What is machado-joseph disease (MJD)?

MJD is a hereditary disorder affecting the nervous system and motor skills, clinically called Spinocerebellar Ataxia Type 3. It is described as a neurodegenerative disease, meaning nerve cells are progressively lost over time. When neurons in the brain and spinal cord slowly lose their function and die, signals between nerve cells slow down or stop completely, leading to trouble in motor coordination, muscle contraction, and sometimes the ability to process sensory information, such as touch or pain.^1,2

Ataxia mainly affects the central nervous system (the brain and spinal cord), especially the cerebellum( a key area of motor control), brainstem and some areas of the spinal cord.³

Magnetic Resonance Imaging (MRI) shows that neurodegenerative damage is not only confined to these control centres but also to the connective networks between these. For example, the pons, an area in the brainstem that transfers messages from the brain to the body and vice versa, shrinks. The cerebellum and its connecting "wires", called the peduncles, thin out.  Even areas responsible for fine-tuning muscle activity, such as the globus pallidus, change due to neurodegeneration.⁴

In some cases, peripheral nerves (nerves that reach into the arms and legs) and oculomotor nerves (that control eye movement) are affected, showing that neurodegeneration occurs across multiple parts of the nervous system.⁵

See our article on What is Machado-Joseph Disease here!

Why is it an inherited disorder?

The key problem in MJD stems from its hereditary nature, involving a mutation in the ATXN3 gene. This mutation is inherited in an autosomal dominant manner, meaning that if one parent has it, there is a 50% chance that their child will inherit the condition as well.¹

Genetic information is an instruction manual for your body to build the necessary proteins for survival, and mutations are “typos” in these instructions. ATXN3 would usually code for the ataxin-3 protein, an enzyme essential in removing "ubiquitin tags" from proteins. The removal of these tags means that the protein is ready to be recycled and reused for other metabolic or functional purposes, and to remove any misfolded or damaged proteins that could cause stress to the cells. This keeps your nerve cells healthy and ready to fire. When the mutation (in this case, an expanded CAG repeat) occurs, the enzyme becomes unstable and is no longer able to function properly. Instead, it overwhelms the neurons by misfolding and clumping together, blocking the very system it is supposed to regulate.^6,7

What is genetic testing?

Genetic testing involves various techniques that look at an individual's genes and identify possible mutations, helping doctors to diagnose a hereditary disease. It is incredibly useful for MJD, as it allows for the disorder to be distinguished from other similar spinocerebellar ataxias. Although genetic testing is essential, it cannot alone diagnose a disease. Diagnosis may also rely on clinical data such as electrophysiological tests.⁸

How are nerves and muscles connected?

Movement starts in the brain's motor control centres, like the cerebellum or motor cortex.⁹ These regions send electrical signals down the connecting wires of the brainstem and into the spinal cord. From there, the signals travel along motor neurons to the peripheral nerves, branching out like electrical cables reaching specific muscles.¹⁰

Nerves and muscles work together like an electric cable and a motor. The nerves carry the electrical current to the muscle, while the muscle acts as a motor and turns that message into movement and contractions. The "plug" where these two meet is called the neuromuscular junction.¹¹ Here, a chemical signal called acetylcholine (ACh), a "neurotransmitter ", is released into the synaptic cleft. ACh then binds to the receptors on the muscle membrane (sarcolemma), which then depolarises (changes its electrical charge) and releases calcium. Calcium then enters and interacts with muscle fibres to contract via the actin-myosin bridge. Think of muscles as doors which stay locked until the right key is used. In this case, opening the door is contracting the muscles, the lock is the myosin-actin bridge, and the key is calcium.¹²

Muscles cannot contract unless calcium unlocks them, and this is only done when the nerve signals are able to travel from the regions responsible for motor control in the central nervous system to the peripheral nervous system and successfully interact with the muscle receptors.

Why is nerve and muscle testing important?

Clinicians use nerve and muscle tests to evaluate the health of the nervous system and the connections between your nerves and muscles.¹³ The tests look at how well neurons are working not only in the brain, but also in the peripheral nerves, which can be incredibly useful in.¹⁴

• Identifying the source of damage: whether nerves are weak, slow, or blocked
• Tracking progression: showing how far and how fast neuropathy is spreading over time
• Differentiating diseases: e.g. distinguishing Machado-Joseph Disease from conditions like ALS

This guides doctors into making correct choices about diagnosis, treatment options, physical therapy techniques or pain relief approaches.  A very simple example of testing nerve and muscle function is the knee-jerk reflex test. Electromyography and nerve conduction studies operate on the same principle — assessing the health and function of the nerves and muscles based on their electrical activity —  but they provide a much more precise and detailed picture.

Nerve and muscle testing can be used together with genetic testing (confirms inherited changes linked to MJD) and imaging techniques reflecting which brain and spinal regions are shrinking or affected, such as MRI. A combination of these tools gives doctors a clearer picture of the disease.

What tests do clinicians use for MJD?

Nerve conduction study(NCS)

NCS looks at the speed at which a signal passes through a nerve ( or the conduction velocity) and the strength (or amplitude) of the signal.¹⁵ This is usually done before EMGs. The process involves applying a small electrical stimulus to the nerve and measuring the response over a muscle or another point along the nerve. The speed and the strength of the nerve signal can tell us much about the health of the nerve.¹⁶

Speed (conduction velocity): Slow signal = myelin damage

Strength (amplitude): Weak signal = axon itself (the core of the nerve fibre) is damaged

Electromyography (EMG)

This test detects the electrical signals in motor neurons and muscles. This is done using small needles with electrodes that are inserted through the skin and into the muscle.^16,17

Electrical activity in a muscle is examined in three phases during an EMG:

• Insertion: A brief burst of activity when the needle goes in
• Resting: A healthy muscle is silent at rest
• Contraction: Healthy muscles show a full, dense pattern of activity

Transcranial stimulation (TMS)

Magnetic stimulation tests give doctors a way to check the ‘highways’ that carry signals from the brain down the spinal cord. It is used as a research tool that measures central motor conduction.¹⁸

By studying these patterns and comparing TMS, NCS and EMG results, doctors can tell whether the problem lies in the nerves (CNS or PNS), muscles, or a combination of both.¹⁶

What NCS and EMG results are found in MJD?

Electrophysiological studies in MJD reveal what is happening not only in the brain and spinal cord, but also in the nerves and muscles.

NCS often reveals peripheral neuropathy affecting both sensory and motor nerves. Studies using NCS reveal that nerve potentials, or the signal strength, in both sensory and motor nerves are significantly reduced compared to what is physiologically normal.¹⁹

Interestingly, the speed of the signal can be unaffected, which points to damage in the axon itself (the core of the nerve fibre) rather than the myelin coating. This means the nerves, especially those in the legs, send weaker messages. Muscle changes indicating loss of nerve supply can sometimes be detected years before symptoms are visible.  

And this makes a lot of sense! MJD is not a myelin disorder but a neurodegenerative disease, so finding weaker signals but normal speeds gives doctors clues to what the disease could be during tests, leading up to diagnosis. Building on this, another study has shown that when NCS is combined with genetic testing, a clear pattern emerges: people with larger ATXN3 gene mutations tend to exhibit a faster decline in nerve signal strength.²⁰

EMGs in MJD often pick up early signs that nerves are not reaching the muscles properly. This denervation can look like an abnormally present signal when the muscle is resting, or a weaker pattern when the muscle is contracting. This is sometimes visible years before the symptomatic muscle weakness becomes notable.¹⁹ In some cases, abnormal twitches (fasciculations) and cramps appear in the face as well.

In MJD, TMS tests often show that signals travel more slowly and are weaker than normal, which is a sign that the brain-to-spine pathways (corticospinal tracts) are damaged.¹⁸ This complements nerve and muscle testing in the limbs, proving that both central and peripheral parts of the nervous system are affected.

How does testing help?

Put simply: these tests show that MJD can weaken nerves and muscles long before you notice symptoms, and the size of the genetic change helps predict how fast it happens.

Although there is currently no cure, understanding the disease and the electrophysiological aspect at this detailed level means progress is being made. These tests can not only diagnose MJD earlier but also track how new treatments might slow or change its course.

Summary

Machado-Joseph Disease (MJD)is a hereditary neurodegenerative disorder caused by a mutation in the ATXN3 gene. Neurodegeneration occurs mainly in the brain's motor control systems(cerebellum, brainstem, and spinal pathways) but can also involve peripheral nerves and muscles. Genetic testing and imaging can help in diagnosis, but electrophysiological tests such as Electromyography, nerve conduction tests, and transcranial magnetic stimulation can offer important insights into differentiating the disease, the severity, the spread and into developing new treatments. 

FAQs

Are these tests painful?

Some people feel mild discomfort during nerve conduction studies or EMG, but the procedures are generally well-tolerated.

Can these tests predict how fast MJD will progress?

Not exactly. They show how much the nerves are affected at the time of testing, but cannot predict the future course with certainty.

Can these tests detect MJD before symptoms appear?

Genetic testing can identify carriers, while EMG/NCS sometimes pick up early nerve changes before notable muscle weakness.

If I have a positive genetic test result, should my family members be tested?

Yes. Due to the autosomal dominant nature of the gene, there is a 50% chance of a child inheriting the disease if the parent has it. 

What are the treatment options for MJD?

Treatments focus on easing symptoms. For example, physiotherapy to help with balance, medications for muscle stiffness or cramps, and support for speech and daily activities. Researchers are also testing gene-targeted therapies that may slow or change the course of the disease in the future.