HISTORY AND EPIDEMMIOLOGY
Machado-Joseph disease was first described in North America among immigrants from the Portugese Azores. Many of the New England families trace their ancestry to the isle of San Miguel, where the prevalence (1:4000) is roughly that observed among the Azorean population in Massachusetts. A similiar illness was described by Rosenberg et al in California in descendants of Atone Joseph, from the island of Flores. The prevalence of the disease is highest in Flores. In other parts of the weorld Machado-Joseph disease has been recognized with increaseing frequency. It is among the commonest of the inherited ataxias in Japan, and families with MJD have been found in Brazil, China , India, Isreal. MJD has even been found among the aboriginal natives of Australia. The mutation most likely originated in mainland Portugal and was concewntrated in the Azores in the 15th and 16th century. We believe it was disseminated along Portuguese ruotes of trade, coming to new England in the 19th century with the whaling business.
CLINICAL PRESENTATION
Machado-Joseph disease is a dominently-inherited disorder with a wide range of clinical expression. In general terms, all patients with MJD have an affected parent. Each of their siblings and children has a %50 chance of developing the disorder, and is considered "at risk". The mean age of onset is 35 in the New England families, but the range(10-64) includes patients with onset into the seventh decade. There appears to be a relation between the clinical ppresentation, the age of onset, and the rate of progression.
Progressive incoordination (Ataxia) is the most consistant manifestation. Balance is impaired and stumbling is an early and typical feature. Other associated features include slurred speech (dyarthria) and abnormal eye movements. In some of the affected patients lid retraction produces a characteristic staring expression. Some experience double vision.
There is a great deal of variability in other features of the illness. Some patients have a great deal of muscular rigidity, stiffness, and abnormal postures (dystonia). Such individuals are said to have type I MJD. They usually experience onset of symptoms before age 25. For others, the illness begins later in life and is associated with muscle atrophy and sensory loss in the legs, with depressed reflexes. This is known as type III MJD. In the late stages of the illness, many affected patients experience wieght loss and sleep disturbance. The has been complete preservation of intelectulal function in all patiens.
PATHOLOGY
Machado-Joseph disease is classified as one of the spinocerebeller degenerations. Carefum autopsy studies involving the central nervouse system have been done on more then twenty patients. The main finding is cell loss in the brain stem asnd spinal tracts which communicate with the cerebellum. The cerebeller cortical cells appear nurmal, but the input and output connections are compromised, resulting in ataxia and impaired balance The cerebral cortex is normal, but some cell loss has been found in the substantia nigra, which can couse Parkinson's likke rigidity. Peripheral nerves are abnormal in some of the late onset patients with muscle atrophy and sensory loss.
GENETICS
In 1994, the mutation responsibe for MJD was identified at chromosime 14q32.1. An expannded CAG repeat in the DNA code was identified on the affected part of chromosome 14. Patients with MJD have 68-79 repeats at this site, compared with 13-36 repeats in the normal copy of chromosome 14. There is an inverse correlation between repeat lenght and age of onset. Patients with more repeats tend to have a more severe illness with an earlier onset, though the numbers are not predictive for the course of illness in an individual. Knowledge of th mutation reponsible for MJD is an excititng development, as new insights about disease mechanism and treatment may be forthcoming. With methods now available, it is possible to examine DNA from a blood sample to determine whether an individual carries the MJD mutation.
In 1993 another dominantly inherited ataxia was reported in several large European families with no connection to Portugal or the Azores. Linkage studies place the locus for SCA-3 on chromosome 14 in the same area where MJD has been mapped. Genetic studies in two families suggest that the mutation is the same for SCA-3 as MJD. SCA-3/MJD may be among the commonest of the inherited ataxias worldwide. Further studies are required to define wether the illness in these families can be traced back to a single founder, or whether there are several independant mutations at this site.
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