Spinocerebellar ataxias including Machado-Joseph disease

Spinocerebellar ataxias (SCA) refer to a group of rare, genetic neurological disorders that cause loss of muscle control, coordination, and balance. The SCAs involve loss of structure and function (degeneration) of the cells of the hindbrain, which includes the cerebellum (the part that helps control muscle movement and balance), the brain stem and upper part of the spinal cord, and sometimes other parts of the nervous system.

There are more than 30 distinct types of SCA, and they are numbered in order of the discovery of the gene mutation that causes each type. The term “spinocerebellar ataxia” refers to those ataxias that are inherited in an autosomal dominant manner. Machado-Joseph disease (SCA3) is one of these disorders.

The types and severity of symptoms vary among SCAs, but they are progressive, meaning the symptoms worsen with time. Some forms of SCA may progress slowly over a period of years, while others worsen within months. Generally, people with SCA will require a wheelchair within 10 to 20 years of diagnosis. SCA can be fatal although some people with the disease have an average lifespan.

Symptoms of SCA

Depending on the type of SCA, symptoms will most often appear in adulthood but can appear in childhood. Several SCAs may have their own clinical signs, but most include:

• Progressive loss of coordination and balance
• Progressive lack of coordination in the arms and legs, including tremor
• Slowness of movement
• Problems with walking (gait)
• Decreased muscle tone
• Vision problems, particularly with focusing the eyes and unwanted eye movements
• Difficulty speaking (dysarthria) and swallowing (dysphagia)
• Cognitive problems (thinking, remembering, and concentration)

Most common forms of SCA. The most common forms of SCA are types 1, 2, 3, and 6, which account for most of the disorders.

• SCA1 involves weakness and paralysis of the muscles of the eye and eyelid, blurred and double vision, and problems with moving the eyes. There will be ataxia—the loss of control and coordination of muscles we can willingly move—of the arms and legs, and problems speaking and swallowing. Other symptoms may include muscle stiffness (spasticity), peripheral neuropathy (damage to or loss of signaling of the nerves that connect the brain and spinal cord to the rest of the body), and overactive muscle reflexes. Individuals with SCA1 may have difficulty processing, learning, and remembering information (cognitive impairment). Disease onset is usually between 30 and 40 years of age but can appear much earlier or later.
• SCA2 (also known as olivopontocerebellar atrophy) involves vision problems, eye muscle control, and degeneration of the retina (the light-sensing part of the eye). Additional symptoms may include peripheral neuropathy, tremor, muscle wasting (atrophy), and brief, unplanned twitching of a muscle or group of muscles (myoclonus). People with SCA2 also may have problems with short-term memory, planning, and problem solving, or experience an overall decline in intellectual function (dementia). Depending on its severity, disease onset can be as early as infancy or into adulthood.
• SCA3 (also known as Machado-Joseph disease) is characterized by slowly progressive clumsiness in the arms and legs, a staggering or lurching gait, difficulty with speech and swallowing, impaired eye movements sometimes accompanied by double vision or bulging eyes, and lower limb spasticity. Some individuals develop dystonia (sustained muscle contractions that cause twisting of the body and limbs, repetitive movements, and distorted postures) or symptoms similar to those of Parkinson's disease, such as slowness of movement and muscle stiffness (rigidity). Other people may develop twitching of the face or tongue, neuropathy, sleep disorders, or problems with urination and the autonomic nervous system, which regulates body functions like breathing, digestion, heart rate, and blood pressure. Cognitive impairments can include problems speaking and remembering.
  • There are different types of Machado-Joseph disease:
    • Type I—Characterized by onset at about 10 to 30 years of age with faster progression and more dystonia and rigidity than ataxia.
    • Type II—The most common type, generally begins between the ages of about 20 and 50 years of age, has an intermediate rate of progression, and causes various symptoms, including prominent ataxia, spastic gait, and enhanced reflex responses.
    • Type III—Characterized by the latest onset of disease at around 40 and 70 years of age. Progresses relatively slowly and features peripheral neuromuscular involvement (muscle twitching, weakness, atrophy, and abnormal sensations such as numbness, tingling, cramps, and pain in the hands and feet) as well as ataxia.
• SCA6 involves ataxia, problems walking, problems speaking, and involuntary side to side/up and down motions of the eyes that may include limited or reduced vision. Other symptoms may include peripheral neuropathy, decreased vibration, problems with sense perception, spasticity, exaggerated reflexes, and problems moving the eyes. SCA6 generally begins between the ages of 20 and 50 years, and progresses slowly.

Who is more likely to get spinocerebellar ataxias?

SCAs are passed from parent to child in an autosomal dominant pattern, meaning that only one parent needs to carry the gene mutation that causes signs or symptoms of the disease (genes come in pairs, with one copy inherited from each parent). A mutation causes a gene to make proteins that impair nerve cell function. When a parent has SCA, each child has a 50 percent chance of inheriting the mutated gene and, if they do, they will eventually develop symptoms of the disease. A child who does not inherit the SCA mutation will not develop the disease and cannot pass it to future generations.

SCAs belong to a class of genetic disorders called expanded repeat diseases. People with SCA have a repetitive, greatly expanded three-letter code (or triplet) in the DNA sequence that is found in genes. DNA uses triplets to prescribe the order and identity of amino acids—a protein's building blocks. This three-base repeat—called a triplet repeat expansion—is also known to cause many other neurological diseases. The repeat expansions can vary greatly in size, even among affected persons in the same family. Longer repeat expansions tend to cause more severe disease that begins earlier in life and shows a broader range of neurological symptoms.

One unusual feature of SCAs and many other expanded repeat diseases is a phenomenon called anticipation, in which the signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This is due to the tendency for the expanded repeat mutation to further expand when being passed to the next generation, especially when passed from the male parent.

How are spinocerebellar ataxias diagnosed and treated?

Diagnosing SCA. Physicians diagnose SCA through various neurological tests and by taking a family history of any disease. They ask detailed questions about family members who show (or showed) symptoms of the disease, the kinds of symptoms seen in these relatives, the age(s) of disease onset, and the progression and severity of symptoms. Neuroimaging, using computed tomography (CT) and magnetic resonance imaging (MRI), can show atrophy of the cerebellum and other brain structures. Other forms of imaging can show changes in brain function.

A definitive diagnosis of SCA can only be made with a genetic test. Genetic testing can confirm mutations of a known gene to cause SCA. The genetic test for Machado-Joseph disease (SCA3) is highly accurate. Those individuals who are at risk for Machado-Joseph disease or another SCA (for example, those who have an affected parent) but do not have any symptoms can undergo presymptomatic testing to determine whether they carry the gene mutation (and therefore will likely develop the disease later in life). Genetic testing is voluntary. Because testing has benefits as well as limitations and risks, the decision about whether to be tested is a personal and complex one. A geneticist or genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing.

Treating SCA. There is no definitive treatment to cure SCAs or slow their progression, but some symptoms can be treated in the following ways:

• Coordination and balance can be assisted by using physical aids such as canes, walkers, crutches, and wheelchairs to help with everyday activities and maintain independence.
• Special glasses can reduce blurred or double vision. Eye surgery only has short-term benefits due to the progressive degeneration of eye muscles.
• Stiffness and slowness of movement can be treated using levodopa therapy (used in treating individuals with Parkinson's disease), but the benefit may be limited. Antispasmodic drugs, such as baclofen, can help reduce spasticity. Botulinum toxin can treat severe spasticity and some symptoms of dystonia, but has possible side effects, such as swallowing problems (dysphagia).
• Speech and swallowing problems can be treated with medication and speech therapy. Computer devices can assist individuals with severe speech difficulties.
• Maintaining strength and movement can be aided by physical therapy. Physiotherapy can help individuals cope with gait problems.
• Daytime sleepiness, a common complaint in Machado-Joseph disease (as is sleep disturbance in general), can be treated with medicines and should call for a formal sleep evaluation.
• Other problems, such as cramps and urinary dysfunction, can be treated with medications and medical care. Occupational therapy can help individuals learn ways to better perform daily tasks such as feeding and bathing.

What are the latest updates on spinocerebellar ataxias?

The National Institute of Neurological Disorders and Stroke (NINDS) supports research on SCAs including Machado-Joseph disease in an effort to learn how to better treat, prevent, and even cure these diseases. Ongoing research includes efforts to better understand the genetic, molecular, and cellular mechanisms that underlie repeat expansion diseases related to SCAs including Machado-Joseph disease, and other triplet repeat expansion diseases.

Overlapping mechanisms may be involved in triplet repeat disorders, regardless of whether or not the repeat is in a protein-producing or coding region of the gene. Modifications of the mutant protein can impact toxicity, which may explain why some triplet repeat diseases have onset later in life.

Clinical trials include investigating treatments for SCAs including Machado-Joseph disease, identifying biomarkers (signs that can be used to diagnose a disease and monitor its progression), a natural history study of and genetic modifiers in the SCAs, and developing a patient registry for rare diseases, including the SCAs, to allow individuals living with these disorders and researchers to connect as easily as possible.

Other research includes work to better understand the molecular mechanisms involved with SCAs, improve current diagnostic procedures, and develop disease-modifying and other therapies.

More information on NIH efforts on SCA research and related disorders can be found using NIH RePORTER, a searchable database of current and past research projects supported by NIH and other federal agencies. RePORTER also includes links to publications and patents citing support from these projects.

How can I or my loved one help improve care for people with spinocerebellar ataxias?

Consider participating in a clinical trial so clinicians and scientists can learn more about SCAs and related disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.

All types of volunteers are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with SCAs at Clinicaltrials.gov.

Where can I find more information about spinocerebellar ataxias?

Information about SCAs including Machado-Joseph may be available from the following organizations and resources:

American Speech-Language-Hearing Association (ASHA)
Phone: 800-638-8255

Dystonia Medical Research Foundation
Phone: 312-755-0198

Genetic Alliance
Phone: 202-966-5557 or 800-336-4363​​​​

National Aphasia Association
Phone: 212-267-2814 or 800-922-4622

National Ataxia Foundation (NAF)
Phone: 763-553-0020

National Organization for Rare Disorders (NORD)
Phone: 203-744-0100 or 800-999-6673

Content source: https://www.ninds.nih.gov/health-information/disorders/spinocerebellar-ataxias-including-machado-joseph-disease Accessed June 29, 2023.

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