Connecting genetic repeats to symptom variability in SCA3/MJD

Written by Terry Suk Edited by Dr. Hayley McLoughlin

In this classic article, researchers describe how CAG repeat number variation can inform differences in the way SCA3/MJD symptoms present.

Machado-Joseph Disease (MJD) was first described in the 1970’s in four families of Azorean descent. However, it was not initially clear that these families had the same disease, since the symptoms they displayed were highly variable. These symptoms included differing degrees of motor incoordination, muscular atrophy (i.e., loss of muscle mass), spasticity, and rigidity. Later, these four diseases were labeled using the single title of MJD due to their similar genetic inheritance and irregularly high symptom variability1.

In the early 1990’s, a group of French families were diagnosed with Spinocerebellar Ataxia Type III (SCA3), a disease that appeared similar to SCA1 and SCA2 but was shown to be caused by distinct genetic mutation. The symptoms of SCA3 were similar to those of MJD and, importantly, also showed a high degree of variability. The major differences between the two diseases, however, were mostly based on geographical origin (Azorean versus French descent) and family history. Thus, these were considered separate diseases, and very few (if any) ataxia researchers studied both.

Small human figurine standing on a map of the world, specifically on top of France
Initial research done by Cancel and colleagues focused on four French families. Photo by slon_dot_pics on

Then, in 1994, MJD-1 was discovered to be the gene responsible for MJD. The disease-causing mutation in MJD-1 was found to be an expansion of a repetitive DNA sequence in the gene, described as “CAG repeats” (CAG = Cytosine, Adenine, and Guanine)2. Around this time, another research group narrowed down the location of the gene responsible for SCA33. Interestingly, this happened to reside in the same area of the genome as MJD‑1, which was appropriately named the “SCA3/MJD region” soon after. As mentioned above, both SCA3 and MJD patients displayed a wide variety of symptoms. This lead one group of researchers, Cancel and colleagues, to ask the following question in their 1995 publication: What is it about the SCA3/MJD region that leads SCA3 and MJD patients to exhibit such broad symptomatic variability?

Inspired by the discovery of CAG repeats in MJD-1 and the explosion in molecular genetics research at that time, Cancel and colleagues decided to investigate how CAG repeats affected the way disease symptom present in SCA3 patients. Cancel enrolled research subjects from three unrelated families diagnosed with SCA3 and compared them to MJD patients. All subjects exhibited a similar age of symptom onset and the presence of cerebellar ataxia (loss of muscle coordination) but varied widely in additional disease presentations.

Blood samples were taken from patients and individuals who were “at risk” of disease based on family history. Blood samples were also taken from unaffected individuals to serve as a control group (used as a reference for the DNA differences observed in the SCA3/MJD region). They found that unaffected individuals had between 14 and 34 CAG repeats, whereas affected individuals had almost three times more, with a range between 66 and 82 CAG repeats. The age at which each affected individual started to show symptoms and the number of CAG repeats they carried was also compared. They reported that more CAG repeats an individual had in the SCA3/MJD locus, the earlier symptom onset occurred.

Although the increased number of CAG repeats helped to genetically define both SCA3 and MJD, it still did not reveal why there is so much variability in these diseases. However, when analysing the number of repeats from blood samples, the  scientists also noticed that there was some variation in the number of repeats in the blood of most single patients. For example, the predominant number of CAG repeats in one patient’s blood sample may have been 65 CAG repeats, but there was evidence in the sample that some blood cells contained 62 CAG repeats in their DNA, while other cells contained 67 CAG repeats. Sperm DNA exhibited even larger variation of CAG repeats, which seemed to be the reason why the children of patients do not have the same number of repeats as their parents. This work was ground-breaking, as it showed for the first time that CAG repeats can be variable in different cells of the same patient. Together, CAG repeat variation observed within the blood and sperm DNA of patients provide a clue regarding the variability of symptoms in these diseases – why two patients with the same diagnosis can display a large variety of symptoms.

It is important to note that Cancel and colleagues were not the only group trying to answer questions about SCA3 disease variation and its association with MJD. In 1995, Matilla and colleagues from Huda Zoghbi’s lab also published their findings, which demonstrated that CAG repeats in a single region of DNA were responsible for both SCA3 and MDJ4. That same year, a team of German researchers, Haberhaussen and colleagues, also published that SCA3 and MJD, were “genetically identical” diseases despite a variety of symptoms5. Together, these groups helped to set the groundwork in identifying MJD and SCA3 as the same disease. The gene that contained the disease-causing CAG repeat expansion was later named Ataxin-3.

These groups reported important findings for patients and individuals at risk for SCA3 and MJD. Because of the high variability of symptoms in these diseases, doctor had been finding SCA3 and MJD difficult to diagnose accurately. These new findings enabled the creation of a DNA test to identify if a patient has an abnormal increase in CAG repeats. To this day, this test is how SCA3/MJD is diagnosed. Understanding the relationship between the number of repeats and the age that symptoms start to arise is also important for individuals at risk. In addition to allowing for an accurate SCA3/MJD diagnosis, determining CAG repeat size can also help estimate whether individuals will develop symptoms earlier or later in life.

As one of the first groups to establish the foundation of cell-type specific CAG repeat differences in SCA3, Cancel and colleagues were pioneers in ataxia research. Based on these findings, cell-specific studies focused on the mechanisms of SCA3/MJD variability are ongoing by research groups around the world.

Key Terms

DNA: DNA stands for deoxyribonucleic acid. It is a molecule made up of nucleotides that carries the genetic code in the body’s cells.

Trinucleotide repeats: Repeats of three units of DNA (nucleotides)

Locus (Plural – Loci): A position or region of DNA on a chromosome

Polyglutamine Expansion Disease / CAG-repeat diseases: A family of diseases caused by an expansion of glutamine amino acids in certain proteins.

Conflict of Interest Statement

The authors and editor declare no conflict of interest.

Citation of Article Reviewed

Cancel, G., Abbas, N., Stevanin, G., Dürr, A., Chneiweiss, H., Néri, C., Duyckaerts, C., Penet, C., Cann, H.M., Agid, Y., and Brice, A. Marked Phenotypic Heterogeneity Associated with Expansion of a CAG Repeat Sequence at the Spinocerebellar Ataxia 3/Machado-Joseph Disease Locus. American Journal of Human Genetics. October 1995. 57(4): 809-816. (PMID: 7573040)


  1. Couthino, P. & Andrade, C. Autosomal dominant system degeneration in Portuguese families of the Azores Islands: A new genetic disorder involving cerebellar, pyramidal, extrapyramidal and spinal cord motor functions. Neurology 28, 703–703 (1978).
  2. Kawaguchi, Y. et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat. Genet. 8, 221–228 (1994).
  3. Stevanin, G. et al. The gene for machado-joseph disease maps to the same 3-cm interval as the spinal cerebellar ataxia 3 gene on chromosome 14q. Neurobiol. Dis. 1, 79–82 (1994).
  4. Matilla, T., McCall, A., Subramony, S. H. & Zoghbi, H. Y. Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado‐Joseph disease. Ann. Neurol. 38, 68–72 (1995).
  5. Haberhausen, G., Damian, M. S., Leweke, F. & Müller, U. Spinocerebellar ataxia, type 3 (SCA3) is genetically identical to Machado-Joseph disease (MJD). Journal of the Neurological Sciences 132, (1995).