Machado–Joseph disease (MJD), also known as Machado–Joseph Azorean disease, Machado's disease, Joseph's disease or spinocerebellar ataxia type 3 (SCA3), is a rare autosomal dominantly inherited neurodegenerative disease that causes progressive cerebellar ataxia, which results in a lack of muscle control and coordination of the upper and lower extremities. The symptoms are caused by a genetic mutation that results in an expansion of abnormal "CAG" trinucleotide repeats in the ATXN3 gene that results in an abnormal form of the protein ataxin which causes degeneration of cells in the hindbrain. Some symptoms, such as clumsiness and rigidity, make MJD commonly mistaken for drunkenness or Parkinson's disease. Machado–Joseph disease is a type of spinocerebellar ataxia and is the most common cause of autosomal-dominant ataxia. MJD causes ophthalmoplegia and mixed sensory and cerebellar ataxia.
Symptoms and signs Symptoms of MJD are memory deficits, 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.
Genetics Flores and São Miguel are centers of the Machado–Joseph disease in the Azores. Machado Joseph's disease has multiple origins as SCA3 comes from haplotype of four different origins and was not from one origin in the Azores. Japan, Brazil and France all have been founder effects in areas with SCA3. Spinocerebellar ataxia type 3 (SCA3) on the Azores are believed to have come from Portugal's northeast where Sephardic Jews lived. Belgium, French-Guiana and Algeria have their own MJD mutation origins. Portuguese have two mutations, while Brazil and France have one mutation, and Germans make up the majority of MJD patients in the United States. Individuals with Azorean MJD have their locus on the 14q24.3–32 chromosome, the same as some Japanese with MJD. It was an Azorean, William Machado, whose offspring in New England were the first to be diagnosed with MJD. The Azorean Joseph family, living in California, were also diagnosed with MJD. The same origin for MJD is found in the Azores and in America's north-west coast. Not only Portuguese have it since African Americans, Indians, Italians and Japanese also developed MJD. In China, the mutation causing SCA type 3 has been estimated to have occurred 8,000 to 17,000 years ago. In Japan, the oldest causative mutation appears to have occurred about 5774 +/- 1116 years ago. Among aboriginal Australians, the founder mutation appears to have occurred about 7000 years ago. As this mutation is shared with other families based in Asia it seems likely that it was imported into Australia. MJD affected Azoreans and Japanese had haplotypes in common while Azoreans also had haplotypes of two different origins.
Pathophysiology The disease is caused by a mutation in the ATXN3 gene, which is located on chromosome 14 (14q32.1). In exon 10 the gene contains lengthy irregular CAG repeats, producing a mutated protein called ataxin-3. (Normally, the number of copies is between 13 and 41.) 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 has this condition and the other parent does not, there will be a 50% chance of their child inheriting the condition. The pons in the brainstem 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. 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.
Diagnosis 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. The direct detection of the genetic mutation responsible for MJD has been available since 1995. 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.
Classification There are five sub-types of MJD 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. However, assigning individuals to a specific sub-type of the disease is of limited clinical significance.
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