What is Ataxia?

Ataxia is defined as a loss of voluntary motor control and is often used as an umbrella term to classify a group of diseases that effects movement coordination. Ataxia can affect all age groups, with the age of first ataxia symptoms varying widely from early childhood to late-adulthood. While not all ataxia diseases are created equal, there are common symptoms of ataxia diseases that include slurred speech, stumbling, falling, and incoordination. Often there is a progressive nature to these diseases which overtime can affect a person’s ability to walk, talk, use fine motor skills, and may ultimately be life-shortening.

Below are some more detailed overviews of specific types of ataxia.

Spinocerebellar Ataxia Type 1 (SCA1)

Spinocerebellar Ataxia Type 1 or SCA1 is a rare neurodegenerative disease with a prevalence of approximately 1-2 affected in 100 000 individuals worldwide. It is caused by the expansion of a trinucleotide repeat in the ATXN1 gene. The expansion results in a larger number of cytosine, adenine and guanine nucleotides in the ATXN1 gene, leading to an increase in the number of consecutive glutamine amino acids in the ataxin-1 protein. The expanded protein causes toxicity and degeneration of certain neuronal populations in the brain including the cerebellar Purkinje cells and brainstem neurons.

Usually, first symptoms manifest around 30-40 years of age, though earlier onset of symptoms can occur in rare cases. The age of onset is hereby inversely correlated with the number of repeats. This means that patients with longer repeat sizes in ATXN1 are more likely to have an earlier age of onset and a more severe and progressive disease. The initial symptoms of SCA1 include loss of coordination and balance. As the disease progresses over a period of time, these symptoms worsen and the patients further develop difficulties with swallowing, breathing and speaking.

SCA1 is typically inherited in an autosomal dominant fashion, meaning that individuals of either gender are equally likely to inherit the disease. Each child of a person affected with SCA1 has a 50% chance of inheriting the expanded ATXN1 gene and developing SCA1 themselves. Currently, there are no treatments available to cure SCA1. Treatment options primarily focus on the management of symptoms to maintain quality of life.

Spinocerebellar Ataxia Type 2 (SCA2)

Spinocerebellar ataxia type 2 (SCA2) is one of the seven polyglutamine ataxias, which together make up the majority of SCA cases. SCA2 occurs due to a polyglutamine expansion in the ATXN2 gene, a DNA code that informs our cells how to make the protein known as ataxin-2. Though we don’t yet fully understand its function, we do know that ataxin-2 is likely an important part of the process that generates other proteins in our cells. These other proteins that are eventually affected include some of the necessary components for keeping the cells in our cerebellum healthy and active. So, for patients with SCA2, certain cells in the cerebellum are abnormal and, eventually, become completely non-functional.

Currently, we do not definitively know the prevalence of SCA2. However, it appears to be one of the most common forms of SCA, with a maximum observed frequency of approximately 40 cases per 100,000 people. Symptoms of SCA2 usually start as abnormal walking patterns, leg cramps, and/or a slight tremor, then eventually progress to much more severe forms of movement dysfunction over the course of 10-15 years. Treatments are currently limited, though certain vitamin supplements and mechanical assistance (weighted eating utensils, canes/walkers, communication devices, etc.) are typically used to maintain quality of life as the disease progresses. As of this summary’s writing, we are awaiting results for nearly a dozen clinical trials for treatments that have been designed to help diagnose or combat SCA2.

Spinocerebellar Ataxia Type 3 (SCA3)

Spinocerebellar ataxia type 3 (SCA3) is the most common of the seven polyglutamine ataxias, which together make up the majority of SCA cases. SCA3 can also be referred to as Machado-Joseph Disease (MJD) based on the first description of this disease in patients from both the Machado and Joseph families. SCA3/MJD occurs due to a polyglutamine expansion (PolyQ expansion glossary term) in the ataxin-3 gene, a DNA code that informs our cells how to make the protein known as ataxin-3. Ataxin-3 is expressed throughout the body, in all cell types, and mainly functions as a key component of the cell’s main system for controlled protein degradation. In disease, some cell populations in the brain are particularly vulnerable to expanded PolyQ ATXN3 protein, including cells in the pons (glossary term), cerebellum (glossary term) and striatum (glossary term). These affected brain regions are important for the regulation of balance and movement, which is compromised in patients with SCA3/MJD. Additionally, SCA3/MJD patients can show abnormal movements of the eye, tremor and stiff muscles that resembles Parkinson disease, and some individuals may have twitching movements of the face and tongue resembling ALS. These symptoms are progressive over the course of 10-20 years. As with the other SCA’s treatments, options for SCA3 treatment are currently limited to the treatment of symptoms. There is however strong support for SCA3/MJD treatment reported in preclinical studies of small molecules and gene silencing therapies that will be pursued in future clinical trials

Spinocerebellar Ataxia Type 4 (SCA4)

Spinocerebellar Ataxia Type 4 or SCA4 is a rare neurodegenerative disease. Patients typically manifest first symptoms in their fourth or fifth decade of life, though cases with earlier onset have been reported. Similar to other types of Spinocerebellar Ataxia, the symptoms include muscle weakness, problems in coordinating body movements and difficulties in speaking. A distinct feature of SCA4 is the progressive loss of feeling or sensation in hands and feet as well as the loss of reflexes. The symptoms usually worsen as the disease progresses over a period of time.

SCA4 is inherited in an autosomal dominant fashion, meaning that one affected parent has a chance to pass the disease to their children 50% of the time and is affecting both genders equally. Human genetic studies showed that SCA4 is linked to a location on chromosome 16 (16q22.1), but the exact gene which causes SCA4 has not been identified thus far. Diagnosis is mainly based on the symptoms consistent with the disease and the familial history. Unfortunately, there is no cure for SCA4. Treatments for this disease are mainly directed on slowing down its progression.

Spinocerebellar Ataxia Type 5 (SCA5)

Spinocerebellar Ataxia Type 5 or SCA5 is a rare neurodegenerative disease caused by mutations in the SPTBN2 gene. The gene encodes the beta-III spectrin protein which is essential for the proper development and function of certain groups of neurons in the brain. The mutations in this gene cause dysfunction in certain brain regions, foremost the cerebellum, leading in patients to loss of coordination, slurred speech, and abnormal eye movements. Compared to other types of Spinocerebellar Ataxia, SCA5 is considered to be a milder form that progresses slowly. The onset of this disease can occur between the age of 20 to 30 years old, though cases with earlier and much older age of onset have been reported.

SCA5 is inherited in an autosomal dominant fashion, meaning that individuals of either gender are equally likely to be affected. Each child has a 50 percent chance of inheriting SCA5 from an affected parent. As with other Spinocerebellar Ataxias, there is no cure for SCA5 thus far. Treatments options usually focus on slowing down the progression and the management of symptoms.

Spinocerebellar Ataxia Type 6 (SCA6)

Spinocerebellar ataxia type 6 (SCA6), is one of the genetically inherited ataxias that primarily affects the cerebellum, the little brain, in the central nervous system. This neurological disease, like other spinocerebellar ataxias, is characterized by progressive impairment in movement and coordination (ataxia). Other early symptoms may include speech difficulties (dysarthria), and involuntary eye movements (nystagmus) and double vision (diplopia). As the condition worsens, individuals with SCA6 develop loss of coordination in their arms and legs, tremors, and are forced to use a wheelchair for the rest of their lives. This slow progressing disease is not known to shorten the lifespan.

It is one of the polyglutamine diseases that is caused due to CAG-repeat expansion mutation. The defective gene in the SCA6 makes two proteins, an ion channel (a protein that controls the flow of ions from the environment into the brain cells), and a transcription factor (a protein which controls the production of other proteins in the cerebellum), which are essential for many functions in the brain cells. SCA6 leads to the death of brain cells in the cerebellum called Purkinje cells.

This condition is inherited in an autosomal dominant fashion, meaning that this disease will be inherited equally in both sexes from generation to generation, and it does not skip generations. SCA6 is mostly a late-onset disease, typically symptoms first appearing between 43 and 52 years of age. However, SCA6 has been known to manifest anywhere between the late teens and the early seventies.

SCA6 is considered to be a rare disorder, on average affecting 1-5 people in 100,000 individuals depending on the geographic area. For instance, SCA6 represents 2% in Italy, 15% in the United States, and as high as 31% in Japan of all dominantly inherited spinocerebellar ataxias.

A neurological examination can decipher if the person has symptoms of ataxia. Note that another neurological disease, episodic ataxia type 2, which is caused due to a different type of mutation in the gene that causes SCA6, results in episodes of ataxia and shares symptoms with SCA6. Therefore, a final DNA test for SCA6 mutation can accurately confirm the condition.

Research activities in SCA6 is focussing on understanding the pathogenic mechanisms underlying SCA6. Recent evidence suggests that SCA6 might follow a complex pathogenic mechanism. Like many other CAG-repeat diseases, it is thought that the defective transcription factor in SCA6 affects the production of protein from several other genes that are essential for normal function. In addition to this, one of the defective proteins is also an ion channel, and it is thought that defective functioning of this channel contributes to SCA6. Research is also underway to devise treatment strategies to alleviate the symptoms of SCA6.

There is no specific treatment available neither to cure the disease nor to delay or stop the progression of the disease. Current treatments focus on managing the symptoms effectively to improve the quality of life. Future research holds the key to devise effective treatment strategies that could treat the underlying pathogenic mechanism, not just the symptoms.

Spinocerebellar Ataxia Type 7 (SCA7)

SCA7 is a genetic neurodegenerative disease like many of the other SCAs and it is a part of a family of diseases called polyglutamine expansion disorders. SCA7 occurs as a result of mutations in the ATXN7 (pronounced ‘ataxin-7’) gene, which is located on the third chromosome.

When a region at the front part of this gene has too many repeats of the DNA bases cytosine (C), adenine (A), and guanine (G), things become messy. As we know genes contain the recipe for cells to manufacture specific proteins, and when there are too many of these ‘CAG’ repeats in a gene, it can change the structure of the protein that the gene is responsible for encoding. In the case of SCA7, this is exactly what happens when ATXN7 has too many CAG repeats, and the altered or ‘mutant’ ataxin-7 protein that is created is thought to be the main culprit in causing disease.

The way in which mutant ataxin-7 causes SCA 7 is still being uncovered and one of the prevailing ideas is that in the presence of the altered protein, a cell’s ability to regulate its energy production and respond to outside stressors is impaired. Research has also shown that cells with mutant ataxin-7 protein have considerably higher levels of reactive oxygen species.

SCA7, like many other SCAs, primarily affects the region of the brain called the cerebellum, which is responsible for movement and coordination. Degenerative changes are also seen to a lesser extent in other brain areas, including the inferior olive, pontine nuclei, basal ganglia, thalamus, midbrain, and cerebral cortex. SCA 7 is unique amongst the SCAs in that it also affects an area outside of the brain: the eye. Here, SCA 7 affects the cells of the retina, which is the structure at the back of the eye responsible for communicating what we see with the brain. This retinal degeneration leads to difficulty with vision, although complete blindness is rare.

In the clinic, SCA7 presents uniquely from other SCAs in that trouble with vision is often the first symptom. Like other SCAs, however, over time, SCA7 also leads to trouble with movement (ataxia), trouble swallowing (dysphagia), and difficulty with speech (dysarthria). For more on SCA , check out some of the articles below.

Spinocerebellar Ataxia Type 8 (SCA8)

Spinocerebellar ataxia type 8 (SCA8) is a genetically inherited neurodegenerative disease caused by a DNA repeat expansion mutation in the ATXN8 gene. SCA8 most frequently presents as an adult-onset disease, however, there are also reports of patients with symptom onset in early childhood and adolescence. Typically, the first symptoms a patient experiences are difficulty speaking and balance problems; these initial symptoms occur alongside problems coordinating body movements, limb stiffness, reduced vibration sense, and involuntary eye movements. The symptoms of SCA8 usually worsen slowly as the disease progresses, typically over several decades.

SCA8 is inherited in an autosomal dominant manner with reduced penetrance. This means that each child has a 50 percent chance of inheriting the DNA repeat expansion mutation from an affected parent but that not everyone with the DNA repeat expansion will develop symptoms of SCA8. Similar to other spinocerebellar ataxias, while there are currently no treatments available to cure SCA8, there are supportive therapy options to help manage the symptoms.

Spinocerebellar Ataxia Type 13 (SCA13)

Spinocerebellar ataxia type 13 (SCA13) is a rare neurological disease affecting patients of all ages. Mutations in a gene encoding the potassium channel KCNC3 are responsible for SCA13. These potassium channels help neurons — particularly the Purkinje neurons in the cerebellum — exchange potassium ions with their environment. This process prepares the Purkinje neurons to transmit information in a rapid-fire fashion through electrochemical impulses (commonly referred to as “firing”). SCA13 mutations cause the death and/or their abnormal development of these neurons, as evident from the shrunken cerebella seen in patient MRIs.

Neurological examinations of SCA13 patients show considerable variation in the type and severity of symptoms across individuals, families, and the specific mutation on the potassium channel. Common symptoms include tremors, a loss of coordination in the movement of limbs and eyes, auditory defects, and problems with speech. In a few cases, younger patients with SCA13 symptoms are able to overcome some of these deficits with age. In other cases, symptoms get progressively worse.

SCA13, like the other SCAs, is inherited in an ‘autosomal dominant’ manner, meaning that each of a patient’s children will have a 50% chance of being affected with SCA13 (irrespective of the child/parent’s gender). There are currently no cures for this disease, though patients are often prescribed disease management strategies to slow progression.

Spinocerebellar Ataxia Type 17 (SCA17)

Spinocerebellar Ataxia Type 17 (SCA17) is a progressive neurodegenerative disease caused by the expansion of a trinucleotide repeat encoding a polyglutamine tract in the TATA box-binding protein (TBP). Healthy individuals carry between 25 to 44 repeats, whereas SCA17 patients have between 47 to 63 repeats. The expanded protein causes toxicity and degeneration of neurons in the brain regions including the cerebrum, brainstem, and cerebellum.

The age of onset and the symptoms of SCA17 are highly variable. Patients manifest the first sign of symptoms as early as 3 years old and as late as 75 years old. The most prominent symptoms include problems with motor coordination as well as difficulties in speaking. Other symptoms can include personality changes, depression, dementia, and involuntary movements. Because its clinical features are similar to those of Huntington’s disease, SCA17 is also alternatively called Huntington’s disease-like 4.

SCA17 is typically inherited in an autosomal dominant fashion, meaning that individuals of either gender are equally likely to inherit the disease. A child of an affected parent with SCA17 has a 50 percent chance of inheriting the expanded TBP gene and developing SCA17. The diagnosis of SCA17 relies on molecular genetic testing to detect the expansion in the TBP gene. Thus far no cure for SCA17 is available. Treatment options primarily focus on slowing down the progression and management of symptoms to maintain the quality of life.

This page was contributed to by David Bushart, Sriram Jayabal, Hannah Shorrock, Hayley McLoughlin, Logan Morrison, Siddharth Nath, Swati Khare, and Larissa Nitschke.

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