Machado-Joseph disease

Definition

Machado-Joseph disease (MJD), also known as spin-ocerebellar ataxia Type 3 (SCA 3), is a rare hereditary disorder affecting the central nervous system , especially the areas responsible for movement coordination of limbs, facial muscles, and eyes. The disease involves the slow and progressive degeneration of brain areas involved in motor coordination, such as the cerebellar, extrapyramidal, pyramidal, and motor areas. Ultimately, MJD leads to paralysis or a crippling condition, although intellectual functions usually remain normal. Other names of MJD are Portuguese-Azorean disease, Joseph disease, Azorean disease.

Description

Machado-Joseph disease was first described in 1972 among the descendants of Portuguese-Azorean immigrants to the United States, including the family of William Machado. In spite of differences in symptoms and degrees of neurological degeneration and movement impairment among the affected individuals, it was suggested by investigators that in at least four studied families the same gene mutation was present. In early 1976, investigators went to the Azores Archipelago to study an existing neurodegenerative disease in the islands of Flores and São Miguel. In a group of 15 families, they found 40 people with neurological disorders with a variety of different symptoms among the affected individuals.

Another research team in 1976 reported an inherited neurological disorder of the motor system in Portuguese families, which they named Joseph disease. During the same year, the two groups of scientists both published independent evidence suggesting that the same disease was the primary cause for the variety of symptoms observed. When additional reports from other countries and ethnic groups were associated with the same inherited disorder, it was initially thought that Portuguese-Azorean sailors had been the probable disseminators of MJD to other populations around the world during the sixteenth century period of Portuguese colonial explorations and commerce. Presently, MJD is found in Brazil, United States, Portugal, Macau, Finland, Canada, Mexico, Israel, Syria, Turkey, Angola, India, United Kingdom, Australia, Japan, and China. Because MJD continues to be diagnosed in a variety of countries and ethnic groups, there are current doubts about its exclusive Portuguese-Azorean origin.

Causes and symptoms

The gene responsible for MJD appears at chromosome 14, and the first symptoms usually appear in early adolescence. Dystonia (spasticity or involuntary and repetitive movements) or gait ataxia is usually the initial symptoms in children. Gait ataxia is characterized by unstable walk and standing, which slowly progresses with the appearance of some of the other symptoms, such as hand dysmetria, involuntary eye movements, loss of hand and superior limbs coordination, and facial dystonia (abnormal muscle tone). Another characteristic of MJD is clinical anticipation, which means that in most families the onset of the disease occurs progressively earlier from one generation to the next. Among members of the same family, some patients may show a predominance of muscle tone disorders, others may present loss of coordination, some may have bulging eyes, and yet another sibling may be free of symptoms during his/her entire life. In the late stages of MJD, some people may experience delirium or dementia .

According to the affected brain area, MJD is classified as Type I, with extrapyramidal insufficiency; Type II, with cerebellar, pyramidal, and extrapyramidal insufficiency; and Type III, with cerebellar insufficiency. Extrapyramidal tracts are networks of uncrossed motor nerve fibers that function as relays between the motor areas and corresponding areas of the brain. The pyramidal tract consists of groups of crossed nerves located in the white matter of the spinal cord that conduct motor impulses originated in the opposite area of the brain to the arms and legs. Pyramidal tract nerves regulate both voluntary and reflex muscle movements. However, as the disease progresses, both motor systems tracks will eventually suffer degeneration.

Diagnosis

Diagnosis depends mainly on the clinical history of the family. Genetic screening for the specific mutation that causes MJD can be useful in cases of persons at risk or when the family history is not known or a person has symptoms that raise suspicion of MJD. Initial diagnosis may be difficult, as people present symptoms easily mistaken for other neurological disorders such as Parkinson and Huntington diseases , or even multiple sclerosis .

Treatment

Although there is no cure for Machado-Joseph disease, some symptoms can be relieved, The medication Levodopa or L-dopa often succeeds in lessening muscle rigidity and tremors , and is often given in conjunction with the drug Carbidopa. However, as the disease progresses and the number of neurons decreases, this palliative (given for comfort) treatment becomes less effective. Antispasmodic drugs such as baclofen are also prescribed to reduce spasticity. Dysarthria , or difficulty to speak, and dysphagia, difficulty to swallow, can be treated with proper medication and speech therapy. Physical therapy can help patients with unsteady gait, and walkers and wheelchairs may be needed as the disease progresses. Other symptoms also require palliative treatment, such as muscle cramps, urinary disorders, and sleep problems.

Clinical Trials

Further basic research is needed before clinical trials become a possibility for MJD. Ongoing genetic and molecular research on the mechanisms involved in the genetic mutations responsible for the disease will eventually yield enough data to provide for future development and design of experimental gene therapies and drugs specific to treat those with MJD.

Prognosis

The frequency with which such genetic mutations trigger the clinical onset of disease is known as penetrance. Machado-Joseph disease presents a 94.5% penetrance, which means that 94.5% of the mutation carriers will develop the symptoms during their lives, and less than 5% will remain free of symptoms. Because the intensity and range of symptoms are highly variable among the affected individuals, it is difficult to determine the prognosis for a given individual. As MJD progresses slowly, most patients survive until middle age or older.

Resources

BOOKS

Fenichel, Gerald M. Clinical Pediatric Neurology: A Signs and Symptoms Approach, 4th ed. Philadelphia: W. B. Saunders Company, 2001.

OTHER

National Institute of Neurological Disorders and Stroke. Machado-Joseph Disease Fact Sheet. May 5, 2003 (June 7, 2004). <http://www.ninds.nih.gov/health_and_medical/pubs/machado-joseph.htm>.

ORGANIZATIONS

Dystonia Medical Research Foundation. 1 East Wacker Drive, Suite 2430, Chicago, IL 60601-1905. (312) 755-0198; Fax: (312) 803-0138. [email protected]. <http://www.dystonia-foundation.org>.

International Machado-Joseph Disease Foundation, Inc. P.O. Box 994268, Redding, CA 96099-4268. (530) 246-4722. [email protected]. <http://www.ijdf.net>.

National Ataxia Foundation (NAF). 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447-4752. (763) 553-0020; Fax: (763) 553-0167. [email protected]. <http://www.ataxia.org>.

National Organization for Rare Disorders (NORD). P.O. Box 1968 (55 Kenosia Avenue), Danbury, CT 06813-1968. (203) 744-0100 or (800) 999-NORD (6673); Fax: (203) 798-2291. [email protected]. <http://www.rarediseases.org>.

Worldwide Education & Awareness for Movement Disorders (WE MOVE). 204 West 84th Street, New York, NY 10024. (212) 875-8312 or (800) 437-MOV2 (6682); Fax: (212) 875-8389. [email protected]. <http://www.wemove.org>.

Sandra Galeotti