MJD Fact Sheet

This article submitted by Dr. Lewis Sudarsky on 1/9/96.

HISTORY AND EPIDEMIOLOGY

Machado-Jospeh disease was first described in North America among immigrants
from
the Portuguese Azores. Many of the New England families trace their ancestry
to the island of
San Miguel, where the prevalence (1:4000) is roughly that observed among the
Azorean
population in Massachusetts. A similar illness was described by Rosenberg et
al in California
in descendants of Anton Joseph, from the island of Flores. The prevalence of
the disease is
highest in Flores. In other parts of the world. Machado-Joseph disease has
been recognized
with increasing frequency. It is among the commonest of the inherited
ataxias in Japan, and
families with MJD have been described in Brazil, India, China, Israel. MJD
has even been found
among aboriginal natives of Australia. The mutation most likely originated
in mainland
Portugal, and was concentrated in the Azores in the 15th and 16th century.
We believe it was
disseminated along Portuguese routes of trade, coming to New England in the
19th century with
the whaling business.

CLINICAL PRESENTATION

Machado-Joseph disease is dominantly-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
relationship between the
clinical presentation, the age of onset, and the rate of progression.
Progressive incoordination (ataxia) is the most consistent 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 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 esperience 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 weight loss and sleep
disturbance. There has been
complete preservation of intellectual function in all the patients.

PATHOLOGY

Machado-Joseph disease is classified as one of the spinocerebellar
degenerations.
Careful autopsy studies involving the central nervous system have been done
on more than
twenty patients. The main finding is cell loss in the brain stem and spinal
tracts which
communicate with the cerebellum. The cerebellar cortical cells appear
normal, but the input
and output connections are compromised, resulting in ataxia and impaired
balance. The
cerebral cortex is normal, but some cell loss is found in the substantia
nigra, which can cause
Parkinson's like rigidity. Peripheral nerves are abnormal in some of the
late onset patients
with muscle atrophy and sensory loss.

GENETICS

In 1994, the mutation responsible for MJD was identified at chromosome
14q32.1. An
expanded 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 chromosoem 14. There is an inverse correlation between repeat length
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 patient.
Knowledge of the mutation responsible for MJD is an exciting 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 apparent connection to Portugal or the Azores. Linkage
studies place the
locus for SCA-a on chromosome 14, in the same area where MJD has been
mapped. Genetic
studies in two famimlies 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 whether the illness in these famimlies can be traced back to a single
founder, or whether
there are several independent mutations at this site.

SELECTED READINGS

1. Sequieros J, Coutinho P, Epidemiology and clinical aspects of
Machado-Joseph disease, in
Harding A. Deife; T. Inherited Ataxias. Raven Press 1993.
2. Sudarsky L, Coutinho P, Machado-Joseph disease. Clinical Neuroscience
3:17-22, 19954 (the
issue is devoted to the problem of inherited ataxia, with an overview by
Rosenberg)
3. Kawaguchi Y, Okamoto T, taniwaki M, et al. CAG expansions in a novel gene
for Machado-
Joseph disease at chromosome 14q32.1 Nature Genetics 8:221-7, 1994.
4. Maciel P, Gaspar C, DeStefano A. et al. Correlation between CAG repeat
length and clinical
features in Machado-Joseph disease. American Journal of Human Genetics
57:54-61, 1995

This fact sheet was compiled and written by Dr. Lewis R. Sudarsky, MD.
Department of
Neurology, VA medical center, West Roxbury, MA. The MJD Family Network
Newsletter thanks
Dr. Sudarsky for his time and effort in producing this fact sheet.d

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