Course:MEDG550/Student Activities/Machado-Joseph Disease

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Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia Type 3, is a rare genetic condition which causes difficulty with muscle control[1][2][3]. This difficulty gets worse over time and can start anywhere from a person’s teens to late in life depending on their genetics[2]. It is caused by a gene change in a gene called ATXN3 which makes the gene longer. Although it is rare, it is the most common of a family of diseases which doctors call inherited ataxias[1][2][3].

Clinical Features

Machado-Joseph disease causes a loss of muscle control which gets worse over time. The disease is caused by a genetic change that effects neurons[3]. Neurons are cells that carry messages from the brain to the rest of the body.

People with MJD may experience muscle stiffness, rigidity, and tremors. Most people who have the disease will not have symptoms until they are adults[2]. The most common symptoms are unsteady walking, trouble with balance, and problems with speech[2]. As the disease progresses, many patients have problems with eye and eyelid movement[2]. As the muscles around the eyes become affected, the eyes can look like they are bulging[4]. At very advanced stages of disease, people with MJD may develop difficulties with swallowing and need a wheelchair to get around[2]. Some people with MJD may have cognitive difficulties, but these are not usually severe[2][5].

Doctors have named 3 types of MJD based on the age of onset and severity of symptoms[2]. Type 1 MJD is characterized by early onset of symptoms in a person’s twenties or sooner. Type 2 MJD refers to an onset of symptoms in a person’s early to mid adult life. Type 3 MJD has the latest onset of symptoms at about 50 years of age. In general, symptoms that start earlier in life get worse than those that start later. Not every patient will fit neatly into one category.

Diagnosis

The diagnosis of Machado-Joseph disease is made by a physical exam followed by a genetic test[6]. During the exam, a doctor will check a person’s balance, eye movements, and other measures of muscle control. The doctor or a Genetic Counsellor will also take the person’s family history to see if anyone else in the family has had problems with muscle control.

If a doctor thinks that a person’s physical exam and family history suggest that they may have MJD, genetic testing may be offered. The test looks for a change in the ATXN3 gene. This is a gene that everybody has, but in some people it has acquired a change that leads to MJD. Genetic testing is needed after the physical exam because other conditions can cause similar symptoms. The genetic test involves either a blood sample or cheek swab. It is very accurate and can detect the gene change even before someone experiences symptoms.

Treatment

There is no cure for MJD, but symptoms can be managed with medication as well as physical and occupational therapy[6][7].

Exercise

Doctors have found that physical therapy can make symptoms progress more slowly[8].

Medicines

While doctors have not been able to stop the underlying cause of the disease, some symptoms respond well to medicines. Levodopa is a drug used to treat people with Parkinson's Disease, and can help people with MJD control their muscle contractions[9]. Other medicines can be used to manage muscle stiffness, dizziness, and tremors. Symptoms that do not have to do with a person's muscles, such as depression or trouble sleeping, can also be treated with medicine.

Safety and Independence

As walking and balance become more severely affected, it is important that people with MJD avoid falls. For some people, using a walker or wheelchair can be an important step to maintain independence and safety.

Prognosis

People with Machado-Joseph disease usually live 20 - 35 years after the initial onset of their symptoms.

Genetics

An analogy for a trinucleotide repeat. A) a normal sentence with the correct number of each word. B) one of the words was repeated too many times.

Machado-Joseph disease is caused by a change in the ATXN3 gene which makes the gene longer. The amount that the gene is lengthened seems to change how badly a person is affected by the disease[2]. However, doctors cannot yet predict how badly a person will be affected just by the length of the gene.

Repeat Expansion and Anticipation

Autosomal dominant inheritance. A parent with the MJD gene will have a 1 in 2 chance to pass the gene to any of their children.

All genes are made up of a sequence of molecules called nucleotides. There are 4 nucleotides, named A, C, G, and T. Nucleotides are read by cells in groups of 3, like CAG, TCG, GTA, and so on. These triplets are then read by the cell to create proteins. In the normal ATXN3 gene, there is a long stretch of many repeats of a CAG triplet[10].  Sometimes when DNA is copied before a cell divides, a sequence with a long repeat of the same triplet can gain more copies of that triplet[11]. This is called repeat expansion. Repeat expansions can lead to major changes in a gene’s sequence which changes the protein that gene makes[11].

Sometimes, the number of repeats can increase from one generation to the next[11]. This means a parent who does not have Machado-Joseph may have a child who does have the disease. This also means that a parent with a mild form of the disease can have a child with a much more severe form. This is called anticipation[11].

People with a normal ATXN3 gene have 12 to 44 CAG repeats[10]. People with 45 to 60 repeats of CAG may or may not experience symptoms of Machado-Joseph[10]. People with over 60 repeats of CAG are most likely to have symptoms[10]. While the number of repeats is often related to how bad a patient’s symptoms are, this is not always the case.

Inheritance

The disease is passed from parent to child in an autosomal dominant pattern[2][3]. This means that only one copy of the gene has to have the difference in order for a person to have the disease. Since each child gets 1 copy of each gene from each parent, a parent who has the disease will have a 50% or 1-in-2 chance to pass their disease-causing gene on to each child that they have.

If neither parent has Machado-Joseph, that does not rule out the possibility of disease in the child. The disease can look different in parents and children because the length of the CAG repeat can change from generation to generation. A parent may also have more CAG repeats in their sperm or eggs than in the rest of their cells.

Prevalence

Machado-Joseph is thought to affect about 1 to 5 of every 100,000 people worldwide[12], making it a very rare disease. The rarity and the need for genetic testing to confirm diagnosis have made it difficult for doctors to find accurate numbers. The disease is more common in certain ethnic groups such as Chinese, Portuguese, Japanese, and some indigenous Australian peoples[3][12].

Genetic Counselling

A Genetic Counsellor can help facilitate decisions around genetic testing and family planning.

Genetic Testing

Since there is no cure for MJD, some people do not want to get tested until they develop symptoms. Others do not want to get tested at all. A Genetic Counsellor can help a patient explore what they hope to get out of testing to allow them to make the decision that is right for them. If the patient wants to go ahead with testing, the Genetic Counsellor can make arrangements to have that done.

Reproduction and Family Planning

Some couples may not want to have a child with MJD. It is possible to test a baby's genetics before they are born to see if they have the gene change that causes the disease[13]. Even if it is found during pregnancy, there is no cure for MJD. Couples should meet with a Genetic Counsellor to work through the pros and cons of prenatal testing if it is offered in their country. A Genetic Counsellor can also provide information on other ways to get pregnant, like through IVF, to make it less likely that a child will have MJD.

Resources for Patients and Families

For more information on MJD and news about the latest research, please visit:

To connect with patients and families, please visit:

References

  1. 1.0 1.1 Matos, C. A., de Almeida, L. P., & Nóbrega, C. (2019). Machado–Joseph disease/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy. Journal of neurochemistry, 148(1), 8-28.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Paulson, H. (2012). Machado–Joseph disease/spinocerebellar ataxia type 3. Handbook of clinical neurology, 103, 437-449.
  3. 3.0 3.1 3.2 3.3 3.4 Bettencourt, C., & Lima, M. (2011). Machado-Joseph Disease: from first descriptions to new perspectives. Orphanet journal of rare diseases, 6(1), 1-12.
  4. Moro, A., Munhoz, R. P., Arruda, W. O., Raskin, S., & Teive, H. A. G. (2013). Clinical relevance of" bulging eyes" for the differential diagnosis of spinocerebellar ataxias. Arquivos de neuro-psiquiatria, 71, 428-430.
  5. Kawai, Y., Takeda, A., Abe, Y., Washimi, Y., Tanaka, F., & Sobue, G. (2004). Cognitive impairments in Machado-Joseph disease. Archives of neurology, 61(11), 1757-1760.
  6. 6.0 6.1 Klockgether, T., Mariotti, C., & Paulson, H. L. (2019). Spinocerebellar ataxia. Nature reviews Disease primers, 5(1), 1-21.
  7. Duarte-Silva, S., & Maciel, P. (2018). Pharmacological therapies for Machado-Joseph disease. Polyglutamine Disorders, 369-394.
  8. Milne, S. C., Corben, L. A., Georgiou-Karistianis, N., Delatycki, M. B., & Yiu, E. M. (2017). Rehabilitation for individuals with genetic degenerative ataxia: a systematic review. Neurorehabilitation and Neural Repair, 31(7), 609-622.
  9. Bettencourt, C., Santos, C., Coutinho, P., Rizzu, P., Vasconcelos, J., Kay, T., ... & Lima, M. (2011). Parkinsonian phenotype in Machado-Joseph disease (MJD/SCA3): a two-case report. BMC neurology, 11(1), 1-5.
  10. 10.0 10.1 10.2 10.3 do Carmo Costa, M., & Paulson, H. L. (2012). Toward understanding Machado–Joseph disease. Progress in neurobiology, 97(2), 239-257.
  11. 11.0 11.1 11.2 11.3 Budworth, H., & McMurray, C. T. (2013). A brief history of triplet repeat diseases. Trinucleotide Repeat Protocols, 3-17.
  12. 12.0 12.1 Li, T., Martins, S., Peng, Y., Wang, P., Hou, X., Chen, Z., ... & Jiang, H. (2019). Is the high frequency of Machado-Joseph disease in China due to new mutational origins?. Frontiers in genetics, 9, 740.
  13. Tsai, H. F., Liu, C. S., Chen, G. D., Lin, M. L., Li, C., Chen, Y. Y., ... & Hsieh, M. (2003). Prenatal diagnosis of Machado‐Joseph disease/spinocerebellar ataxia type 3 in Taiwan: Early detection of expanded ataxin‐3. Journal of clinical laboratory analysis, 17(5), 195-200.