An interactive journey through the human genome to understand why motor neurons die — and what role genes like C9orf72, SOD1 and TDP-43 play.
The entire journey of this page, summarized in steps.
Before diving into the genetics, it helps to know the disease that these genes help explain.
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. The neurons that control voluntary movement —the upper motor neurons (in the brain) and the lower motor neurons (in the spinal cord and brainstem)— degenerate progressively. The muscle stops receiving signals, weakens and atrophies. Most cases share a single hallmark: aggregates of the TDP-43 protein.
In 1869, the French neurologist Jean-Martin Charcot described and named the disease, linking the loss of strength to the degeneration of the motor pathways. For more than a century it was a purely clinical entity; the genetic era began in 1993 with the discovery of SOD1.
Symptoms depend on which motor neurons are affected first, and they combine as the disease progresses:
Stiffness and spasticity, brisk reflexes and clumsy movements. It is the signature of the motor pathways descending from the brain.
Weakness, muscle atrophy and fasciculations (small twitches visible under the skin) when the neuron that reaches the muscle is damaged.
Difficulty speaking and swallowing when the brainstem motor neurons are affected. Sometimes this is the first sign of the disease.
Up to ~15% develop associated frontotemporal dementia (changes in behavior and language). ALS, by contrast, spares the senses and sphincter control.
Around 90% of cases appear with no clear family history. Genetics still contributes risk, alongside aging and environmental factors.
Inheritance is usually dominant. The most common genes are C9orf72, SOD1, TARDBP and FUS.
ALS and frontotemporal dementia share genes (above all C9orf72) and pathology (TDP-43): they are two ends of a single continuum.
ALS usually begins focally (in a hand, a leg or speech) and spreads to other regions of the body.
Weakness or clumsiness in a specific area: a hand, a foot or problems with speech/swallowing.
Weakness and atrophy propagate to adjacent regions and to the other side of the body.
Several muscle groups are affected; dependence for daily activities increases.
Weakness reaches the respiratory muscles: ventilatory support becomes key.
There is no cure, but a multidisciplinary approach improves quality of life and survival, and genetics is opening specific therapies.
Riluzole (reduces excitotoxicity) and edaravone (an antioxidant) offer a modest benefit on progression. They do not stop the disease.
Respiratory support (ventilation) and nutritional support, physical therapy, speech therapy and communication aids: the cornerstone of care.
Tofersen, an antisense oligonucleotide (ASO), treats ALS caused by SOD1 mutations: the first gene-targeted therapy in this disease.
Educational content with a scientific basis (Charcot, 1869; SOD1, Rosen et al. 1993; C9orf72, DeJesus-Hernandez/Renton 2011; tofersen, Miller et al. 2022). It does not replace assessment by a healthcare professional.
DNA (deoxyribonucleic acid) is the molecule that stores the genetic instructions of every living being, distributed across some 3 billion base pairs.
Four bases — A, T, C and G — form the double helix. In ALS, many variants affect proteins that handle RNA or clear other proteins: when they fail, toxic aggregates form in the motor neurons.
ALS genes are spread across the entire genome. Click on a chromosome to see its regions, the evidence and the genes involved.
Causal and risk genes for ALS. Search and filter by cellular mechanism; click a card to see its function and the studies.
ALS genes converge on a few motor neuron processes. Hover over a node to identify the gene; click to see the details.
Two key pieces of ALS: the GGGGCC expansion in C9orf72 and the motor neuron → muscle circuit. Explore them.
The C9orf72 gene contains a stretch where the GGGGCC hexanucleotide is repeated. Healthy people have few repeats; when it expands to hundreds or thousands, it generates toxic RNA and dipeptides and reduces the normal protein. Slide to see the effect.
The command to move travels in two relays. In ALS both degenerate. Click on each step of the diagram.
From Charcot's description to the C9orf72 gene and the first approved antisense therapy.
How ALS genes damage the motor neurons that control voluntary movement.
Most ALS cases are sporadic: around 90%. Only ~10% are familial, although both share the same mechanisms.
C9orf72 is the most common genetic cause (familial and sporadic) and links ALS to frontotemporal dementia. SOD1, the first gene discovered, already has a targeted drug. Even in "sporadic" cases, genetics contributes a substantial part of the risk.
The essentials about the genetics of amyotrophic lateral sclerosis:
The most important point: identifying the gene already changes treatment. SOD1 ALS has an approved antisense therapy (tofersen), and others are being investigated for C9orf72 and FUS. Genetics is, at last, opening targeted therapies.
ALS is a neurodegenerative disease. It is worth dispelling some misconceptions:
The so-called "Ice Bucket Challenge" (2014) was a viral awareness campaign that raised funds for ALS research; it is not a cause or a risk factor, but a public-awareness milestone.
Genetics is turning ALS into an increasingly targetable disease.
Tofersen (approved in 2023) silences SOD1 RNA and has been shown to reduce neurofilaments. It is the proof of concept that treating the gene works, and it opens the door to ASOs for other genes.
Because C9orf72 is the most frequent genetic cause, ASOs that reduce the toxic RNA from the GGGGCC expansion are one of the great hopes; several are in clinical trials.
Neurofilaments in blood and cerebrospinal fluid make it possible to estimate neuronal damage and the response to treatment, accelerating trials.
Sequencing each person to choose the therapy according to their gene: ALS is moving toward treatment personalized by mutation.
Restoring TDP-43 function and blocking the cryptic exons (such as the one in UNC13A) could help most cases, not only the genetic ones.
Detecting the disease —even before symptoms in known carriers— in order to intervene while there are still motor neurons left to protect.
Research is advancing quickly and some of these findings are preliminary: specific dates and figures may change as the trials mature.
The questions that come up most when learning about ALS.
Milestones and scientific sources on which this page is based.
A synthesizing educational page; it is not a primary clinical source. For medical decisions, consult professionals and the official resources of ALS associations.
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