Machado-Joseph Disease
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Enfermedad de Machado-Joseph
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What is Machado-Joseph Disease?What is Machado-Joseph Disease? Machado-Joseph disease (MJD)-also called spinocerebellar ataxia type 3-is a rare hereditary ataxia. (Ataxia is a general term
meaning lack of muscle control.) The disease is characterized by clumsiness and weakness in the arms and legs, spasticity,
a staggering lurching gait easily mistaken for drunkenness, difficulty with speech and swallowing, involuntary eye movements,
double vision, and frequent urination. Some patients have dystonia (sustained muscle contractions that cause twisting of the
body and limbs, repetitive movements, abnormal postures, and/or rigidity) or symptoms similar to those of Parkinson's disease.
Others have twitching of the face or tongue, or peculiar bulging eyes.
The severity of the disease is related to the age of onset, with earlier onset associated with a more severe form of the disease.
Symptoms can begin any time between early adolescence and about 70 years of age. MJD is also 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. For those who die early from the disease, the cause of death is often aspiration
pneumonia.
The name, Machado-Joseph, comes from two families of Portuguese/Azorean descent who were among the first families described
with the unique symptoms of the disease in the 1970s. The prevalence of the disease is still highest among people of Portuguese/Azorean
descent. For immigrants of Portuguese ancestry in New England, the prevalence is around one in 4,000. The highest prevalence
in the world, about one in 140, occurs on the small Azorean island of Flores. Recently, researchers have identified MJD in
several family groups not of obvious Portuguese descent, including an African-American family from North Carolina, an Italian-American
family, and several Japanese families. On a worldwide basis, MJD is the most prevalent autosomal dominant inherited form of
ataxia, based on DNA studies.
What are the different types of Machado-Joseph Disease? The types of MJD are distinguished by the age of onset and range of symptoms. Type I is characterized by onset between 10
and 30 years of age, fast progression, and severe dystonia and rigidity. Type II MJD generally begins between the ages of
20 and 50 years, has an intermediate progression, and causes symptoms that include spasticity (continuous, uncontrollable
muscle contractions), spastic gait, and exaggerated reflex responses. Type III MJD patients have an onset between 40 and 70
years of age, a relatively slow progression, and some muscle twitching, muscle atrophy, and unpleasant sensations such as
numbness, tingling, cramps, and pain in the hands, feet, and limbs. Almost all MJD patients experience vision problems, including
double vision (diplopia) or blurred vision, loss of ability to distinguish color and/or contrast, and inability to control
eye movements. Some MJD patients also experience Parkinson's-like symptoms, such as slowness of movement, rigidity or stiffness
of the limbs and trunk, tremor or trembling in the hands, and impaired balance and coordination.
What causes Machado-Joseph Disease? MJD is classified as a disorder of movement, specifically a spinocerebellar ataxia. In these disorders, degeneration of cells
in an area of the brain called the hindbrain leads to deficits in movement. The hindbrain includes the cerebellum (a bundle
of tissue about the size of an apricot located at the back of the head), the brainstem, and the upper part of the spinal cord.
MJD is an inherited, autosomal dominant disease, meaning that if a child inherits one copy of the defective gene from either
parent, the child will develop symptoms of the disease. People with a defective gene have a 50 percent chance of passing the
mutation on to their children.
MJD belongs to a class of genetic disorders called triplet repeat diseases. The genetic mutation in triplet repeat diseases
involves the extensive abnormal repetition of three letters of the DNA genetic code. In the case of MJD the code "CAG" is
repeated within a gene located on chromosome 14q. The MJD gene produces a mutated protein called ataxin-3. This protein accumulates
in affected cells and forms intranuclear inclusion bodies, which are insoluble spheres located in the nucleus of the cell.
These spheres interfere with the normal operation of the nucleus and cause the cell to degenerate and die.
One trait of MJD and other triplet repeat diseases is a phenomenon called anticipation, in which the children of affected
parents tend to develop symptoms of the disease much earlier in life, have a faster progression of the disease, and experience
more severe symptoms. This is due to the tendency of the triplet repeat mutation to expand with the passing of genetic material
to offspring. A longer expansion is associated with an earlier age of onset and a more severe form of the disease. It is impossible
to predict precisely the course of the disease for an individual based solely on the repeat length.
How is Machado-Joseph Disease diagnosed? Physicians diagnose MJD 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 these relatives had, the ages of
disease onset, and the progression and severity of symptoms. A definitive diagnosis of MJD can only be made with a genetic
test. Unfortunately, many legal and ethical considerations, such as loss of health insurance and employment discrimination,
may discourage some individuals with symptoms from getting tested. For the same reasons, many physicians recommend against
genetic testing for those individuals who have a family history of the disease but do not show symptoms. For more information
on genetic testing and counseling, please consult the organizations listed in the section titled "Where can I get more information?"
How is Machado-Joseph Disease treated? MJD is incurable, but some symptoms of the disease can be treated. For those patients 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. However, botulinum toxin should be used as a
last resort due to the possibility of 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 patients
cope with disability associated with gait problems, and physical aids, such as walkers and wheelchairs, can assist the patient
with everyday activities. Other problems, such as sleep disturbances, cramps, and urinary dysfunction, can be treated with
medications and medical care.
What research is being done? The National Institute of Neurological Disorders and Stroke (NINDS) supports research on MJD and other neurodegenerative diseases
in an effort to learn how to better treat, prevent, and even cure these diseases. Ongoing research includes efforts to better
understand the genetic, molecular, and cellular mechanisms that underlie triplet repeat diseases. Other research areas include
the development of novel therapies to treat the symptoms of MJD, efforts to identify diagnostic markers and to improve current
diagnostic procedures for the disease, and population studies to identify affected families.
For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at:
BRAIN
P.O. Box 5801
Bethesda, MD 20824
(800) 352-9424
http://www.ninds.nih.gov
Information also is available from the following organizations:
National Ataxia Foundation (NAF) 2600 Fernbrook Lane North Suite 119 Minneapolis, MN 55447-4752 naf@ataxia.org http://www.ataxia.org Tel: 763-553-0020 Fax: 763-553-0167 |
National Organization for Rare Disorders (NORD) P.O. Box 1968 (55 Kenosia Avenue) Danbury, CT 06813-1968 orphan@rarediseases.org http://www.rarediseases.org Tel: 203-744-0100 Voice Mail 800-999-NORD (6673) Fax: 203-798-2291 |
Dystonia Medical Research Foundation 1 East Wacker Drive Suite 2430 Chicago, IL 60601-1905 dystonia@dystonia-foundation.org http://www.dystonia-foundation.org Tel: 312-755-0198 Fax: 312-803-0138 |
American Speech-Language-Hearing Association
(ASHA) 10801 Rockville Pike Rockville, MD 20852-3279 actioncenter@asha.org http://www.asha.org Tel: 800-638-8255 Fax: 301-571-0457 |
Family Caregiver Alliance/
National Center on Caregiving 180 Montgomery Street Suite 1100 San Francisco, CA 94104 info@caregiver.org http://www.caregiver.org Tel: 415-434-3388 800-445-8106 Fax: 415-434-3508 |
National Family Caregivers Association 10400 Connecticut Avenue Suite 500 Kensington, MD 20895-3944 info@thefamilycaregiver.org http://www.thefamilycaregiver.org Tel: 301-942-6430 800-896-3650 Fax: 301-942-2302 |
NIH Publication No. 02-2716
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National Institute of Neurological Disorders and Stroke
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Last updated June 03, 2008