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Complex phenotypes in an Indian family with homozygous SCA2 mutations.

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Complex Phenotypes in an
Indian Family with
Homozygous SCA2
Mutations
Mona Ragothaman, MBBS,1
Nagaraja Sarangmath, MBBS,1 Shashi Chaudhary, MSc,2
Vishwamohini Khare, MSc,3 Uma Mittal, MSc,4
Sangeeta Sharma, BSc,4 Sreelatha Komatireddy, MSc,5
Subhabrata Chakrabarti, PhD,5 Mitali Mukerji, PhD,4
Ramesh C. Juyal, PhD,3 B. K. Thelma, PhD,2
and Uday B. Muthane, DM1
We describe a consanguineous Indian family having
spinocerebellar ataxia type 2 (SCA2) expansions with
complex phenotypes (early-onset, dopa-responsive parkinsonism, ataxia and retinitis pigmentosa). The two probands having homozygous SCA2 mutations presenting
with early-onset dopa-responsive parkinsonism without
ataxia develop dyskinesias within a year of starting levodopa. Their siblings, heterozygous for SCA2 mutations,
had retinitis pigmentosa with or without ataxia. Approximately 38% of family members with SCA2 mutations
were asymptomatic.
Ann Neurol 2004;55:130 –133
Spinocerebellar ataxia type 2 (SCA2) mutation infrequently causes dopa-responsive parkinsonism.1–3 Autopsies on ataxic patients with SCA2 show marked
neuronal loss in the substantia nigra,4 but parkinsonism was only recently reported.1 SCA2 is the commonest hereditary ataxias among Indians, and Wadia and
colleagues have highlighted the significance of slow saccades in its clinical diagnosis.5
We describe a large Indian family with complex phenotypes including early-onset dopa-responsive parkinsonism, ataxia, and retinitis pigmentosa (RP) with presence of SCA2 expansions but no mutations in
From the 1Department of Neurology, National Institute of Mental
Health and Neurosciences, Bangalore; 2Department of Genetics,
University of Delhi South Campus; 3National Institute of Immunology; 4Institute of Genomics and Integrative Biology, Center for
Scientific and Industrial Research, New Delhi; and 5Brien Holden
Eye Research Center, L.V. Prasad Eye Institute, Hyderabad, India.
Received Jul 17, 2003, and in revised form Sep 15. Accepted for
publication Sep 16, 2003.
Address correspondence to Dr Muthane, Department of Neurology,
National Institute of Mental Health and Neurosciences, Bangalore
560 029, India. E-mail: umuthane@usa.net
130
␣-synuclein and Parkin genes or association with candidate genes for RP.
Patients and Methods
Clinical Information
The two probands initially were seen by one of us (U.M.) for
routine evaluation of Parkinson’s disease (PD). The probands
were originally from Kembathalli, a village in Dharamapuri
district in Southern India. Two of us (M.R. and U.M.) evaluated members of this four-generation family (Fig). Family
members underwent a computed tomography scan (n ⫽ 9),
electroretinogram (ERG, n ⫽ 7), fundus photography (n ⫽
2), visual field assessment (n ⫽ 7), and cardiovascular autonomic testing (n ⫽ 3). Approximately 5 to 10ml of peripheral blood was collected from family members (n ⫽ 29) for
genetic analysis with prior informed consent approved by the
institute’s ethics committee.
Genetic Analyses
DNA was extracted using standard protocols and used for genetic analysis. The two probands, three other members with
parkinsonism and seven unaffected members from the family
were screened for partial/whole exon deletion(s) and mutations
in ␣-synuclein,6 PARKIN genes,7 and trinucleotide expansions
in SCA genes.8 The portion of the pedigree (see Fig) containing the RP affected individuals (V:11, V:12, and V:14) were
screened for association with 27 RP candidate genes reported
in the Retinal Information Network database9 in addition to
the mitochondrial candidate region containing ATPase6.10 After identification of SCA2 expansion in the two probands, other
available family members also were evaluated for this mutation.
Results
Clinical Analysis: Examination of Probands
PROBAND 1. Proband 1 (V:16; aged 25 years) presented with progressive asymmetric bradykinesia for 3
years. Rest tremor in the upper limbs was symmetrical.
He had no cognitive impairment.
Examination showed postural tremors in upper extremities (L ⬎ R), generalized rigidity (R ⬎ L), bradykinesia, and mild postural instability. Ocular movements were normal. He had no limb or gait ataxia.
United Parkinson’s Disease Rating Scale motor score
improved by 52% with two pills of carbidopa/L-dopa
(25/100). Amantadine (300mg) helped him for the initial 3 years, and in the last 4 years carbidopa/ L-dopa
has helped considerably. A year after adding L-dopa, he
had dyskinesia (Goetz scale 3), and for the past 3 years
he has had motor fluctuations. His cardiovascular autonomic testing was normal. Initial computed tomography scans showed mild cortical atrophy but a recent
scan shows mild vermian and pontine atrophy.
PROBAND 2. Proband 2 (V:18; aged 19 years) presented
with a 4-year history of dysarthria. She had right-sided
bradykinesia and rigidity with mild postural instability
(Hoehn and Yahr stage 2.5). She had normal eye move-
© 2003 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Fig. Family pedigree. (squares) men; (circles) women; (diagonal line) individual who died. (filled symbols) Parkinsonism; (shaded
lower right-hand corner) retinitis pigmentosa; (shaded top left-hand corner) retinitis pigmentosa with ataxia; (vertical line in
center of symbol) ataxia; (shaded bottom half of symbol) Parkinson’s disease with ataxia. Arrows indicate probands.
ments. Challenge with carbidopa/ L-dopa (2 pills of 25/
100) improved her United Parkinson’s Disease Rating
Scale scores by 50%. Initially, she did well with amantadine (300mg) and has developed mild dopa-induced
dyskinesia approximately 1 year after starting L-dopa.
Cerebellar signs and RP were absent. Her cardiovascular
autonomic testing was normal. Computed tomography
scan done at presentation was normal but a recent scan
shows mild pontine and vermian atrophy.
Other Family Members
Thirty subjects in four generations were examined (Table). Ataxia was noticed in seven members; five had
ataxia alone, and of the proband’s two elder sisters one
has ataxia with RP and one had PD and ataxia. Their
brother (V:14) has RP without ataxia. Parkinsonism
was noticed in five members, that is, the two probands
and three others (III:11, III:13, III:27). All members
with ataxia had slow saccades except V:11.
Clinical Analysis: Examination of Parents
MOTHER (IV:33). Examination of the mother (aged 56
years) approximately 6 months before death showed a
20-year history of cerebellar ataxia with normal eye
movements. She had no parkinsonism.
Retinitis Pigmentosa
Fundus photography, electroretinogram, and visual
field charting in three siblings of the probands showed
typical RP phenotype.
The father (aged 68 years) is asymptomatic but in the past few months makes occasional
mistakes on tandem walking. A brain computed tomography shows mild brainstem and vermian atrophy.
Diagnosis of PD was based on presence of two of
the four cardinal features, namely, rest tremors, rigidity, bradykinesia and postural imbalance, and a positive
response (⬎30%) to L-dopa.
FATHER (III: 16).
Genetic Analyses
No deletions or mutations were observed in any exons
of ␣-synuclein and Parkin genes in the patients.
Expansions at SCA2 (ⱖ34 repeats) were observed in
several members in the family (see Fig; Table). Interestingly the two probands (V:16 and V:18) with parkinsonism had homozygous SCA2 expansion without
ataxia. Six family members had ataxia, either with parkinsonism and/or RP and were heterozygous for SCA2.
Ragothaman et al: SCA2 and Complex Phenotypes
131
Table. Description of Pedigree, Age, Clinical Features, and Genotype
Phenotype (age of onset, yr)
Pedigree
No.
Age
(yr)
Sex
PD
Ataxia
RP
Saccades
III:11
III:13
III:16
III:23
III:27
III:31
IV:34
III:39
III:43
IV:22
IV:33
IV:35
IV:39
IV:46
IV:67
IV:69
IV:72
IV:73
V:1
V:2
V:11
V:12
V:14
V:15
V:16
V:17
V:18
VI:5
VI:6
†IV:49
90
67
68
56
76
50
42
65
36
50
56
33
42
36
50
26
21
21
22
27
37
35
34
28
32
26
23
8
4
17
M
F
M
M
M
M
M
M
M
M
F
M
M
M
F
M
F
F
M
M
F
F
M
F
M
F
F
M
M
F
⫹(75)
⫹(60)
—
—
⫹(74)
—
—
—
—
—
—
—
⫹(72)
—
—
—
⫹(30)
⫹(20)
⫹(46)
—
—
—
—
—
—
—
⫹(19)
⫹(15)
⫹(37)
⫹(27)
—
—
—
—
—
—
—
⫹(14)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
⫹(27)
⫹(29)
⫹(22)
—
—
—
—
—
—
—
N
Slow
N
N
Slow
N
N
N
N
Slow
N
N
N
N
N
N
N
N
Slow
Slow
N
Slow
N
N
N
N
N
N
N
—
a
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
⫹(22)
—
⫹(15)
—
—
—
CT Scan
ND
ND
Cbl
ND
Cbl and
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Cbl
ND
Cbl and
Cbl and
Cbl
NA
Ctl, Cbl
NA
Cbl and
NA
NA
Cbl
Bnst
Bnst
Bnst
and Bnst
Bnst
Dopa
Response
ERG
Genotype
(SCA2)
ND
ND
NA
NA
26%
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
52%
NA
50%
NA
NA
NA
ND
ND
N*
NA
N*
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
RP
RP
RP
NA
N*
NA
N*
NA
NA
NA
22,37
22,36
22,35
22,34
22,36
22,22
22,36
—
22,37
22,39
—
—
—
—
—
22,33
—
—
22,45
22,44
22,38
22,41
22,39
—
35,37
22,22
36,39
—
—
ND
Data from hospital clinical record and CT image.
PD ⫽ parkinsonism; RP ⫽ retinitis pigmentosa; CT ⫽ computed tomography; ERG ⫽ electroretinogram; SCA2 ⫽ spinocerebellar ataxia 2;
N ⫽ normal; ND ⫽ not done; Cbl ⫽ cerebellum; NA ⫽ not applicable; N* ⫽ reduced functions of cones and rods; Bnst ⫽ brainstem; Ctl ⫽
cortical.
Expansions at SCA2 also were observed in four members asymptomatic for both ataxia and parkinsonism.
No association with any candidate genes for RP nor
any mutation in the mitochondrial candidate region
containing ATPase 6 was observed in cases with RP.
Discussion
This study presents a unique family manifesting an entire spectrum of neurological disorders described with
SCA2 mutation, namely, ataxia, parkinsonism, and RP.
The two probands presented with early-onset, doparesponsive parkinsonism and normal eye movements
without ataxia or RP and were homozygous for SCA2
expansions. They develop dyskinesia within 1 year of
starting L-dopa. Family members have either ataxia, RP,
or parkinsonism either in isolation or in combination.
Slow saccades characteristic of SCA25 occur early in
patients presenting with ataxia but were absent in those
with parkinsonism.2,3 In this family, all older members
with parkinsonism had slow saccades, suggesting that
132
Annals of Neurology
Vol 55
No 1
January 2004
saccadic slowing may be delayed in the Parkinsonian
phenotype. However, some elderly SCA2 Parkinsonian
patients2,3 had normal eye movements suggesting that
saccadic slowing is not an accurate clinical marker in
SCA2 patients with parkinsonism.
A strong negative correlation between CAG repeat
length and age of onset of ataxia has been reported.11
Parkinsonism secondary to SCA21–3,12,13 has a mean
age at onset of 45 years (standard deviation, 13; range,
20 – 62 years). Interestingly, the two probands described here are clear exceptions because they have
early-onset (⬍22 years) parkinsonism. This could be
caused by homozygosity at the SCA2 locus because
those with heterozygous expansions develop parkinsonism at a much later age (⬎60 years). Although anticipation is observed here, the early age at onset in our
probands with parkinsonism cannot be ascribed to the
repeat length because no expansion of repeats occurs
during transmission. Most likely the decrease in age at
onset in this pedigree is caused by homozygosity at the
SCA2 locus. Normally, young-onset PD patients have
significantly higher frequency for both dyskinesias and
fluctuations after 3 and 5 years of L-dopa, respectively.14
Strikingly, L-dopa–induced dyskinesia occurred within a
year of starting L-dopa in the homozygous probands,
which is earlier than reported in SCA2 heterozygotes
wherein dyskinesia developed after 10 years.12 Individuals with homozygous Parkin mutations have significantly
younger age at onset of PD compared with heterozygotes.15 Importantly, all ataxic individuals have a higher
number of CAG repeats in heterozygous condition,
whereas those with homozygous SCA2 expansions have
dopa-responsive parkinsonism. A direct role of ataxin-2
in RNA splicing and protein interactions16 in the pathogenesis of dopa-responsive parkinsonism in SCA2 requires more evidence.
Retina has a higher threshold of damage compared
with the brain, and two patients with RP have large expansions at SCA2 locus.17,18 RP, in this family, manifesting for the first time in three siblings with moderate
CAG repeat (38 – 41) size may possibly be caused by
consanguinity leading to homozygosity at a locus for RP.
Analysis of modifier genes19 in this family may provide
critical insight into pathogenesis and varied manifestation of dopa-responsive parkinsonism, ataxia, and RP.
Distinguishing parkinsonian patients with SCA2
from patients with idiopathic PD can be difficult clinically. When the probands first presented to us, little
was known of SCA2 and parkinsonism; hence, SCA2
was suspected on seeing family members with ataxia
and slow saccades and confirmed after genetic analysis.
Dopa-responsive parkinsonism with SCA2 expansion
can be suspected in those with a family history of
ataxia and/or in those with imaging showing brainstem
and cerebellar atrophy. Presence of slow saccades
would help but may not be mandatory unlike SCA2
patients with ataxia. Parkinsonism possibly may be
more frequent in SCA2 than is known, because pathologically marked neuronal loss occurs in the substantia
nigra. This report confirms that SCA2 may cause parkinsonism and RP in different ethnic communities.
Keeping in mind the clinical and genetic heterogeneity in this family, it is unclear, as is in many genetic
diseases, what determines a particular phenotype. The
known phenotypes are expanding sometimes beyond
clinical recognition in the face of genetic analysis, and a
day might come when the classification will have to be
unavoidably genetic, whether clinicians like it or not.
This work was supported by grants from the Department of Biotechnology, Government of India (BT/PR1357/Med/13/046/98,
S.C.; BT/PR2425/Med/13/089/2001, R.C.J., B.K.T., and U.B.M.),
Indian Council of Medical Research, Government of India (63/130/
2001-BMS, S.C.; 63/98/2001-BMS, U.B.M.), the Hyderabad Eye
Research Foundation and Council for Scientific and Industrial Research, Government of India (M.M.).
We thank members of the family for their cooperation in this study.
We are extremely grateful to Drs N. H. Wadia, S. H. Subramony,
S. Jain, and S. K. Brahmachari for their critical comments on the
manuscript. We thank Dr D. Balasubramanian for providing the
necessary facilities for the RP work.
References
1. Shan DE, Soong BW, Sun CM, et al. Spinocerebellar ataxia
type 2 presenting as familial levodopa-responsive parkinsonism.
Ann Neurol 2001;50:812– 815.
2. Lu CS, Chou YW, Yen TC, et al. Dopa-responsive parkinsonism phenotype of spinocerebellar ataxia type 2. Mov Disord
2002;17:1051.
3. Furtado S, Farrer M, Tsuboi Y, et al. SCA-2 presenting as parkinsonism in an Alberta family: clinical, genetic, and PET findings. Neurology 2002;59:1627.
4. Orozco G, Estrada R, Perry TL, et al. Dominantly inherited
olivopontocerebellar atrophy from eastern Cuba. J Neurol Sci
1989;93:37–50.
5. Wadia N, Pang J, Desai J, et al. A clinicogenetic analysis of six
Indian spinocerebellar ataxia (SCA2) pedigrees. The significance
of slow saccades in diagnosis. Brain 1998;121:2341–2355.
6. Farrer M, Wavrant-De Vrieze F, Crook R, et al. Low frequency
of alpha-synuclein mutations in familial Parkinson’s disease.
Ann Neurol 1998;43:394 –396.
7. Kitada T, Asakawa S, Matsumine H. Mutations in the parkin
gene cause autosomal recessive juvenile parkinsonism. Nature
1998;392:605– 608.
8. Saleem Q, Choudhry S, Mukerji M, et al. Molecular analysis of
autosomal dominant hereditary ataxias in the Indian
population: high frequency of SCA2 and evidence for a common founder mutation. Hum Genet 2000;106:179 –187.
9. RetNet: Retinal Information Network. Available at: http://
www.sph.uth.tmc.edu/Retnet/. Accessed April 4, 2003.
10. MITOMAP: A Human Mitochondrial Genome Database.
Available at: http://www.mitomap.org. 2003.
11. Cancel G, Durr A, Didierjean O, et al. Molecular and clinical
correlations in spinocerebellar ataxia 2: a study of 32 families.
Hum Mol Genet 1997;6:709 –715.
12. Gwinn-Hardy K, Chen JY, Liu HC, et al. Spinocerebellar
ataxia type 2 with parkinsonism in ethnic Chinese. Neurology
2000;55:800 – 805.
13. Payami H, Nutt J, Gancher S, et al. SCA2 may present as
levodopa-responsive parkinsonism. Mov Disord 2003;18:
425– 429.
14. Kostic V, Przedborski S, Flaster E, et al. Early development of
levodopa-induced dyskinesias and response fluctuations in
young-onset Parkinson’s disease. Neurology 1991;41:202–205.
15. Foroud T, Uniacke SK, Liu L, et al. Heterozygosity for a mutation in the Parkin gene leads to later onset Parkinson’s disease. Neurology 2003;60:796 – 801.
16. Huynh DP, Del Bigio MR, Ho DH, et al. Expression of
ataxin-2 in brains from normal individuals and patients with
Alzheimer’s disease and spinocerebellar ataxia 2. Ann Neurol
1999;45:232–241.
17. Babovic-Vuksanovic D, Snow K, Patterson MC, et al. Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG
repeat expansion. Am J Med Genet 1998;79:383–387.
18. Rufa A, Dotti MT, Galli L, et al. Spinocerebellar ataxia type 2
(SCA2) associated with retinal pigmentary degeneration. Eur
Neurol 2002;47:128 –129.
19. Fernandez M, McClain ME, Martinez RA, et al. Late-onset
SCA2: 33 CAG repeats are sufficient to cause disease. Neurology 2000;55:569 –572.
Ragothaman et al: SCA2 and Complex Phenotypes
133
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