Machado Joseph disease
by Yael Rosenberg, RN
• Incidence and Carriers
• Resources and More
• Support Group
Joseph disease is a fatal autosomal dominant genetic disorder of the nervous system that cripples and paralyzes while leaving the intellect intact. The disease is characterized by weakness in the arms and legs and a general loss of motor control that eventually confines the patient to a wheelchair.
Symptoms appear when a defective gene causes a breakdown and loss of cells in a specific areas of the brain known as the striatum, the cerebellum, and the substantia nigra, but what sets this process in motion is still unknown.
Machado Joseph disease, first documented in the 1970's, is named for Antone Joseph, a Portuguese sailor with the defective gene who came to California in 1845. The disease occurs primarily in people of Portuguese ancestry, but it has also been found in other ethnic groups, nationalities, and races.
At least two Brazilian families originated in mainland Portugal, and another one claims to descend from Portuguese Jews in Amsterdam. Another affected family migrated directly from northeastern Portugal to the United States.
Taking into account the family names and traditional professions, physical phenotype, and places of residence of the affected families in mainland Portugal and of the Bastiana (Joseph) family, it is suggested that the original MJD mutation may have arisen among the settlements of Sephardic Jews in northeastern Portugal. The Sephardic Jews, having arrived on the Iberic peninsula mainly with the Moorish invasions, later came to Portugal seeking refuge from imminent expulsion from Spain in 1492, and they settled mainly along the Spanish-Portuguese border, subject to varying periods of tolerance and repression. When forced conversion or expulsion was decreed also in Portugal in 1496, most of the Jews chose to stay and had to practice their faith in secret or assimilate. Mixed religious practices and cultures can still be found in those areas, although local Sephardic communities can no longer be well identified. Interestingly, many of the Portuguese with MJD, both in Portugal
and the United States, still bear family names traditionally attributed to the Sephardim.
Some symptoms of Joseph disease resemble those of other neurological disorders such as multiple sclerosis and Parkinson's disease. A careful diagnosis is therefore important and should be made by a physician with expertise in neurology. Symptoms of Joseph disease include:
• Weakness in the arms and legs
• Spasticity, especially in the legs
• Awkward body movements
• Staggering, lurching gait-easily mistaken for drunkenness
• Difficulty with speech and swallowing
• Involuntary eye movements
• Bulging appearance of the eyes
• Frequent urination
Joseph disease is diagnosed by identifying the typical symptoms in a family in which the disease occurs. Characteristic features include progressive difficulty in walking an speech beginning in the late teen years or in the 20's through the 50's. The gait is abnormal due to spasticity and speech is slurred because of spastic weakness in the throat muscles. The Joseph disease patient may be unable to look upward or inward, and the eyes may oscillate from side to side.
Late-onset Joseph disease, the type that begins when a patient is 70 or older, is characterized by an uncoordinated gait that may cause the patient to stumble or fall, the slurring speech, and the loss of muscle in the arms and legs.
Neurologists have classified Joseph disease into three types, depending on age at onset and characteristic symptoms. But it is uncertain whether the three types are subtypes of the same disease or three separate diseases. Because the three types have at times borne different names, the plural term Joseph diseases has been used.
The disease progresses relentlessly and death occurs from 6 to 29 years after onset.
Incidence and Carriers
Joseph disease is an autosomal dominant disorder. This means that each child of an affected parent has a 50 percent chance of inheriting the defective gene. Joseph disease does not skip generations, but people at risk who escape the disease will not pass it on to their children or future generations. People at risk must decide whether to have children without knowing for sure whether they might pass the gene on. As with any inherited disorder, Joseph disease is not contagious and cannot be "caught" by people who are not at risk.
Currently there is no cure for Machado Joseph Disease, but some symptoms of the disease can be treated. Spasticity as well as sleep disturbances can be treated with medications. Physical therapy can help patients with gait disturbances.
The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) conducts and supports research on all disorders of the nervous system, including Joseph disease. Much of this research is relevant to different aspects of Joseph disease, and may lead to treatment, a cure, and eventually prevention.
NINVDS is studying normal and defective genes to understand how inherited characteristics are transmitted. With such knowledge and improved genetic engineering techniques, intervention and a cure for inherited disorders like Joseph disease might be possible.
A number of other neurological disorders share symptoms with Joseph disease, and research conducted on these disorders should benefit Joseph disease patients. NINCDS scientists are studying the degeneration of the brain's cerebellum that occurs in the ataxias. This type of degeneration produces the kind of spasticity and tremor seen in Joseph disease. NINCDS research on motor neuron diseases, including amyotorphic lateral sclerosis and spastic paraplegia, focuses on the deterioration of certain nerve cells in the spinal cord that also degenerate in Joseph disease.
Much NINCDS-supported research on Parkinson's disease is relevant to Joseph disease. The brain's substantia nigra area is under study because it deteriorates in both disorders. The development of drugs that will increase dopamine-a brain chemical missing in Parkinson's disease-may produce an effective therapy for symptoms of Joseph disease. Investigators using a special imaging technique called positron emission tomography (PET) have already produced the first pictures of dopamine at work in the living brain. Further studies with PET may increase our understanding of dopamine's possible connection to Joseph disease.
Some scientists are studying the role of enzymes in olivonpontocerebellar atrophy, a rare inherited neurological disorder similar to Joseph disease. These studies may uncover an enzyme defect that could also be responsible for Joseph disease.
Some patients with Joseph disease have high blood glucose levels and abnormal glucose tolerance test
results. Research has also shown that some patients have reduced levels of homovanillic acid (a nervous system chemical) in their spinal fluid. These abnormalities are of special interest to scientists studying Joseph disease.
The National Institute of Neurological and Communicative Discords and Stroke and the National Institute of Mental Health support two national human brain specimen banks, one at the Wadsworth Veterans Administration Hospital in Los Angeles and the other at McLean Hospital near Boston. These banks supply investigators around the world with tissue from patients with neurological and psychiatric diseases. Both banks need brain tissue from Joseph disease patients to enable scientists to study this disorder more intensely. Prospective donors would write to:
Dr. Wallace W. Tourtellotte, Director
Human Neurospecimen Bank
VA Wadsworth Medical Center
Building 212, Room 31
Los Angeles, Ca 90073
Telephone: 213-824-4307 (Call Collect)
Dr. Edward D. Bird, Director Brain Tissue Bank, Mailman Research Center McLean Hospital 115 Mill Street Belmont, Massachusetts 02178 Telephone (617) 885-2400 (Call collect 24 hours a day.)
Resources and More
International Joseph Diseases Foundation, Inc.
Executive Director: Sheri Bashor
P.O Box 994268
Redding, CA 96064
Ataxia MJD Research Project, Inc.
875 Mahler Road, Suite 161
Burlingame, CA 94010-1621
Fax: 650-259-3983 fax
For additional information concerning Joseph disease research supported by the National Institute of Neurological and Communicative Disorders and Stroke, contact:
Office of Scientific and Health Reports
National Institute of Neurological and Communicative
Disorders and Stroke
Building 31, Room 8A-06
National Institutes of Health
Bethesda, Maryland 20892
The International Joseph Diseases Foundation is a voluntary, nonprofit organization of concerned people including patients, their families and friends, and health- care professionals. The foundation provides information about the disease, supports and conducts clinical research, and helps patients find medical, social, and genetic counseling services.
International Joseph Diseases Foundation, Inc.
P.O. Box 2550
Livermore, California 94550