowly destroys the nerve cells that carry movement commands from the brain to the body's voluntary muscles. This documentary follows several questions. Why does the damage begin in one hand, one foot, or the voice, and then creep outward? What goes wrong inside a motor neuron? Why can doctors name a cause in only a small share of cases? And what can medicine offer when no cure exists?

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• 2. Two Kinds Of Neuron

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  To move a single finger, a signal must leave the motor cortex of the brain and travel down an upper motor neuron through the spinal cord. There it crosses a synapse to a lower motor neuron, which connects directly to the muscle. Damage to the upper neuron typically brings spasticity, meaning stiffness and exaggerated tendon reflexes. Damage to the lower neuron typically brings weakness, muscle atrophy, and fasciculations, which are small twitches.

  Classical ALS involves both kinds of neuron and accounts for about 70% of all cases. Primary lateral sclerosis, or PLS, mainly affects the upper motor neurons and makes up about 5% of cases. Progressive muscular atrophy, or PMA, mainly affects the lower motor neurons and also makes up about 5%. Doctors debate whether PLS and PMA are separate diseases or variants of ALS.

  More than 75% of people who seem to have PLS develop lower motor neuron signs within four years of their first symptoms. A definite PLS diagnosis therefore cannot be made until several years have passed. PLS progresses more slowly than classical ALS and does not affect breathing. PMA is linked to longer survival on average, but it still progresses toward respiratory failure.

  Some people have a regional variant, in which symptoms stay in a single area of the body. Flail arm syndrome affects the arms, usually starting in the upper arms and moving down to the hands. Flail leg syndrome causes uneven weakness and wasting in the legs, starting around the feet. A regional diagnosis is only considered when symptoms fail to spread for at least 12 months.

  Age offers another way to sort the disease. About 10% of all cases begin before age 45, and about 1% begin before age 25. Juvenile ALS is more often genetic, and the genes most often involved are FUS, ALS2, and SETX. Familial ALS tends to start about five years earlier than apparently sporadic ALS.

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• 3. How It Begins

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  Buttoning a shirt, writing, or turning a key in a lock can suddenly become awkward. For some people, that clumsiness in the hands and arms is the first sign of ALS. For others it starts in the legs, with tripping, stumbling, or a dropped foot that drags gently along the ground. Limb-onset ALS, also called spinal-onset, accounts for about two-thirds of classical cases.

  Bulbar-onset ALS accounts for about 25% of classical cases. Speech turns slurred, nasal, or quieter, and swallowing becomes difficult as the tongue loses mobility. About 3% of patients have respiratory-onset ALS, in which the intercostal muscles that support breathing weaken first. Breathlessness appears during exertion, at rest, or when lying flat.

  Early signs can be so subtle that they are overlooked, and they usually appear on one side of the body. After that, the spread follows patterns. The region hit first generally stays the most affected, and symptoms usually travel to a neighbouring region. A weak arm tends to be followed by the opposite arm or the leg on the same side. Bulbar-onset patients usually feel the next symptoms in the arms. Arm-onset patients usually move on to the legs, and leg-onset patients to the arms.

  Most people eventually lose the ability to walk, use their hands, speak, and swallow. The feature that shortens life is weakness of the respiratory muscles, which removes the ability to cough and to breathe without mechanical support. Some people lose all voluntary movement, a state called locked-in syndrome.

  The damage is selective, though. Sensory nerves and the autonomic nervous system are generally unaffected, so most people keep hearing, sight, touch, smell, and taste. Bladder and bowel control are usually spared. The muscles that move the eyes usually keep working, so eye tracking technology can often support communication. The disease does not cause pain directly, but most people feel pain because they move less. Many people in an advanced stage still report satisfactory well-being when supportive measures are in place.

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• 4. Mind And Emotion

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  Between 30% and 50% of people with ALS show some cognitive or behavioral change, and it appears more often in later stages. Language and executive function are the most commonly reported problems, along with difficulty reading social cues and trouble with verbal memory. These changes turn up more often in people with C9orf72 repeat expansions, bulbar onset, a family history of ALS, or mainly upper motor neuron disease.

  About half of people with ALS also experience pseudobulbar affect. They may cry, smile, yawn, or laugh with no emotional trigger, or while feeling the opposite of what they express. It is more common with bulbar-onset ALS. The outbursts are relatively benign compared with other symptoms, but they can be frequent and public. Bystanders often do not know how to react, and the result can be stigma and social isolation.

  Around 10-15% of people show signs of frontotemporal dementia, or FTD. Repeating phrases or gestures, apathy, and loss of inhibition are the most frequently reported behavioral features. Because of shared genetic, clinical, and pathological features, ALS and FTD are now seen as parts of one disease spectrum called ALS-FTD.

  These changes affect prognosis. They can reduce a person's ability to follow medical advice. Deficits in empathy and social understanding can also add to the burden on caregivers.

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• 5. Causes And Patterns

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  Roughly 90-95% of ALS cases have no known cause. These sporadic cases are described as idiopathic, meaning their origin is unknown. Genetic and environmental factors are thought to matter about equally. A multi-step model proposes that cellular damage builds up over a lifetime, from genetic factors present at birth and from exposures along the way.

  About 5-10% of cases have a known genetic cause and are called familial or hereditary. More than 40 genes have been linked to ALS. Four of them account for nearly half of familial cases and around 5% of sporadic ones. C9orf72 is behind about 40% of familial cases and 7% of sporadic ones. SOD1 accounts for 12% of familial cases, and FUS and TARDBP each account for 4%. Repeat expansions in C9orf72 also explain about 25% of genetic FTD, which is why ALS and FTD share a spectrum. First-degree relatives of someone with ALS face roughly a 1% risk.

  A missing family history does not rule out genetics. Records may be lacking, a family may be small, or older relatives may have died of other causes first. The gene therapy tofersen, for carriers of SOD1 ALS, has prompted calls to counsel and test every patient. A shortage of genetic counselors and unequal access to testing around the world stand in the way.

  Among environmental exposures, the most consistent are heavy metals such as lead and mercury, pesticides and solvents, electric shock, head injury, and smoking, more so in men. Each effect is small. Lifetime risk of roughly 1 in 400 might rise to between 1 in 300 and 1 in 200 after heavy metal exposure. Agricultural work can involve as many as five of these risk factors. Weaker evidence points to professional sports, military service, and exposure to a compound called BMAA.

  Immune and viral clues are emerging too. In 1991, researchers at Baylor College of Medicine used antibodies to target motor neurons in mice and produced limb weakness resembling ALS. In 2025, researchers at Columbia University Medical School and the La Jolla Institute for Immunology published the first study showing inflammatory T cells aiming at a specific target on motor neurons in patients. Many patients also show raised activity of endogenous retroviruses, which are ancient viral remnants embedded in the human genome.

  On a map, the disease is uneven. ALS is the third most common neurodegenerative disease after Alzheimer's and Parkinson's. Worldwide, about 1.9 people per 100,000 develop it each year. In Guam, the Kii Peninsula of Japan, and Western New Guinea, reported prevalence was 50-100 times higher than elsewhere, and the cause remains unknown. Cases worldwide are projected to rise from 222,801 in 2015 to 376,674 in 2040, an increase of 69%.

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• 6. Misfolded Proteins

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  At autopsy, some of ALS can be seen without a microscope. The skeletal muscles and the motor cortex have shrunk. The corticospinal and corticobulbar tracts are hardened, and the hypoglossal nerves that control the tongue are thin, as are the anterior roots of the spinal cord.

  Under the microscope, the hallmark is the Bunina body, an abnormal clump of protein inside the cytoplasm of motor neurons. In about 97% of people with ALS, the main ingredient is a protein called TDP-43. In people with SOD1 or FUS mutations, the clumps are made of SOD1 or FUS protein instead. Misfolded proteins may spread from cell to cell in a prion-like way, which could explain why the disease starts in one area and then moves to others.

  The known ALS genes fall into three groups by normal function: protein degradation, the cytoskeleton, and RNA processing. Mutant SOD1 forms clusters inside cells that block protein disposal. TDP-43 was the first RNA-binding protein found to be involved, and it aggregates in the cytoplasm of motor neurons in almost every case. Mutations in its gene, TARDBP, are a rare cause of ALS.

  The C9orf72 mutation is a hexanucleotide repeat, a series of six nucleotides repeated over and over. People with up to 30 repeats are considered normal. People with hundreds or thousands can develop familial ALS, frontotemporal dementia, or sometimes sporadic ALS. The damage comes from three routes: RNA deposits in the nucleus, toxic dipeptide repeat proteins in the cytoplasm, and lower levels of the normal C9orf72 protein.

  Excitotoxicity is thought to play a part in every form of ALS. This is nerve cell death from too much calcium inside the cell, caused by overstimulation by the neurotransmitter glutamate. Motor neurons are especially vulnerable because they buffer calcium poorly and carry an AMPA-type glutamate receptor that lets in more calcium. In ALS, levels of the transporter EAAT2, which clears glutamate from the synapse, are reduced. Researchers still do not know whether the drug riluzole, which inhibits glutamate release, helps through this mechanism.

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• 7. Diagnosis And Naming

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  In the United States, the average wait from first symptom to confirmed diagnosis runs from 11.5 to 15 months. Patients may see three or four clinicians before reaching an ALS specialist, and much of the delay happens under the care of neurologists without neuromuscular training. The ALS Association assembled a workgroup of specialists, industry experts, and people with ALS to tackle the problem. It produced the thinkALS tool, which helps doctors recognize ALS and refer patients to specialty centers sooner.

  No single test proves ALS. Doctors rely on clinical assessment after ruling out other diseases. Electromyography detects electrical activity in muscles, and nerve conduction tests can point toward peripheral neuropathy or myopathy instead. An MRI is often normal early on, but it can reveal a spinal cord tumor, multiple sclerosis, or a herniated disc in the neck. Infections such as HIV, Lyme disease, and syphilis can imitate ALS, as can post-polio syndrome and myasthenia gravis.

  The diagnostic criteria evolved over decades. Electrodiagnostic testing entered the evaluation of suspected ALS in the 1950s, and in 1969 Edward H. Lambert published the first criteria built on four findings. The El Escorial criteria came in 1994 and were revised in 1998. The Awaji criteria of 2006 used electrical tests to catch the disease earlier. The Gold Coast criteria of 2019 simplified diagnosis, added cognitive change, and no longer required several regions to be affected.

  The disease itself was described long before it had a name. Charles Bell wrote about it in 1824, and in 1850 François-Amilcar Aran described progressive muscular atrophy. In 1869 the French neurologist Jean-Martin Charcot connected the symptoms to the underlying nerve damage, and in 1874 he introduced the term amyotrophic lateral sclerosis. In Greek, a- means no, myo- means muscle, and trophḗ means nourishment. Lateral points to where in the spinal cord the affected neurons sit, and sclerosis means hardening or scarring. Alfred Vulpian described flail arm syndrome in 1886, and Pierre Marie and his student Patrikios described flail leg syndrome in 1918.

  Other names followed. Charcot's disease honors the man who made the connection. The British neurologist Russell Brain coined motor neuron disease in 1933. In the United States, the disease carries the name of baseball player Lou Gehrig, who was diagnosed in 1939. In the United Kingdom and Australia, motor neuron disease covers all forms, while ALS means only the classical form.

  Public awareness has come through stories. Hawking's life became the biopic The Theory of Everything. Sociology professor Morrie Schwartz was the subject of the memoir Tuesdays with Morrie and a film of the same name. In August 2014, the Ice Bucket Challenge went viral online. Participants poured ice water over themselves, nominated others, and many gave to groups including the ALS Association and the Motor Neurone Disease Association in the UK.

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• 8. Treatment And Time

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  The ALS Functional Rating Scale - Revised is a 12-item questionnaire that scores a person from 48, normal function, down to 0, severe disability. On average, people lose about 1 point per month. Brief plateaus and small reversals happen, but large or lasting improvements are rare, below 1%. Clinicians rated a 20% change in the slope as meaningful, so it is a common benchmark for new treatments in trials.

  Prognosis varies. Most people die between two and four years after diagnosis. About 50% die within 30 months of symptoms beginning, about 20% live between five and ten years, and about 10% survive ten years or more. A population-based study found a median survival of 2.0 years for bulbar onset, with 3% alive at ten years. Limb onset had a median of 2.6 years, with 13% alive at ten years. Respiratory onset had a median of 1.4 years and no ten-year survivors.

  There is no cure. Riluzole modestly prolongs survival by about two to three months. Edaravone modestly slows functional decline in some people with early-stage disease. In April 2023, tofersen, sold as Qalsody, was approved in the United States for SOD1-associated ALS. In a study of 108 patients, it showed a non-significant trend toward slower progression and a significant fall in neurofilament light chain, a marker of nerve damage.

  Breathing support has the strongest record. Non-invasive ventilation uses a face or nasal mask and was the first treatment shown to improve both survival and quality of life. A 2006 trial found it prolonged survival by about 48 days overall. For people with normal or only moderately impaired bulbar function, the gain was about seven months. Still, about 25-30% of people cannot tolerate it. Invasive ventilation through a cut in the trachea prolongs survival but does not stop the disease. About 30% of people with ALS in Japan choose it, against less than 5% in North America and Europe.

  Nutrition and therapy matter as well. Dysphagia develops in about 85% of people at some point. A feeding tube should be considered if someone loses 5% or more of body weight. Speech-language pathologists can provide voice amplifiers, speech-generating devices, and low-tech tools such as alphabet boards. Attending a multidisciplinary ALS clinic is associated with longer survival and fewer hospitalizations.

  Palliative care should begin shortly after diagnosis, so people can set out their wishes in advance directives before speech or thinking fails. Most people die at home, usually from respiratory failure. Many fear choking to death, yet that happens less than 1% of the time.

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