Introduction

Brief overview of MJD

Machado-Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a neurodegenerative disorder that is inherited. MJD is very rare, and affects about 1-5 people out of 100,000 people globally.^1,2 It affects one’s ability to control their muscles which further leads to problems with coordination. The 3 types of MJD are as follows: 

• Type 1: Starts between the ages of 10-30
• Type 2: Symptoms present themselves from the age of 20-50
• Type 3: Symptoms present between the ages of 40-70 

However, symptoms tend to get worse over time across all three types of MJD. 

Genetic basis

MJD is an autosomal dominant disorder, meaning that only one gene inherited from one parent can lead to the disease. The disorder originates from a mutation, which is when one’s DNA sequence alters, that occurs in the ATXN3 gene. Further leading to an alteration in a protein named ataxin-3. It becomes toxic and leads to a build up in one’s nerve cells.

Purpose of outline 

This article aims to explore the different neurological symptoms of MJD. The focus of this article will be on the progress from ataxia (a term used to describe problems with balance, speaking, swallowing, walking and co-ordination) to spasticity (involuntary muscle movements).

Core neurological symptoms of MJD

Cerballar antaxia 

This is a movement disorder that is caused by the cerebellum being damaged, the part that controls muscle coordination.³ Damage of the cerebellum is manifested in the following symptoms: 

• Poor balance and coordination
• Speech and swallowing difficulties
• Impacted vision 
• Dizziness

Oculormotor abnormalities

This occurs when the oculomotor nerve is damaged, which controls the eye muscles and eyelid function.⁴ This could lead to the following symptoms:

• Impaired vision 
• Unaligned eyes 
• Drooping eyelids
• Trouble shifting eyes 

Pyramidal signs and spasticity

Pyramidal signs are when there are problems in the pyramidal tract. The pyramidal tract sends signals from the brain to the muscle to help one move on purpose, for example, when one smiles, walks or picks something up. The signal starts in the brain, travels down the 

spinal cord, and then reaches the muscles.⁵ If the pyramidal tract is damaged, as in MJD, it causes:

• Muscle stiffness (spasticity)
• Tight or weak muscles
• Overactive reflexes

Development of spasticity

Spasticity develops when an upper motor neurone or part of the spinal cord is damaged. This affects one's ability to control their reflexes, thereby leading to increased muscle tone and stiffness. Spasticity also reduces an individual's function and increases dependency on others to assist in day-to-day activities.⁶ Individuals with type 1 or 2 MJD tend to have severe symptoms compared to those with type 3 MJD.⁷ This is because those who develop MJD symptoms at an earlier age tend to develop spasticity. 

Additional neurological manifestations 

Parkinsonism features 

Parkinson's disease occurs when areas of the brain get progressively damaged as one ages⁹. This can lead to symptoms such as: 

• Involuntary shaking
• Muscle stiffness
• Slow movement
• Inflexible muscles
  

However, only a few cases of MJD develop Parkinsonian features and manifests symptoms such as:¹⁰

• Slow movements
• Muscle stiffness
• Chronic pain
• Vocal chord paralysis

Peripheral neuropathy

Peripheral neuropathy occurs when a specific nerve is damaged in one’s hands and feet ¹¹ and is extremely common in MJD. However, it tends to be seen in older individuals with MJD⁸. 

Peripheral neuropathy causes:¹²

• Pain¹³
• Muscle twitching
• Weakness
• Twitching
• Tingling
• Cramps

All these symptoms are concentrated around the hands and feet.

Dystonia and myoclonus

Dystonia describes painful and involuntary contractions leading to abnormal and repetitive movements. Myoclonus is described by involuntary muscle jerks. These symptoms are extremely common in MJD cases with dystonia often being severe.¹⁴

Speech and swallowing difficulties

The lack of control over muscles can cause slurred speech, known as dysarthria, and difficulty in swallowing, which is known as dysphagia^.15 Dysarthia is recognised as an early sign of MJD and can progressively lead to anarthria, which is complete loss of speech. Furthermore, dysphagia can lead to a risk of aspiration. This is when food or liquid enters the lungs,¹⁶ which could further lead to aspiration pneumonia, an infection caused by anything other than air being inhaled into your lungs. These difficulties are a common cause of death for people with MJD.¹⁷

Cognitive and non-motor symptoms 

Cognitive impairment

MJD negatively impacts memory and the ability to perceive and understand visual information.¹⁸ This happens if the frontal subcortical system in the brain is damaged.^19,20 However, cognitive impairment could also be due to poor learning ability.²¹

Psychiatric manifestations

Some people may develop psychosis; however, this is only seen in the older population who developed the disease later in life.²² Apart from psychosis, depressive symptoms are also common.²³ 

Sleep disturbances

Research has revealed that MJD can also cause sleep disturbances such as:²⁴

• Daytime sleepiness
• Insomnia
• Sleep apnea 
• Rapid eye movements 
• Restless leg syndrome 

Symptom progression and variability 

It is possible that some symptoms are present in some people and not others and this can depend on multiple factors such as:²⁵ 

Age of onset and severity

• Earlier onset equals faster progression
• Developing MJD at an earlier age manifests symptoms that are more severe and will get severe progressively
• Those who develop MJD earlier on in life have more severe symptoms and may have shorter life expectancy
• Research has demonstrated that the average age for the symptom being developed is 36 years, and those who develop the disease after the age of 21 are more likely to survive²⁶

Variability among individuals

• The disease varies among individuals based on genetics. 
• The severity will depend on the number of repeats of the mutation. More the number of repeats, the earlier the disease will develop (making it type 1 or 2)²⁷ 
• Lastly, depending on whether an individual develops type 1, 2 or 3 MJD will affect the symptoms one experiences

Treatment 

Currently there is no cure for MJD. However, there is specific medication that can help with the individual symptoms for example:²⁸ 

• Antispasmodic drugs are used to treat spasticity as it relaxes muscles.
• Botulinum toxin is also used for spasticity and dystonia (should be used carefully as it has a lot of side effects) 
• Levodopa can be used for those who have Parkinson's features such as tremor
  • This drug is used to create dopamine in the brain, a hormone that those with parkinsonism lack 
  • It is also said that the benefits may be limited

Different types of therapies may also be useful:

• Physiotherapy may help deal with ataxia symptoms such as walking 
• Occupational therapy may further be helpful in easing ataxia symptoms²⁹ 

FAQs

Does ataxia get worse with age?

Ataxia can tend to disappear with age, but, as MJD varies among individuals it can sometimes get worse with age. 

Does cerebellar ataxia cause spasticity?

They tend to coexist, however, it is much more rare.^30,31 

How is spastic antaxia diagnosed?

A neurological exam, neuroimaging (MRI) and genetic tests³² are done. 

Summary 

MJD has a lot of variability depending on multiple factors which means that the severity of the disease can vary. Depending on the age of onset of symptoms and the number of repetitions of genetic mutations, the severity varies. There are 3 different types of MJD, i.e., type 1, type 2 and type 3. Type 2 predominantly shows the symptoms of ataxia and spasticity. The two core neurological symptoms of MJD are ataxia and oculomotor abnormalities. Spasticity often develops due to the pyramidal tract being damaged. Other neurological manifestations include parkinsonian features, peripheral neuropathy, dystonia, myoclonus, speech and swallowing difficulties. There is also a possibility for other cognitive problems to develop such as problems with memory and complications with learning due to the other side effects. Additionally, individuals with MJD also tend to have poor mental health as well as difficulty sleeping. Unfortunately, there is no cure for MJD but there are different medications to target symptoms along with different therapies for support.