Machado Joseph disease

Machado Joseph disease

Machado Joseph disease also called spinocerebellar ataxia type 3, is an inherited movement disorder. People with Machado Joseph disease initially experience problems with coordination and balance (ataxia). Other early signs and symptoms of Machado Joseph disease include speech difficulties, uncontrolled muscle tensing (dystonia), muscle stiffness (spasticity), rigidity, tremors, bulging eyes, and double vision. People with Machado Joseph disease may experience sleep disorders such as restless leg syndrome or REM sleep behavior disorder. Restless leg syndrome is a condition characterized by numbness or tingling in the legs accompanied by an urge to move the legs to stop the sensations. REM sleep behavior disorder is a condition in which the muscles are active during the dream (REM) stage of sleep, so an affected person often acts out his or her dreams. These sleep disorders tend to leave affected individuals feeling tired during the day.

Over time, individuals with Machado Joseph disease may develop loss of sensation and weakness in the limbs (peripheral neuropathy), muscle cramps, muscle twitches (fasciculations), and swallowing difficulties. Individuals with Machado Joseph disease may have problems with memory, planning, and problem solving.

Three forms of Machado-Joseph Disease are recognized: Machado Joseph disease type 1, Machado Joseph disease type 2, and Machado Joseph disease type 3. The differences in the types of Machado Joseph disease relate to the age of onset and severity. Earlier onset usually produces more severe symptoms.

Signs and symptoms of Machado Joseph disease typically begin in mid-adulthood but can appear anytime from childhood to late adulthood. People with Machado Joseph disease eventually require wheelchair assistance. They usually survive 10 to 20 years after symptoms first appear.

On a worldwide basis, Machado Joseph disease or spinocerebellar ataxia type 3 appears to be the most prevalent autosomal dominant inherited form of ataxia. The prevalence of Machado Joseph disease is unknown. Machado Joseph disease is thought to be the most common type of spinocerebellar ataxia; however, all types of spinocerebellar ataxia are relatively rare. Machado Joseph disease appears to be more common in certain populations, such as some Aboriginal Australian populations (Top End of Australia) and individuals of Portuguese descent, especially those from the Azores, an island colonized by Portuguese people 1. For example, prevalenace estimates for the Groote Eylandt Archipelago in Australia are ~743/100 000, compared with ~39/100 000 for the Azores Archipelago in Portugal, where Machado Joseph disease is also common 2

Machado Joseph disease is caused by a mutation in the ATXN3 gene and inheritance is autosomal dominant. Machado Joseph disease is incurable, there is no medication that slows the progressive course of Machado Joseph disease; management aims to relieve some symptoms and improve quality of life 3. For those individuals who show parkinsonian features, levodopa therapy can help for many years. Treatment with antispasmodic drugs, such as baclofen, can help reduce spasticity. Botulinum toxin can also treat severe spasticity as well as some symptoms of dystonia. Speech problems and trouble swallowing can be treated with medication and speech therapy. Physiotherapy can help patients cope with disability associated with gait problems. Physical aids, such as walkers and wheelchairs, can assist with everyday activities.

Many trials are underway to find a cure for a range of spinocerebellar ataxias 4. Other research efforts have focused on physiotherapeutic interventions to address impairments and activity limitations resulting from a range of hereditary ataxias 5. These interventions have been shown to enhance mobility and potentially delay symptom progression 6. For people with Machado Joseph disease, current recommended physiotherapeutic interventions are based on findings from studies on other spinocerebellar ataxias 7.

Machado Joseph disease life expectancy ranges from the mid-30s for those with the most severe forms, to a nearly normal life expectancy for those with milder forms 8.

What are the different types of Machado-Joseph disease?

All persons with Machado Joseph disease have the same disease gene mutation: a DNA repeat expansion in the ATXN3 gene. The wide range in symptoms among affected individuals led researchers to separate Machado Joseph disease into distinct types that are broadly distinguished by age of onset and range of symptoms.

  • Type 1 Machado Joseph disease is characterized by onset between about 10 and 30 years of age, with faster progression and more dystonia and rigidity than ataxia.
  • Type 2 Machado Joseph disease, the most common type of Machado Joseph disease, generally begins between the ages of about 20 and 50 years, has an intermediate rate of progression, and causes various symptoms, including prominent ataxia, spastic gait, and enhanced reflex responses.
  • Individuals affected by type 3 Machado Joseph disease have the latest onset of disease (beginning between approximately 40 and 70 years of age) which progresses relatively slowly and is characterized as much by peripheral neuromuscular involvement (muscle twitching, weakness, atrophy, and abnormal sensations such as numbness, tingling, cramps, and pain in the hands and feet) as by ataxia.

Most individuals with Machado Joseph disease, but especially those with types 1 and 2, experience one or more problems with vision, including double vision or blurred vision, loss of ability to distinguish color and/or contrast, and inability to control eye movements. Some individuals also experience prominent Parkinson’s disease-like symptoms, such as slowness of movement, rigidity or stiffness of the limbs and trunk, and tremor or trembling in the hands.

Machado Joseph disease causes

Mutations in the ATXN3 gene cause Machado Joseph disease. Machado Joseph disease 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 Machado Joseph disease, the code sequence “CAG” (Cytosine-Adenine-Guanine) is repeated in the ATXN3 gene, which produces the disease protein called ataxin-3, which is found in cells throughout the body. Ataxin-3 is involved in a mechanism called the ubiquitin-proteasome system that destroys and gets rid of excess or damaged proteins. The molecule ubiquitin is attached (bound) to unneeded proteins, which tags them to be broken down (degraded) within cells. Ataxin-3 removes the ubiquitin from these unwanted proteins just before they are degraded so that the ubiquitin can be used again. Researchers believe that ataxin-3 also may be involved in regulating the first stage of protein production (transcription). Ataxin-3 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.

The ATXN3 gene mutations that cause Machado Joseph disease involve a DNA segment known as a CAG trinucleotide repeat (sometimes called triplets). This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG (Cytosine-Adenine-Guanine) segment is repeated 12 to 43 times within the gene. Most people have fewer than 31 CAG repeats. In people with Machado Joseph disease, the CAG segment is repeated more than 50 times. People who have 44 to 52 CAG repeats are described as having an “intermediate repeat.” These individuals may or may not develop Machado Joseph disease. People with 75 or fewer repeats tend to first experience signs and symptoms of Machado Joseph disease in mid-adulthood, while people with around 80 repeats usually have signs and symptoms by their teens.

An increase in the length of the CAG segment leads to the production of an abnormally long version of the ataxin-3 enzyme that folds into the wrong 3-dimensional shape. This nonfunctional ataxin-3 enzyme cannot remove ubiquitin from proteins that are no longer needed. As a result, these unwanted proteins, along with ubiquitin and ataxin-3, cluster together to form clumps (aggregates) within the nucleus of the cells. It is unclear how these aggregates affect cell function, because they are found in healthy cells as well as those that die.

Nerve cells (neurons) and other types of brain cells are most affected by mutations in the ATXN3 gene. Machado Joseph disease is associated with cell death in the part of the brain that is connected to the spinal cord (the brainstem), the part of the brain involved in coordinating movements (the cerebellum), and other areas of the brain. This condition is also associated with the death of neurons in the spinal cord. Over time, the loss of cells in the brain and spinal cord cause the signs and symptoms characteristic of Machado Joseph disease.

One unusual feature of Machado Joseph disease 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.

Machado Joseph disease inheritance pattern

Machado Joseph disease is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.

Often autosomal dominant conditions can be seen in multiple generations within the family. If one looks back through their family history they notice their mother, grandfather, aunt/uncle, etc., all had the same condition. In cases where the autosomal dominant condition does run in the family, the chance for an affected person to have a child with the same condition is 50% regardless of whether it is a boy or a girl. These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

  • When one parent has the abnormal gene, they will pass on either their normal gene or their abnormal gene to their child. Each of their children therefore has a 50% (1 in 2) chance of inheriting the changed gene and being affected by the condition.
  • There is also a 50% (1 in 2) chance that a child will inherit the normal copy of the gene. If this happens the child will not be affected by the disorder and cannot pass it on to any of his or her children.

Figure 1 illustrates autosomal dominant inheritance. The example below shows what happens when dad has the condition, but the chances of having a child with the condition would be the same if mom had the condition.

As the altered ATXN3 gene is passed down from one generation to the next, the length of the CAG trinucleotide repeat often increases. A larger number of repeats is usually associated with an earlier onset and faster progression of signs and symptoms. This phenomenon is called anticipation. Anticipation may be more prominent when the ATXN3 gene is inherited from a person’s father (paternal inheritance) than when it is inherited from a person’s mother (maternal inheritance).

In rare cases, individuals have been reported with expanded CAG repeats on both copies of the ATXN3 gene in each cell. These people tend to have more severe signs and symptoms than people with only one mutation, and features of the condition appear in childhood.

Figure 1. Machado Joseph disease autosomal dominant inheritance pattern

Machado Joseph disease autosomal dominant inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Machado Joseph disease symptoms

The symptoms of Machado Joseph disease type 1 present between the ages of 10 and 30 years and progress rapidly 9. They may include severe weakness in the arms and legs (dystonia), spasticity or muscle rigidity, (hypertonia), awkward body movements (ataxia) often involving a slow, staggering, lurching gait (athetosis) that may be mistaken for drunkenness, slurred speech and swallowing (dysarthria), and possible damage to the muscles that control eye movements (ophthalmoplegia) and bulging eyes (exophthalmia). Mental alertness and intellectual capacities are unaffected.

Machado Joseph disease-type 2 symptoms are similar to those of type 1, but the disease progresses at a slower rate 9. Onset of type 2 Machado-Joseph disease is usually between 20 and 50 years of age. The distinctive characteristic of type 2 is increased dysfunction of the cerebellum that results in an unsteady gait (ataxia) and difficulty coordinating movements of the arms and legs, as well as spastic muscle movements.

Machado Joseph disease-type 3 presents later in life, between years 40 and 70, and is characterized by an unsteady gait (ataxia) and is distinguished from the other forms of this disease by loss of muscle mass (amyotrophy) due to inflammation and degeneration of the peripheral nerves (motor polyneuropathy). Loss of feeling, lack of sensitivity to pain, abnormal sensations, impaired ability to coordinate movement of the arms and legs, and diabetes are also common. The progression of Machado Joseph disease-type 3 is slowest of the three types.

A number of the symptoms, and their appearance in combination, resemble the symptoms of other neurologic disorders such as Parkinson’s disease or multiple sclerosis. A proper diagnosis is therefore difficult and should be the responsibility of an experienced neurologist.

Machado Joseph disease diagnosis

Physicians diagnose Machado Joseph disease by recognizing the symptoms of the disease and by taking a family history. They ask detailed questions about family members who show (or showed) symptoms of the disease, the kinds of symptoms seen in these relatives, the age(s) of disease onset, and the progression and severity of symptoms.

A definitive diagnosis of Machado Joseph disease can be made only with a genetic test. The genetic test for Machado Joseph disease (spinocerebellar ataxia type 3) is highly accurate. The gold standard of diagnostic tests that detects 100% of the cases is the direct determination of the number of suspect CAG triplets in a patient’s DNA. This may be readily done at a specialized genetic clinical laboratory. Those individuals who are at risk for Machado Joseph disease (i.e. have an affected parent) but do not have any symptoms can undergo presymptomatic testing to determine whether they carry the disease allele (and thus will later develop the disease). Obtaining presymptomatic testing is a highly personal decision that at-risk individuals should make only after fully considering the potential pros and cons. Many at-risk persons choose not to undergo this test out of concern for job discrimination and difficulty in obtaining or maintaining insurance, among other reasons.

Machado Joseph disease treatment

Machado Joseph disease is incurable, but some symptoms of the disease can be treated. Levodopa (L- dopa) therapy (used in treating individuals with Parkinson’s disease) can ease parkinsonian features (stiffness and slowness of movements, often accompanied by a tremor) for many years. Antispasmodic drugs, such as baclofen, can help reduce spasticity. Botulinum toxin can treat severe spasticity and some symptoms of dystonia, but it should be used as a last resort due to possible side effects, such as swallowing problems (dysphagia). Speech problems (dysarthria) and dysphagia can be treated with medication and speech therapy. Wearing prism glasses can reduce blurred or double vision, but eye surgery has only short-term benefits due to the progressive degeneration of eye muscles. Physiotherapy can help individuals cope with disability associated with gait problems, and physical aids, such as walkers and wheelchairs, can assist people with everyday activities. Daytime sleepiness, a common complaint in Machado Joseph disease (as is sleep disturbance in general), can be treated with modafanil and should prompt a formal sleep evaluation. Other problems, such as cramps and urinary dysfunction, can be treated with medications and medical care.

Individuals with at least one family member who has been diagnosed with Machado Joseph disease should consider genetic counseling.

Machado Joseph disease prognosis

The severity of Machado Joseph disease is related to the age of onset, with earlier onset associated with more severe forms of the disease. Symptoms can begin any time between early adolescence and about 70 years of age. Machado Joseph disease is a progressive disease, meaning that symptoms get worse with time. Life expectancy ranges from the mid-thirties for those with severe forms of MJD to a normal life expectancy for those with mild forms. The cause of death for those who die early is often aspiration pneumonia.

  1. Ruano L, Melo C, Silva MC, et al. . The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 2014;42:174–83. 10.1159/000358801
  2. Machado Joseph disease Foundation – Disability Service Delivery Model – A review of the Machado Joseph disease Foundation’s disability service delivery model: contrast and comparison to traditional disability service models. Alyangula, Northern Territory: Machado Joseph disease Foundation, 2018.
  3. Paulson H, Shakkottai V. Spinocerebellar Ataxia Type 3. 1998 Oct 10 [Updated 2020 Jun 4]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from:
  4. Zesiewicz TA, Wilmot G, Kuo S-H, et al. . Comprehensive systematic review summary: treatment of cerebellar motor dysfunction and ataxia: report of the Guideline development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2018;90:464–71. 10.1212/WNL.0000000000005055
  5. Milne SC, Corben LA, Georgiou-Karistianis N, et al. . Rehabilitation for individuals with genetic degenerative ataxia: a systematic review. Neurorehabil Neural Repair 2017;31:609–22. 10.1177/1545968317712469
  6. Synofzik M, Ilg W. Motor training in degenerative spinocerebellar disease: ataxia-specific improvements by intensive physiotherapy and exergames. Biomed Res Int 2014;2014:583507 10.1155/2014/583507
  7. Miyai I, Ito M, Hattori N, et al. . Cerebellar ataxia rehabilitation trial in degenerative cerebellar diseases. Neurorehabil Neural Repair 2012;26:515–22. 10.1177/1545968311425918
  8. Machado-Joseph Disease Fact Sheet.
  9. Machado-Joseph Disease.
Health Jade Team

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