Exploring the Similar Pathology “Genetic Doppelgängers” ALS and SCA36

Recently, scientists from Emory University set out to discover whether there was any pathological link between spinocerebellar ataxia type 36 (SCA36) and amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Both neurodegenerative disorders seem to have similar causes and presentations. Yet the former progresses at a much slower rate, prompting researchers to question why these “genetic doppelgängers” have such different outcomes. Read their full study in Neuron

The Two Conditions: ALS and SCA36


Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease causing brain stem, spinal cord, and brain nerve cell death. This results in muscle damage and weakness, as well as a loss of bodily control. Symptoms of ALS include slurred speech, muscle twitching and cramps, difficulty with movement or balance, muscle weakness, and a gradual inability to control or move muscles across the body.

ALS does not cognitively or intellectually impact patients. So, those with ALS are aware of their surroundings. Ultimately, ALS becomes fatal as patients lose the ability to breathe or function properly. The disease tends to affect males more than females. 

The disease can impact the frontal and temporal lobes of the brain, which affect personality, behavior, and movement. According to the Association for Frontotemporal Degeneration, ALS is sometimes linked with frontotemporal dementia (FTD), as both can be caused by a mutated C9orf72 gene. For patients with both conditions, the Association for Frontotemporal Degeneration suggests the use of the phrase “ALS-Frontotemporal spectrum disorder.” 

Learn more about ALS here

Spinocerebellar Ataxia Type 36 (SCA36)

Spinocerebellar ataxia is a group of inherited nervous system conditions in which movement is affected. Parts of the brain and spinal cord responsible for movement degenerate. This leads to issues with coordination and balance, involuntary eye movements, abnormal speech, processing and learning difficulties, and vision problems. 

There are multiple types of SCA. Emory University focused on a rare form called spinocerebellar ataxia type 36, or SCA36. According to the NIH, symptom onset for SCA36 starts between 40 and 50. However, it can occur in younger or older individuals. This does not usually impact life span, with many people living 15-20 years past diagnosis. 

SCA36 causes problems with balance and coordination, tongue twitching, difficulty swallowing or speaking, droopy eyelids, hearing loss, exaggerated reflexes, and atrophy of tongue, leg, forearm, and hand muscles. Additionally, SCA36 results in motor neuron atrophy, negatively impacting muscle function. Imaging shows progressive brain atrophy as well. Learn more about spinocerebellar ataxia.

Emory University Research

Researchers noticed that ALS/FTD and SCA36 resulted from abnormal DNA repetition. Thus, they were “genetic doppelgängers” in a sense. But while ALS is typically fatal with 2 years of diagnosis, patients with SCA36 can live for decades. It is believed that protein products created by the disease turn toxic in ALS/FTD. However, researchers did not know if similar protein products formed in patients with SCA36.

Researchers analyzed the nonsense mutations using patient data sourced from neurologists and the ALS Clinic biorepository. As stated above, ALS/FTD occur from a mutated C9orf72 gene. Six DNA letters are wrongfully repeated multiple times. ScienceCodex explains that this is like going to type something and instead just writing, “ABABABAB,” or “CLCLCLCL.” This causes created proteins to simply repeat amino acids.

Then, the proteins accumulate within brain cells, causing cell death and degeneration. In ALS, the repetitions can be chimeric: “GAGAGAPGPGPG,” which suggests the toxicity of these complex proteins.

In SCA36 caused by a C9orf72 mutation, there are also 6-letter genetic repetitions. Yet researchers discovered that the repetitions differ between ALS and SCA36. Additionally, the repetitions collect in the cells of patients with ALS, but not in the cells of patients with SCA36. 

DNA repeats also occur in Huntington’s disease and myotonic dystrophy. As researchers learn more about these repetitions, they can better develop targeted drug therapies to halt production of toxic proteins. One potential avenue being explored is the use of antisense oligonucleotides, which can target specific diseases, conditions, and genetic mutations (ASOs).

Read the original article on ScienceCodex.

Jessica Lynn

Jessica Lynn

Jessica Lynn has an educational background in writing and marketing. She firmly believes in the power of writing in amplifying voices, and looks forward to doing so for the rare disease community.

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