What is Machado–Joseph disease?

Introduction

Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a rare and hereditary neurodegenerative disorder that affects the central nervous system.¹ This condition is characterized by a progressive loss of muscle control, coordination, and balance. Named after the two families who were initially described with the disease, MJD falls under the category of spinocerebellar ataxias, a group of genetic disorders that primarily impact the cerebellum (part of the brain) and spinal cord.

The underlying cause of Machado–Joseph disease lies in a genetic mutation involving the ATXN3 gene.² This gene is responsible for producing a protein called ataxin-3, which plays a crucial role in maintaining the health and function of nerve cells. However, in individuals with MJD, there is an abnormal expansion of a specific DNA sequence within the ATXN3 gene. This sequence consists of repeating units of the nucleotides cytosine, adenine, and guanine (CAG repeats).

Machado–Joseph disease follows an autosomal dominant inheritance pattern.³ This means that an affected individual has a 50% chance of passing the mutated gene to their offspring. Each child of an affected parent has an equal chance of inheriting the mutated gene and potentially developing the disease. Due to the nature of autosomal dominant inheritance, the disease can affect multiple generations within a family.

It's important to note that the presence of the expanded CAG repeats in the ATXN3 gene is not a guarantee that an individual will develop MJD. Some individuals may have the expanded gene but remain asymptomatic, which is referred to as being a "carrier" of the mutation. The exact reasons for this variation in symptom expression are not fully understood and continue to be an area of research.

In the next section, we will delve deeper into the clinical features associated with Machado–Joseph disease, shedding light on how this genetic mutation translates into the neurological symptoms that characterize the condition.

Signs and symptoms

Machado–Joseph disease presents a wide range of clinical features that primarily affect the nervous system and progressively impact an individual's physical and functional abilities.⁴ The onset of symptoms can vary significantly, with some individuals experiencing them in early adulthood, while others might not show signs of the disease until later in life. The following symptoms can be associated with MJD:

Ataxia

Loss of coordination and control over voluntary muscle movements. This leads to unsteady gait, tremors, and difficulty with fine motor skills. As the disease progresses, individuals may find it increasingly challenging to perform everyday tasks such as walking, writing, and buttoning clothing.

Lack of coordination

The cerebellum, a region of the brain responsible for coordinating movement and maintaining balance, is heavily affected by MJD. This results in a lack of coordination, which becomes more pronounced over time. Individuals with MJD may exhibit jerky or uncontrolled movements, and they might sway or stumble while walking.

Speech and swallowing difficulty

MJD affects muscles used in speech and swallowing. Speech difficulties can include slurred speech, changes in voice pitch, and difficulty articulating words. Swallowing problems, known as dysphagia, can lead to choking, weight loss, and an increased risk of aspiration pneumonia.

Visual impairment

MJD often affects the muscles responsible for controlling eye movements. This can lead to various ocular symptoms, including double vision (diplopia), difficulty tracking objects, and involuntary eye movements (nystagmus). These eye-related issues can contribute to further difficulties with balance and coordination.

The progression and severity of Machado–Joseph disease can vary widely among affected individuals, even within the same family. Factors that influence this variability include the specific number of CAG repeats in the ATXN3 gene, as well as genetic and environmental factors that are not yet fully understood. Some individuals may experience a relatively slow progression of symptoms and a milder impact on their daily lives, while others may face a more rapid decline in motor function and quality of life.

Diagnosis

The diagnostic journey often begins with a detailed medical history review, focusing on the patient's personal and family medical histories.⁵ Information about the onset, progression, and characteristics of symptoms is collected to identify patterns consistent with MJD. A thorough neurological examination is conducted to assess motor coordination, reflexes, muscle strength, and other neurological functions.

Genetic testing is a key component of the Machado–Joseph disease diagnostic process. It involves analyzing a blood sample to determine the number of CAG repeats in the ATXN3 gene. The number of repeats is directly correlated with the likelihood of developing the disease and the severity of its symptoms. Genetic testing not only confirms the diagnosis but also aids in predicting the potential course of the disease.

Neuroimaging methods such as magnetic resonance imaging (MRI) and computed tomography (CT) scans may be used to assess changes in the brain and spinal cord. These imaging techniques help rule out other conditions and provide insight into the structural abnormalities associated with MJD. MRI scans can reveal atrophy (shrinkage) of specific brain regions, such as the cerebellum, that are commonly affected by the disease.

Machado–Joseph disease shares some clinical features with other spinocerebellar ataxias and neurodegenerative disorders, making accurate diagnosis challenging. Neurologists often need to differentiate MJD from conditions like Friedreich's ataxia, other types of spinocerebellar ataxias, and multiple system atrophy. The differentiation is crucial for selecting appropriate management strategies.

Once a diagnosis of Machado–Joseph disease is confirmed, genetic counselling becomes an important aspect of patient care. Genetic counsellors work with individuals and families to explain the inheritance pattern, the risk of passing on the mutation to offspring, and available options for family planning.

Underlying mechanisms

The development and progression of Machado–Joseph disease stem from the abnormal expansion of CAG repeats in the ATXN3 gene.⁵ The CAG repeats contribute to the dysfunction and degeneration of nerves, particularly in regions of the brain responsible for motor control and coordination.⁶

The mutated ATXN3 gene leads to the production of an abnormal protein called ataxin-3. In healthy individuals, ataxin-3 helps regulate various cellular processes, including protein quality control. However, in MJD patients, the expanded CAG repeats cause the ataxin-3 protein to aggregate abnormally within neurons. These aggregates interfere with cellular functions and disrupt neural signaling.⁷

The aggregation of mutant ataxin-3 protein is a hallmark feature of Machado–Joseph disease. These protein aggregates accumulate within nerves, particularly in brain regions such as the cerebellum and brainstem. The presence of these aggregates is thought to contribute to cellular dysfunction and lead to nerve damage and death.

The brain structures most affected by Machado–Joseph disease include the cerebellum and brainstem. The cerebellum is responsible for coordinating movement and maintaining balance, while the brainstem controls vital functions like breathing and heart rate. The damage to these structures leads to motor impairments, coordination difficulties, and other symptoms characteristic of MJD.⁷

The disruption of neural signaling and cellular processes due to the aggregation of mutant ataxin-3 protein directly affects the circuits responsible for motor control and coordination. This leads to the unsteady gait, tremors, and difficulty with fine motor skills seen in individuals with MJD. As the disease progresses and more neurons are affected, these symptoms become more pronounced.

Management and treatment

Managing Machado–Joseph's disease revolves around alleviating the symptoms and improving the quality of life for affected individuals.³ Currently, there is no cure for MJD, so treatment approaches focus on addressing specific symptoms, slowing disease progression, and providing comprehensive care. A multidisciplinary approach involving various medical professionals is essential to address the complex array of symptoms associated with MJD.

A team of healthcare providers, including neurologists, physical therapists, occupational therapists, speech therapists, and nutritionists, collaborates to develop a tailored treatment plan for each individual with MJD. Physical therapy helps maintain mobility and muscle strength, while speech therapy assists in managing communication and swallowing difficulties.

Medications may be prescribed to alleviate specific symptoms of Machado–Joseph disease. For example, medications targeting muscle stiffness and tremors, such as muscle relaxants, may provide some relief. However, these medications are often limited in their effectiveness and may not fully reverse the symptoms.

Ongoing research aims to develop targeted therapies that can address the underlying molecular mechanisms of MJD. Experimental approaches include gene silencing techniques to reduce the production of mutant ataxin-3 protein, as well as strategies to enhance cellular quality control mechanisms. While these therapies are still in the experimental stages, they hold promise for potential future treatments.

Impact on quality of life

Machado–Joseph's disease not only affects physical health but also has a profound impact on the overall quality of life for individuals with the disease and their caregivers.⁸ The progressive nature of the disorder and the wide range of symptoms contribute to various challenges that extend beyond the realm of physical health.

The motor impairments, coordination difficulties, and other symptoms of MJD can significantly limit an individual's ability to perform daily tasks and activities independently. As the disease progresses, routine tasks become increasingly challenging. This loss of independence can lead to frustration, lowered self-esteem, and reduced overall quality of life.

Living with a chronic and degenerative condition like Machado–Joseph disease can take a toll on an individual's emotional and psychological well-being.⁹ Feelings of anxiety, depression, and isolation are not uncommon, as individuals grapple with the uncertainty of the disease's progression and the limitations it imposes on their lives. Moreover, the visible physical symptoms may impact self-image and self-confidence.

The role of caregivers, often family members, is crucial in supporting individuals with Machado–Joseph disease. Caregivers provide practical assistance with daily activities, as well as emotional support. However, the demands of caregiving can also lead to caregiver burnout, as they juggle their own needs with those of their loved ones.

Support groups, counselling services, and online communities can provide a platform for individuals with MJD and their caregivers to connect, share experiences, and seek advice. These resources play a vital role in fostering a sense of community and reducing the sense of isolation often experienced by those affected by the disease.

Summary

Machado–Joseph disease, or spinocerebellar ataxia type 3, is a complex and challenging neurodegenerative disorder with a genetic basis. While there is no cure, advances in genetics and neuroscience are paving the way for potential therapeutic breakthroughs. As research progresses, the hope is that a comprehensive understanding of the disease's mechanisms will lead to effective treatments that can improve the quality of life for individuals with MJD. Additionally, ongoing support systems for patients and caregivers play a crucial role in managing the emotional and psychological aspects of the disease.