Introduction

Have you ever wondered why someone who was once steady on their feet would suddenly begin to stumble, slurring with speech, or feeling weak, even at a young age? 

Often being interpreted as stress, fatigue, or clumsiness, they can also sometimes be the earliest signs of a rare, genetic brain disorder, Machado-Joseph Disease (MJD), also Spinocerebellar Ataxia Type 3 (SCA3). 

MJD is a subtype of ataxia that progressively affects voluntary movement and muscle control, resulting in the gradual loss of balance and coordination. Though uncommon, symptoms may start subtly, like tripping over flat ground, struggling to follow moving objects with the eyes, or unexplained muscle stiffness. As progressiveness can bring profound impact not only on the affected individual but also across families, the general public, by recognising these earliest warning signs, can make a meaningful difference through timely intervention. 

This article aims to explore the clinical presentation of MJD, with a focus on early symptoms that may be overlooked and misinterpreted. Though varying across the affected, understanding the early warning signs can help individuals and families to proactively initiate medical care and support on time for slower functional decline and better quality of life. 

What is machado-joseph disease? 

Machado-Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an inherited, ataxic neurodegenerative disorder. It is caused by the ATX3 gene mutation in abnormally repeated CAG DNA sequencing, resulting in faulty protein production that gradually damages nerve cells (neurons). With lesions covering various parts of the central nervous system (CNS), particularly the cerebellum, brainstem, basal ganglia, and even the upper spinal cord, causing wide-spreading effects on voluntary movement and coordination.^1,2

Being a subtype of spinocerebellar ataxia (SCA), MJD typically follows an autosomal dominant pattern of inheritance; a child with a faulty gene carrier parent will have a 50% chance of contracting the disease. 

Despite its clear genetic cause, the age of onset can still be highly variable, ranging from 10-70, most typically between 20-50, with diverse severity and progression speed according to further MJD I, II, III.

While MJD is most commonly seen, 1 in every 140 people of Azorean or Portuguese descent, on the island of Flores in the Azores. It can still affect any ethnic group.  

Early clinical symptoms

Movement and coordination issues 

Balancing problem or gait abnormalities

One of the earliest and most noticeable signs of MJD is difficulty with balance. While people may begin to find themselves uncertain when walking, stumbling or tripping on flat ground, in need of holding onto walls, furniture, or railings for support. They may start walking with a wider stance with swaying, often being described as an ataxic, staggering or lurching gait, to compensate for the instability of extra body balance and postural stability. 

Daily tasks like climbing stairs, walking in crowded areas, and even standing still for long periods/ with eyes closed, become more and more challenging. 

This unsteadiness is caused by progressive damage to the cerebellum, a part of the brain for voluntary movement coordination. Despite being easily underestimated as clumsiness, fatigue, or even stress. The loss of balance becomes more obvious and persistent, affecting even the balance for the seated position, unable to stably hold the head and trunk up.³

Clumsiness with fine motor tasks 

Another early sign of MJD is the increasing clumsiness with fine motor movements. While fine motor tasks like buttoning a shirt, writing, or picking up tiny objects (e.g., coins) may suddenly become largely time and energy-consuming, needing extra concentration. Individuals may describe their hands as “less cooperative” and dropping objects more often than before. 

Fine motor disability is the typical impairment of communication between various brain areas and muscles, especially changes to the cerebellum and motor pathway (corticospinal tract). The automation and sequencing of all necessary gestures in arriving at a goal become disrupted, making handwriting a huge struggle from the start of picking up a pencil to the alignment of words on a sheet of paper.³

Despite seemingly minor symptoms, being underestimated as tiredness, “clumsy”, or stress, these also signify the precursor of more critical coordinating dysfunctions like those for speech and swallowing in the context of MJD. 

Muscle and motor symptoms 

Muscle stiffness or spasticity

Some people with MJD may experience muscle stiffness and spasticity in the early stage. Caused by disrupted signals at the motor pathway between the brain and spinal cord (corticospinal tract), leading to increased muscle tone (hypertonia), which is more significant in the legs. Movements may feel rigid, with resistance to motion, making walking awkward and effortful, either for taking on a step or for proper balance.  

Notwithstanding the potential of being mistaken for overexertion or poor posture, it may further spread to the hands in impairing dexterity, and bulbar muscles in the lead of spastic/hypertonic speech (dysarthria) and swallowing difficulties (dysphagia).^3,4

Muscle cramps 

Unexplained muscle cramps can be associated with spasticity in early MJD. These contractions are often sudden and painful, particularly in the legs and feet. Resulted from nerve and muscle dysfunctions of the disease in effect of motor control, they are more frequent, severe, and persistent enough to wake individuals at night or interrupt daily activities, compared to those occasional ones in the healthy population.^3,4

Tremors or involuntary movements 

Some people with MJD can have tremors and involuntary movements at the early stage. These may appear as shaky hands when sustaining a posture (postural) or approaching a target (intention), at rest like subtle head nodding, when standing (orthostatism), or jerky in arms and legs like Parkinson’s disease (PD). Involuntary movements like dystonia and muscle twitches (fasciculations) may also arise from degeneration of the cerebellum and extrapyramidal system.^2,5,6

They notably interfere with daily tasks like eating, writing, use of utensils, and self-care that often cause frustration. 

Speech and swallowing changes 

Speech difficulties

Individuals may notice subtle changes in their speech during the early phase of MJD. Speech difficulties (dysarthria) in MJD are mainly articulation, tonality, and delivery instabilities. While people may find themselves having difficulty pronouncing words or sounding drunk, with variable pitch and loudness due to poor oral muscle coordination that affects breathing and sound resonance.^3,7,8

Conversations can become more tiring and difficult to understand over time, especially in noisy environments. 

Swallowing difficulties 

Swallowing difficulties (dysphagia) may become more noticeable. As muscles involved in swallowing are coordinating less efficiently over time, one may start choking on liquids, cough during meals, or have an incomplete swallow, with food stuck in the throat. 

Despite the intermittent occurrence of being identified as eating too fast, stress, or normal ageing at first, malnutrition or even aspiration pneumonia may occur.^3,9

Breathing difficulties 

Although breathing difficulties are less common in the early stage, some people may experience them secondary to impaired swallowing from aspiration pneumonia, central respiratory insufficiency, diaphragm weakness, and mucus retention from poor coughing. 

This can manifest as breathlessness, shallow and laboured breathing when lying flat (orthopnea) or during sleep, plus recurrent respiratory infections.^3,10,11

Eye movement abnormalities 

Difficulty controlling eye movements, blurred or double vision

Struggling to control eye movement that comes and goes can be an early ocular sign in MJD. While people may have rhythmic, shaky eye movements (nystagmus), blurred or double vision (diplopia) can be induced, making the trace of moving objects and saccades (gaze shifting) increasingly difficult, in lead to dizziness, further impairing balance and coordination, whilst heightening the risk of fall.³

Other non-motor early signs 

Fatigue 

Fatigue that is disproportionate to activities is a common early sign of MJD. While individuals may feel drained after simple tasks, they need long rest periods. This is unlike ordinary tiredness, in which the brain becomes unable to coordinate movement and muscle control that impact daily routines and independence.^12,13

Mild cognitive and mood changes

Some people with MJD may notice subtle cognitive and mood changes. As concentration may slip, memory feels less sharp, or decision-making becomes slower. Mood shifts like anxiety, irritability, and low motivation may also emerge. Yet, often being overlooked as stress.¹⁴

Challenges in recognising early symptoms 

Identifying early MJD signs can be taxing due to the subtle, intermittent emergence that often overlaps with other conditions. Some key challenges are:  

Normalisation and overlapping of symptoms

Individuals may dismiss the subtle, early signs of MJD, like stumbling, clumsiness, and fatigue, as stress, normal ageing, or even simply lack of sleep. The universality of symptoms may also be misattributed to various conditions like eye strains, arthritis, Parkinson’s disease, or Multiple Sclerosis (MS). 

Gradual progression 

While symptoms generally start minor, intermittent, and develop slowly over many years, it can be hard to notice until it becomes obvious and significantly impacts daily functioning and independence. 

Variability between individuals 

Early signs of MJD can be highly individual, with symptomatic and severity variations, even in the same family, inducing confusion. 

Discuss variability in symptom presentation, as MJD affects individuals differently based on genetics and other factors.

Emotional denial

Individuals may avoid acknowledging the symptoms out of fear and anxiety in the future, delaying medical consultation. 

Limited awareness 

Given the rarity of MJD, both patients and medical practitioners may not suspect it right away, despite ruling out all other potential causes. 

What to do if you notice early symptoms

If you or your loved ones are experiencing early signs of MJD, such as unsteady walking, frequent tripping or falling over, visual, or subtle speech changes, it’s important not to ignore them. 

Schedule a medical appointment 

The first step is to schedule a medical evaluation with a general practitioner or neurologist.  While mentioning your family medical history, especially that of or similar to MJD, is important. A thorough neurological assessment, alongside appropriate investigations like genetic tests or neuroimaging, is expected. 

Symptom diary 

Keeping up a symptom diary, noting the frequency and severity of symptoms, can be further valuable information for doctors in progression tracking, also to evaluate the provision of therapies, emotional resources, and lifestyle adjustment guidelines. 

Summary

Machado-Joseph Disease (MJD), a subtype of spinocerebellar ataxia, is a genetic neurodegenerative disorder that worsens voluntary muscle control and coordination over time.  

While the first signs of MJD, like frequent tripping during walking, mild vision changes, occasional speech and swallowing difficulties, can easily be mistaken for stress, normal ageing, and other minor health issues.

This misattribution can delay medical help-seeking, contributing to functional decline, hence further challenges of symptom management, even the identification of other neurological conditions. This stresses the importance of early symptom recognition for symptom management. 

With continuous effort upon early symptomatic identification, timely management, ongoing research and resources provision, the affected individuals and their loved ones can still enjoy a fulfilling life despite relentless physical challenges.