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.
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.
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.
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?"
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.
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.
Keeping on Top of Your Condition
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BRAIN
P.O. Box 5801
Bethesda,
Maryland 20824
800-352-9424
http://www.ninds.nih.gov/
International Joseph Disease Foundation, Inc.
P.O. Box
2550
Livermore, CA 94531-2550
925-371-1288
http://www.ijdf.net/
National
Ataxia Foundation (NAF)
2600 Fernbrook Lane, Suite 119
Minneapolis, MN 55447-4752
763-553-0020
http://www.ataxia.org/
National Organization for Rare Disorders, Inc. (NORD)
55 Kenosia
Avenue
P.O. Box 1968
Danbury, CT 06813-1968
(203)
744-0100
(800) 999-6673 (voicemail only)
Fax: (203) 798-2291
http://www.rarediseases.org/
Dystonia Medical Research Foundation
1 East Wacker Drive, Suite
2430
Chicago, IL 60601-1905
312-755-0198
http://www.dystonia-foundation.org/
Worldwide
Education & Awareness for Movement Disorders (WE MOVE)
204 West
84th Street
New York, NY 10024
800-437-MOV2
(-6682)
212-875-8312
http://www.wemove.org/
National
Aphasia Association
156 Fifth Avenue, Suite 707
New York, NY 10010
212-255-4329
800-922-4NAA (-4622)
http://www.aphasia.org/
American
Speech-Language-Hearing Association (ASHA)
10801 Rockville Pike
Rockville, MD 20852-3279
301-897-5700
800-638-8255
http://www.asha.org/
Family
Caregiver Alliance
690 Market Street, Suite 600
San Francisco, CA
94104
415-434-3388
http://www.caregiver.org/
National
Family Caregivers Association
10400 Connecticut Avenue, Suite
500
Kensington, MD 20895-3944
301-942-6430
800-896-3650
http://www.nfcacares.org/
The
following organizations can provide information on genetic testing and
counseling:
National Society of Genetic Counselors, Inc.
233
Canterbury Drive
Wallingford, PA 19086-6617
610-872-7608
www.nsgc.org/GeneticCounselingYou.asp
Alliance
of Genetic Support Groups
4301 Connecticut Avenue, NW, Suite
404
Washington, DC 20008-2304
202-966-5557
800-336-GENE
(-4363)
http://www.geneticalliance.org/
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