More than forty inherited ataxias that disrupt the coordination of movement. An interactive journey through the ATXN genes, the CAG triplet expansion, toxic polyglutamine, and the cerebellum of spinocerebellar ataxias.
The entire journey of this page, summarized in six steps.
Before diving into the genetics, it helps to understand the group of diseases that these genes explain.
Spinocerebellar ataxias (SCA) are a group of more than 40 inherited ataxias that are neurodegenerative, progressive and have no cure. The most common are caused by CAG triplet expansions that encode polyglutamine. They gradually damage the cerebellum —especially its Purkinje cells— and the spinocerebellar tracts, which disrupts coordination, balance, speech and eye movements.
In 1893 the neurologist Pierre Marie separated the late-onset inherited ataxias from Friedreich's ataxia, establishing the classic clinical classification. For a century they were recognized only by their symptoms; in the 1990s their molecular causes were identified —CAG triplet expansions in genes such as ATXN1 (1993), ATXN3 (1994) or ATXN2 (1996)—, the starting point for the rest of this page.
All SCAs share a core of cerebellar symptoms, with additional features depending on the type:
Loss of coordination and an unsteady gait (broad-based, "drunken-like"), clumsy hands and dysmetria. It is the feature that gives the group its name and is usually the first to appear.
Speech that is slow, scanning and poorly articulated due to cerebellar involvement. Later, difficulty swallowing (dysphagia) may appear.
Nystagmus and slow eye movements. Depending on the type, other signs are added: retinal degeneration (SCA7), neuropathy, spasticity or parkinsonism.
The most common subtype in the world (gene ATXN3). It combines ataxia with variable signs: dystonia, spasticity, bulging eyes, parkinsonism or neuropathy depending on the case.
SCA1 (ATXN1) often involves pyramidal signs; SCA2 (ATXN2) stands out for very slow saccadic eye movements and neuropathy. Both are classic adult-onset forms.
SCA6 (CACNA1A) is usually an almost pure cerebellar ataxia with very slow progression. SCA7 (ATXN7) adds a unique feature: retinal degeneration with vision loss.
Decades can pass between inheriting the gene and the advanced stages. It is a gradual progression, not an abrupt leap.
The person carries the expansion but has no symptoms. It can last for decades.
Subtle signs years before diagnosis: mild clumsiness, occasional unsteadiness or fine oculomotor abnormalities.
Diagnosed by gait ataxia and dysarthria. The person still walks, often with support.
Incoordination, dysarthria and dysphagia limit daily life; a wheelchair is usually needed.
Significant dependence and marked dysphagia. Death is usually due to complications (e.g. aspiration pneumonia).
Today, treatment is symptomatic and multidisciplinary: it does not stop the disease, but it improves quality of life. Therapies that target the cause —the gene and the protein— are reviewed at the end, once the genetics are understood.
Physiotherapy and balance training to maintain gait and prevent falls; assistive devices (cane, walker, wheelchair) depending on the stage. It is the cornerstone of ataxia management.
Speech therapy for dysarthria and dysphagia, and nutritional support when swallowing becomes difficult. It improves communication and reduces the risk of choking.
Occupational therapy, management of associated symptoms (spasticity, tremor, sleep), psychological support and genetic counseling for the person and their family.
Educational content with a scientific basis (clinical classification of ataxias, Pierre Marie 1893; identification of the SCA genes in the 1990s; current clinical practice). It does not replace assessment by a healthcare professional.
DNA is read in triplets of bases. The genes of the most common SCAs —such as ATXN1, ATXN2, ATXN3— contain a stretch in which the CAG triplet repeats over and over. Each CAG encodes the amino acid glutamine.
In most people the stretch is short. When it expands above the threshold specific to each type, the corresponding ataxin protein carries an abnormally long tail of glutamines (polyglutamine) that misfolds, aggregates and becomes toxic to cerebellar neurons.
There is no single gene: each SCA type resides on a different chromosome. The most common one, SCA3 / ATXN3, is on the long arm of chromosome 14, in band 14q32.12. Others live on 6 (ATXN1), 12 (ATXN2), 19 (CACNA1A) or 3 (ATXN7).
DNA is transcribed into RNA, and this is translated into protein. Each CAG adds a glutamine (Gln). If there are too many CAGs, the ataxin carries a polyglutamine tail that makes it toxic.
The number of CAG repeats determines whether the disease appears and, to a large extent, when. The ranges below use SCA3 (Machado-Joseph) as an example. Click on each range or use the slider to see how the repeat grows.
The pathogenic threshold varies greatly by SCA type: shown here are those for SCA3 (normal ≤ 44, pathogenic ≥ 60), but in SCA1 the threshold is around 39 repeats, in SCA2 around 33, and in SCA6 about ~20 is enough.
They share their mechanism with other repeat-expansion diseases: a short stretch of DNA that repeats too many times. The gene, the "letter" that repeats and the mode of inheritance change.
| Disease | Gene | Repeat | Threshold | Inheritance |
|---|---|---|---|---|
| SCA ataxias (CAG) view → | ATXN1/2/3… | CAG | ≥ 33–60* | Autosomal dominant |
| Huntington's disease | HTT | CAG | ≥ 36–40 | Autosomal dominant |
| Myotonic dystrophy type 1 | DMPK | CTG | ≥ 50 | Autosomal dominant |
| Spinal and bulbar muscular atrophy (Kennedy) | AR | CAG | ≥ 38 | X-linked |
| Fragile X syndrome | FMR1 | CGG | ≥ 200 | X-linked |
| Friedreich's ataxia | FXN | GAA | ≥ ~70 | Autosomal recessive |
*The threshold changes by SCA type. Click any row to learn why the same idea —a growing repeat— produces such different diseases. Many share anticipation (the expansion grows between generations).
Each SCA type has its own gene. Most of the common forms share the same mechanism —a CAG / polyglutamine expansion— with some nuances. Click on a card to see the details.
SCAs at the center and, around them, the genes that cause them, grouped by mechanism. Hover over a node to identify it; click to see the details.
From the classic classification of ataxias to the SCA genes and the therapies that silence ataxin.
How the mutant ataxin with its polyglutamine tail and the ongoing CAG expansion damage neurons, especially the Purkinje cells of the cerebellum.
The CAG is not a fixed number: it keeps growing inside neurons with age. Move the age and turn the DNA-repair genes on or off to see how it changes (model based on SCA3).
An illustrative model of the trend (starts from 70 inherited CAGs, SCA3 range), not an exact clinical scale.
Click each brain region to see why some are more vulnerable than others.
They allow the disease to be detected, its progression measured, and whether a therapy is working to be checked, all objectively:
Values illustrating the trend, not real clinical scales: NfL begins to rise years before symptoms, while the cerebellum atrophies progressively.
CAG-expansion SCAs are autosomal dominant: inheriting a single copy of the expanded gene from one parent is enough. Each child has a 50% chance of inheriting it.
That 50% is not an abstract statistic: for many families it is a shadow that shapes major life decisions —parenthood, work, plans for the future. That is why the genetics of SCA is never separated from support and genetic counseling.
The more CAG repeats, the earlier symptoms tend to appear. In addition, the stretch can expand when transmitted —especially through the paternal line— so the disease can begin earlier in each generation (anticipation).
Adjust the parent's repeats and choose the line of transmission. You will see the allele's tendency to grow as it is passed to the children.
An illustrative model of the trend, not an individual prediction: the expansion is a random process that varies greatly from one family to another.
It is a statistical trend, not an exact prediction: at the same number of repeats, the age of onset varies greatly between people (that is where modifier genes come in).
The essentials about the genetics of spinocerebellar ataxias:
The most important point: knowing the gene and its mechanism in each SCA type is opening up therapies that target the cause, not just the symptoms. Genetics does not only explain SCAs: it is paving the way to their treatment.
Expansion SCAs are purely genetic diseases. They are not caused by lifestyle or environmental factors:
General health can influence how the disease is experienced, but not its cause: that depends solely on the inherited CAG expansion.
SCA research is accelerating, largely thanks to lessons from Huntington's disease. This is what is changing right now —and where it is headed.
The same strategy tested in Huntington's is being moved to the SCAs: ASOs that reduce the production of the expanded ataxin (anti-ATXN3 in SCA3, anti-ATXN2 in SCA2). Several programs are advancing in models and early trials.
Neurofilament light (NfL) in blood and cerebellar MRI make it possible to track progression and detect damage before symptoms: key to designing and evaluating future trials.
The DNA-repair genes that modulate the somatic expansion of the CAG (such as MSH3) are also emerging in the SCAs: stopping the CAG from growing before neurons reach the toxic threshold would be a different strategy.
Relying on biomarkers such as NfL to detect early damage, the goal is to intervene years before the ataxia appears.
Allele-selective therapies and base editing or prime editing that correct or switch off the expanded allele while sparing the healthy copy of the gene.
Since each SCA has its own gene and threshold, trials advance type by type (SCA1, SCA2, SCA3…), combining silencing, slowing of the expansion and neuroprotection.
Research is moving very fast and some of these results are preliminary: specific dates and figures may change as the clinical trials mature.
The questions that come up most often when learning about the genetics of SCA ataxias.
Milestones and scientific sources on which this page is based.
An educational synthesis page; it is not a primary clinical source. The threshold and prevalence figures are approximate and vary by SCA type and population. For medical decisions, consult professionals and the official resources of ataxia associations.
Six questions to check what you take away. It grades itself: click an answer and you'll instantly see whether you're right, with the explanation.