Introduction

Machado-Joseph Disease (MJD) is better known as Spinocerebellar Ataxia type III. Spinocerebellar ataxias are autosomal dominant inherited neurodegenerative disorders that are characterized by progressive cerebellar dysfunction and other symptoms of the central and peripheral nervous systems. Spinocerebellar Ataxia type III is typically late-onset, progressive and often fatal. Spinocerebellar Ataxia III is on of six or seven polyglutamate diseases (such as Huntington's Disease) that are caused by unstable expansions of the trinucleotide (CAG) repeat sequence found within mRNA. The result of this mutation is the disease gene product protein, ataxin-3. The role of ataxin-3 in the body is not completely understood, but it is known to be widely expressed in the neurons of the Central Nervous System. The results of extraneous amounts of ataxin-3 within the central nervous system are neuronal loss spreading throughout different structures of the body.



Anatomical Structures

The expression of the ataxin-3 genetic mutation in terms of phenotype takes many different forms. Patients' clinical presentations vary so widely that it became understood that Machado-Joseph Disease can affect a number of different anatomical structures. The main structures that are affected by Spinocerebellar Ataxia III are: The Cerebellum (dentate nucleus) the Pons, the Basal Ganglia (particularly the Substantia Nigra and the Globus Pallidus) the Thalamus, neurons of the spinal cord (anterior horn cells and Clarks' Column) the vestibular nuclei, and many of the cranial motor nuclei.

The role of the Cerebellum in movement is broken down based upon which part of the Cerebellum is being talked about. The Cerebellum can be broken down into the Anterior and Posterior lobes, the Vermis, the Intermediate an Lateral Zones, and the Flocculonodular lobe. The involvement of the cerebellum in Machado-Joseph Disease is thought to be majorly associated with the Spinocerebellum. This is largely due to the way in which the disease manifests itself clinically. People with MJD tend to have a lot of difficulty in maintaining postural balance (often degenerating past the point of any functional walking stability) and it has been found that that is the area that is responsible for it.

Similar to Huntington's Disease, MJD often is responsible for damage to the Basal Ganglia. There are two different motor pathways in the Basal Ganglia, a direct and an indirect pathwayBasal Ganglia.jpg.
  • Direct Pathway: The purpose of the direct pathway is to cause activation of intended motor programs. The Cortex releases glutamate to the Striatum (the Caudate and Putamen the striatum then responds with increased inhibition (through the use of GABA/Sub P) on the Substantia Nigra pars reticulata (SNr) and the Globus Pallidus Internus (GPi). From there the GPi and SNr would decrease their tonic inhibition (through GABA) on the thalamus, allowing for the desired motor program to be sent via the thalamus back to the cortex to produce the movement.
  • Indirect Pathway: The purpose of the indirect pathway is to cause inhibition of undesired movements during a desired motor program. The Cortex releases glutamate to the Striatum, causing it to have increased inhibition (via GABA/enk) on the Globus Pallidus Externus (GPe). With the increased inhibition the GPe lowers its tonic inhibition on the Subthalamic Nucleus (STN), which is responsible for tonic excitation of the GPi and SNr. The lowered tonic inhibition will cause an increase in the excitation of the GPi and SNr, resulting in increased inhibition (via GABA) on the thalamus, which will in turn lower its excitatory effect on the cortex (lessen undesired movements).

The selection of the neurons that become damaged during MJD is not completely understood yet, although the local of the damage can be determined by way of MRI or determination of the damage via the symptoms expressed.


Three Types of MJD

There are three types of Machado-Joseph Disease. Named after the families in which they were first discovered they are called Joseph (type 1) Thomas (type 2) and Machado (type 3).
  • Joseph (type 1)- Type 1 of MJD characteristically has an early age of onset (mean 24.3 years) of symptoms and is followed by a rapid progression of Cerebellar Ataxia, External Progressive Opthalmoplegia, and pyramidal and extrapyramidal signs (such as dystonia, dyskinesia, or akathisia).
  • Thomas (type 2)- Type 2 of MJD that tends to present at an intermediate age of onset (mean 40.5 years). It tends to show signs of Cerebellar Ataxia and External Progressive Opthalmoplegia, and can either be present with or without pyramidal signs (which, if they are present, are very slight). This type of MJD has a tendency to evolve into either type 1 or type 3 MJD depending on the eventual manifestation of the extrapyramidal and pyramidal signs.
  • Machado (type 3)- Type 3 of MJD, marked by a later age of onset (mean 46.8 years). It also presents Cerebellar Ataxia, External Progressive Opthalmoplegia, and associated with peripheral alterations with or without pyramidal and extrapyramidal signs.


Clinical Symptoms

Machado-Joseph Disease has a high variation of symptoms from patient to patient. The symptoms presented in each case being specific to what part of their nervous system had become degenerated the most.
  • Gait Ataxia- Usually one of the first symptoms that will be noticed with MJD. Most often associated with damage of the cerebellum and the pyramidal pathways.
  • Diplopia- The second most common symptom presented. This is brought on by the External Progressive Opthalmoplegia and the degeneration of the neural control of the eyes.
  • Dysarthria- Disarticulate or unclear articulation of speech that is otherwise linguistically coherent.
  • Dysphagia- Discomfort in swallowing
  • Spasticity
  • Hyperreflexia

Treatment

If an individual is diagnosed with MJD, there is a 50% chance that each of their siblings are also carriers of the disease. Not all individuals who transmit the gene actually express its symptoms (although MJD is considered to be nearly fully penetrant) and the chance that the carrier of the disease will present symptoms (express the disease) diminish as the individual gets older, all the way to about age 70 when their chance of presenting MJD (after 70 years of having no clinical signs) is approximately 0%. The following table shows the correlation between age and likely-hood of expression of MJD symptoms.

Age-Dependant Risk of Asymptomatic MJD.png
At age 70 the percent probability of detecting whether or not an individual carries the MJD gene is 100% (it increases with age). Also the Percent chance of remaining asymptomatic with MJD increases the older the individual gets.
Treatment of MJD has been looked at in a number of different ways. There are currently no adequate pharmalogical treatments for MJD itself, but there are a number of drugs that have been tested and found to improve the symptoms and expression of MJD. Following is a list of drugs that have been tested and the symptoms to which they provide alleviation.
  • Sulfamethoxazole/ Trimethoprim: Lessens spasticity during gait and has mild improvements of hyperreflexia of the knee.
  • Taltirelin Hydrate: Ataxic speech.
  • Tandospirone: Reduction of ataxia and depression levels, and alleviates insomnia and leg pains induced by MJD.
  • Lamotrigine (LTG): Has been found as having a possibility of alteration of the expression of ataxin-3 and by that to relieve the gait disturbances caused by MJD
*(Note that the study dealing with the effects of Lamotrigine was a small study carried out over a short period of time, meaning that its validity would require much more research).Physiotherapy also helps with patients with MJD but aiding them in gait problems through practice. Physical aids such as walkers and wheelchairs are major tools that help people's mobility when there becomes an overbearing level of neurodegeneration. Also people with MJD often take part in speech therapy, to aid with swallowing and speech problems, and occupationaly therapy as well.


Summary

The degenerative effects of Machado-Joseph Disease can be seen throughout the body, and results in extreme loss of motor control. Like Huntington's Disease, Machado-Joseph Disease is a progressive disease, meaning that with time it expresses symptoms and then slowly the individual loses the majority control over their nervous system eventually to the point of death. Machado-Joseph disease is a genetic disease that has been found to be highly related to geographical origins, with most cases presenting from the Azores Islands off the coast of Portugal. Also the disease presents with a 50% chance of inheritance from parents who either carry the symptomatic or asymptomatic for of the disease. MJD is a disease that often goes hand in hand with depression, so family counseling is a common recommendation along with the symptomatic treatments that are available.

Glossary

Akathisia: Inability to sit still (often a parkinsonian side effect)
Diplopia: Double vision
Dyskinesia: Diminished voluntary control of movements, often coupled with the presence of involuntary movements
Dystonia: Movement disorder that causes sustained muscle contractions, twisting and repetitive movements or abnormal postures
External Progressive Opthalmoplegia: Progressive loss of control of eye and eyebrow movements
Extrapyramidal signs: Signs or symptoms due to degeneration or lesions of the extrapyramidal pathway
Neurodegenerative: Loss of structure or functions of neurons
Penetrant: Ability to affect the genetic integrity of the patient
Phenotype: Physical manifestations of genetic traits
Pyramidal signs: Signs or symptoms due to degeneration or lesions of the pyramidal pathway

Test Your Knowledge

True/False
1. Machado-Joseph Disease is a genetic neurodegenerative disease, but the chances of inheriting the gene are VERY low.
2. Machado-Joseph Disease a recessive gene that causes the generation of ataxin-3.
3. The causes of Machado-Joseph Disease are sometimes difficult to diagnose because there is such a wide range of anatomical structures that can be effect by MJD.
4. The most common drug used to reverse the effects of MJD is Tandospirone.


Answers

1- F, 2- F, 3- T, 4- F

References

Bettencourt, Conceição, and Manuela Lima. "Machado-Joseph Disease: From First Descriptions to New Perspectives." National Center for Biotechnology Information. U.S. National Library of Medicine, 02 June 2011. Web. 19 Dec. 2013. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123549/>.Gilman, S. "The Spinocerebellar Ataxias." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 19 Dec. 2013. <http://www.ncbi.nlm.nih.gov/pubmed/11575863>.Rüb, U., R. I. De Vos, C. Schultz, and E. R. Brunt. "Spinocerebellar Ataxia Type 3 (Machado–Joseph Disease): Severe Destruction of the Lateral Reticular Nucleus." Oxford Journals: Brain (A Journal of Neurology). N.p., 19 Dec. 2001. Web. 19 Dec. 2013. <http://brain.oxfordjournals.org/content/125/9/2115.long>.