What are the causes of Machado Joseph Disease?

By  ,  National Institute of Health
Jan 06, 2013

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MJD is classified as one of many dominantly inherited ataxias, specifically the spinocerebellar ataxias or SCAs.  In the SCAs, of which nearly 30 separate genetic causes have been identified, degeneration of cells in the hindbrain leads to impaired coordination of movement.  The hindbrain includes the cerebellum (a large bundle of brain tissue resembling a bun located at the back of the head), the brain stem, and the upper part of the spinal cord.  MJD is inherited in an autosomal dominant pattern, meaning that an affected person has a single disease-causing MJD allele (an allele is half of a pair of genes located at the same position on a person’s chromosomes) and a normal MJD allele, and can pass on either allele to the next generation.  Any child of an affected parent has a 50 percent chance of inheriting the disease allele. 


If the child inherits the disease-causing gene, he or she will eventually develop symptoms of the disease.  A child who does not inherit the disease allele will not develop the disease and cannot pass it on to the next generation.


MJD belongs to a class of genetic disorders called expanded repeat diseases.  Mutations in expanded repeat diseases are abnormally long repeats of a normal repetition of three letters of the DNA genetic code.  In the case of MJD, the code sequence “CAG” is repeated in the ATXN3 gene, which produces the disease protein called ataxin-3.  This protein, when mutated, is prone to fold abnormally and accumulate in affected brain cells.  The accumulated ataxin-3 protein forms abnormal clumps known as inclusion bodies, which are located in the nucleus of the cell.  While the clumps themselves may not be toxic to brain cells, they do reflect a problem in protein folding that likely affects normal properties of the ataxin-3 protein.


One unusual feature of MJD and many other expanded repeat diseases is a phenomenon called anticipation.  Anticipation is the remarkable fact that children of affected parents tend to develop symptoms of the disease earlier in life and may experience more severe symptoms.  This is due to the tendency for the expanded repeat mutation to further expand when being passed to the next generation, especially when passed from the father.  Because longer expansions tend to cause earlier and more severe disease, this molecular growth from one generation to the next likewise causes, on average, an earlier age of onset in subsequent generations.  Though longer repeats tend to cause earlier onset disease, it is impossible to predict precisely the time and course of the disease for an individual based solely on the repeat length.


On a worldwide basis, MJD or SCA3 appears to be the most prevalent autosomal dominant inherited form of ataxia.



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