An interactive journey through the human genome to understand why loss of the SMN1 gene weakens the muscles — and how the backup gene SMN2 and three new therapies have transformed the disease.
The whole journey of this page, summarized in steps.
Before diving into the genetics, it helps to know the disease that these genes explain.
Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by the degeneration of the lower motor neurons in the anterior horn of the spinal cord. The muscle stops receiving the command to move, and proximal, symmetric muscle weakness and atrophy appear (the muscles closer to the trunk are affected first). One important feature: cognition is preserved — intelligence and the senses are not affected.
The Austrian physician Guido Werdnig (1891) and the German Johann Hoffmann (1893) described the most severe infantile form, today known as Werdnig-Hoffmann disease. For a century it was a clinical entity with no known cause; the genetic era began in 1995 with the identification of the SMN1 gene. Before today's therapies, SMA was the leading genetic cause of death in infancy.
Symptoms depend on the type and age of onset, but share a common pattern:
Muscle weakness and hypotonia (low tone, "floppy baby"), predominantly proximal and symmetric. It is the hallmark of lower motor neuron damage.
In the most severe types, weakness affects the respiratory muscles and swallowing, which historically determined the prognosis.
SMA preserves cognition, sensation, and vision and hearing. Children with SMA usually have normal or above-average intellectual development.
Reduced or absent reflexes, tongue fasciculations and, in forms that reach sitting or walking, scoliosis and contractures.
SMA is classified into types according to the age of onset and the maximum motor milestone reached. The SMN2 copy number is the main modulator.
Onset before 6 months, very severe. The baby never sits without support. Usually associated with 2 copies of SMN2.
Onset between 6 and 18 months. The child sits but never walks independently. Usually associated with 3 copies.
Onset after the first year or in childhood. The person walks, though may lose that ability over time. 3–4 copies.
Onset in adulthood, the mildest form. Slowly progressive proximal weakness. Usually associated with 4 or more copies.
There is also a prenatal Type 0, the most severe form, with very little movement already before birth and usually 1 copy of SMN2.
SMA is today the great success story of gene therapy: there are three approved therapies that modify its course, especially when started early.
Nusinersen (2016) is an intrathecal ASO that makes SMN2 include exon 7 and produce more functional SMN protein.
A gene therapy (2019) that delivers a functional copy of SMN1 via an AAV9 vector in a single dose.
Risdiplam (2020) is an oral drug that modifies SMN2 splicing so it produces more full-length protein.
Educational content with a scientific basis (Werdnig 1891; Hoffmann 1893; SMN1 gene, Lefebvre et al. 1995; nusinersen, Finkel et al. 2017; Zolgensma, Mendell et al. 2017; risdiplam, 2020). It does not replace assessment by a healthcare professional.
DNA (deoxyribonucleic acid) is the molecule that stores the genetic instructions of every living thing, spread across about 3 billion base pairs.
Four bases — A, T, C and G — form the double helix. In SMA, the problem lies in a region of chromosome 5 that contains two nearly identical genes, SMN1 and SMN2: when SMN1 is lost, the motor neuron is left without enough SMN protein.
The genetic heart of SMA is on chromosome 5, but there are genes that accompany or modulate it on other chromosomes. Click a chromosome to see its regions, the evidence, and the genes involved.
The causal gene, the backup modifier gene, and the SMA complex and modifier genes. Search and filter by cellular mechanism; click a card to see its function and the studies.
The SMA genes revolve around the SMN protein and the lower motor neuron. Hover over a node to identify the gene; click to see the detail.
Two key pieces of SMA: how many copies of SMN2 there are (and how much protein they make) and the lower motor neuron → muscle circuit. Explore them.
When SMN1 is missing, the only source of SMN protein is SMN2. But a single base change (c.840C>T) makes most of its RNA skip exon 7 and produce an unstable protein; only a small fraction is full-length. That is why, the more copies of SMN2, the more functional protein and the milder the disease. Slide to see the effect.
Indicative. The SMN2 copy number explains much of the severity, but it is not an exact rule: there are genetic modifiers (such as PLS3) and other factors. The definitive type is established by the clinical course.
In SMA the lower motor neuron (the one in the anterior horn of the cord) degenerates; it connects directly to the muscle. Click each step of the diagram to compare the healthy and degenerated states.
From Werdnig and Hoffmann's description to the SMN1 gene and the three therapies that have changed the disease.
How the lack of SMN protein damages the lower motor neurons that control movement.
Yes. SMA is autosomal recessive: it requires inheriting a missing or mutated copy of SMN1 from each parent. When both are healthy carriers, each pregnancy has a 25% chance of an affected child, 50% carrier, and 25% unaffected.
Around 1 in 50 people is a healthy carrier of an SMN1 loss, without knowing it and without symptoms. That is why many countries offer carrier screening to couples and newborn screening of newborns, which makes it possible to detect and treat SMA before symptoms appear.
The essentials about the genetics of spinal muscular atrophy:
The most important point: SMA is the great success story of gene therapy. In just a few years it went from being the leading genetic cause of infant death to having three approved therapies (nusinersen, Zolgensma, and risdiplam). Treating early — ideally before symptoms, thanks to newborn screening — dramatically changes the prognosis.
SMA is a genetic motor neuron disease. It is worth dispelling a few misconceptions:
Being an SMA carrier causes no symptoms: it is completely normal and compatible with a healthy life. It only matters for family planning, if the partner is also a carrier.
With the disease now treatable, the frontier shifts to treating earlier and better.
Detecting the loss of SMN1 with a drop of blood from the newborn makes it possible to start treatment before symptoms, when there are more motor neurons to protect.
Studies in babies treated before symptoms show near-normal motor development: SMA teaches that in these diseases timing is almost everything.
Combining those that restore SMN with drugs that improve the muscle (such as apitegromab) aims to squeeze even more strength recovery.
Better vectors and routes of administration so that the SMN1 copy reaches more motor neurons and lasts longer over time.
Beyond protecting the motor neuron, regaining muscle mass and strength with drugs targeting the muscle itself.
Explore natural modifiers such as PLS3, which protects some carriers within a family, as a possible therapeutic target.
Research is advancing quickly and some of these results are preliminary: the dates and specific data may change as the trials mature.
The questions that come up most when learning about SMA.
Milestones and scientific sources on which this page is based.
A synthesizing educational page; not a primary clinical source. For medical decisions, consult professionals and the official resources of SMA associations.
How SMA sits relative to other genetic atlases in this collection.
| Disease | Neuron affected | Inheritance | Key gene |
|---|---|---|---|
| SMA (this page) | Lower motor neuron | Autosomal recessive | SMN1 / SMN2 |
| ALS | Upper and lower motor neuron | Mostly sporadic | C9orf72, SOD1, TARDBP |
| Duchenne dystrophy | Muscle (not the neuron) | X-linked recessive | DMD (dystrophin) |
Links to other atlases are indicative; they may not be available in this collection.
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