What are the early diagnostic criteria for Machado-Joseph disease (MJD) in a patient presenting with balance (ataxia) and other neurological symptoms?

From the Guidelines

Early diagnosis of Machado-Joseph disease (MJD) relies primarily on genetic testing for the CAG trinucleotide repeat expansion in the ATXN3 gene, which should be performed as soon as subtle neurological symptoms appear, such as balance problems, coordination difficulties, or abnormal eye movements, as stated in the study 1. To diagnose MJD, the following steps can be taken:

• Genetic testing for the CAG trinucleotide repeat expansion in the ATXN3 gene, which involves a simple blood sample that detects the abnormal expansion of CAG repeats, with individuals having more than 52 repeats typically developing the disease 1.
• Clinical evaluation by a neurologist, including assessment of gait, coordination tests, eye movement examination, and evaluation for muscle stiffness or weakness.
• Brain MRI may show atrophy of the cerebellum and brainstem in affected individuals, though these changes often appear after symptoms begin, and MRI of the entire brain without and with IV contrast is the preferred modality for initial assessment for a mass, any process that may result in edema and enhancement, and neurodegenerative disorders, as mentioned in the study 1. It is essential to note that early diagnosis is crucial because while there is no cure for MJD, early intervention with physical therapy, occupational therapy, and speech therapy can help manage symptoms and maintain quality of life for longer periods. The study 1 highlights the importance of MRI in the diagnosis of ataxia, stating that MRI offers much better visualization compared to CT, especially for the posterior fossa, and is especially preferred if the cerebellar finding is subtle. In the context of MJD, it is vital to prioritize genetic testing and clinical evaluation, as these are the most effective methods for early diagnosis and management of the disease, as supported by the study 1.

From the Research

Early Diagnosis of Machado Joseph Disease

To early diagnose Machado Joseph disease, several factors need to be considered:

• The disease is caused by an expansion of an unstable CAG tract in exon 10 of the ATXN3 gene, located at 14q32.1 2.
• The size of the CAG tract correlates with the range and severity of the clinical manifestations and inversely correlates with age of disease onset 3.
• Genetic tests are available for MJD, and Genetic Counseling Programs have been created to better assist the affected families 2.
• The clinical variability of MJD is only partially explained by the size of the CAG tract, leaving a residual variance that should be explained by still unknown additional factors 2, 3.

Diagnostic Approaches

Some diagnostic approaches include:

• Analyzing the size of the (CAG)n tract in genomic DNA (gDNA) and mRNA 4.
• Sequencing the 5' regulatory regions of the ATXN3 gene to identify potential variations that may influence expression levels 5.
• Recognizing the non-motor symptoms observed in patients, such as pain, cramps, fatigue, and depression 3.

Current Limitations

Currently, there are no disease-modifying treatments available for MJD/SCA3, and the standard of care includes genetic counseling, exercise/physical therapy programs, and speech and swallow evaluation 3, 6. Recent therapeutic prospects, such as DNA-targeted and RNA-targeted therapies, are being developed and show promise for future effective treatments 6.