Second edition

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Some words are required regarding the synonym for this
disorder, namely autosomal dominant cerebellar ataxia or
ADCA. This name was initially utilized by Harding (1982,
1984), who went on to divide ADCA into three different
subtypes, namely types III, II, and I. Type III was described
as being characterized solely by cerebellar signs, without
any associated features. Types II and I, by contrast, did
encompass associated features, the difference between type
II and type I being that type II could be accompanied by
pigmentary retinopathy, whereas type I cases were specifically
free of this sign. The nosologic status of this proposed
subdivision is, however, in doubt, on both clinical and etiologic
grounds. From a clinical point of view, it appears that
type III cases are exceedingly rare, perhaps (with a sufficiently
long follow-up) non-existent, and that, when comparing
types II and I, type I patients (that is to say, those
with associated features but without pigmentary retinopathy)
comprise the overwhelming majority. Furthermore,
from an etiologic point of view, it appears that this subdivision
does not ‘cleave’ nature at the genetic ‘joints’, in that
mutations at the same gene locus may cause two different
clinical types (e.g., spinocerebellar ataxia type 6 [SCA6] is
associated with both type III [Ishikawa et al. 1999] and type
I [Schols et al. 1998]). Given this nosologic uncertainty, it
may be prudent, for the time being, to refrain from subtyping
cases as III, II, or I, but rather to concentrate on
making sure that one has a case of ADCA and then proceeding
to identify the responsible genetic locus.
Clinical features
The clinical hallmark of SCA is the appearance of a gradually
progressive cerebellar ataxia, which is generally accompanied
by dysarthria and nystagmus. The onset, although
generally in the early to mid-adult years, may occur anywhere
from childhood to senescence. With disease progression,
almost all patients will also develop one or more
of the following associated features: hyper-reflexia and
extensor plantar responses; decreased vibratory sense,
atrophy, and fasciculations; supranuclear ophthalmoplegia;
tremor (including titubation), dystonia, chorea,
myoclonus or parkinsonism; or pigmentary retinopathy.
Seizures may also occur; however, they are uncommon and
may be grand mal, simple, or complex partial in type.
Dementia may occur in a minority as may a personality
change (often of the frontal lobe type), and some patients
may develop delusions and hallucinations. Rarely, SCA may
present with dementia, a personality change, or a psychosis.
The plenitude of these associated features should not,
however, distract attention from the central feature of this
syndrome, namely a progressive cerebellar ataxia; the associated
features, usually few in number in any given case, generally
play only a minor part in the overall clinical picture.
Genetic testing is available. Interestingly, given the wide
phenotypic heterogeneity, it does not appear possible to
reliably predict which SCA type is present based on the
8.17 Spinocerebellar ataxia 363
clinical picture (Giunti et al. 1998; Schols et al. 1998; Tang
et al. 2000).
Magnetic resonance scanning may reveal atrophy of the
cerebellum, pons, and inferior olives (Arpa et al. 1999;
Ueyama et al. 1998).
Etiology
As noted, SCA is an autosomal dominantly inherited syndrome,
and 26 different loci have been identified (Duenas
et al. 2006): SCA1 on chromosome 6 (Goldfarb et al. 1989,
1996; Sasaki et al. 1996; Schols et al. 1997a; Tang et al.
2000), SCA2 on chromosome 12 (Adams et al. 1997; Burk
et al. 1999; Giunti et al. 1998; Hsieh et al. 1999; Schols et al.
1997a,b; Tang et al. 2000; Ueyama et al. 1998; Zhou et al.
1998), SCA3 (also known as Machado–Joseph disease) on
chromosome 14 (Durr et al. 1996; Lopes-Cendes et al.
1996; Schols et al. 1996, 1997b; Takiyama et al. 1994; Tang
et al. 2000; Zhou et al. 1997), SCA4 on chromosome 16
(Nagaoka et al. 2000), SCA5 on chromosome 11 (Stevanin
et al. 1999), SCA6 on chromosome 19 (Arpa et al. 1999;
Ikeuchi et al. 1997; Ishikawa et al. 1999; Kaseda et al. 1999;
Matsumara et al. 1997; Schols et al. 1998; Stevanin et al.
1997), SCA7 on chromosome 3 (Benton et al. 1998; Jobsis
et al. 1997; Modi et al. 2000), SCA8 on chromosome 13
(Ikeda et al. 2000), SCA10 on chromosome 22 (Grewal
et al. 2002; Matsuura et al. 1999), SCA11 on chromosome 15
(Worth et al. 1999), SCA12 on chromosome 5 (Seltzer et al.
1999), SCA13 on chromosome 19, SCA14 on chromosome
19 (Yamashita et al. 2000), SCA 15 on chromosome 3,
SCA16 on chromosome 8, SCA17 on chromosome 6
(Lasek et al. 2006; Maltecca et al. 2003; O’Hearn et al.
2001), SCA18 on chromosome 7, SCA19 on chromosome
1, SCA20 on chromosome 11, SCA21 on chromosome
7, SCA23 on chromosome 20, SCA24 on chromosome 1,
SCA25 on chromosome 2, SCA26 on chromosome 19,
SCA27 on chromosome 13, and SCA28 on chromosome
18. Some authors also include dentatorubropallidoluysian
atrophy among the SCAs (specifying it as ‘SCA9’), but
given that patients with dentatorubropallidoluysian atrophy
may have little or no ataxia, and often have prominent
chorea, this inclusion may not be warranted, and, in this
text, dentatorubropallidoluysian atrophy is discussed separately,
in its own section.
Most of the known mutations involve trinucleotide
repeat expansions, as has been found for SCA1, -2, -3, -6,
-7, -12, and -17; a CTG trinucleotide repeat expansion has
been noted for SCA8, a pentancleotide repeat expansion
for SCA10, and missense mutations for SCA5, -23, -14,
and -27.
The pathologic hallmark of this syndrome is atrophy of
the cerebellum, pons, and inferior olives; in addition to
these findings, associated atrophy may also be found in one
or more of the following structures: the spinocerebellar
tracts, Clarke’s column, the globus pallidus, the subthalamic
nucleus, the substantia nigra, and the cerebral