Machado-Joseph Disease (Spinocerebellar Ataxia Type 3)

Clinically Relevant Anatomy

Machado- Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is the most common spinocerebellar ataxia worldwide.^[1] MJD can have widespread symptoms due to the the many anatomical structures that can be affected. These structures include:

• Cerebellum (dentate nucleus)^[1]
• Basal ganglia (substantia nigra and globus pallidus)^[1]
• Midbrain^[1]
• Pons^[1]
• Thalamus^[1]
• Spinal cord (anterior horn and Clarke’s Column)^[2]
• Cranial nerves^[2]
• Peripheral nerves^[1]

Of the aforementioned structures the common finding is degeneration. For example, the encephalon has decreased mass, the cerebellum, pons, medulla oblongata are atrophied and there is loss of neuronal cell bodies in the dentate nucleus, substantia nigra and anterior horn of the spinal cord.^[1]

Mechanism of Injury / Pathological Process

MJD is an autosomal dominant inherited disease. This means that a parent who has MJD has a 50% chance of passing down the affected allele to their offspring. Due to the fact that MJD presents its inheritance in a dominant pattern, there cannot be any recessive carriers of the disease. If a person has the affected allele they will always show the symptoms of the disease.^[3] A unique feature of MJD and most repeat genetic diseases is called ‘anticipation’. Anticipation is observed when children show an increased progression of the disease with earlier and worse symptoms than their parents. This is thought to occur due to increased repeats of the mutation when passed down from generation to generation.^[3]

The affected gene in MJD is named ATXN3. A long and abnormal repeat of the “CAG” code is what causes the disease and the reason for the mutated protein called ataxin-3. This mutation causes the protein to fold abnormally which forms clumps called inclusion bodies in the nucleus of affected central and peripheral nerve cells.^[3] The ataxin-3 is found in both neural and non-neural tissue throughout the body and is thought to help with protein quality control pathways. The exact mechanism of the toxic effects of the mutated protein ataxin-3 is presently unknown and the repeated CAG code only partially explains the effects of MJD.^[4]

Clinical Presentation

Diagnostic Procedures

Molecular testing for the MJD mutation must be performed to confirm diagnosis.^[15] A physiotherapist may refer patient to a doctor when suspecting MJD with observation of symptoms indicating progressive ataxia and pyramidal signs.

Genetic testing revealing CAG repeats are indicative of MJD diagnosis.^[1] The number of these repeats correlates with severity of the disease; increasing number of repeats corresponds with increased reflexes and mortality rate, and vise versa with decreased number of repeats.^[12] Type 3 MJD is specifically characterized by fasciculations.^[6] Health care practitioners must be cautious to rule out amyotrophic lateral sclerolsis (ALS), as the involvement of motor neurons causes the two conditions to present similarly.^[1]

Upon autopsy, the following findings may be present; encephalon of decreased mass, pale-coloured substantia nigra, atrophied cerebellum, medulla oblongata and pons, as well as a decreased number of neuron bodies in the dentate nucleus, substantia nigra and anterior horn of the spinal cord.^[1]

Outcome Measures

In order to assess the severity of MJD several scales specific to ataxia can be used. The International Cooperative Ataxia Rating Scale (CARS) and Scale for the Assessment of Rating of Ataxia (SARA) have been shown to be both reliable and effective when used with MJD. (Zhou et al, 2011).

• SARA
• CARS

Common assessment measures that are not specific to MJD but may be useful outcome measures for core symptoms include:

• Berg Balance Scale (BBS),
• Romberg Test
• Ashworth Scale
• Tardieu Scale/Modified Tardieu Scale
• Functional Independence Measure (FIM)
• 6 Minute Walk Test
• Time Up and Go (TUG)
• Psychological General Well-being (PGWB) Index

Differential Diagnosis

The clinical presentation of MJD can often appear like other neurodegenerative diseases that affect movement, the most common differential diagnoses are:

• Parkinson’s Disease
• Multiple Sclerosis (MS)
• Amyotropic Lateral Sclerosis (ALS)
  

References

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