[SCA3, Machado-Joseph
disease, Azorean Ataxia. Subset of Autosomal Dominant
Cerebellar Ataxia
Type I (ADCA I)]
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Last update:
1 October 98
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Summary
Disease characteristics.
SCA3 is characterized by progressive cerebellar
ataxia and variable
findings including a dystonic-rigid syndrome, a
Parkinsonian syndrome,
or a combined syndrome of dystonia and peripheral
neuropathy. Neurologic
findings tend to evolve as the disease progresses.
Diagnosis.
The diagnosis of SCA3 rests upon the use of DNA-based testing
to detect an abnormal
CAG trinucleotide repeat expansion of the SCA3 gene
on chromosome
14q21. Affected individuals have alleles with 56 to 86 CAG
trinucleotide
repeats. Such testing detects 100% of cases and is widely
available.
Genetic counseling.
SCA3 is an autosomal dominant disorder. It is
necessary to confirm
the diagnosis in an affected family member using
DNA-based testing
of the SCA3 gene to determine the size of the CAG
trinucleotide
repeat as part of genetic counseling and testing of
asymptomatic at-risk
family members. Offspring of affected individuals have
a 50% chance of
inheriting the gene mutation. Prenatal testing by direct
DNA testing is
possible for fetuses at 50% risk, but few requests have been
made for this
testing.
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Diagnosis
The diagnosis of
SCA3 rests upon the detection of a CAG trinucleotide
repeat expansion
in the SCA3/MJD1 gene (chromosomal locus 14q21) in a
patient with cerebellar
ataxia. Such testing detects 100% of cases.
Clinical Diagnosis
The diagnosis of
SCA3 is suggested [Lima & Coutinho 1980] in individuals
with the following:
*
Cerebellar ataxia and pyramidal signs (type II) associated in variable
degree with a dystonic-rigid extrapyramidal syndrome (type I) or
peripheral amyotrophy (type III)
*
Minor (but more specific) clinical signs such as progressive external
ophthalmoplegia, dystonia, action-induced facial and lingual
fasciculation-like movements, and bulging eyes
*
A family history consistent with an autosomal dominant mode of
inheritance
These findings,
however, are not specific and are shared with many other
dominantly inherited
ataxias; thus, diagnosis rests upon molecular genetic
testing.
Molecular Genetic Testing
A highly polymorphic
CAG repeat in the SCA3/MJD1 gene is unstable and is
expanded in all
individuals with SCA3/MJD. DNA-based mutation analysis of
the SCA3/MJD
CAG repeat will diagnose 100% of affected individuals. The
number of CAG
repeats ranges from 12 to 43 in normal alleles and from 56 to
86 repeats in
disease-causing alleles. The presence of one disease-causing
allele is diagnostic.
The clear separation of the range of the expanded CAG
repeats from the
range of the normal repeats avoids ambiguities in
interpreting test
results.
Table 1. Testing Used in the Molecular Diagnosis of SCA3/MJD
% of
Patients
Genetic Mechanism Test Type
Test Availability
CAG trinucleotide repeat
Clinical
100% expansion in SCA3/MJD
Direct DNA (PCR, [SCA3 testing]
gene
Southern)
Clinical Description
The age of onset
of SCA3 is variable but is usually in the second to the
fourth decade.
In a large cohort of patients reported from the Azores, the
mean age of onset
was 37 years. Presenting features include gait problems,
speech difficulties,
clumsiness, and, often, visual blurring and diplopia.
Progressive ataxia,
hyperreflexia, nystagmus, and dysarthria occur early in
the disease.
As the disease
evolves, increasing problems with ambulation occur, leading
to the need for
assistive devices including a wheelchair in 10 to 15 years
after onset. Saccadic
eye movements become slow and an ophthalmoparesis
evolves, resulting
initially in up-gaze restriction. Disconjugate eye
movements result
in diplopia. At the same time, a number of other "brain
stem" signs develop,
including temporal and facial atrophy, characteristic
action-induced
perioral twitches, tongue atrophy and fasciculations,
dysphagia, and
poor ability to cough and clear secretions. Often, a staring
appearance to
the eyes is observed, but neither this nor the perioral
fasciculations
are specific for SCA3/MJD. Upper motor neuron signs often
become prominent
during the initial phases.
Later, evidence
of a peripheral polyneuropathy appears with loss of distal
sensation, loss
of the ankle reflex and sometimes other reflexes as well,
and some degree
of muscle wasting. Late in the disease, the patients are
chairbound, have
severe dysarthria, dysphagia, facial and temporal atrophy,
poor cough, and
often dystonic posturings, ophthalmoparesis, and
occasionally blepharospasm.
Severe ataxia of limbs and gait, either with
hyperreflexia
or areflexia, associated with muscle wasting is observed.
Even sitting posture
is compromised, with the patients assuming various
tilted positions.
Death ensues from pulmonary complications and cachexia
[Sequiros &
Coutinho 1993, Sudarsky et al 1992].
Occasionally, family
members with the same gene mutation may exhibit other
clinical features
such as a dystonic-rigid syndrome, a Parkinsonian
syndrome, or a
combined syndrome of dystonia and peripheral
neuropathy.Patients
with a later adult onset often have a disorder that
combines ataxia,
generalized areflexia, and muscle wasting. Based on this
phenotypic variability,
Portuguese workers classified MJD into several
types. Type I
disease (13% of the cases) is characterized by a young age of
onset and prominent
spasticity, rigidity, and bradykinesia, often with
little ataxia.
Type II phenotype is the most common (57%) and is
characterized
by ataxia and upper motor neuron signs. Finally, type III
disease (30%)
manifests at a later age with ataxia and peripheral
polyneuropathy.
Many patients evolve from one of these types into another
[Fowler 1984].
The disease progresses
relentlessly and death occurs from 6 to 29 years
after onset.
Brain imaging studies
reveal pontocerebellar atrophy [Burk et al 1996].
Peripheral nerve
conduction studies often reveal evidence for involvement
of the sensory
nerves as well as the motor neurons. Neuropathologic studies
typically reveal
prominent loss of pontine neurons, neurons of the
substantia nigra,
anterior horn cells, and Clarke's column in the spinal
cord as well as
neurons in many cranial motor nuclei. The vestibular
nucleus is often
prominently involved. The cerebellar Purkinje cells and
inferior olivary
neurons are relatively spared compared to the other
dominantly inherited
ataxias [Sequiros & Coutinho 1993].
Genotype-Phenotype Correlations
As with other CAG
expansion disorders, an inverse relationship exists
between the age
of onset and the number of repeats in the abnormal allele,
with correlation
coefficient ranging from -0.67 to -0.92. Also, a loose
correlation appears
to exist between the repeat number and the clinical
phenotype. Patients
classified as having type I tend to have larger repeat
sizes than patients
with type II and type III SCA3. In general, patients
with type III
have later onset in adulthood and more prominent
polyneuropathy
and have 73 or fewer repeats. In the study by Sasaki et al,
patients with
type I had a mean CAG repeat size of 80, those with type II
had 76, and those
with type III had 73. Some, but perhaps not all, observed
anticipation in
age of onset can be accounted for by the intergenerational
expansion of the
repeat size. Some of the largest expansions, reported by
Zhou et al from
China, in children with onset at 11 and 5 years, had repeat
sizes of 83 and
86 [Zhou et al 1997].
The severity of
disease manifestation, although related to the age of
disease onset,
varies among families. An example is a Yemenese family in
which two groups
of patients were distinguished by the age of onset [Lerer
et al 1996]. An
obligate heterozygote died at the age of 70 having no
symptoms, and
another person with 68 repeats was asymptomatic at the age of
66. In addition,
a more severe disease has been reported in several
homozygous individuals
in this family as well as in other families.
However, many
of the homozygotes in the Yemenese family are no more
severely affected
than many heterozygotes in other families.
Prevalence
No accurate data
are available regarding the prevalence of SCA3/MJD in the
general population.
Overall, the inherited ataxias are rare. The prevalence
of inherited ataxias
and paraplegias has ranged from 4.8 to 20.2 per
100,000 [Sridharan
et al 1985, Polo et al 1991]. The proportion of SCA3
among the dominantly
inherited ataxias has been variable. About 10 to 20%
of the cases in
U.S. series have had the SCA3 mutation [Matilla et al 1995,
Ranum et al 1995],
a figure similar to the 28% prevalence among 120 French
families [Durr
et al 1996]. In the study by Silveira et al, the overall
prevalence of
SCA3 among 67 dominant ataxia families was 55%; among
Portuguese families,
it was 84% [Silveira et al 1996]. German and Japanese
series have found
MJD to account for 50% of the families [Schols et al
1996, Inoue et
al 1996]. In contrast, Filla (1996) did not detect any SCA3
gene mutations
in 36 families from southern Italy. Thus, some geographic
variation appears
to exist in the occurrence of the disease.
Differential Diagnosis
It is difficult
to distinguish SCA3 from other dominantly inherited
ataxias. The occurrence
of progressive ataxia, often associated with
evidence of upper
motor neuron dysfunction such as brisk tendon reflexes
and extensor plantar
responses, can be seen in SCA3 as well as in many
other dominantly
inherited ataxias. Some phenotypic clues to SCA3 include
the occurrence
of variant clinical features in affected members in the same
family. Thus,
the occurrence of an akinetic-rigid syndrome often responsive
to dopaminergic
agonists or cerebellar ataxia associated with significant
peripheral amyotrophy
and generalized areflexia may serve as phenotypic
clues to the presence
of the SCA3 mutation. See Ataxia Overview.
Management
Management of patients
remains supportive as there is no known therapy to
delay or halt
the progression of the disease. Tremor-controlling drugs do
not work well
for cerebellar tremors. No dietary factor has been shown to
curtail symptoms;
however, vitamin supplements are recommended,
particularly if
caloric intake is reduced. Although neither exercise nor
physical therapy
has been shown to stem the progression of incoordination
or muscle weakness,
patients should maintain activity. Canes and walkers
help prevent patients
from falling. Modification of the home with such
conveniences as
grab bars, raised toilet seats, and ramps to accommodate
motorized chairs
may be necessary. Speech therapy and communication devices
such as writing
pads and computer-based devices may benefit those with
dysarthria. Weighted
eating utensils and dressing hooks help maintain a
sense of independence.
Weight control is important because obesity can
exacerbate difficulties
with ambulation and mobility. When dysphagia
becomes troublesome,
video esophagrams can identify the consistency of food
least likely to
trigger aspiration.
Some of the manifestations
of the illness may respond dramatically to
certain drugs
for variable periods of time. This is especially true for the
extrapyramidal
syndromes resembling Parkinsonism that occur in some
patients [Subramony
et al 1993]. Other problems such as spasticity,
drooling, and
sleep problems also respond variably to appropriate agents
such as lioresal,
atropine-like drugs, and hypnotic agents.
Some studies have
suggested that drugs such as tremethoprim sulfa may have
a specific beneficial
effect, but large scale studies are needed [Sakai et
al 1995, 1998].
Genetic Counseling
Genetic counseling
is the process of providing individuals and families
with information
on the nature, inheritance, and implications of genetic
disorders to help
them make informed medical and personal decisions. This
section deals
with genetic risk assessment and the use of genetic testing
to clarify genetic
status. It is not meant to address all personal or
cultural issues
that individuals might face or to substitute for
consultation with
a genetics professional. To find a genetics or prenatal
diagnosis clinic,
see [clinic directory] . —ED.
Mode of Inheritance
SCA3 is an autosomal
dominant disorder. Offspring of affected individuals
have a 50% chance
of inheriting the gene.
Risk to Family Members
Most individuals
diagnosed as having SCA3 will have an affected parent.
Clinical and laboratory
investigation of the parents of index cases is
therefore appropriate.
Occasionally, neither parent will be identified as
having the disease
and the family history will be "negative." Family
history may be
negative because of social circumstances such as alternate
paternity or adoption,
or may appear to be negative if one of the parents
actually has the
disease-causing allele and it has not been recognized.
Reasons that the
disease-causing allele has not been identified in a parent
might include:
failure to recognize the disorder in family members, early
death of the parent
before the onset of symptoms, and late onset of the
disease in the
affected parent.
Offspring of affected
individuals have a 50% chance of inheriting the
altered SCA3 gene
at conception. Instability of the repeat has been
documented in
parent-child pairs. Overall, repeat expansion is more
frequent than
contraction and the volatility of the instability may be
greater with paternal
than with maternal inheritance. The age of onset,
severity, specific
symptoms, and progression of the disease are variable
and cannot be
predicted by the family history or molecular (DNA) testing.
For the asymptomatic
person, the probability of having the disease-causing
mutation remains
50% during childhood and young adulthood, but gradually
decreases with
increasing age.
Prenatal Testing
Before considering
prenatal testing, its availability should be confirmed.
Note: Prior testing
of family members is usually necessary. —ED.
Prenatal testing
for SCA3 is possible using the same DNA-based techniques
described in Molecular
Genetic Testing. DNA can be extracted from fetal
cells obtained
by amniocentesis or chorionic villus sampling (CVS). To
date, however,
prenatal testing for SCA3 has not been reported. Requests
for prenatal diagnosis
of (typically) adult-onset diseases are difficult
situations requiring
careful genetic counseling. A significant issue to
consider is the
continuation of pregnancies in which test results are
positive. In this
situation, the genetic status of the at-risk child is
known at a time
that is typically long before symptoms develop. The issues
related to testing
of at-risk asymptomatic children pertain.
Other Genetic Counseling Issues
Testing of at-risk
asymptomatic adults. Testing of asymptomatic adults at
risk for SCA3
is available using the same techniques described in Molecular
Genetic Testing.
This testing is not useful in predicting age of onset,
severity, type
of symptoms, or rate of progression in asymptomatic
individuals. When
testing at-risk individuals for SCA3, an affected family
member should
be tested first to confirm that the disorder in the family is
actually SCA3.
In the circumstance of testing at-risk individuals with
equivocal symptoms,
the presence of the mutation does not prove or even
imply that the
questionable symptoms are related to the presence of the
mutation.
Testing for the
disease-causing mutation in the absence of definite
symptoms of the
disease is "predictive testing" and needs to be approached
with a well-thought
out genetic counseling plan. Predictive testing occurs
when at-risk asymptomatic
adult family members seek testing in order to
clarify their
risk to develop the disease. Often they are making personal
decisions regarding
reproduction, financial matters, and career planning.
Others may have
different motivations including simply "the need to know."
Testing of asymptomatic
at-risk adult family members usually involves
pre-test assessment
of the motives for requesting the test and the
individual's knowledge
of SCA3, the possible impact of positive and
negative test
results, and neurologic status. Those seeking testing should
be counseled about
possible problems they may encounter with regard to
health, life,
and disability insurance coverage, as well as employment and
educational discrimination
and status changes in social and family
interaction. Other
issues to consider are implications for the at-risk
status of other
family members. Informed consent should be procured and
records kept confidential.
Individuals with a positive test result need
arrangements for
long term follow-up and evaluations.
Testing of at-risk
asymptomatic children. Consensus holds that children at
risk for adult-onset
disorders should not have testing in the absence of
symptoms. The
principle reasons against testing children are that it
removes their
choice to know or not know this information, it raises the
possibility of
stigmatization within the family and in other social
settings, and
it could have serious educational and career implications
[Bloch & Hayden
1990, Harper & Clarke 1990]. Children who are symptomatic
usually benefit
from having a specific diagnosis established. (See also the
National Society
of Genetic Counselors statement on genetic testing of
children.)
Molecular Genetics
Table 2. Molecular Genetics of Spinocerebellar Ataxia 3
Gene Chromosomal Normal
Symbol Locus
Gene Genomic Databases
Product
SCA3/MJD1 14q21 Ataxin 3 [OMIM] [LocusLink] [HGMD]
*
Gene symbol: MJD1; MJD locus
*
Chromosome locus: 14q21
*
Normal allele variants: The nucleotide sequence of the MJD1 gene
consists of four exons within a 1776 base pair coding region with one
long open reading frame (ORF) [Kawaguchi et al 1994]. A polymorphic
CAG repeat occurs near the C-terminus within the 4th exon, followed by
an Alu repeat sequence at the 3' non-coding region. Variations in the
(CAG)n sequence exist. In many alleles examined, the 3rd, 4th, and 6th
CAG unit is replaced by CAA, AAG, and CAA, respectively. These variant
triplets were commonly found both in normal and abnormal alleles. The
CAG repeat is highly polymorphic in normal individuals with the (CAG)n
in different alleles varying from 12 to 43 [Mattila et al 1995, Ranum
et al 1995, Sasaki et al 1995, Cancel et al 1995, Maciel et el 1995,
Matsumura et al 1996, Takiyama et al 1995, Limprasert et al 1996]. In
many studies, the distribution of CAG repeat numbers in normal alleles
has shown a bimodal or trimodal pattern with peaks around 14, 22-24,
and 27. Rubinsztein et al looked at 748 normal chromosomes from 8
different ethnic backgrounds and found a similar bimodal distribution
of normal CAG repeat numbers with peaks at 14 and 21 to 23
[Rubinsztein et al 1995]. The proportion of heterozygotes among
different populations was somewhat different with higher figures among
Melanesians (98%), Polynesians (92%), and African blacks (88%), and
the least among East Anglican (58%). Limprasert et al [1996] found 14
and 23 (CAG)n repeat sizes to be the most common among different
populations. Furthermore, in analyzing the (CAG)n tracts in different
species, including humans, it was observed that usually the CAG repeat
was flanked with a guanine, but when the repeat numbers were 20 or 21,
the guanine was replaced with cytosine. In addition, cytosine occurred
in 54.5% of normal alleles with repeat numbers between 27 and 40, with
a frequency distribution of 23-100% among different ethnic
populations. All expanded alleles also contained cytosine at the first
nucleic acid residue following the (CAG)n tracts. It appears that
cytosine at this point may play a role in determination of instability
of polyglutamine tracts. Overall, 93.5% of normal chromosomes carry
less than 31 repeat numbers. Chimps, gorillas, and orangutans contain
fewer repeats in their normal alleles than do humans [Rubinsztein et
al 1995].
*
Disease-causing allelic variants: SCA 3 (MJD) is a classic example
of
a disorder caused by the unstable expansion of a CAG repeat sequence
in the MJD1 gene. Since the original publication of Kawaguchi et al,
numerous other workers have documented the expansion as the causative
mutation in a sizable proportion of families with dominantly inherited
ataxias from a variety of ethnic backgrounds [Ranum et al 1995,
Mattila et al 1995, Maciel et al 1995, Cancel et al 1995, Silveira et
al 1996, Takiyama et al 1995, Takiyama et al 1997, Schols et al 1996].
Both somatic and gametic instability of the repeat have been reported
[Hashida et al 1997]. Typically, spermatozoa contain a larger repeat
size than leukocytes in the same individuals [Watanabe et al 1996]. In
the CNS, cerebellar tissues often tend to have smaller repeat sizes
than other regions of the brain. Haplotype analysis has revealed that
patients from different populations often shared the same haplotype,
suggesting presence of a founder effect [Takiyama et al 1995].
However, in the restricted populations of the Azores, 2 distinct
haplotypes have been found, a fact that could overrule the one founder
mutation theory [Gaspar et al 1996].
*
Normal gene product: The MJD gene codes for a novel protein with
a
predicted molecular weight of 42kDa. On Western blots the protein is
expressed as a 75kDa polypeptide [Paulson et al 1997a]. Such anomalous
migration appears to be a common feature of all polyglutamine
proteins. Immunocytochemical studies reveal that the protein is
expressed in neuronal as well as non-neuronal cells in a
predominantly, but not exclusively, cytoplasmic localization. The
reaction product often extends into the neuronal process as well.
*
Abnormal gene product: Western blot studies using polyclonal antibody
to ataxin-3 have shown that both the normal and expanded repeat
ataxin-3 are also widely expressed in diseased brain [Paulson et al
1997b]. The product of the abnormal allele migrates as a higher
molecular weight band corresponding to the excess number of glutamine
residues coded for by the larger number of CAG repeats. Interestingly
enough, expression of both alleles can also be seen in a widespread
distribution both in areas affected by the disease as well as those
areas of the CNS that are spared. In addition, the subcellular
distribution of ataxin-3 has been shown to be different in diseased
brain compared to normal brain. In many brain regions that are known
to be the site of neuronal degeneration in SCA3, both monoclonal and
polyclonal antibodies to ataxin-3 recognize intensely stained
intranuclear inclusions that vary in diameter from 0.5 to 6 microns
[Paulson et al 1997b]. These inclusions are particularly abundant in
pontine neurons but are also seen in neurons in substantia nigra,
globus pallidus, dentate nucleus, and, rarely, the inferior olive.
These inclusions are also recognized by a monoclonal antibody 1C2 at
dilutions that tend to preferentially recognize expanded polyglutamine
domains, which suggests that the pathologically expanded polyglutamine
domain is present within the inclusions. The inclusions are also
ubiquitinated, indicating the presence of aberrant protein folding or
degradation. The occurrence of a similar nuclear inclusion has been
modeled in a cell transfection system using a truncated cDNA construct
containing the expanded CAG repeat. Further evidence that supports the
importance of protein truncation in the pathogenesis of SCA3 comes
from a transgenic mouse model [Ikeda et al 1996]. In this system,
phenotype expression occurs only when a truncated gene is expressed as
opposed to the full-length gene.
Resources
GeneClinics provides
information about selected national organizations and
resources for
the benefit of the reader. GeneClinics is not responsible for
information provided
by other organizations. —ED.
Patients and families
with hereditary ataxia often benefit from referral to
a lay support
group. In the United States, the National Ataxia Foundation
is an organization,
with several chapters nationwide, that provides
information about
research to clinicians and lay people and sponsers
support groups.
The International Network of Ataxia Friends (INTERNAF)
serves as an umbrella
organization for ataxia support groups in many
countries throughout
the world.
*
National Ataxia Foundation
2600 Fernbrook Lane, Suite 119
Minneapolis, MN 55447
Phone: 763-553-0020
Fax: 763-553-0167
Email: naf@ataxia.org
Web: www.ataxia.org
*
Spinocerebellar Ataxia: Making an Informed Choice about Genetic
Testing
(Acrobat reader required)
Web: depts.washington.edu/neurogen/AtaxiaBrochure99.pdf
*
WE MOVE (Worldwide Education and Awareness for Movement Disorders)
204 E 84th St
New York, NY 10024
Phone: 212-875-8312; 1-800-437-MOV2
Fax: 212-875-8389
Email: wemove@wemove.org
Web: www.wemove.org
*
International Network of Ataxia Friends (INTERNAF)
Web: http://internaf.merseyside.org
*
NCBI Genes and Disease Webpage
www.ncbi.nlm.nih.gov/disease/SCA.html
