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 Pexels.com

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?

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Blurred lines: how spinocerebellar ataxia type 7 impacts vision

Written by Siddharth Nath Edited by Dr. Ray Truant

Spinocerebellar ataxia type 7 (SCA7) is unique amongst the SCAs in that it involves an organ besides the brain – the eye. Rather than problems with movement, the first hint that something may be wrong for SCA7 patients is often a subtle change in vision. Research done by Dr. Al La Spada in the early 2000s helps explain how and why this happens. 

It’s not all in your head

The spinocerebellar ataxias (SCAs) are, for the most part, similar in how they affect the body. They cause disordered movement (ataxia), trouble with speech (dysarthria), trouble swallowing (dysphagia), and other neurological symptoms. This holds true for all of the polyglutamine-expansion SCAs except for SCA7. In SCA7, doctors have long observed that patients report problems with vision, and in some cases may be entirely blind. Interestingly, these symptoms often appear ahead of any other signs that the patient might have a chronic illness, suggesting that SCA7 affects the eye before it begins to affect the brain.

In the early 2000s, while at the University of Washington, Dr. Al La Spada conducted research into how SCA7 affects the eye. He and his team set out to understand why patients with this disease experience a loss of vision.

Close up photo of a human eye from the side. The eye is hazel in colour.
Close up of a human eye. Photo by Pixabay on Pexels.com

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Hunting for a needle in a haystack: Scientists identify the gene that causes ARSACS

Written by Dr. Sriram Jayabal Edited by Dr. Brenda Toscano-Marquez

Scientists uncover SACS, a gene containing the largest exon identified in vertebrates, which leads to ARSACS when mutated.

What is your morning routine? Coffee first, right? Now, try to think of all the diverse movements you need to make to accomplish this routine. For instance, just to get a cup of coffee, you have to complete a sequence of motor tasks: you start by pulling the pot out of the machine, then you walk to the tap, fill the pot with water, walk back, pour the water into the machine, put your coffee in, and then finally turn on the machine.

needle in haystack
Picture courtesy of Pixabay

To perform any of these movements, your brain needs to communicate with dozens of muscles in your body. Unfortunately, in people who are affected by hereditary ataxias, the brain loses the ability to coordinate these precise movements. These diseases primarily affect the way patients walk (the symptom that defines “ataxia”), eventually forcing them to use a wheelchair for the rest of their lives.

Hereditary ataxias can be broadly classified as either dominant or recessive. Dominantly-inherited ataxias can be passed down even if only one of the parents is affected; therefore, the disease does not skip generations. Recessive ataxias are inherited from parents who are both carriers of the disease mutation (and who do not usually show any symptoms). Therefore, recessive ataxias can skip generations.

One such recessive ataxia is called Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS). It was first discovered in people from the Charlevoix-Saguenay-Lac-Saint-Jean region of Quebec, Canada [1]. In this region, it is estimated that one out of every 22 individuals is a carrier for the disease mutation [2]. Though prevalent in this specific area of Canada, ARSACS has now been identified all across the world. Symptoms usually start in early childhood when toddlers are learning to walk. These children experience stiffness in the legs (spasticity) and incoordination in their gait (ataxia), leading them to fall more often. They also have difficulties writing, speaking, and performing tasks that require manual dexterity (usually actions that involve hand movements, like reaching for and grasping an object). They continue to experience worsening gait as they age, often needing a cane or handrail to move around by the time they reach adolescence. Around this time, many patients also experience retinal hypermyelination (an eye abnormality) and peripheral neuropathy (damage to the nerves throughout the body). By their thirties, they become dependent on a wheelchair. There is currently no cure for ARSACS, so it is imperative to study this disease’s underlying causes to identify effective treatments.

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Spinocerebellar Ataxia Type 1 is Caused by a Trinucleotide DNA Repeat

Written by Hillary Handler  Edited by Dr. David Bushart

How researchers found that SCA1 is caused by an expanded, repetitive DNA sequence – a discovery that has allowed for accurate SCA1 diagnosis and more focused research strategies

Before the true genetic basis of Spinocerebellar Ataxia Type 1 (SCA1) was discovered, researchers and medical doctors noticed that SCA1 causes motor dysfunction, death of specific types of brain cells, and premature death in affected patients. By assessing health outcomes in multiple families affected by SCA1, scientists also recognized that the disease is inherited in an autosomal dominant manner. This means that each person with an SCA1 diagnosis has a 50% chance of passing the disease to each of his or her children. In addition, researchers noticed that affected members of SCA1 families displayed a disease feature called anticipation: a trend of increasing symptom severity and earlier age-of-onset as the disease is passed from generation to generation. Despite these discoveries, the specific genetic mutation responsible for causing SCA1 had not yet been identified or described. Determining the genetic cause of an inherited disease is critical for allowing accurate diagnosis of the condition. Furthermore, understanding the genetics of SCA1 would provide researchers with important clues about disease pathology that could help with designing and developing treatments.

Researcher looking through a microscope
Photo by Pixabay on Pexels.com

 

One of the groups that sought to identify the specific genetic cause of SCA1 was led by Dr. Harry Orr. These researchers published their findings in a landmark 1993 paper (Nature Genetics, 1993), which described the process by which they made their discovery. First, a technique called “linkage analysis” was used to determine the general location of the SCA1 gene within the human genome. By tracking how SCA1 is inherited relative to other, well-characterized genetic locations, the team was able to narrow their search to a small portion of chromosome 6’s short arm known as region 6p22-6p23. The researchers also noted that anticipation is often indicative of a particular DNA feature known as a trinucleotide repeat. To determine if a trinucleotide repeat was indeed causing SCA1, these scientists used DNA cloning and screening techniques within the identified region of chromosome 6. These experiments identified a CAG trinucleotide repeat within the SCA1 genomic target region of DNA.

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Connecting the dots between genetics and disease in SCA13

Written by Dr. David D. Bushart  Edited by Dr. Carolyn J. Adamski

How one research group worked to identify previously unknown causes of SCA13, and what we can learn from their strategy.

With so many different causes of cerebellar ataxia, how are doctors able to make an accurate diagnosis? This is an extremely important question for doctors, research communities, and patients. For doctors, knowing the underlying genetic cause for a case of ataxia is critical not only for formulating a more specific treatment plan, but also for performing informed genetic screens to determine if a patient’s family members are at risk for developing ataxia. For researchers, knowing what causes a certain type of ataxia allows for the development of new treatment strategies. And for patients, an accurate diagnosis can, importantly, provide peace-of-mind.

Unfortunately, getting to this point of diagnosis can still be a difficult task in a lot of cases – up to 20 percent of ataxia cases do not have a confirmed genetic cause (Hadjivassiliou et al., Journal of Neurology, Neurosurgery, and Psychiatry 2016). This is clearly an area for improvement in the field of ataxia research. Fortunately, many research groups are making efforts to improve our knowledge of the many different causes for cerebellar ataxia, how frequently they appear, and how we might be able to better treat them.

two puzzle pieces being connected together by hands
Two puzzle pieces being connected together, much like how researchers connect pieces of data together to understand disease. Photo by Pixabay on Pexels.com

Though there are many studies that are continuously being performed and are constantly improving our knowledge of the specific causes of cerebellar ataxia, this summary will focus on the work of one group (Figueroa et al., PLoS One 2011). The research team, led by Dr. Stefan Pulst at the University of Utah, sought to better identify the frequency of different genetic mutations causing SCA13, a rare, dominantly-inherited form of spinocerebellar ataxia caused by mutations in a gene called KCNC3.

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