Amyotrophic Lateral Sclerosis (ALS)

The disease that kills motor neurons in the brain and spinal cord: symptoms, genetics (SOD1, C9orf72, TDP-43), Lou Gehrig and Stephen Hawking, the Ice Bucket Challenge, and the first gene-targeted treatment.

Naming the disease

Jean-Martin Charcot described ALS in 1869. The name describes it: amyotrophic (muscle wasting), lateral (the side regions of the spinal cord where upper motor neuron axons run) and sclerosis (hardening, as those regions scar). In the United States it's often called Lou Gehrig's disease, after the New York Yankees baseball star diagnosed in 1939; in the UK it's commonly known as motor neurone disease (MND).

What happens

ALS kills both upper motor neurons (in the motor cortex) and lower motor neurons (in the brainstem and spinal cord). It often starts with weakness in one hand or foot, or with slurred speech and swallowing difficulty (bulbar onset), then spreads. Signs include muscle wasting, twitching (fasciculations), cramps, stiffness and exaggerated reflexes. Eye movements and bladder control are usually spared. Average survival after diagnosis is roughly two to five years, often ending in respiratory failure, but variation is large — the physicist Stephen Hawking lived with an unusually slow form for over 50 years.

ALS and FTD

Up to half of people with ALS develop some changes in thinking or behaviour, and some develop frontotemporal dementia (FTD). In 2006 researchers found that in most cases of ALS and many cases of FTD, a protein called TDP-43 abnormally clumps in neurons, revealing the two as part of one disease spectrum.

Genetics

About 10% of cases run in families. In 1993, mutations in SOD1 were the first genetic cause found. In 2011, an expansion of a repeated stretch of DNA in C9orf72 was identified as the most common genetic cause of both ALS and FTD.

Research and treatment

The Ice Bucket Challenge went viral in 2014, raising over $100 million for the ALS Association in the US alone and funding research that helped identify new ALS genes. Treatments include riluzole and edaravone, which offer modest benefits, and in 2023 tofersen — an antisense oligonucleotide that reduces production of the SOD1 protein — became the first gene-targeted ALS therapy approved in the US, for people with SOD1 mutations. Multidisciplinary care — breathing support, feeding tubes, communication technology including eye-tracking and brain-computer interfaces — extends and improves life.