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.
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.
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.
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.
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 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.
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