Introduction

In this article, the role of the Ataxin 3 (ATXN3) gene is explored in Machado-Joseph disease (MJD), which is a type of spinocerebellar ataxia (SCA). Ataxia refers to a condition characterised by deficient muscular control, resulting in clumsy movements. Spinocerebellar is a term that defines a series of nervous pathways that extend from the spinal cord to the cerebellum (the bottom part of the brain). 

SCA causes a series of rare, genetic neurological disorders that cause loss of muscle control, coordination and balance. Machado-Joseph disease is an SCA type 3 disorder, the most common spinocerebellar ataxia subtype in the world.¹

The ATXN3 gene is located on chromosome 14, and its normal role is to produce the Ataxin 3 protein that helps remove other damaged proteins from cells.²

Studying the ATXN3 gene is crucial for understanding MJD, as it has been previously seen that a change in the structure of this gene provokes MJD/SCA3.³

In the following sections, you will learn about MJD, as well as the importance of the ATXN3 gene. Also, some of the most common symptoms are detailed, as well as the treatment and diagnosis. 

Understanding Machado-Joseph disease

Autosomal dominant inheritance

MJD is an autosomal dominant inheritance disease; in other words, a person only needs one copy of the altered gene from either parent to develop this condition. 

For example, if one parent carries the mutation, there is a 50% chance for the child to develop the condition. The person who does not inherit the gene will not develop the condition and therefore will not pass it to future generations.

Characteristics of Machado-Joseph disease

Some of the clinical features this disease presents are: progressive weakness in arms and legs, difficulty speaking and swallowing and impaired eye movements, among others. Some patients develop symptoms similar to those in Parkinson's disease. Others have issues with the autonomic nervous system, which regulates involuntary bodily functions, such as heart rate, breathing, and digestion.¹

Depending on the age of onset, there are three types of MJD and different types of progression of the disease: 

• Type I: people from 10 to 30 years of age with faster progression, more involuntary muscle contractions, and rigidity
• Type II: people from 20 to 50 years of age, an intermediate rate of progression causes symptoms such as prominent involuntary muscle stiffness and contractions and an exaggerated muscle response
• Type III: people from 40 to 70 years of age, relatively slow progress. Some of the features are: muscle twitching and weakness, cramps and pain in hands and feet¹

What are the symptoms of Machado-Joseph disease?

The most common symptoms are:

• Having difficulty walking
• Abnormal posture that is often painful and can be generalised, focal or task-specific 
• Parkinsonism
• Abnormal eye movements
• Involuntary muscle contraction, leading to repetitive movements and abnormal postures
• Muscle stiffness or tightness
• Abnormal sensations in the skin
• Some people also may experience sleeping disorders such as insomnia, sleep apnoea and daytime sleepiness
• Mood disorders
• Urinary retention
• Pain
• Other neurological issues may be slurred speech, cramps and fatigue²

Global prevalence and population

An odd fact about MJD is that the name of the disease derives from two families that reported the condition in the 70s, whose origin was Azorean; they were the Machado and Joseph families.²

Originally, it was thought that only people from the Azores Islands and Portugal were able to develop this condition. However, it has been demonstrated that it can affect any ethnic group, so the original belief is no longer considered.^2,6

The global prevalence of MJD is 1 in 40,000 individuals, with people of all genders equally affected.²

Genetic mutations in ATXN3 and disease mechanism

Genes: structure and function 

To understand the cause of this genetic disorder, firstly, it is important to introduce some of the basics in molecular biology. Inside our cells, there is a process called protein synthesis that is ongoing. Proteins are essential molecules that carry out an immense number of functions throughout the body. 

A gene is a section of DNA that stores instructions. This DNA goes through a process to make an intermediate molecule called mRNA, organised in codons. Codons are groups of three nucleotides (or “bases”) from: A: Adenine, G: Guanine, C: Cytosine, T: Thymine. Each successive codon tells the cell which amino acid to add. Finally, amino acids join together simultaneously to build a protein, a functioning molecule. 

In summary, the process is: DNA (gene) – mRNA (codons) – Amino acids – Protein.

Consequences of the ATXN3 gene mutation

The ATXN3 gene undergoes the process of protein synthesis to produce a functional protein to carry out its role in our cells. The function of the ATXN3 gene is to do protein maintenance, making sure proteins are of good quality, and to remove faulty ones. This process is called proteostasis.⁸

Under normal conditions, when proteins have the wrong structure, they are degraded (broken down). The ATXN3 gene regulates this system, ensuring proteins are recycled properly. 

The ATXN3 gene normally helps clear damaged proteins, thereby maintaining cell health. However, its mutation alters this function, leading to an accumulation of toxic, faulty proteins that cause nerve death, especially in the cerebellum and brainstem. The protein accumulation thereby causes MJD´s symptoms such as loss of coordination, muscle weakness and balance problems.

In MJD/SCA type 3, this gene is mutated due to an abnormally expanded CAG (Cytosine-Adenine-Guanine) base repeat in its DNA sequence. Because the codon CAG codes for the amino acid glutamine, the repetitions in the mutated gene are also called polyglutamine repeats.

Healthy individuals have around 12 to 42 polyglutamine repeats (CAG), while people with this disease have from 56 to 87 repeats.⁷

Diagnosis, treatment and prevention

The diagnostic approach to this disease involves a physical examination and genetic testing to determine whether the patient has the gene mutation. Also, the family history may be consulted, and if it is unknown or there is a need to study more, a brain MRI can be used as an alternative to aid diagnosis.² As it was explained before, knowing the CAG repeating length can help predict the severity of the condition.⁴

The current way to manage this disease is treating the symptoms with medication, physical therapy for movement issues and patient supportive care. At present, MJD remains incurable. 

Currently, no treatment exists to prevent this condition.⁹ However, there are several options available to prevent passing the mutation on to future generations, like testing the embryos and selecting those that do not have the mutation. Genetic counselling should be sought before considering any options in this route.

There are promising alternative treatments, such as electrical neuromuscular stimulation and gene therapies, that may slow the progression of the disease in the future. 

FAQs

What causes Machado-Joseph Disease?

MJD is caused by a mutation in the ATXN3 gene, specifically an abnormal expansion of the base repeat “CAG”. This leads to the formation of a damaged protein called Ataxin 3, which damages nerve cells.

How is MJD inherited?

MJD follows an autosomal dominant pattern, meaning the person only needs one copy of the mutated gene from a parent to develop the disease. Each child of affected parents has a 50% chance of developing the condition.

What are the main symptoms of MJD?

Symptoms include unsteady walking, involuntary movements, muscle stiffness, eye movement problems and sleep disorders. Symptoms usually worsen over time.

Is there a cure for MJD?

Currently, there is no cure for MJD. Treatment focuses on managing symptoms, like physical therapy for movement problems and medications. Research is ongoing into therapies that may slow down the disease progression. 

Summary

Machado-Joseph disease (MJD), also known as SC3, is a rare neurodegenerative disorder due to a genetic mutation in the ATXN3 gene. 

The ATXN3 gene mutation expands a multiple repetition of the DNA base pattern CAG (see above), which alters the function of the protein and results in the accumulation of toxicity in the neuronal cells, provoking neurodegeneration. 

This neurodegeneration results in a series of symptoms, including unsteady walking, loss of coordination, stiff muscles, and eye movement abnormalities. 

Although treatments currently aim to relieve symptoms, research is ongoing to provide Machado-Joseph Disease patients with promising alternative treatments, such as electrical stimulation and gene therapies, that may slow down the disease in the future.