Spinocerebellar Ataxia

What is Spinocerebellar Ataxia?

Ataxia refers to a lack of muscle control or coordination of voluntary movements. This condition can affect stability while walking, eye movements, and speech. One type of ataxia, known as Spinocerebellar ataxia (SCA), is a hereditary condition passed down through families. This disease causes progressive nerve damage, mainly impacting the part of the brain known as the cerebellum.

SCA is one type of hereditary ataxia, a group of conditions affecting the brain and nerves. While it’s rare, SCA appears in many different forms; thus far, more than 40 unique genetic types have been identified. These various types of SCA are classified based on their genetic markers, with SCA1 being the first discovered, and other types numbered sequentially as they are found.

Contrary to what the name suggests, SCA doesn’t always affect just the cerebellum and spinal cord. It can also impact other parts of the central nervous system, including parts of the brain, nerve fibers running through the body, and more. However, this varies depending on the variant of SCA- for example, SCA6 affects only the cerebellum, while SCA2 does not have any impact on the cerebellum.

The most common types of SCA are SCA1, SCA2, SCA3, and SCA6, accounting for more than half of all cases. Other less common variants make up the remainder. Understanding SCA can be complex, both in terms of its genetics (genotypically) and its physical manifestation (phenotypically), and it is difficult to describe all the variants at once.

What Causes Spinocerebellar Ataxia?

Spinocerebellar ataxia, a group of disorders that affect balance and coordination, comes in several forms. Some types have a characteristic where they get worse as they pass from one generation to the next, a phenomenon known as anticipation. This happens due to the gradual expansion of CAG repeats, a specific pattern in our genetic code, in each new generation. This situation occurs in several types (SCA 1, 2, 3, 6, 7, 8, 12, and 17).

Other forms of the disorder are caused by the expansion of different genetic patterns: SCA 10 comes from the expansion of the ATTCT pattern, while SCAs 31, 36, and 37 are due to the expansion of TGGAA, GGCCTG, and ATTTT patterns respectively.

There are also rarer types of this disorder caused by other expanded patterns or changes in a single part of our genetic code, known as single nucleotide variants. For example, SCA5, SCA13, SCA14, and SCA19 are typically caused by a type of genetic mutation known as a ‘missense mutation’. Meanwhile, SCA15, SCA20, and SCA39 tend to occur due to the removal or duplication of certain genes.

Risk Factors and Frequency for Spinocerebellar Ataxia

Spinocerebellar ataxia, also known as SCA, is a disorder that affects between 1 and 5 people out of 100,000 worldwide. In Europe, the prevalence ranges from 0.9 to 3 people in every 100,000, but this varies by country. For example, the rate is 2 in every 100,000 people in Italy, 4 in Norway, and 5 in Portugal.

The most common type of this disorder is SCA3, affecting between 25 to 50% of cases. This is followed by SCA2 (13 to 18% of cases), SCA6 (13-15% of cases), and SCA7. However, the frequency of these different types can change depending on the geographic region. For instance, while little data is available from Asian countries, some studies from India, China, Singapore, Japan, and Korea suggest that SCA2 is the most common type in South Korea and India, despite SCA3 being the most common type worldwide.

Signs and Symptoms of Spinocerebellar Ataxia

Family history is a crucial part of diagnosing health conditions like spinocerebellar ataxia (SCA), a group of conditions that affect movement. While it’s harder in cases of non-biological family members (like adoptions), it’s usually a gradual and slow progression over several years. Importantly, the symptoms can vary a lot between different family members even if they have the same version of SCA.

Research has shown that some genetic factors can impact the severity and age of onset of symptoms – more of a specific genetic mutation, called a ‘triplet repeat’, tend to worsen the condition and cause it to appear earlier. Additionally, different forms of the condition bring different symptoms.

• Hyperactive reflexes and jerky eye movements can be characteristic of certain SCAs but are unlikely in SCA type 2.
• Weakness, numbness, and pain (signs of peripheral neuropathy) are common in SCA1, 2, 3, 4, and 18, but SCA4 is mostly associated with sensory neuropathy.
• Visual issues like macular degeneration are more common in SCA7.
• Eye muscle weakness, involuntary eye movement (nystagmus), bulging eyes, muscle twitching, and Parkinson-like symptoms are typical of SCA1, 2, and 3.
• Certain features like tension in muscles (spasticity), muscle weakness and hyperactive reflexes are common across most subtypes.
• Seizures are more common with SCA10, jerky muscle movements (myoclonus) with SCA14, facial and tongue twitching with SCA36, chaotic movements (chorea) and tremors with SCA12 and 27, and scaly skin (ichthyosiform plaques) with SCA34.
• Changes in movement or posture, cognitive and mental health issues, tremors, jerky involuntary movements (chorea), and hearing loss are also common symptoms.

Testing for Spinocerebellar Ataxia

Before analyzing the genes, it’s important to understand the visible symptoms of the disease. However, for different forms of spinocerebellar ataxia (SCA), a group of genetic diseases that cause uncoordinated movements and balance issues, this can be challenging as their symptoms are often similar. Therefore, gene testing has become the most reliable way to diagnose different forms of this disease. The more we understand about the different symptoms, the easier it is to identify the specific genetic variations causing them.

Genetic Testing

Recent advances in gene analysis and testing have made it faster to classify and diagnose SCA. By identifying a specific gene mutation, we can then test for it in other family members. If there’s a history of the disease in the family, gene testing is the most definite way to identify the specific form of SCA. This is done through a technique called Polymerase Chain Reaction (PCR), which detects specific repeated sections in different SCA genes.

When we suspect a patient has SCA, we first test for the most common forms like SCA1, 2, and 3, and if those tests come back negative, we test for other subtypes. This approach is more practical and efficient as it’s likely to yield positive results sooner, which also reduces the time and cost involved in the testing process. However, for patients with unique or complex symptoms, we may need to conduct further genetic examinations to identify the specific gene mutation.

Lastly, prenatal screening can be done through gene testing, but it comes with the risk of ending the pregnancy and lack of follow-up. In most common and well-known SCA types like SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, and SCA10, we perform blood tests to detect any mutations.

Neuroimaging

Neuroimaging is a technique that gives us a detailed look at the brain. In SCA, it often shows significant shrinkage of the brain’s cerebellum, particularly in the case of SCA2, and to a lesser extent in other types. We also often see brain ventricle enlargement and shrinkage of other parts of the brain. There may be some specific abnormalities in certain forms of SCA, such as SCA3 showing severe shrinking in the bridge between the cerebellum and the rest of the brain. However, some subtle changes that don’t appear in standard imaging may be detected by more advanced techniques like positron emission tomography (PET) scans and magnetic resonance spectroscopy, though these are not commonly used due to their cost and availability.

Electrophysiologic Testing

This type of testing checks the state of nerve conduction action potential. It’s useful because in SCA, the Purkinje cells, which control coordination, lose functionality and the sensory neurons, which send information from the body to the brain, experience axonal neuropathy, a condition that affects nerves’ functionality. However, this testing cannot differentiate between different SCA subtypes.

Treatment Options for Spinocerebellar Ataxia

Spinocerebellar ataxia is a medical condition passed down through families (genetic disease) with no definite cure. The main focus of treatment is easing symptoms like seizures, shakes, low mood, difficulties with body movement and coordination, and problems with eyesight. Medications such as antiepileptic drugs for seizures, botulinum toxin injections for muscle disorders, beta-blockers and primidone for shakes, antidepressants for low mood, and levodopa for a condition similar to Parkinson’s disease, can all be used to alleviate these symptoms.

The use of N-acetyl cysteine, a medication used for a variety of health issues, has shown some benefits for neurological disorders and spinocerebellar ataxia. Citalopram, often used to treat depression, benefits patients by reducing the level of a harmful protein (ataxin-3) and improves patients’ mood and behavior. Dantrolene works by blocking the release of calcium in cells, which protects a type of nerve cell called Purkinje cells. Chlorzoxazone is a medication used to improve muscle movements, normalizing the function of Purkinje cells.

Misfolded proteins tend to accumulate in cells leading to disorders such as spinocerebellar ataxia. Treatments that can clear these faulty proteins may be helpful. The body normally gets rid of these proteins using two main systems – ubiquitin-proteosome and autophagy. Several treatments that can speed up the removal of these proteins have been studied. For example, certain chemicals can accelerate the degradation of the faulty protein.

Rapamycin, a drug that suppresses the body’s immune system, can upregulate a system in the body called autophagy and helps in degrading faulty proteins. Other treatments that can regulate cellular pathways involved in clearing misfolded proteins are under study.

Researchers have also explored the use of antisense oligonucleotides, a type of drug that can alter the patient’s genetic information, to decrease the expression of the problematic protein causing spinocerebellar ataxia. This led to delay in the onset of symptoms, improved motor function, and increased the function of Purkinje cells.

Other therapeutic options include molecules that interfere with RNA, antioxidants, and NMDA (a neurotransmitter in the brain) that can help forestall deterioration of nerve cells.

Physical therapy and rehabilitation play an essential role in spinocerebellar ataxia management. It focuses on helping patients regain and maintain balance, walking ability, and physical strength which assists them in maintaining their independence. Research has shown that people in the early stages of the disease can improve their balance and walking ability after six months of therapy. Occupational therapy can provide patients with tools such as wheelchair support, crutches, walkers, and devices to assist with writing and eating to make everyday tasks more manageable. Speech therapy along with communication devices and behavioral interventions can also be beneficial.

What else can Spinocerebellar Ataxia be?

Diagnosing spinocerebellar ataxia can be complicated because the symptoms vary widely from person to person. Several other conditions can also cause similar symptoms, such as:

• Nongenetic Ataxia: This type of difficulty with balance and coordination can be caused by various factors, including nutritional deficiencies, exposure to radiation, alcoholism, specific infections, or certain tumors.
• Drug-induced Movement Disorder: Certain medications may cause movement disorders that resemble those seen in spinocerebellar ataxia.
• Acute Viral Cerebellitis and Postinfectious Ataxia: Some viral and bacterial infections can lead to inflammation in the cerebellum, resulting in balance and coordination problems.
• Focal Ataxia: This type of ataxia usually affects one side of the body and can be caused by stroke, bleeding in the brain, or other similar conditions.
• Other Autosomal Recessive Ataxias: These genetic disorders produce symptoms similar to spinocerebellar ataxia and will often require a genetic test for accurate diagnosis.
• Dentatorubral Pallidoluysian Atrophy: This condition has a wide range of symptoms, including progressive ataxia, which closely resemble those of spinocerebellar ataxia.
• Fragile X Associated Tremor Ataxia Syndrome: This typically affects older adults and can cause ataxia and tremors. One unique feature of this syndrome is premature ovarian failure, which does not occur in spinocerebellar ataxia.
• Gerstmann-Straussler-Schenker Syndrome: This is a prion disease that can cause symptoms similar to spinocerebellar ataxia.
• Episodic Ataxia: These inherited disorders can cause intermittent bouts of ataxia, often triggered by physical activity or sudden movements.
• Chorea: This group of diseases can cause movement, eye, and cognitive disorders, similar to symptoms observed in spinocerebellar ataxia.
• Immune-mediated Ataxia: These are rare diseases where the body’s immune system mistakenly attacks the body, resulting in ataxia.

Because of these diverse possibilities, doctors have to carry out a thorough evaluation that includes testing for genetic and other factors to confirm a diagnosis of spinocerebellar ataxia.

What to expect with Spinocerebellar Ataxia

Understanding the specific relationship between the genetic type and the symptoms of spinocerebellar ataxia (a group of hereditary diseases that lead to slow but progressive loss of movement coordination) can help improve disease forecasts. Indeed, it usually takes a long time to observe and understand the full range of symptoms, and once they become obvious, they are almost impossible to reverse.

Yet, treatment that aims to alleviate symptoms can often enhance the disease’s outlook. Survival rates can depend on the size of the CAG genetic segment. A longitudinal study (looking at subjects over a long period of time) showed that the average 10-year survival rate of SCA1 (a subtype of spinocerebellar ataxia) is about 57%, while for SCA6 (another subtype), it’s higher at 87%. Those with the disease who also struggle with dysphagia (difficulty swallowing) have the shortest survival rate.

Many patients with spinocerebellar ataxia will need a wheelchair within 10 to 15 years of the disease onset, but physical therapy can help delay this need.

Possible Complications When Diagnosed with Spinocerebellar Ataxia

Long-term effects and complications from spinocerebellar ataxia, a movement disorder, often depend on how far the disease has spread and which parts of the brain and spinal cord are affected. The severity of the disease can also cause various symptoms and complications, and these can disrupt normal life activities.

• Parkinsonism: This disorder of the nervous system is associated with the breakdown of specific neurons. It is most commonly seen in subtype SCA2 of spinocerebellar ataxia, and hardly ever seen in SCA3 and SCA17.
• Progression of Dystonia, Tremors, and Other Movement Disorders: The presence of dystonia, a condition of abnormal muscle tension, along with ataxia can lead to a more severe course of the disease. Dystonia is a common disorder that can occur with spinocerebellar ataxia.
• Depression, Dementia, and Cognitive Disorders: Depression is a key factor that influences how patients with neurodegenerative diseases, including spinocerebellar ataxia, perceive their health. It can be influenced by issues such as sexual and urinary dysfunction, altered personality, and cognitive impairment. Cognitive difficulties are mainly associated with SCA1, and dementia can occur in severe cases, as reported in a case study from Japan for SCA31.
• Eye Complications: Problems with eye movement and retinal disease are common in SCA7, where degeneration of the central retina occurs, which can cause central vision loss that progresses to complete vision loss. Rapid, uncontrolled eye movements and a condition called “blepharospasm” (where your eyelids close or twitch uncontrollably) are rare symptoms that can occur in SCA31.
• Difficulty Swallowing and Speaking: The breakdown of motor neurons in the brainstem can cause problems with swallowing and speaking in SCA2, SCA3, SCA6, and SCA7. These conditions can lead to life-threatening complications such as aspiration pneumonia, infection caused by inhaling food or drink.
• Seizures and Excessive Sleepiness: People with the SCA10 subtype of spinocerebellar ataxia have a 6 to 10 times greater chance of having seizures due to the repetition of a specific sequence of DNA.

Preventing Spinocerebellar Ataxia

It’s important for patients and their families to understand the details about any ailments they might have, including how it’s passed down through genetics, what course the disease might take, the treatment options, potential risks to other family members, and the significance of family medical history. It’s crucial that any information provided is delivered in a way that the patient and family can fully comprehend.

Bluntly put, the more a patient knows about their illness, the better they’ll be at managing it. Patient education can cut through the confusion often associated with medical diagnoses and treatment plans. This not only improves the patient’s adherence to medical advice but also eases the burden of treatment and establishes a strong relationship between the patient and doctor. Doctors should strive to address, in an honest and straightforward manner, any questions or doubts a patient might have about their illness, as this is a part of their rights as a patient.

Before any medical procedure, it’s important that the patient is fully informed about the treatment plans available and that they are given the chance to choose the option they feel is best after comprehensive description and counseling. Moreover, knowledge about the signs and symptoms can help patients to become alert at the early stages of the disease or the progression of complications. This allows them to seek medical help promptly, potentially leading to better health outcomes.