What Is Spinocerebellar Ataxia?

Spinocerebellar ataxia is a neurodegenerative disease which predominantly affects movement and speech. Whilst there is currently no cure, treatment options are available to assist in disease management and reduce symptoms. 

In this article, we will explain what spinocerebellar ataxia is along with the causes, associated symptoms, and management of the disease. 

Overview

Ataxia involves the loss of control of voluntary muscle movement, resulting in poor coordination, walking difficulties, and lack of balance. This happens when a portion of the brain, known as the cerebellum, becomes damaged. This damage ultimately results in cerebellar atrophy and peripheral/ sensory neuropathy. 

Spinocerebellar ataxia (SCA) is a specific form of ataxia and is a rare, hereditary, neurodegenerative disease. This spinocerebellar ataxia affects mainly the cerebellum and spinal cord cortex, alongside other areas of the central nervous system, including the pontine nuclei, peripheral nerves, and basal ganglia like other neurodegenerative diseases which involve atrophy of these regions.

SCA is a progressive cerebellar ataxia, meaning that symptoms worsen with time. In most cases of SCA, this, unfortunately, also means a decreased life expectancy. 

Whilst there is currently no cure for this disease, there are multiple options available to help in its management and a multitude of clinical trials which aim to slow its progression. 

Common types of spinocerebellar ataxia

There are 48 categorized types of spinocerebellar ataxia, numbered SCA1 through to SCA 48 in the order of their discovery. In some cases, there are still uncategorised variants of the SCA gene. 

The most common forms of spinocerebellar ataxia include SCA type 1, SCA type 2 (or olivopontocerebellar atrophy), SCA type 3 (or Machado-Joseph disease), and SCA type 6.¹ Machado-Joseph disease is the most common of all the SCA variants and is estimated to account for  25-50% of all SCA cases worldwide.

There are also five types of autosomal recessive disorders that involve ataxia. These include;

• Friedreich ataxia
• Oculomotor apraxia (involving retinal degradation)
• Spastic ataxia
• Ataxia-telangiectasia

• Ataxia with vitamin E deficiency

Causes of spinocerebellar ataxia

As previously mentioned, spinocerebellar ataxia mainly affects the cerebellum and the spinal cord. In normal brain function, the spinal cord and brain relay signals through brain cells to the cerebellum via the brainstem. 

By the coordination of signals via the Purkinje neurons, the output of information from the cerebellar cortex permits the regulation of fine movement and muscle coordination. However, this disease causes degeneration and subsequent death of these nerve cells within the cerebellum. This results in atrophy, or shrinking, of the cerebellum and leads to the manifestation of clinical symptoms characteristic of the disease. 

Spinocerebellar ataxia is caused by a DNA mutation (a change in normal DNA) located at the SCA gene. This mutation causes individuals to have more than the normal number of CAG trinucleotide repeat codes in the DNA. CAG is the genetic code for the amino acid polyglutamine, which is crucially involved in building proteins. It is understood the mutated gene instructions contain too many repeats of the CAG code which causes an excessive amount of polyglutamine to be produced within the nerve cells, which then causes them to die. 

SCA mutation results in progressive atrophy of the cerebellum and spinal cord tissues due to the progressive death of neurons. Whilst the exact mechanism by which these neurons die is not yet fully understood, research into SCA has identified multiple stages in which normal cellular replication or typical cellular function is disrupted. ^1,2

The SCA mutation is an inherited autosomal dominant mutation, which means that it takes only one copy of the mutated gene from one biological parent to cause the condition. Therefore, there is a 50% chance that a child will have the disease if one parent carries the mutation.

Due to the processes of DNA replication, there is also a chance that the child may also produce more CAG code repeats. In this case, the protein RNA polymerase (responsible for protein synthesis) misreads the CAG repeats, increasing glutamine buildup. This can result in an even earlier onset of symptoms.

Signs and symptoms of spinocerebellar ataxia

Progressive cerebellar ataxia results in symptoms arising after the age of 18, depending on the type of SCA variant and the amount of CAG repeats present. 

Generally, symptoms of spinocerebellar ataxia involve coordination problems involving the hands, eyes, legs, mobility and speech and include; 

• Involuntary eye movement (nystagmus, visual problems)
• Gait instability, or ataxic gait (walking is clumsy, staggering with a wide stance) 
• Problems with coordination and balance 
• Speech difficulties such as slurred speech (dysarthria)
• Difficulty swallowing (dysphagia)
• Reduced voluntary muscle coordination, including tremors  
• Loss of fine motor controls, such as poor hand-eye coordination
• Learning disabilities involve problems processing and recalling information. 

Management and treatment for spinocerebellar ataxia

Whilst there is currently no cure for spinocerebellar ataxia, there are multiple options available to aid in the management of the disease. These include: 

Assistive devices aim to assist the mobility of the patient. This can be through the use of a walking stick, leg braces or a wheelchair.

Physical therapy and rehabilitation – aims to:

• Develop the use of the upper limbs and core muscles
• Improve posture 
• Improve joint stabilisation
• Improve posture and balance
• Correct gait (walking pattern)

Medications – such as varenicline or acetazolamide, can be used to help relieve the ataxic symptoms associated with SCA. These can help alleviate tremors, depression, seizures, ataxia, and eye issues.

Speech therapy – SCA symptoms include dysarthria, a speech disorder which occurs due to weakness of the muscles used to speak. Speech therapy intervention can help strengthen these muscles and improve speech function.  

Clinical studies – While there is currently no cure available, there are several clinical trials in progress that aim to reduce the speed of disease progression by interacting with the genes involved in toxic protein production or by delaying disease progression. 

As SCA  is a highly complex disease, treatments currently focus on alleviating symptoms using pharmacological therapy. However, promising research studies have identified potential novel treatments which aim to slow the disease's progression. With further testing, these may progress to clinical trials in the future. Some promising targeted therapies include the use of: 

• Antisense oligonucleotides

Antisense oligonucleotides aim to target specific genes to reduce the levels of toxic proteins they make, or to provide non-toxic modifications to reduce their neurodegenerative effect. In animal models ( where interventions are tried on animal forms of the disease), this form of therapy has been identified as a way to reduce the progression of motor symptoms and improve overall survival rates in certain situations. ^3,4

• RNA-based therapy 

RNA interface looks to silence abnormal gene expression of proteins involved in disease - i.e. the mutant genes are blocked from making the abnormal proteins. 

Studies have shown this technique is successful in reducing mutant protein expression in cases such as SCA3 (or Machado-Joseph disease) in mouse models (where interventions are tried on forms of the disease in mice), thereby improving motor symptoms. ^5,6

• Stem cell-based therapy 

Studies utilizing stem cells have shown promising results in mouse models.⁷ This research has indicated a reduced loss of Purkinje cells for SCA1 models and delayed onset of motor dysfunction in SCA2 and ALS models.⁸

Further human clinical trials have shown some success, with patients continuing to remain stable 6-9 months post-transplantation.⁹ This type of treatment is still undergoing further testing. 

Diagnosis

Diagnosis of SCA involves neurological testing and looking at your family history. 

Further genetic testing will be required to understand the specific SCA mutation a patient has, although some SCA genes remain unspecified as yet. 

A diagnosis of SCA will be concluded following an examination of: 

• Personal medical history
• Family history
• Physical examination to assess the causes of symptoms 

Family history and genetic testing

Because SCA is mainly hereditary ataxia, a family history of SCA where one parent also has the disease is an indicator as to whether a patient also has the genetic mutation.

Genetic testing involves taking a blood sample and testing it against known gene variants which cause ataxia. 

As previously mentioned, some types of SCA are yet to be classified; therefore, medical professionals may conduct further testing.

MRI and CT scans

Brain scans, such as MRI and CT scans, can be used to identify physical abnormalities associated with the disease. By imaging the brain, medical professionals can differentiate between neurological symptoms caused by hereditary ataxia and by other diseases such as brain tumours. 

FAQs

How can I prevent spinocerebellar ataxia?

As SCA is an inherited gene disorder, there is no way of preventing the disease if you have the mutant gene. Prospective parents with this disease may consider the possibility of passing the mutation on to their children and consider genetic counselling.

How common is spinocerebellar ataxia?

SCA is a rare neurodegenerative disease, affecting around 1 to 5 per 100,000 people. This can vary regionally, with some populations experiencing a higher number of cases, particularly in areas which experience the ‘founder effect’. This effect occurs when a small population of people establishes a new, small, isolated community, causing less genetic variation and an increased likelihood of spreading hereditary diseases.  

Who is at risk of spinocerebellar ataxia?

A child born to an affected parent is most at risk of developing the disease. There is a 50% chance of the mutant gene being inherited by the child if one parent is affected. 

When should I see a doctor? 

SCA life expectancy varies depending on the classification and the severity of the disease. Almost all categories of SCA decrease the overall lifespan of an affected individual, and therefore it is crucial for sufferers to seek medical attention to assist in managing the disease and improving their quality of life. 

Summary

• Spinocerebellar ataxia refers to a group of hereditary, neurodegenerative brain disorders.
• This disease affects movement, coordination, balance, and speech.
• Due to the progressive nature of this disease, symptoms will worsen over time.
• Options are available to help manage symptoms, and you should seek medical consultation if you begin to show symptoms of SCA.