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.
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?