Dominantly inherited ataxia and dysphonia with dentate calcification: Spinocerebellar ataxia type 20

Abstract

We describe a pedigree of Anglo-Celtic origin with a phenotypically unique form of dominantly inherited spinocerebellar ataxia (SCA) in 14 personally examined affected members. A remarkable observation is dentate nucleus calcification, producing a low signal on MRI sequences. Unusually for an SCA, dysarthria is typically the initial manifestation. Mild pyramidal signs and hypermetric saccades are noted in some. Its distinguishing clinical features, each present in a majority of affected persons, are palatal tremor, and a form of dysphonia resembling spasmodic dysphonia. Repeat expansion detection failed to identify either CAG/CTG or ATTCT/AGAAT repeat expansions segregating with the disease in this family. The testable SCA mutations have been excluded. On linkage analysis, the locus maps to chromosome 11, which rules out all the remaining mapped SCAs except for SCA5. While locus homogeneity with SCA5 is not formally excluded, we consider it rather unlikely on phenotypic grounds, and propose that this condition may represent an addition to the group of neurogenetic disorders subsumed under the rubric SCA. The International Nomenclature Committee has made a provisional assignment of 'SCA20', although firm designation will have to await a definite molecular distinction from SCA5.

Full text

Dominantly inherited ataxia and dysphonia with
dentate calci®cation: spinocerebellar ataxia type 20
Melanie A. Knight,1,3 R. J. McKinlay Gardner,1,2,3 Melanie Bahlo,4Tohru Matsuura,8
Judith A. Dixon,6Susan M. Forrest3,5 and Elsdon Storey2,7
1Murdoch Childrens Research Institute and 2Genetic
Health Services Victoria, Royal Children's Hospital,
3Department of Paediatrics, University of Melbourne,
4Genetics and Bioinformatics Division, and 5Australian
Genome Research Facility, Walter and Eliza Hall Institute,
6Department of Otolaryngology, Alfred Hospital,
7Department of Medicine (Neurosciences), Monash
University (Alfred Hospital Campus), Melbourne, Australia
and 8Department of Molecular and Human Genetics,
Baylor College of Medicine, Houston, TX, USA
Correspondence to: Professor Elsdon Storey, Department
of Neurosciences, Alfred Hospital, Melbourne,
Victoria 3004, Australia
E-mail: elsdon.storey@med.monash.edu.au
Summary
We describe a pedigree of Anglo-Celtic origin with a
phenotypically unique form of dominantly inherited spi-
nocerebellar ataxia (SCA) in 14 personally examined
affected members. A remarkable observation is dentate
nucleus calci®cation, producing a low signal on MRI
sequences. Unusually for an SCA, dysarthria is typically
the initial manifestation. Mild pyramidal signs and
hypermetric saccades are noted in some. Its distinguish-
ing clinical features, each present in a majority of
affected persons, are palatal tremor, and a form of dys-
phonia resembling spasmodic dysphonia. Repeat expan-
sion detection failed to identify either CAG/CTG or
ATTCT/AGAAT repeat expansions segregating with the
disease in this family. The testable SCA mutations have
been excluded. On linkage analysis, the locus maps to
chromosome 11, which rules out all the remaining
mapped SCAs except for SCA5. While locus homogen-
eity with SCA5 is not formally excluded, we consider it
rather unlikely on phenotypic grounds, and propose
that this condition may represent an addition to the
group of neurogenetic disorders subsumed under the
rubric SCA. The International Nomenclature
Committee has made a provisional assignment of
`SCA20', although ®rm designation will have to await a
de®nite molecular distinction from SCA5.
Keywords: autosomal dominant spinocerebellar ataxia; spinocerebellar ataxia type 20; dentate nucleus calci®cation; palatal
tremor; linkage analysis
Abbreviations: ADCA = autosomal dominant cerebellar ataxia; AGAAT, adenine±guanine±adenine±adenine±thymine
pentanucleotide; ATTCT, adenine±thymine±thymine±cytosine±thymine pentanucleotide; CAG, cytosine±adenine±guanine
trinucleotide; cM = centiMorgans; CTG, cytosine±thymine±guanine trinucleotide; DRPLA = dentatorubral-pallidoluysian
atrophy; GDB = Genome Database; LOD = logarithm of odds; NCBI = National Center for Biotechnology Information;
RED = repeat expansion detection; SCA = spinocerebellar ataxia; VOR = vestibulo-ocular re¯ex
Received July 30, 2003. Revised December 26, 2003. Accepted January 8, 2004
Introduction
The autosomal dominant cerebellar ataxias (ADCAs) have
been classi®ed clinically according to the presence or absence
of extracerebellar involvement, and genetically according to
the demonstration of a speci®c mutation or a mapped locus.
The genetic classi®cation is based upon the demonstration of
locus heterogeneity, and each newly identi®ed ataxia is
ascribed a spinocerebellar ataxia (SCA) number (Margolis,
2002; Chung et al., 2003). Many SCAs remain to be
discovered (Subramony and Filla, 2001). Worldwide, about
a third of the ADCA pedigrees remain unmapped (Zu et al.,
1999), and a survey of pedigrees with dominantly inherited
SCA in south-eastern Australia showed that only about half
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were accounted for by the more common SCAs, namely
SCAs 1, 2, 3, 6 and 7 (Storey et al., 2000). We have reviewed
our neurogenetic clinic population to assess those families in
which analysis might potentially be fruitful, and we report
here the observations and ®ndings from one such ADCA
family. Notable additional clinical ®ndings are dysphonia,
resembling spasmodic dysphonia, which is superimposed on
the cerebellar dysarthria, and palatal tremor. The striking
correlate on neuroimaging is dentate nucleus calci®cation.
The genetic rubric which has been applied following
submission to the Human Gene Nomenclature Committee is
SCA20, although formal proof of its distinction from SCA5,
which maps to the same chromosomal region, is yet to be
adduced.
Material and methods
Clinical studies on the family
The pedigree of the family is presented in Fig. 1. The propositus
(III:11) was judged to have a spasmodic dysphonia superimposed
upon his cerebellar dysarthria, and his report that other affected
family members also had `squeaky voices' led to further investiga-
tion of the pedigree. All known living affected family members were
personally examined by the senior author (E.S.), neuroradiological
examinations initiated, and previous studies reviewed. Formal voice
analysis, using stroboscopic evaluation of vocal fold vibration and
acoustic analysis of phonation of isolated vowels and connected
speech samples, was undertaken in the propositus. Some affected
persons had blood samples drawn for testing of calcium homeostasis.
The study was approved by the Women's and Children's Hospital
(Melbourne) Human Ethics Committee.All participants gave
informed consent.
Genotyping and linkage analysis
Blood was collected from affected individuals and other appropriate
and available family members for genotyping and direct gene
testing, and genomic DNA prepared. The trinucleotide expansions of
SCAs 1±3, 6±8, 17 and dentatorubral-pallidoluysian atrophy
(DRPLA) were tested in representative family members.
Microsatellite markers reported in the literature were used to test
linkage to the loci of SCAs 4±6 and 10±16, as follows: for the SCA4
Fig. 1 Partial pedigree of the kindred and haplotyping results. In generation III, only those actually examined are included, and in
generation IV, only those examined and diagnosed as affected, and it is upon these data that the linkage exercise is based (no de®nite
judgement could be made about the genotypes of the unaffected individuals of generation IV, and they were therefore excluded).
Haplotypes with respect to chromosome 11 markers have been constructed according to the most parsimonious requirement for
recombination, the markers being ordered, from top to bottom, from p-terminal to q-terminal. The haplotype segregating with the disease
is boxed, and arrows show limits of the shortest region of overlap, which thus de®nes the SCA20 candidate region, in the individuals in
whom this could be inferred. The SCA5 region, which extends from FGF3 to PYGM, is included within this SCA20 region. Filled
symbols = clinically affected on personal examination and/or dentate calci®cation on neuroradiology; N = no symptomatology, no signs of
cerebellar disease on examination; ? = no reliable information (earlier generations); open symbols = unaffected spouse; diagonal line
through symbol = deceased.
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locus at 16q22.1, markers D16S397 and D16S3050 (Flanigan et al.,
1996; Nagaoka et al., 2000); the SCA5 locus at 11p12±q12, markers
D11S903 and D11S913 (Ranum et al., 1994); the SCA6 locus,
markers D19S221, D19S1150 and D19S226 (Yue et al., 1997); the
SCA10 locus at 22q13, markers D22S274 and D22S928 (Zu et al.,
1999); the SCA11 locus at 15q14±21.3, markers D15S994, D15S123
and D15S1039 (Worth et al., 1999); the SCA12 locus at 5q31±q33,
markers D5S436 and D5S470; the SCA13 locus at 19q13.3±13.4,
marker D19S902 (Herman-Bert et al., 2000); the SCA14 locus at
19q13.3±qter, markers D19S206 and D19S605 (Yamashita et al.,
2000); the SCA15 locus at 3p24.2±3pter, markers D3S3630,
D3S3050 and D3S1560 (Knight et al., 2003); and for the SCA16
locus at 8q22.1±24.1, markers D8S514 and D8S284 (Miyoshi et al.,
2001). Markers from the ABI PRISM Linkage Mapping Set, version
2 (PE Applied Biosystems), at a marker density of 10 centiMorgans
(cM), were used for a genome-wide scan. Fine-mapping markers
with respect to chromosome 11 were obtained from NCBI and GDB
databases (National Center for Biotechnology Information; Genome
Database).
Simulation studies using SIMLINK Version 4.1 (Ploughman and
Boehnke, 1989) indicated that the family had the potential to
demonstrate linkage, with a theoretical maximum logarithm of odds
(LOD) score of 6.9 (average LOD score of 4.62), and would be
capable of excluding linkage to 10.6 cM on either side of an unlinked
marker. Transmission of SCA20 was assumed to be autosomal
dominant, with estimates of age-speci®c penetrance derived from a
Kaplan±Meier plot of data from the affected persons (which gave an
almost straight-line graph from 0.1 at age 30 to 1.0 at 65 years). The
disease allele was assigned a frequency of 0.0002 with 0%
phenocopy rate. All markers with <10 alleles were given the equal
allele frequency of 0.1, and markers with >10 alleles were given the
frequency 1/(number of observed alleles). Equal rates of male and
female recombination were assumed. Information on additional
markers to con®rm and re®ne the interval was accessed through the
NCBI and GDB databases.
The data were prepared for input by genotyping error-cleaning
and pedigree checking with PREST (McPeek and Sun, 2000),
PEDCHECK (O'Connell and Weeks, 1998) and UNKNOWN
(Terwilliger and Ott, 1994). Genotyping errors were removed and
one pedigree error corrected. Two-point analysis was performed
using the MLINK program of the LINKAGE package (version 5.1)
(Lathrop et al., 1984). The Elston±Stewart algorithm in the form of
the program VITESSE was applied for a limited multipoint analysis
(5±10 marker blocks including the disease locus), using a single
penetrance model with penetrances of Pr(disease|DD) = 0.0,
Pr(disease|Dd) = 0.99, Pr(disease|dd) = 0.99.
Repeat expansion detection (RED) analysis
The RED technique was performed essentially as described in
Schalling et al. (1993) to test for the presence of unstable CAG/CTG
trinucleotide repeats, in samples from several family members. In
addition to testing CAG/CTG repeats via RED, a modi®ed version of
the technique was used to investigate the ATTCT/AGAAT
pentanucleotide repeat associated with SCA10 (Matsuura et al.,
2000; Knight et al., 2003).
Results
Phenotype: clinical characterization of the SCA
family
The pattern of transmission of the disease is consistent with
autosomal dominant inheritance. A partial pedigree is shown
Table 1 Summary of certain clinical observations
Case Onset age/
duration/age
examined
(years)
First symptom `Dysphonia'
(see text)
Ballistic
overshoot
Bradykinesia* Tremor
III:3 57, 20, 77 Dysarthria Mild to
moderate
Moderate Bilaterally ¯2.5 SD Palatal
III:6 64, 10, 74 Gait ataxia Mild Moderate Bilaterally 1.5 SD Nil
III:8 45, 20, 65 Dysarthria
and ataxia
Nil Moderate right,
marked left
Right ¯1 SD, left ¯2 SD Palatal,
lower lip
III:10 60, 8, 68 Dysarthria Mild Moderate Right 1.5 SD, left 0.5 SD Palatal
III:11 48, 20, 67 Dysarthria Moderate Moderate Bilaterally ¯1 SD Nil
III:12 62, 3, 65 Dysarthria
and ataxia
Very mild Mild right,
moderate left
Right 1 SD, left average Palatal
III:13 40, 24, 64 Dysarthria Moderate Mild to moderate Bilaterally 0.5 SD Palatal,
upper lip
III:15 19, 43, 62 Dysarthria Moderate Marked Bilaterally ¯3 SD Palatal
III:16 56, 1, 56 Dysarthria Very mild Nil right, mild left Right 1 SD, left average Palatal
IV:1 55, 3, 58 Gait ataxia Nil Marked right,
moderate left
Bilaterally ¯3.5 SD Palatal
IV:2 42, 15, 57 Dysarthria Nil Mild Bilaterally ¯2.5 SD Palatal
IV:3 38, 16, 54 Dysarthria
(sudden onset)
Mild Marked Bilaterally ¯2 SD Palatal,
head, arm
IV:4** 33, 5, 38 Tremor Nil Mild right, nil left Not tested Nil
IV:5 34, 5, 39 Dysarthria
(sudden onset)
Very mild Moderate right,
mild left
Bilaterally ¯3 SD Nil
*Index tapping rate per 10 s (Bornstein, 1985); **affected status con®rmed on neuroradiology (dentate calci®cation on CT scan).
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in Fig. 1, restricted for the most part to showing those family
members who could be assessed/sampled. In all, 14 affected
members underwent systematic neurological history and
examination (Table 1). The age at onset of ®rst symptom, as
self-reported, ranged from 19 to 64 years, mean and median
both 46.5 years. Three parent±child pairs (III:3/IV:2±3 and
III:13/IV:5) were documented by self-report with respect to
age of onset, with an average of a 10 year earlier onset in the
child. One member (IV:4) was judged to be possibly affected
on clinical assessment at age 38 years, showing only postural/
action tremor and impaired visual suppression of the
vestibulo-ocular re¯ex (VOR), but was shown subsequently
on CT to have the characteristic dentate calci®cation (see
below), con®rming his status as affected. In generation IV
(age range 30±50 years), among the 26 offspring of known
affected persons, ®ve were affected (Fig. 1), ®ve we
con®rmed to be clinically unaffected, and the remaining 16
were anecdotally reported to be unaffected. None is reported
to be affected in generation V, the oldest now entering their
30s. There was no instance of an affected offspring of an
apparently unaffected parent.
The ®rst symptom was dysarthria in nine of 14, gait ataxia
in two, and both together in two. The dysarthria was reported
to have been of sudden onset in two out of nine. The second
symptom in those initially manifesting dysarthria was
typically gait ataxia (seven out of nine), which followed
from 3 months to 25 years later. In the other two out of nine,
the second symptom was of upper limb ataxia (hammering
nails, handwriting). In one out of 14, the only symptom was
tremor. At the time of examination, illness duration had
varied from 1 to 43 years. As judged by these cross-sectional
data, progression is probably slow, with one affected
becoming wheelchair-dependent after 40 years of symptoms,
and one other requiring percutaneous gastrostomy feeding
after 15 years of symptoms.
Upper limb ataxia typically was more prominent on
ballistic tracking than ramp (slow ®nger/nose) movements
(11 out of 14). Two affected members had a postural and
action tremor affecting the head and arms, this being the only
sign in one (IV:4). Index ®nger tapping rate was reduced (>2
SD below normal for age, sex, education and hand) in at least
one hand in seven out of 13 (IV:4 not tested). Plantar
responses were ¯exor in 13 and equivocal in one, but ®ve had
minor pyramidal signs (hyper-re¯exic knee jerks without
increased tone; crossed adductor responses). Sensation at the
toes (vibration perception, two-alternative forced choice
method; pinprick; two-point discrimination) was typically
unremarkable, although three out of 14 had an increased two-
point discrimination threshold of >2 cm (i.e. greater than the
diameter of their great toes).
Clinical examination of eye movements typically revealed
hypermetric saccades into down gaze (10 out of 14), with
eight also hypermetric on horizontal gaze. Smooth pursuit
showed saccadic interruptions in three, while four had a mild
or moderate excess of square wave jerks in the primary
position. Nystagmus was typically absent, but two out of 14
showed slight, non-sustained down and lateral nystagmus in
down and lateral gaze (`side pocket nystagmus'). The VOR
gain was uniformly normal as judged by dynamic versus
static visual acuity and by estimation of VOR gain by
ophthalmoscopy during head oscillation (Zee, 1978). Visual
suppression of the VOR was impaired in eight out of 14.
Visual acuity and colour vision (Farnsworth-Munsell 15D
test) were normal in all, apart from III:8 who had a typical and
presumably unrelated protanopia.
The clinical syndrome is thus of a relatively pure
cerebellar ataxia, without prominent pyramidal features. In
addition, two distinctive features were usually present. A
dysphonia sounding super®cially similar to adductor
spasmodic dysphonia was present in nine out of 14,
although in two of these it was mild, discernible on
reading a prose paragraph but not in ordinary conversa-
tion. In those in whom it was more prominent, it was
usually reported to have followed the development of
dysarthria by several years. Palatal tremor of ~2 Hz,
unassociated with ear click, was seen in 10 out of 14; in
two out of these 10, it was also evident in the lips.
Phenotype: imaging, clinical and laboratory
investigations of the SCA family
CT showed pronounced dentate calci®cation in nine out
of nine in whom scanning was done, including in three
who had been symptomatic for <3 years, and in the one
in whom the only clinical sign was tremor. In only two
of these nine was there pallidal calci®cation, and in one
of these it was very slight (IV:3). MRI showed mild to
moderate pancerebellar atrophy, along with low dentate
signal on both T1 and T2 sequences in four out of four
subjects scanned. Brainstems were normal, apart from
increased inferior olivary T2 signal in two, which is a
neuroimaging correlate of symptomatic palatal tremor
(Yokota et al., 1989). Illustrative scans are shown in
Fig. 2. Reports on MRI scans in two other individuals,
the ®lms having now been destroyed, also refer to
markedly decreased density in the region of the dentate
nucleus, attributed to calci®cation.
Voice analysis was performed in the index case (III:11).
The initial impression was of an ataxic dysarthria with
spasmodic dysphonia. Stroboscopic laryngoscopy showed
movement of laryngeal structures synchronously with the
palatal tremor, with no evidence of adductor spasmodic
dysphonia. Speech frequency analysis demonstrated abnor-
mal pitch spread with pitch elevation, and voicing of non-
voiced sounds (Fig. 3). Nerve conduction studies (sural
sensory, tibial motor) were performed in three, including one
of those in whom the great toe two-point discrimination
threshold was >2 cm. All were normal. Calcium homeostasis
was assessed (serum calcium, phosphate, magnesium, alka-
line phosphatase, parathyroid hormone, 25-hydroxy vitamin
D) in ®ve affected persons, with normal ®ndings apart from a
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borderline low and borderline high level, respectively, of 25-
hydroxy vitamin D in IV:1 and IV:5, and borderline elevated
parathyroid hormone levels in III:13 and IV:4, which we
interpreted as being of no material signi®cance. One
individual (III:8) had a balanced chromosome translocation,
46,XY,t(1;12)(p22;q11), but this was not seen in several other
family members karyotyped.
Genotyping and linkage analysis
SCAs 1, 2, 3, 6±8, 17 and DRPLA were excluded by direct
CAG repeat expansion testing. Two-point linkage analysis
was performed with respect to SCAs 4±6 and 10±16, and no
evidence of signi®cant linkage was found (data not shown). A
genome-wide scan was undertaken. Single point analysis with
MLINK showed a clear genome-wide maximum LOD = 4.47,
Fig. 2 Neuroradiology. Top three rows: non-contrast axial brain CT scans on eight affected family
members, showing dentate calci®cation in all, and pancerebellar atrophy in most. Cuts at two levels of
the dentate are shown for III:16 and IV:5. Only one individual showed obvious pallidal calci®cation
(III:13b); very slight pallidal calci®cation was seen in one other case (IV:3). Ages at examination range
from 38 (IV:5) to 72 (III:6) years. Bottom two rows: non-contrast brain MRI scans of four affected
family members. III:6: T1 sagittal sequence (a) showing mild vermal atrophy with normal brainstem,
and axial proton density image (b) showing low dentate signal. III:11, IV:3: axial proton density images
showing inferior olivary hypertrophy (a), and low dentate signal (b). IV:5: proton density sagittal image
(a) showing mild vermal atrophy and normal brainstem, and T2 coronal image showing low dentate
signal and mild cerebellar atrophy (b).
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with a recombination fraction of 0, at marker D11S4191
(position 63.4 cM) in the pericentromeric region of chromo-
some 11 (Table 2). No other region tested signi®cantly
positive [thus also enabling exclusion of SCA18 (Brkanac
et al., 2002), SCA19 (Verbeek et al., 2002), SCA21
(Vuillaume et al., 2002) and SCA22 (Chung et al., 2003)].
Analysis of the ®ne-mapping data, using the VITESSE
program, showed a clear peak at position 62.2 cM with a
parametric LOD score of 4.51 (Fig. 4). (A 3-LOD support is
dif®cult to establish using the windowing approach, as an
entire window spans the 3-LOD support interval.)
The haplotype co-segregating with the disease in this
family is shown in Fig. 1. The informative recombination
events observed in affected individuals III:13, IV:4 and IV:5
show that the distal recombination site is between markers
D11S903 and D11S4109, and the recombination events in
affected individuals IV:4 and IV:5 show that the proximal site
is between markers D11S913 and FGF3. Using the genetic
information from these individuals, the candidate region can
be assigned to a 25.4 Mb interval between markers D11S903
and FGF3/INT2.
Triplet repeat analysis
No large CAG/CTG trinucleotide or ATTCT/AGAAT
pentanucleotide repeats were identi®ed.
Discussion
We describe a novel syndrome of cerebellar ataxia, dysphonia
and palatal myoclonus. The rate of progression is slow and
the degree of cerebellar affection is, for the most part, towards
the less severe end of the SCA spectrum. There is no
recognized instance of an affected person having an
unaffected obligate heterozygous parent, thus indicating
that the SCA20 gene is likely to be fully penetrant. The
family data are insuf®cient formally to examine the case for
anticipation. We have noted the datum of an average 10 year
drop in (self-reported) age of onset measured in three
instances; against this, there is an apparent paucity of affected
members in generation IV (possibly some are yet to manifest
symptoms), and none is known to be affected in generation V.
A further point against anticipation is that the RED analysis
was negative, indicating that at least a large tri- or
pentanucleotide expansion is unlikely to be the basis of the
SCA20 mutation; nevertheless, we acknowledge that triplet
repeat expansions exist in SCA8 (in the 3¢-untranslated
region) (Koob et al., 1999) and in SCA12 (in the 5¢-
untranslated region) (Holmes et al., 1999), and that neither of
these SCAs shows anticipation.
The present syndrome may be distinguished clinically from
the other SCAs by the associated features of dysphonia and
palatal myoclonus, and the radiological observation of
dentate calci®cation. Given this unique and rather striking
combination of clinical features, we were expecting that our
genetic analysis would identify a novel chromosomal region
co-segregating with the disease in the family. However, in
fact, the syndrome proved to be linked to the same region of
chromosome 11 within which the SCA5 locus lies. At ®rst
sight, a genetic identity between SCA5 and the present SCA
might seem unlikely on phenotypic grounds, but that
possibility has to remain open until such time as a genetic
distinction might be proven (discussed further below).
Nevertheless, a provisional assignment of the rubric SCA20
has been made by the Nomenclature Committee.
The abnormal dentate radiology is a very notable feature,
and the development of the calci®cation appears to be an
early feature in the evolution of the disease process, with one
very subtly affected (IV:4) and two very mildly affected
(III:12, III:16) persons having obvious signs on brain CT.
Dentate calci®cation may be an incidental ®nding in 0.7% of
those over 65 years of age, typically occurring in conjunction
with pallidal calci®cation (Harrington et al., 1981). It is very
rarely seen in the absence of basal ganglia calci®cation; in
only one case from 4219 consecutive CT scans in the series of
Koller et al. (1979). Hypoparathyroidism with basal ganglia
calci®cation may be dominantly inherited (Smits et al., 1982),
and dominant pseudohypoparathyroidism may cause a similar
Fig. 3 Voice analysis in III:11. Top panel: proportion of frication
(Fx), voiced (Vx) and intervocalic silence (Sx) time periods during
passage reading, showing voicing of normally non-voiced sounds
(Vx and Sx are equal in normal subjects). Bottom panel:
probability (log scale) versus frequency (F) (pitch) during passage
reading. Normal (male) subjects produce a single, bell-shaped
curve, centred on average at ~112 Hz. The frequency spread with
multiple peaks and the high frequency of the maximum peak are
abnormal in this subject.
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picture (Illum and Dupont, 1985; Flint and Goldstein, 1992).
These conditions, for which otherwise there is no clinical
support in our material, have been excluded on appropriate
investigation. Microcalci®cation of the globus pallidus, but
not the dentate, is recorded in Haw River syndrome, an
unusual phenotypic variant of DRPLA (Farmer et al., 1989;
Burke et al., 1994), scarcely a candidate clinical diagnosis in
the present family (and excluded on both DNA and linkage
analysis). Finally, a rare dominantly inherited disorder
`familial idiopathic brain calci®cation' has been described
in some 13 pedigrees (Kobari et al., 1997; Prieto et al., 1997).
This disorder may be asymptomatic despite radiological
evidence of calci®cation; in those with clinical involvement,
cognitive decline and parkinsonism have predominated over
the cerebellar symptomatology. These additional clinical
features were not present in SCA20; conversely, palatal
tremor and dysphonia have not been described in familial
idiopathic brain calci®cation. The distribution of calci®cation
is also different in familial idiopathic brain calci®cation, with
extensive involvement of basal ganglia, thalamus, cerebral
cortex, subcortical white matter and hippocampus, in addition
to dentate calci®cation. Finally, the condition maps, in at least
one family, to a chromosome (number 14) different from
SCA20 (Geschwind et al., 1999). We conclude that no other
syndrome displays the same neuroradiological characteristics
as the syndrome presently described.
Palatal tremor, sometimes also referred to as palatal or
branchial myoclonus, may occur in isolated or symptomatic
forms (Nagaoka and Narabayashi, 1984; Deuschl et al.,
1990). SCA20 clearly falls into the symptomatic category, by
reason of the associated clinical features, the absence of ear
click and the spread of involvement to other branchial
muscles (lips, pharynx) in three affected members. The
abnormal inferior olivary signal on MRI in two of four
members scanned (Fig. 2) is also consistent with the
symptomatic form of palatal tremor, and probably represents
olivary pseudohypertrophy (Yokota et al., 1989). The com-
bination of palatal tremor and progressive ataxia can occur
Table 2 Two-point LOD scores for the SCA20 locus and 24 chromosome 11 markers
Genome-wide
scan markers
Fine-mapping
markers
Location
(cM)
Recombination fraction (q)
0 0.01 0.05 0.1 0.2 0.3 0.4
D11S4046 ±18.11 ±5.89 ±2.58 ±1.32 ±0.34 ±0.02 0.02
D11S1338 ±13.06 ±4.4 ±1.79 ±0.82 ±0.12 0.06 0.04
D11S902 24.7 ±9.82 ±1.99 ±0.74 ±0.31 ±0.02 0.06 0.06
D11S904 37.0 ±3.18 0.74 1.26 1.32 1.12 0.75 0.3
D11S935 49.6 ±8.73 ±0.23 0.93 1.23 1.18 0.84 0.36
D11S905 55.7 ±2.7 1.47 1.94 1.95 1.61 1.1 0.47
D11S903 59.5 ±9.06 ±0.47 0.71 1.04 1.05 0.75 0.31
D11S1357 62.5 3.53 3.47 3.2 2.86 2.15 1.39 0.6
D11S4109 63.3 4.47 4.4 4.1 3.71 2.87 1.94 0.91
D11S4191 63.4 4.47 4.4 4.1 3.71 2.87 1.94 0.91
D11S4076 64.9 4.17 4.1 3.81 3.43 2.63 1.76 0.8
PYGM 2.05 2.01 1.82 1.61 1.19 0.8 0.41
D11S913 70.9 3.04 2.99 2.75 2.46 1.83 1.18 0.51
INT2 (FGF3) ±3.23 0.74 1.26 1.32 1.12 0.75 0.3
D11S987 ±1.95 2.38 2.8 2.73 2.25 1.55 0.72
D11S1314 77.5 ±3 1 1.46 1.46 1.16 0.73 0.28
D11S937 84.6 ±1.93 2.39 2.81 2.75 2.26 1.57 0.73
D11S901 89.8 ±2.77 0.99 1.46 1.46 1.14 0.68 0.23
D11S4175 ±3.36 ±1.01 0.2 0.55 0.64 0.46 0.19
D11S908 ±3.39 ±2.85 ±1.07 ±0.38 0.07 0.14 0.07
D11S925 ±8.65 ±4.29 ±2.78 ±1.52 ±0.45 ±0.03 0.08
D11S4151 ±19.55 ±9.36 ±5.15 ±3.24 ±1.51 ±0.66 ±0.2
D11S1320 ±9.11 ±6.57 ±3.66 ±2.29 ±1.09 ±0.52 ±0.19
D11S968 0.66 0.65 0.57 0.47 0.29 0.14 0.05
Fig. 4 Multipoint LOD score analysis with respect to ®ne-mapping
markers on chromosome 11. The maximum parametric LOD score
achieved is 4.51 at position 62.2 cM.
Spinocerebellar ataxia type 20 Page 7 of 10
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sporadically (Leger et al., 1986; Phanthumchinda, 1999), and
it has been argued that it represents a unique degenerative
syndrome (Sperling and Herrmann, 1985). It may be seen in
the OPCA (olivopontocerebellar) variant of multiple system
atrophy (Kulkarni et al., 1999). Palatal tremor with
nystagmus, bulbar palsy and spastic tetraparesis has also
been seen in autosomal dominant early adult-onset
Alexander's disease (Howard et al., 1993; Schwankhaus
et al., 1995; Okamoto et al., 2002), which is probably the
same disorder as that described by de Yebenes et al. (1988) of
a dominant branchial myoclonus with spastic paraparesis and
cerebellar ataxia. While palatal tremor was consistently
observed in these pedigrees, distinguishing them from SCAs
2 and 3 where it is an occasional feature only, no dentate
calci®cation or dysphonia was evident. Later adult-onset
Alexander's disease maps to chromosome 17 (Namekawa
et al., 2002), although it is not yet clear whether all adult-
onset Alexander's has the same genetic basis. Thus we
conclude that, in all probability, on phenotypic and genetic
grounds, these several families represent a different disorder
from SCA20.
A single cerebellar ataxia disorder otherwise on record
which includes dysphonia in the clinical picture can readily
be separated from the present condition, with the dysphonia
being due to a laryngeal abductor paralysis, and there being a
concomitant motor neuropathy (Barbieri et al., 2001).
The classi®cation of the dominantly inherited SCAs has
shifted from a phenotypic towards a genotypic basis. The
number of genetically de®ned SCA entities reported in the
literature currently has reached 22 and will surely increase
(Margolis, 2002). We need to consider the importance of
SCA20 in the spectrum of the hereditary ataxias. The
syndrome as described here is clinically distinctive enough
that it would probably have been reported in the literature
before now, were it a common cause of inherited ataxia. On
the other hand, dentate calci®cation might well be viewed as
incidental, and palatal tremor is occasionally recognized in
other degenerative ataxias, so that a neurologist seeing a
single member of a pedigree might well not appreciate that
the disorder was novel (as was indeed the case with some in
the present family). Ultimately, assessment of its rarity will
have to await reports from others in other ethnic groups; the
discovery that SCA12 is common in India although rare in the
USA (where it was originally described) and the UK is an
object lesson in this regard (Fujigasaki et al., 2001).
Our genetic analysis excluded all the cloned or mapped
SCAs up to SCA22, with the exception of SCA5. An
assumption of linkage to chromosome 11 can be made in light
of the LOD score of >4. In the present family, informative
recombinations in members III:13, IV:4 and IV:5 (Fig. 1)
enabled narrowing down of the candidate region. One of the
recombination sites is between markers D11S903 and
D11S4109 and the other is between marker D11S913 and
FGF3, and thus the candidate region extends from FGF3 to
D11S903, this region having an estimated size of ~25.4 Mb.
The SCA5 candidate region, of size 5 cM, is bounded by
FGF3 and PYGM, and this segment is wholly included within
the SCA20 region. The exact ordering of markers in this
region is uncertain, and clari®cation of the precise regions of
overlap between the SCA5 and SCA20 candidate regions will
be the subject of further study.
The question thus arises: is this an example of locus
homogeneity, with SCAs 5 and 20 due to different mutations
within the same gene? Or, are SCA5 and SCA20 genetically
separate conditions, whose loci happen to lie quite closely
together in the same chromosomal region? In terms of
precedents for locus homogeneity, a number of neurological
loci are known at which different types or sites of mutation
may lead to different phenotypes. One example among the
SCAs is the calcium channel gene CACNA1A, in which
different mutations may lead to SCA6, hemiplegic migraine
or episodic ataxia type 2 (Margolis, 2002); another potential
example is the PRKCG locus, the basis of SCA14, this being
typically a pure cerebellar ataxia, but in which some
mutations may be associated with extracerebellar features
(Van De Warrenburg et al., 2003; Yabe et al., 2003).
Certainly, SCA5 differs clinically from SCA20. SCA5 was
described initially by Ranum et al. (1994), and one further
family was identi®ed subsequently (Stevanin et al., 1999).
The phenotype in the original family consisted of a pure
cerebellar ataxia, with onset usually in the third or fourth
decade, and a slow progression. In the second SCA5 family,
the picture was similar but included a concomitant slight
facial myokymia, increased re¯exes and decreased vibration
sensation. MRI studies in both families are reported as
showing cerebellar atrophy without brainstem involvement,
and in neither was any mention made of an abnormal dentate
signal.
The alternative interpretation is that of a genetic hetero-
geneity between SCAs 5 and 20. The very distinctive
phenotypic features of SCA20, as discussed above, might
be seen as evidence against a genetic (locus) identity between
the two. Along with the present potential case, two other SCA
examples can be cited in which similar questions arise. SCA4
was reported in the original kindred with an accompanying
axonal peripheral neuropathy, but a second `SCA4 family'
mapping to the same region displayed only a pure cerebellar
ataxia (Nagaoka et al., 2000). We have described a pure
cerebellar ataxia, SCA15, mapping to chromosome 3p26
(Knight et al., 2001; Storey et al., 2001), and a Japanese
group since reported a SCA family with linkage to the same
region, but in which there were the additional clinical features
of tremor and myoclonus (Hara et al., 2002). However,
distinction of the SCA5 and SCA20 genotypes can be made
only in the knowledge of the actual causative gene(s) and,
pending that knowledge, the issue of locus homogeneity
versus coincidental (or possibly functional) locus propinquity
remains open to question.
We conclude that the condition we describe is a clinically
distinctive syndrome, and which may well prove to be a
genetically distinct condition. If so, the assignment of a new
SCA genetic rubric, SCA20, could in due course be
Page 8 of 10 M. A. Knight et al.
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con®rmed. However, given its co-localization to the same
region of chromosome 11 which harbours the SCA5 locus, we
concede that there exists the alternative explanation of
phenotypic heterogeneity residing in SCA5. We intend to
work to answer this question.
Addendum
After these studies had been undertaken, a further case was
identi®ed when the 40-year-old son of individual III:10
presented himself to our clinic. He showed mild dysarthria,
slight dysphonia and subtle palatal myoclonus, and dentate
calci®cation was seen on CT scan. Indices of calcium
function (as above) were all normal.
Acknowledgements
We wish to thank the family members for their willing
cooperation, Ms Janet H. Shaw for SCA gene analysis, and
Mr Harry Rundle of the Alfred Hospital for performing the
stroboscopic laryngoscopy. The study was supported by the
Murdoch Childrens Research Institute, which is the recipient
of a Centre Grant from the National Health and Medical
Research Council of Australia. M.A.K. is a National Health
and Medical Research Council Dora Lush Postgraduate
Scholar. T.M. is supported by the National Ataxia
Foundation, Minneapolis, USA, Ichiro Kanehara
Foundation and Brain Science Foundation, Tokyo, Japan.
The clinical material was presented as a poster at the 37th
annual meeting of the Canadian Congress of Neurological
Sciences, Vancouver, Canada, June 2002, and the genetic
study was presented as a poster at the 52nd annual meeting of
the American Society of Human Genetics, Baltimore, MD,
October 2002.
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