Machado–Joseph disease

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Machado-Joseph disease
Classification and external resources
Specialty neurology
ICD-10 G11.1
ICD-9-CM 334.2
OMIM 109150
DiseasesDB 31961
MeSH D017827

Machado–Joseph disease (MJD), also known as Machado–Joseph Azorean disease or Joseph's disease or Spinocerebellar ataxia type 3 (SCA3), is a rare autosomal, dominantly inherited neurodegenerative disease that causes progressive cerebellar ataxia,[1] [2]which results in a lack of muscle control and coordination of the upper and lower extremities.[3] The symptoms are caused by a genetic mutation that results in an expansion of abnormal "CAG" trinucleotide repeats in the ATXN3 gene [1] that results in an abnormal form of the protein ataxin which causes degeneration of cells in the hindbrain.[3] Some symptoms, such as clumsiness and rigidity, make MJD commonly mistaken for drunkenness and/or Parkinson's disease.

Machado–Joseph disease is a type of spinocerebellar ataxia and is the most common cause of autosomal-dominant ataxia.[1] MJD causes ophthalmoplegia and mixed sensory and cerebellar ataxia.


The disease was first identified in 1972.[4]

Unlike many other medical conditions, Machado–Joseph disease isn't named after researchers. It is named after two men ("William Machado" and "Antone Joseph") who were the patriarchs of the families in which the condition was initially described.[5] The above families are of Azorean descent, an ethnic group in which the disease is most prevalent. The highest prevalence of the condition is on the Azorean island of Flores where around 1 in 140 individuals in the population are diagnosed with MJD.[6]


Symptoms of MJD are memory deficits,[7] spasticity, difficulty with speech and swallowing, weakness in arms and legs, clumsiness, frequent urination and involuntary eye movements. Symptoms can begin in early adolescence and they get worse over time. Eventually, MJD leads to paralysis; however, intellectual functions usually remain the same.


There is no cure for Machado-Joseph Disease. However, treatments are available for some symptoms.[1][3] For example, spasticity can be reduced with antispasmodic drugs, such as baclofen. The Parkinsonian symptoms can be treated with levodopa therapy. Prism glasses can reduce diplopic symptoms.[3] Physiotherapy/Physical Therapy and/or occupational therapy can help patients by prescribing mobility aids to increase the patients' independence, providing gait training, and prescribing exercises to maintain the mobility of various joints and general health to decrease the likelihood of falls or injuries as a result of falls. Walkers and wheelchairs can greatly help the patient with everyday tasks. Some patients will experience difficulties with speech and swallowing, therefore a Speech-Language Pathologist can assist the patients to improve their communicating abilities and their issues with swallowing.[3]


Life expectancy ranges with people who have the disease. A normal life expectancy is expected in patients with a mild form of MJD.[3] Those with severe forms of MJD are expected to live only to their mid-thirties.[3] The cause of death of those who die early is often aspiration pneumonia.[3]


The disease is caused by a mutation in the ATXN3 gene, which is located on chromosome 14q. The gene contains lengthy irregular repetitions of the code "CAG", producing a mutated protein called ataxin-3. (Normally, the number of copies is between 13 and 41.)[8] MJD is an autosomal dominant disease, meaning that if either parent gives the defective gene to a child, the child will show symptoms of the disease. Therefore, if one parent suffers from this disease and the other parent does not, there will be a 50% chance of their child inheriting the disease.[3]

The pons (a structure located on the brain stem) is one of the areas affected by MJD. The striatum (a brain area connected to balance and movement) is also affected by this disease, which could explain both of the main motor problems cause by MJD: the tightening and twisting of the limb and the abrupt, irregular movements.[9]

In affected cells, this protein builds up and assembles intranuclear inclusion bodies. These insoluble aggregates are hypothesized to interfere with the normal activity of the nucleus and induce the cell to degenerate and die.[citation needed]


There are five sub-types of MJD [1] that are characterized by the age of onset and range of symptoms. The sub-types illustrate a wide variety of symptoms that patients can experience.[1] However, assigning individuals to a specific sub-type of the disease is of limited clinical significance.[1]

  • Type I is distinguished by arrival between the ages of 10 and 30 and represents approximately 13% of individuals.[1] It usually has fast development and severe rigidity and dystonia.
  • Type II is the most common sub-type (approximately 57% of individuals with MJD [1]) and typically begins between 20 and 50 years of age . It has an intermediate progression and causes symptoms that include spasticity, exaggerated reflex responses and spastic gait, ataxia [1] and upper motor neuron signs.[1]
  • Type III MJD has a slow progression. Patients typically have an onset between the ages of 40 and 70 and represent approximately 30% of MJD patients.[1] Symptoms include muscle twitching, tingling, cramps, unpleasant sensations such as numbness, pain in the feet, hands and limbs and muscle atrophy. Nearly all patients experience a decline in their vision such as blurred vision, double vision, inability to control eye movements, and loss of capability to distinguish color. Some patients also experience Parkinsonian symptoms.
  • Type V appears to resemble Hereditary Spastic Paraplegia; however, more research is needed to conclude the relationship between Type V MJD and hereditary spastic paraplegia.[1]


MJD can be diagnosed by recognizing the symptoms of the disease and by taking a family history. Physicians ask patients questions about the kind of symptoms relatives with the disease had, the progression and harshness of symptoms, and the ages of onset in family members.

Presymptomatic diagnosis of MJD can be made with a genetic test.[10] The direct detection of the genetic mutation responsible for MJD has been available since 1995.[11] Genetic testing looks at the number of CAG repeats within the coding region of the MJD/ATXN3 gene on chromosome 14. The test will show positive for MJD if this region contains 61-87 repeats, as opposed to the 12-44 repeats found in healthy individuals. A limitation to this test is that if the number of CAG repeats in an individual being tested falls between the healthy and pathogenic ranges (45-60 repeats), then the test cannot predict whether an individual will have MJD symptoms.[10]

Notable cases[edit]

Brazilian comedian, actor and TV personality Guilherme Karan was diagnosed with Machado–Joseph disease.[12]

Ethical Consideration[edit]

Ethicists have used Machado–Joseph disease as a paradigmatic illness to discuss the rights of a community of patients to control "ownership" of their disease, particularly when it comes to research on genetic testing.[13] Also, as there currently is no clinical intervention to prevent the onset of the disease symptoms, there is discourse over whether individuals should get tested or not.[11] The benefits of having MJD testing include a reduction in anxiety and uncertainty, and the ability to plan for the future. Some disadvantages include the anticipation of negative results and the individual's difficulties in adapting to this outcome.

For an ethnographic case study exploring some of the social and ethical consequences of living with Machado–Joseph disease, see João Biehl's Vita: Life in a Zone of Social Abandonment (Berkeley: University of California Press, 2006).


  1. ^ a b c d e f g h i j k l m n Paulson, H. (2011, March 8). Spinocerebellar Ataxia Type 3. In R. A. Pagon, T. D. Bird, C. R. Dolan, & K. Stephens (Eds.), GeneReviews. Seattle, WA: University of Washington. Retrieved from
  2. ^ Bettencourt, Conceição; Lima, Manuela (2011). "Machado-Joseph Disease: from first descriptions to new perspectives". Orphanet Journal of Rare Diseases 6: 35. doi:10.1186/1750-1172-6-35. PMID 21635785. Retrieved 12 April 2015. 
  3. ^ a b c d e f g h i Machado-Joseph Disease Fact Sheet. 11 December 2007. National Institute of Neurological Disorder & Stroke. 24 Mar. 2008 <>
  4. ^ Nakano KK, Dawson DM, Spence A (1972). "Machado disease. A hereditary ataxia in Portuguese emigrants to Massachusetts". Neurology 22 (1): 49–55. doi:10.1212/wnl.22.1.49. PMID 5061839. 
  5. ^ "SCA-3 - Ataxia Center in the Medical School at the University of Minnesota". 
  6. ^ "Machado-Joseph Disease Fact Sheet". Retrieved 2011-05-09. 
  7. ^ Kawai Y, Takeda A, Abe Y, Washimi Y, Tanaka F, Sobue G (November 2004). "Cognitive impairments in Machado-Joseph disease". Arch. Neurol. 61 (11): 1757–60. doi:10.1001/archneur.61.11.1757. PMID 15534186. 
  8. ^ Lima M, Costa MC, Montiel R, et al. (2005). "Population genetics of wild-type CAG repeats in the Machado-Joseph disease gene in Portugal". Hum. Hered. 60 (3): 156–63. doi:10.1159/000090035. PMID 16340213. 
  9. ^
  10. ^ a b Maciel P, Costa MC, Ferro A, et al. (November 2001). "Improvement in the molecular diagnosis of Machado-Joseph disease". Arch. Neurol. 58 (11): 1821–7. doi:10.1001/archneur.58.11.1821. PMID 11708990. 
  11. ^ a b Rolim, L., Zagalo-Cardoso, J.A., Paul, C., Sequeiros, J., & Fleming, M. (2006). The perceived advantages and disadvantages of presymptomatic testing for Machado-Joseph Disease: development of a new self-response inventory. Journal of Genetic Counseling,15(5):375-391.
  12. ^ [1]
  13. ^ Appel J, Friedman JH (January 2004). "Genetic markers and the majority's right not to know". Mov. Disord. 19 (1): 113–4. doi:10.1002/mds.20014. PMID 14743372. 

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