Machado-Joseph Disease

Machado-Joseph Disease

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Machado-Joseph Disease is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Autosomal Dominant Spinocerebellar Degeneration
  • Azorean Neurologic Disease
  • Machado Disease
  • Joseph Disease
  • MJD
  • Nigrospinodentatal Degeneration
  • Striatonigral Degeneration, Autosomal Dominant Type
  • Spinocerebellar Ataxia Type III (SCA 3)

Disorder Subdivisions

  • Machado-Joseph Disease Type I (MJD-I)
  • Machado-Joseph Disease Type II (MJD-II)
  • Machado-Joseph Disease Type III (MJD-III)

General Discussion

Machado-Joseph Disease (MJD-III), also called spinocerebellar ataxia type III, is a rare, inherited, ataxia (lack of muscular control) affecting the central nervous system and characterized by the slow degeneration of particular areas of the brain called the hindbrain. Patients with MJD may eventually become crippled and/or paralyzed but their intellect remains intact. The onset of symptoms of MJD varies from early teens to late adulthood.



Three forms of Machado-Joseph Disease are recognized: Types MJD-I, MJD-II, and MJD-III. The differences in the types of MJD relate to the age of onset and severity. Earlier onset usually produces more severe symptoms.

Symptoms

The symptoms of MJD Type I present between the ages of 10 and 30 years and progress rapidly. 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.



MJD-Type II symptoms are similar to those of Type I, but the disease progresses at a slower rate. Onset of Type II disease is usually between 20 and 50 years of age. The distinctive characteristic of Type II 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.



MJD-Type III 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 Type III disease 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.

Causes

The gene responsible for MJD has been identified and mapped to Gene Map Locus; 14q24.3-q31. This gene is associated with an abnormal number of CAG trinucleotide repeats (sometimes called triplets) in the DNA. (CAG refers to the Cytosine-Adenine-Guanine trinucleotide structure.) "Normal" DNA usually has between 12 and 43 copies of the CAG trinucleotide. In persons with the disease, the DNA contains from 56-86 copies of this trinucleotide. Severity of symptoms and age of onset are related directly to the number of the repeats. Thus, MJD-I will have fewer of these triplets while MJD-III will have the greater number. The number of the CAG triplets found in the DNA of patients with MJD-II lies between the two extremes.



MJD is inherited as an autosomal dominant trait. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 11p13" refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.



Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Affected Populations

MJD is a rare inherited neurological disorder that disproportionately affects individuals of Portuguese descent, especially those from the Azores, an island colonized by Portuguese people. MJD appears to affect slightly more males than females.

Standard Therapies

Diagnosis

While a family history and physical examination help in the diagnosis, 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.



Treatment

Treatment is symptomatic and supportive. The drugs L- dopa and baclofen may relieve muscle rigidity and spasticity. Individuals with at least one family member who has been diagnosed with this disease should consider genetic counseling.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Chang T, Pearl PL. Machado-Joseph Disease. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:555.



Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1472.



Adams RD, Victor M, Ropper AA. Eds. Principles of Neurology. 6th ed. McGraw-Hill Companies. New York, NY; 1997:1087.



REVIEW ARTICLES

Cummings CJ, Zoghbi HY. Trinucleotide repeats: mechanisms and pathophysiology. Annu Rev Genomics Hum Genet. 2000;1:281-328.



Evidente VG, Gwinn-Hardy KA, Caviness JN, et al. Hereditary ataxias. Myo Clin Proc. 2000;75:475-90.



Koeppen AH. The hereditary ataxias. J Neuropathol Exp Neurol. 1998;57:531-43.



JOURNAL ARTICLES

Subramony SH, Hernandez D, Adams A, et al. Ethnic differences in the expression of neurodegenerative disease: Machado-Joseph disease in Africans and Caucasians. Mov Disord. 2002;17:1068-71.



Garcia Ruiz PJ, Mayo D, Hernandez J, et al. Movement disorders in hereditary ataxias. J Neurol Sci. 2002;15:59-64.



Munoz E, Rey MJ, Mila M, et al. Intranuclear inclusions, neuronal loss and CAG mosaicism in two patients with Machado-Joseph disease. J Neurol Sci. 2002;15:19-25.



Lee Y, Oh MR, Kim CH, et al. A simple method for the detection of neurologic disorders associated with CAG repeat expansion using PCR-microtiter plate hybridization. J Biotechnol. 2002;95:215-23.



Isozaki E, Naito R, Kanda T, et al. Different mechanisms for vocal cord paralysis between spinocerebellar ataxia (SCA-1 and SCA-3) and multiple system atrophy. J Neurol Sci. 2002;197:37-43.



Fukutake T, Shinotoh H, Nishino H, et al. Homozygous Machado-Joseph disease presenting as REM sleep behaviour disorder and prominent psychiatric symptoms. Eur J Neurol. 2002;9:97-100.



Maciel P, Costa MC, Ferro A, et al. Improvement in the molecular diagnosis of Machado-Joseph Disease. Arch Neurol. 2001;58:1821-27.



van Alfen M, Simke RJ, Zwarts MJ, et al. Intermediate CAG repeat lengths (53, 54) for MJD/SCA3 are associated with an abnormal phenotype. Ann Neurol. 2001;49:805-07.



FROM THE INTERNET

McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry Number; 109150: Last Edit Date; 12/26/2002.



McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry Number; 607047: Last Edit Date; 12/16/2002.



Subramony SH, McDaniel DO, Smith SC, et al. Spinocerebellar Ataxia Type 3. GENEReviews. Last Update; 24 May 2001:12 pp.

www.geneclinics.org/servlet/access?id8888891&key=ou2



GPnotebook. spinocerebellar ataxia type 3. nd. 3pp.

www.gpnotebook.co.uk/cache/-294977481.htm



Trinucleotide Repeat Disorders. Part 6: Polyglutamine Diseases. Last modified: 9-13-02. 2pp.

www.stanford.edu/group/hopes/rltdsci/trinuc/f6.html



Machado/Joseph's Disease Information. nd. 4pp.

www.lusaweb.com/machado.htm

Resources

WE MOVE (Worldwide Education and Awareness for Movement Disorders)

5731 Mosholu Avenue

Bronx, NY 10471

USA

Tel: (347)843-6132

Fax: (718)601-5112

Email: wemove@wemove.org

Internet: http://www.wemove.org



National Ataxia Foundation

2600 Fernbrook Lane Suite 119

Minneapolis, MN 55447

USA

Tel: (763)553-0020

Fax: (763)553-0167

Email: naf@ataxia.org

Internet: http://www.ataxia.org



International Joseph Disease Foundation, Inc.

P.O. Box 994268

Redding, CA 96099

USA

Tel: (530)246-4722

Fax: (530)232-2773

Email: mjd@ijdf.net



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Canadian Association for Familial Ataxias - Claude St-Jean Foundation

3800 Radisson Street Office 110

Montreal

Quebec, H1M 1X6

Canada

Tel: 5143218684

Tel: 8553218684

Email: ataxie@lacaf.org

Internet: http://www.lacaf.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



For a Complete Report

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