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Spinocerebellar Ataxia Type 3 Phenotypically Resembling Parkinson Disease in a Black Family
Katrina Gwinn-Hardy, MD;
Andrew Singleton, PhD;
Padraig O'Suilleabhain, MD;
Michael Boss, PhD;
David Nicholl, MD;
Amanda Adam, BS;
Jennifer Hussey, BA;
P. Critchley, MD;
John Hardy, PhD;
Matthew Farrer, PhD
Arch Neurol. 2001;58:296-299.
ABSTRACT
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Background Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type
3 (SCA3), can present with parkinsonism. However, classically, atypical features,
including pyramidal and cerebellar signs, peripheral neuropathy, and/or anterior
horn cell dysfunction, are also seen. Levodopa responsiveness is unusual in
this disorder.
Objective To determine the cause of apparent parkinsonism suggestive of Parkinson
disease (PD) in a large family of African origin.
Methods We studied a large family in which apparent autosomal dominant parkinsonism
suggestive of PD occurs in order to find the causal genetic mutation. Affected
and unaffected family members were screened for the presence of a pathogenic
expansion at the MJD/SCA3 locus using a polymerase
chain reaction polyacrylamide gel electrophoresis–based assay.
Results Three of the 4 individuals who were examined have a phenotype reminiscent
of PD. Specifically, they have at least 2 of the cardinal features, are levodopa
responsive, and have no atypical features. All affected family members were
shown to possess pathogenic expansions in the MJD/SCA3
gene.
Conclusions Parkinsonism suggestive of PD due to MJD/SCA3 has not been previously
reported, to our knowledge. However, atypical, though also levodopa-responsive,
parkinsonism has been previously reported to occur in African American families,
suggesting that that this phenotype is associated with African ancestry. In
this regard, it is perhaps significant that all the individuals with parkinsonism
have relatively low numbers of repeats (normal, 16-34; pathologic, 60-84).
In families in which linkage analysis is being performed to determine a locus
for autosomal dominant parkinsonism suggestive of PD, evaluation for the MJD/SCA3 mutation is indicated.
INTRODUCTION
THERE ARE 3 usual typical phenotypes of Machado-Joseph disease (MJD)
(also known as spinocerebellar ataxia type 3 [SCA3]): type 1, which is characterized
by pyramidal and extrapyrimidal signs and early age at onset; type 2, which
is characterized by cerebellar and pyramidal signs; and type 3, which is characterized
by cerebellar signs and anterior horn cell degenerative symptoms.1 A rare, fourth variant, with parkinsonism and peripheral
neuropathy, has also been described.2 In all
the variants described previously, the parkinsonian features occur in combination
with features such as dystonia, ataxia, spasticity, or peripheral neuropathy.
The latter findings often predominate and, if seen in an individual with parkinsonism
in clinical practice, would rule out the diagnosis of typical Parkinson disease
(PD).2, 3 We describe a family
of sub-Saharan African descent living in Antigua, the United States, and England.
Most living affected individuals in the family appear to have parkinsonism
suggestive of PD on standard neurological examination, but they demonstrate
a segregating SCA3 repeat expansion on molecular
analysis.
METHODS
Genomic DNA was isolated from whole blood using genomic DNA purification
kits (Wizard). Polymerase chain reaction amplification was performed in a
25-µL reaction containing 25 ng of genomic DNA, 10 pmol of both forward
and reverse oligonucleotide custom primers (F 5'-CCAGTGACTACTTTGATTCG-3',
5' labeled with Tet; R 5'-TGGCCTTTCACATGGATGTGAA-3' (Life
Technologies, Rockville, Md), 1 x manufacturer's buffer, 1 x Q
solution (Qiagen Inc, Valencia, Calif), 200-µmol/L deoxynucleotide trisphosphates
(Amersham Pharmacia Biotech Inc, Piscataway, NJ), and 0.2 U of Taq DNA polymerase (Qiagen Inc). Polymerase chain reaction was run
on a commercially available machine (Touchdown; Hybaid, Franklin, Mass) using
the following conditions: 5 minutes of denaturation at 95°C, followed
by 35 cycles at 95°C for 30 seconds, 55°C for 20 seconds, and 72°C
for 30 seconds, and then by a final 10-minute incubation at 72°C. Five
microliters of each reaction was run on a 2% agarose gel to confirm amplification
and to exclude the possibility of pathogenic extensions beyond the ladder
size (500 base pairs [bp])used on the automated sequencer. One microliter
of the polymerase chain reaction product at a dilution of 1:50 was electrophoresed
on a 6% polacrylamide gel using an automated sequencer (ABI377 96XL; Applied
Biosystems, Foster City, Calif). Sizing was performed using a 50- to 500-bp
tetramethylrhodamine ladder (TAMRA; Applied Biosystems) according to the manufacturer's
instructions. Also, to confirm that extensions were uninterrupted repeats,
polymerase chain reaction was performed on each case using exactly the same
conditions as mentioned earlier but using an unlabeled forward primer. The
resulting products were then sequenced with these primers and a reaction kit
(BigDye Terminator Ready Reaction Kit; Applied Biosystems) and analyzed using
an automated sequencer (ABI377 96XL; Applied Biosystems) according to the
manufacturer's instructions.
CLINICAL DESCRIPTIONS
The family tree, along with the number of repeats at the SCA3 locus, is shown in Figure 1.
A summary of the clinical characteristics and repeat length is presented in Table 1. The clinical characteristics of
those individuals who were examined by one or more of us are presented in
detail below.
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An abbreviated pedigree is shown. The phenotype of living affected
individuals is given in Table 1.
The phenotype of other individuals is per family report. Historically, the
family settled on Monserrat in the Caribbean 2 generations ago, coming from
Ireland before that. Earlier emigration information is not known. Squares
symbols indicate males, circles females; diagonal lines through symbols, deceased;
question mark, unknown phenotype; solid symbols, parkinsonism; half-darkened
symbol, foot dystonia; and arrow, the proband. The SCA3 (spinocerebellar
ataxia type 3) repeat length is indicated below the symbol for living affected
individuals.
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Phenotypic and Genotypic Characteristics of Affected Individuals in
the Antigua Family
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PROBAND (2001, CORIELL CELL REPOSITORIES NO. GM 15904)
A previously well 36-year-old woman noted the insidious onset and gradual
progression of motor slowing for 5 years. Her legs "would not keep up with
her trunk when walking." Her handwriting became small, and she had muscle
tightness but no resting tremor. She had no change in voice or vision and
no autonomic complaints. She underwent a trial of baclofen, with minor benefit
in the stiffness, although she never had spasticity. She subsequently began
taking pramipexole (1 mg 3 times daily), which has resulted in marked improvement,
and she has gone from being wheelchair bound to walking freely. Results of
magnetic resonance imaging, measurement of serum ceruloplasmin levels, human
T-lymphotropic virus 1 and cerebrospinal fluid studies, and electromyography
with nerve conduction studies were normal.
On examination in the "on" state, her mental status was normal. She
had masked facies, though a normal blink rate. Her speech was normal. Rigidity
was prominent in the left upper extremity, and mild but present in the right
upper extremity, neck, and both lower extremities. Deep tendon reflexes were
normal. She had mild stooped posture and steppage gait. Alternate motion rates
were slow, with breakdown of movement in the lower extremities and borderline
breakdown in the hands. No tremor was seen.
3002
The 60-year-old father of the proband noted symptoms of resting tremor
when he was approximately 30 years old. His sister, who is a nurse, also noted
at that time that his walk was slower and that his face was masked, as their
father's had been. Since then, he has had gradually progressive slowness in
his movements and difficulty with balance. The right-sided tremor continues
to occur intermittently when he is at rest, and a resting tremor has also
developed in his right foot. There is no postural or activation tremor. He
feels stiff all over, especially in his lower extremities. He needs assistance
with most activities of daily living. His greatest current difficulty is walking,
and he tends to fall forward almost daily. He needs full assistance to ambulate.
Carbidopa-levodopa therapy (10/100 3 taken times daily) helped at the
time it was initiated, but the dosage has not been changed in many years,
and he feels that the medication is not helping as much lately. Nonetheless,
he feels that he cannot function without it. His medical history is significant
only for controlled hypertension.
His examination was performed in the "on" state. The findings of his
mental status examination were normal. His handwriting was slow and deliberate,
with mild micrographia. His speech was severely hypophonic. He had occasional
drooling. His extraocular movements were saccadic but full. There was marked
tremor of his chin on the right side. His motor examination revealed a severe
breakdown of movement with rapid alternating movements bilaterally, worse
on the right than on the left, in all extremities. He could not tap his right
foot voluntarily at all, and he could barely tap his left foot. His strength
was normal, as was sensation to light touch, pinprick, and vibration throughout.
His deep tendon reflexes were normal throughout, and his toes were down-going
bilaterally to plantar reflex testing. Rigidity was moderate in his upper
extremities, severe in his lower extremities, and markedly severe in his neck.
He needed full assistance to stand from a seated position and to take small,
hesitant, deliberate steps. He would have fallen spontaneously if not fully
supported. He sat backward, with a large fall onto the furniture, and could
not control the impact.
3012
The 65-year-old half-uncle of the proband developed parkinsonism at
57 years of age characterized by a resting tremor of his left upper extremity,
mild bradykinesia, and a reduced arm swing. Throughout the course of his illness,
his major complaint has been a coarse, predominantly left-sided tremor that
affected both upper and lower extremities. He has been receiving levodopa
replacement therapy for 7 years, with good effect, but over the last year,
he has developed levodopa-related motor fluctuations without dyskinesias.
At the time of examination, he was taking 900 mg/d of levodopa (Madopar).
On examination in the "on" state, his mental status was normal. His
cranial nerves were normal except for slowed saccades. His eye movements were
full. He had moderate masked facies and moderate hypophonia. There was intermittent
resting tremor in all 4 extremities, more marked on the left side of his body.
His posture was slightly stooped, with absence of a postural response on pull
testing. His gait was slightly hesitant, with a reduced arm swing. There was
a mild degree of bradykinesia, with no rigidity. Strength, sensation, and
deep tendon reflexes were normal.
3018
A 51-year-old woman has had difficulty with back pain and stiffness
since her teens. These symptoms have been attributed to scoliosis and have
not been formally evaluated or treated. She has noted in the past 10 to 12
months that her left foot involuntarily turns inward, especially first thing
in the morning. This is only moderately bothersome to her, and she has not
sought the help of a physician.
The findings of her mental status examination were normal. Her cranial
nerve examination was significant for saccadic pursuits. Scoliosis was apparent
during the gait examination. She had left foot dystonia while in repose, which
worsened slightly when she was ambulating. The results of the rest of the
neurological examination were normal.
COMMENT
Parkinsonian features have been previously reported as the predominant
phenotype of the MJD/SCA3 mutation (MJD type 4),
usually accompanied by robust atypical features.2, 4
However, 3 of the 4 individuals from the pedigree described herein have a
phenotype suggestive of PD. Specifically, they have at least 2 of the cardinal
features, are levodopa responsive, and have no atypical features. Although
more extensive testing (eg, electromyography with nerve conduction studies)
might be revealing, this was done in 1 of the 4 individuals, and the results
were normal. Furthermore, we suspect that if these patients walked into the
standard neurology practice today, they would be diagnosed as having PD. While
there has been no neuropathologic examination to date in this kindred, we
would expect it to be unlikely that they would have Lewy body disease.5 To our knowledge, the remarkable combination of symptoms
in MJD/SCA3 that were found in our kindred has not been previously documented,
although it is of interest that an atypical, though also levodopa-responsive,
parkinsonism has been previously reported to occur in African American families.4 Thus, the parkinsonian phenotype encompassing both
"typical" (this work) and "atypical" (see reference 5) features may be associated
with African ancestry, although this theory clearly will require further investigation
in more families of diverse ethnic origin before a secure conclusion can be
reached. In this regard, it is perhaps significant that all the individuals
with parkinsonism have relatively low numbers of repeats (normal, 16-34; pathologic,
60-84),6, 7 although this is likely
not the only factor.
These observations are of importance for 3 reasons. First, MJD/SCA3
should particularly be considered in the differential diagnosis of parkinsonism
that is suggestive of PD in blacks. Second, our findings may imply the possibility
of genetic modifiers, which influence the phenotype of the mutant allele in
different racial groups. Finally, these results emphasize that in other studies
in which familial parkinsonism is being studied, care should be exercised
in identifying individuals in which the mutations is at the MJD/SCA3 locus. In those families in which linkage analysis is being
performed to determine a locus for autosomal dominant parkinsonism that is
suggestive of PD, evaluation for the MJD/SCA3 mutation
is particularly important.
AUTHOR INFORMATION
Accepted for publication September 1, 2000.
This work was supported by grants from the American Parkinson Disease
Association Inc, Staten Island, NY (Dr Gwinn-Hardy); and the Udall Parkinson's
Disease Research Center of the Johns Hopkins School of Medicine and the US
Public Health Service, National Institutes of Health, Bethesda, Md (Drs Gwinn-Hardy
and Farrer and Ms Hussey).
Thanks to the members of the family, without whom this work would not
be possible. Thanks to Valerie Thomas for help in collecting and preparing
the samples and to G. E. M. Thomas, MD, on Antigua for helping us to investigate
her patient.
From the Department of Pharmacology, Mayo Clinic Jacksonville, Jacksonville,
Fla (Drs Gwinn-Hardy, Singleton, Hardy, and Farrer and Mss Adam and Hussey);
the Departments of Neurology, University of Texas Southwestern Medical Center
at Dallas (Dr O'Suilleabhain), Queen Elizabeth Hospital, Birmingham, England
(Dr Nicholl), and the Leicester Royal Infirmary, Leicester, England (Dr Critchley);
and Athena Diagnostics Corporation, Worcester, Mass (Dr Boss).
Corresponding author and reprints: Katrina Gwinn-Hardy, MD, Mayo
Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224 (e-mail: gwinn.katrina{at}mayo.edu).
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