Autosomal dominant cerebellar ataxia type I:
A review of the phenotypic and genotypic
Nathaniel Robb Whaley1,2, Shinsuke Fujioka2and Zbigniew K Wszolek2*
Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia
with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal
dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not
known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder
effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of
presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition
include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar
signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or
supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body
part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings
though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been
identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral
pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism
into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and
DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease
gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense
mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on
clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is
broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies,
infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative
disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in
specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is
therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is
essential. Prognosis is variable depending on the type of ADCA and even among kindreds.
Autosomal Dominant Cerebellar Ataxias, Spinocerebel-
Disease definition/Diagnostic criteria
The definition of spinal cerebellar ataxias (SCAs) despite
significant progress in their understanding is still
imprecise. They can be divided by the mode of inheri-
tance to autosomal dominant, autosomal recessive, or
sporadic conditions, Harding proposed a classification of
autosomal dominant cerebellar ataxias (ADCA) into
three categories, Type I, Type II and Type III. ADCA
Type I comprises syndromes such as SCA1- SCA4,
SCA8, SCA10, SCA12 - SCA23, SCA25, SCA27, SCA28
and DRPLA. ADCA Type II comprises syndromes asso-
ciated with pigmentary maculopathies and includes
SCA7. ADCA Type III comprises pure cerebellar
* Correspondence: firstname.lastname@example.org
2Mayo Clinic Jacksonville Department of Neurology 4500 San Pablo Rd
Jacksonville, FL, USA, 32224
Full list of author information is available at the end of the article
Whaley et al. Orphanet Journal of Rare Diseases 2011, 6:33
© 2011 Whaley et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
syndromes and includes SCA5, SCA6, SCA11, SCA26,
SCA29, SCA30 and SCA31 .
The ADCA Type I are the subject of this review.
ADCA Type I contain at the time of this writing a
group of 22 disorders. There are no fully validated diag-
nostic criteria for ADCA Type I. The diagnosis is based
on clinical history, physical examination and genetic
Clinical and pathological classifications
Phenotypes of ADCA Type I are complex and include
ataxia plus other neurological signs. The clinical spec-
trum ranges from just “pure” cerebellar signs to con-
stellations including spinal cord syndromes, peripheral
nerve disease, cognitive impairment, cerebellar or
supranuclear ophthalmologic signs, psychiatric pro-
blems, and seizure disorders. The ataxia in ADCA
Type I is characterized as disordered voluntary move-
ment in (1) the rate of initiation and cessation called
dyschronometria, (2) the amplitude known as dysme-
tria, (3) the coordination of single movements termed
dyssynergia, (4) the speed of alternating movements
called dysdiadochokinesia, and (5) the continuity
resulting in action tremors . Cerebellar ataxia can
affect virtually any body part causing movement
abnormalities. Gait, truncal, and limb ataxia are often
the most evident cerebellar findings though nystagmus,
saccadic abnormalities, and dysarthria are usually asso-
ciated. Table 1 lists clinical signs commonly observed
in ADCA Type I. Generally, the ADCA Type I mani-
fest in adulthood; however, presentation in childhood
may occur. This can be the result of the phenomenon
of anticipation that results from trinucleotide repeat
expansion mutations that may lengthen in subsequent
generations particularly if transmitted paternally. The
size of the repeat in those associated with trinucleotide
repeat expansions may be inversely related to sympto-
matic age-related onset .
Pathologically the different combination of degenera-
tion of the cerebellum, spinal tracts, peripheral nerve,
cerebral cortex, basal ganglia, pontomedullary systems,
optic nerve, and others is seen .
The prevalence of the SCAs as a whole is similar to
Huntington disease and is estimated to be 2-3 per
100,000 people but may be as high as 5-7 in 100,000 in
some populations [4-13], though the prevalence of
ADCA Type I is unknown. The most common ADCA
Type I is SCA3 followed by SCA2, SCA1, and SCA8 in
descending order . Founder effects doubtless contri-
bute to the variable prevalence between populations.
The pathogenesis of the ADCA Type I is not fully
understood. Categories of ADCA Type I based on pro-
posed pathogenesis have been suggested . Accord-
ingly, there are 3 major subclasses. The first and
probably most common subclass includes SCA1, SCA2,
SCA3, and SCA17; and DRPLA that are associated with
trinucleotide CAG repeat expansions encoding large
uninterrupted glutamine tracts. The prevailing explana-
tion for the mechanism of neuronal injury observed in
these syndromes is that the polyglutamine product is in
some way toxic to the cell at the protein level. The
details supporting this hypothesis are beyond the scope
of this discussion but have been reviewed recently
[3,15]. In brief, the toxic effect may be mediated by
interference of protein aggregation and clearance, tran-
scriptional dysregulation, alteration of the ubiquitin-pro-
homeostasis leading to premature apoptosis . The
second pathogenic subclass includes those ADCA Type
I such as SCA8, SCA10 and SCA12 related to trinucleo-
tide repeat expansions that fall outside of the protein-
coding region of the disease gene. Again, a toxic reac-
tion is the proposed cause of neuronal damage though
in this situation at the RNA level. A similar phenom-
enon is behind the pathogenic mechanism for the Fra-
gile X-associated tremor ataxia syndrome. These RNA
repeat sequences interfere with gene expression in neu-
rons . The last sub-class encompasses SCA13,
SCA14, SCA15/16, SCA27 and SCA28 caused by speci-
fic gene deletions, missense mutations, and nonsense
mutations leading to neurodegeneration .
Interestingly, despite the differences in the proposed
mechanisms, the phenotypes of the syndromes in all
three subclasses is remarkably indistinguishable on clini-
cal grounds. This would seem to suggest that the dis-
ruption of a final common pathway leading to
Table 1 Clinical signs in ADCA type 1
Clinical Signs (other
ADCA type 1
SCA1, SCA2, SCA3, and SCA7
SCA1, SCA2 and SCA3
SCA1, SCA3, and SCA12 (sometimes SCA8)
SCA3, and SCA12 (Parkinsonism)
SCA2, and occasionally SCA1, SCA3, and
SCA12, SCA16, SCA19
SCA17 (Dementia, psychosis, and epilepsy)
SCA1, SCA2, and SCA3
SCA3, SCA4, SCA18
ADCA = autosomal dominant cerebellar ataxia; SCA = spinocerebellar ataxia;
UMN = upper motor neuron
Whaley et al. Orphanet Journal of Rare Diseases 2011, 6:33
Page 2 of 13
neurodegeneration can be mediated through a number
of cellular pathways.
Definitive diagnosis rests on genetic analysis though the
importance of the history of illness including a detailed
family history and physical examination can not be over-
stated. Deriving a specific diagnosis based on genetic
testing is beneficial primarily for individuals of child-
bearing age where genetic counseling would be required
as there are no known cures for the ADCA Type I. Stra-
tegies for selecting the genetic test or tests most likely
to result in diagnosis have been suggested and may
prove beneficial in reducing costs as these tests are too
expensive to send for indiscriminately and are often not
reimbursed by insurance companies . Though the
classification of Harding may be somewhat outdated, it
is practical one and allows the clinician at bedside to
prioritize genetic testing. Importantly, treatable causes
of cerebellar ataxia must be excluded and screening for
these conditions should be part of the evaluation of any
individual presenting with cerebellar signs and symp-
toms. Table 2 includes a differential diagnosis of cere-
Neuroimaging except for the purpose of excluding
other causes of cerebellar ataxia is of little value to the
clinician in distinguishing between the ADCA Type I.
Magnetic resonance imaging (MRI) is superior to com-
puted tomography (CT) for this purpose. Unfortunately,
no pattern of atrophy on MRI is specific for a particular
genotype of ADCA Type I . Cerebellar atrophy is a
typical finding with or without brainstem or cortical
atrophy (Figure 1). Not surprisingly, areas of apparent
neurodegeneration on MRI have been correlated with
clinical signs referable to the areas of atrophy .
Pathological studies in individuals with ADCA Type I
are scant. Studies have demonstrated variable neuronal
loss and gliosis in regions of the rhombencephalon
more than diencephalon and telencephalon and spinal
cord . Like neuroimaging, pathological findings are
not specific and are insufficient in distinguishing
between the ADCA Type I genotypes.
Supportive care remains the mainstay of management as
there is no cure for any of the ADCA Type I at this time.
Occupational and physical therapy for gait dysfunction
and speech therapy for dysarthria is essential. The use of
mechanical aids such as a cane, walker or wheelchair is
beneficial in maintaining safety with ambulation and free-
dom of mobility for as long as possible. Other symptoms
such as insomnia, diplopia, spasticity, and urinary
urgency or frequency should be treated accordingly in
order to improve quality of life . Depression is a poten-
tially treatable and relatively common presenting symp-
tom particularly in SCA3 and should be evaluated for
and treated aggressively when present . Likewise,
pain particularly related to dystonia can be severe and is
an often overlooked component of the ADCA Type I
that may be misdiagnosed and mistreated but success-
fully ameliorated by botulinum toxin therapy .
These disorders are unrelentingly progressive and can
shorten length of life [21-23]. However, the prognosis is
variable between ADCA Type I and even among kin-
dreds. The longitudinal studies have not been per-
formed. Accurate prognostication for an individual
patient is difficult to ascertain; however, the determina-
tion should begin with the assessment of the phenotype
observed in the individual’s family and consider the pro-
band’s age at presentation. A younger age of onset and
longer trinucleotide repeat length generally portends a
Clinical description of subforms
Spinocerebellar Ataxia Type 1 (SCA1)
SCA1 typically presents in the 4thdecade (age range is 4
and 74 years) with dysarthria, hand writing difficulties,
and limb ataxia [18,24]. Nystagmus and saccadic
abnormalities are common. As the syndrome progresses
so does the ataxia, but additional features may emerge
and include proprioceptive loss, hypoactive reflexes,
ophthalmoparesis, and mild optic neuropathy .
Initial presentation with blepharospasm, oromandibular
Table 2 Differential diagnosis of cerebellar ataxia other
Phenytoin, 5-fluorouracil, cytosine arabinoside,
bismuth (Pepto-Bismol®), mercury-containing
fungicides, and lithium
Ethanol, methyl mercurial compounds, solvents
containing toluene and metals such as lead,
manganese, and tin
Vitamin E deficiency, thiamine deficiency
(Wernike-Korsakoff syndrome), Gluten sensitivity
Hypothyroidism and hypopituitarism
HIV, varicella, Epstein-Barr, prion (Creutzfeldt-
Jakob, Kuru etc.)
Guillain-Barre and Bickerstaff’s encephalitis
demyelination, abscess etc.
Neurodegeneration Multiple systems atrophy and recessively
inherited cerebellar ataxias
Small cell, breast, and ovarian cancer
Idiopathic late onset cerebellar ataxia and ataxia
with antiglutamate decarboxylase antibodies
Ischemic infarction, hemorrhage, neoplasm,
ADCA = autosomal dominant cerebellar ataxia; HIV = human
Whaley et al. Orphanet Journal of Rare Diseases 2011, 6:33
Page 3 of 13
dystonia, and retrocollis preceding ataxia has been
reported . Cognition is relatively spared early on;
however, executive dysfunction and impaired verbal
memory may develop in later stages . In the end
stages, usually 10 to 15 years following onset, bulbar
dysfunction secondary to affection of lower medullary
nuclei results in aspiration and death .
SCA1 was the first ADCA Type I to be genetically
classified when Yakura et al. linked this form of ataxia
with the HLA complex and chromosome 6p in 1974
. In 1987, the SCA1 gene was mapped to a region
15cM distal to the HLA complex . By 1993, the
SCA1 critical region was mapped to a <2cM segment on
6p . Later that year the gene was cloned, and the
mutation was determined to be an unstable CAG trinu-
cleotide repeat within the gene’s coding region resulting
in an expanded tract of glutamine amino-amino acids
. SCA1’s product, ataxin-1, results in variable CAG
repeats ranging from 6 to 44 in the general population,
and those with longer repeats (>20) typically have CAT
triplet interruptions within the CAG tract . In con-
trast, affected alleles have repeat expansions over 39
devoid of these CAT triplet interruptions. The patho-
genesis of polyglutamine related syndromes is discussed
above. Diagnosis is confirmed by DNA analysis demon-
strating over 39 uninterrupted CAG repeat expansions
in the SCA1 gene region on chromosome 6p.
Spinocerebellar Ataxia type 2 (SCA2)
SCA2 presents in the third or fourth decade (average
age 30 years; age range is from 2 to 65 years) with
truncal ataxia, dysarthria, slowed saccades and less com-
monly ophthalmoparesis and chorea . Parkinsonism
is also a less common but well documented manifesta-
tion of SCA2 . Despite this, there is no distinct clini-
cal feature that reliably distinguishes this from SCA1.
Recent studies suggest that mitochondrial gene poly-
morphism and a polyQ repeat variation in the CAC-
NA1A calcium channel may play a role in the clinical
variability observed in individuals with SCA2 [36,37].
SCA2 patients were found worldwide, and is among
the three most frequent types of ADCA Type I, together
with SCA3 . In 1993, Gispert et al. located the locus
for SCA2 in a Cuban kindred that mapped to chromo-
some 12 [39,40]. Since then, the gene responsible for
SCA2, ataxin 2, has been identified as a novel cytoplas-
mic protein; its function is yet unknown [41-43]. The
normal CAG repeat length is 15-24. Repeats 35 and
longer are associated with the clinical syndrome. Like
SCA1, anticipation and an inverse relationship between
age at onset and repeat length is observed in kindreds.
Likewise, CAG repeats are uninterrupted in affected
Spinocerebellar Ataxia type 3 (SCA3)
Also known as Machado-Joseph disease, this is likely the
most common SCA in most populations genetically
characterized to date and can be classified into three
clinical phenotypes . Type 1 is associated with
ataxia, ophthalmoparesis, pyramidal signs such as spasti-
city and hyperreflexia, and extrapyramidal signs includ-
ing dystonia and other movement disorders presenting
Figure 1 The MR (T1) brain (A) sagittal, (B) axial in a 54 year old African-American male with clinically genetically confirmed SCA2
who presented with cerebellar ataxia, dysarthria, slowed saccades, and peripheral neuropathy demonstrates cerebellar and brainstem
Whaley et al. Orphanet Journal of Rare Diseases 2011, 6:33
Page 4 of 13
in adolescence. Individuals with Type 2 present in mid-
dle adulthood with ataxia, spasticity, and dystonia. Type
3 occurs after the age of 40 and includes ophthalmopar-
esis and anterior horn cell disease i.e. fasciculations,
atrophy, and weakness. Parkinsonism can also be a fea-
ture of SCA3 . A likely overlooked but common fea-
ture is impairment of temperature sensation involving
the entire body .
The mutation is a CAG repeat expansion in chromo-
some 14q24.3-q32.1 . The normal repeat length is
13-41 whereas repeat lengths causing SCA3 are greater
than 56 [47-49]. SCA3 gene-product, ataxin 3 is a deu-
biqutinating enzyme that edits topologically complex
chains  and found in the cytoplasm of many types of
cells outside of the CNS. Ataxin 3 binds Lys48-linked
ubiquitin chains, and then cleaves Lys63 linkages and
possibly other non-Lys48 linkages. This activity would
help ensure efficient proteasomal degradation of ubiqui-
tinated substrates .
Spinocerebellar Ataxia type 4 (SCA4)
SCA4 is commonly referred to as hereditary ataxia with
sensory neuronopathy and was first described by Bie-
mond in 1954 . SCA4 is relatively rare syndrome,
the kindreds were found in USA (Scandinavian origin
and residing in Utah and Wyoming), Germany and
Japan. This syndrome typically starts in middle age
adults and presents with cerebellar ataxia, pyramidal
signs, and peripheral sensory loss . SCA4 has been
linked to chromosome 16q22.1 in kindreds from Utah
and Germany [53,54]. The mutation is yet unknown but
does not appear to be a trinucleotide repeat disorder
though anticipation has been suggested in both kin-
dreds. Interestingly, a Japanese kindred with a pure cere-
bellar ataxia phenotype without sensory loss and with an
older age of symptomatic onset has been linked to the
same region on chromosome 16 and is strongly asso-
ciated with a C to T substitution in the puratrophin 1
gene [55,56]. This syndrome known as 16q-ADCA
appears to be clinically distinct from SCA4.
Spinocerebellar Ataxia type 8 (SCA8)
SCA8 presents in adulthood with cerebellar ataxia plus
cognitive dysfunction in as many as 71% and pyramidal
and sensory signs in approximately a 3rdof affected
individuals . The age of onset is between 0 to 73
years (mean age of onset is 38.3 years). The kindred has
a worldwide distribution, especially in Europe. A dysexe-
cutive syndrome has been a reported feature as has a
significant occurrence of psychiatric diagnoses [57,58].
First described in 1999, SCA8 is now known to be
associated with a trinucleotide repeat on 13q21 that pro-
duces a polyglutamine expansion, ataxin 8 . Ataxin 8
is transcribed as a part of an untranslated that serves as
a gene regulator . The pathogenesis of SCA8 is
thought to result from RNA-mediated neurotoxicity .
It is also distinguishable because it is associated with a
CTG repeat expansion similar to myotonic dystrophy.
The syndrome has been associated with 107 to 127
CTG repeat expansions. This repeat is bidirectionally
transcribed resulting in both a noncoding CUG tran-
script and a CAG transcript resulting in a pure polyglu-
tamine protein that forms inclusions in mice and
humans . Expansions on 13q21 in 0.7% of nonataxic
controls have lead to controversy regarding a true asso-
ciation between the syndrome and the expansion at this
site . Recent reports appear to confirm an associa-
Spinocerebellar Ataxia type 10 (SCA10)
SCA10 is characterized by slowly progressive cerebellar
syndrome and epilepsy, sometimes mild pyramidal signs,
peripheral neuropathy and neuropsychological distur-
bances are also present. The most common type of epi-
lepsy is generalized motor seizures, but partial motor or
partial complex seizures can occur . The age of
onset ranges from 18 to 45 years (mean age is 32.2
years) [63,64]. Many kindreds has been found in Mexi-
can and Brazilian populations, SCA10 is second com-
mon inherited ataxia in these two countries. Recently,
Argentinian family  and additional Latin American
families  have been reported. SCA10 is caused by an
ATTCT pentanucleotide repeat expansion in intron 9 of
the ATXN10 gene. The expanded alleles range from 800
to 4500, whereas the normal alleles from 10 to 29 .
The pathogenesis has not been elucidated, but proces-
sing of RNA may be involved .
Spinocerebellar Ataxia type 12 (SCA12)
The hallmark of SCA12 is the presence of action tremor
associated with a relatively mild cerebellar ataxia .
Associated pyramidal and extrapyramidal signs and
dementia have been reported . The age of sympto-
matic onset ranges from 8 to 55 with most individuals
presenting in the fourth decade .
SCA12 was first identified in a German-American kin-
dred and more recently has been described in India
where a common founder has been identified [70,71].
Though SCA12 is very rare, except for a single ethnic
group in India, two Italian families have been identified
recently . Along with SCA8, the pathogenesis of
SCA12 seems to be related to a toxic effect at the RNA
level. SCA12 is associated with a CAG expansion at the
5’ end of the gene encoding PPP2R2B of chromosome
5q31-5q32 . PPP2R2B encodes a brain-specific regu-
latory subunit of the protein phosphatase 2 . The
number of repeat expansions associated with this syn-
drome is between 55 and 78 triplets .
Whaley et al. Orphanet Journal of Rare Diseases 2011, 6:33
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Spinocerebellar Ataxia type 13 (SCA13)
Originally described in a French kindred, later in a Fili-
pino family and two additional European families, the
salient feature of SCA13 is onset in childhood marked
by delayed motor and cognitive development followed
by mild progression of cerebellar ataxia [74-76]. While
primarily a cerebellar syndrome, dysphagia, urinary
urgency, and bradykinesia have been described in
affected individuals older than 50.
SCA13 has been mapped to chromosome 19q13.3-
q13.4 and is now known to be associated with two mis-
sense mutations in the KCNC3 gene in this region .
This gene encodes a voltage-gated potassium channel
not previously identified with neurodegeneration.
Spinocerebellar Ataxia type 14 (SCA14)
SCA14 presents in early adulthood with wide range of
symptomatic disease onset from 10 to 70 years (mean
33.9 years). The phenotype of SCA14 is mild and
encompasses slowly progressive ataxia, dysarthria and
nystagmus. In addition to the cerebellar signs, hyperre-
flexia and decreased vibration sense are frequently
observed. Some patients have a cognitive impairment,
parkinsonism characterized by rigidity  as well as
focal dystonia , axial myoclonus [80,81], facial myo-
kymia , choreic movement of hands  and epi-
SCA14 was initially identified in a 4-generation Japa-
nese kindred . At the present time there are pub-
lished reports of more than twenty families from
Europe, the USA, and Australia [78,82,84,85]. SCA14 is
caused by missense mutations in the PRKCG gene
encoding protein kinase Cg (PKCg) . PKC is a family
of serine-and threonine kinases with PKCg being one of
the members. PKCg is expressed abundantly in the neu-
rons especially in Purkinje cells  and is thought to
play important roles in signal transduction, cell differen-
tiation, and synaptic transmission .
Spinocerebellar Ataxia type 16 (SCA16) and type 15
SCA16 was described in a single family from Japan in
2001. Phenotype was reported as a “pure” cerebellar
ataxia . Since then, cognitive dysfunction has been
noted in affected individuals . The age of onset is
from 20 to 66 years with mean of 39.6 years. In this
Japanese family SCA16 has been initially linked to chro-
mosome 3p26.2-pter and a single nucleotide substitution
(4,256C®T) on contactin 4 (CNTN4) gene was pro-
posed in 2006 . However, further studies performed
in 2008 revealed that this substitution represents a rare
Earlier in 2001, SCA15 was identified in Australian
family with “pure” cerebellar ataxia, thus falling into the
broad Harding classifications as ADCA Type III . In
2004, additional two SCA15 families were identified in
Japan with affected individuals having cerebellar ataxia
and some also exhibiting postural and action tremor
. In the same year a longitudinal clinical observa-
tions of the Australian kindred were published reporting
that all affected family members had developed a cogni-
tive impairments . In 2007, Leemput et al. detected
the deletion on inositol 1,4,5-triphosphate receptor 1
(ITPR1) gene and sulfatase-modifying factor 1 (SUMF1)
gene in three SCA15 families including the above men-
tioned Australian kindred and in two newly identified
British families . In 2008, Iwaki et al reported that in
their original Japanese family described in 2001 the
genetic defect represents the same deletion on ITPR1
gene as seen in Australian and British kindreds further
strengthening the argument that both SCA16 and
SCA15 are indeed due to ITPR1 gene mutations [89,94].
This year a British family with ataxia unrelated to pre-
viously reported British kindreds was described .
The protein analysis demonstrated the ITPR1 deletion
. The study by Iwaki et al reveled that previously
implicated SUMF1 gene is not responsibly for clinical
phenotype in SCA15/16 . Therefore, SCA15/SCA16
are produced by the same genetic dysfunction and
should be categorized on the base of predominant clini-
cal phenotype as part of ADCA Type I.
Spinocerebellar Ataxia type 17 (SCA17)
The phenotype of SCA17 is particularly variable and can
be associated with dementia, psychiatric disorders, par-
kinsonism, dystonia, chorea, spasticity, and epilepsy .
Clinical features overlap with many neurodegenerative
syndromes and Huntington disease specifically.
First recognized in 2001, this syndrome has since been
mapped to chromosome 6 and is secondary to a CAG
repeat expansion in the TATA box binding protein gene
(TBP) . TBP encodes for a general transcription
initiation factor. SCA17 mutation has been reported in
families of Japanese, German, French, Chinese, Korean,
Italian, Mexican, Taiwanese, and Indian descent but its
frequency is rather low compared to SCA1 - SCA3 .
In a recent report, areas of atrophy on MRI in indivi-
duals with SCA17 were associated with clinical signs
referable to those areas . In addition, this study
revealed low Mini-Mental State Examination scores cor-
related with atrophy of the nucleus accumbens.
Spinocerebellar Ataxia type 18 (SCA18)
Also known as autosomal dominant sensory/motor neu-
ropathy with ataxia, SCA18 presents initially with an
axonal sensory neuropathy with cerebellar ataxia and
motor neuron dysfunction developing later . SCA18
presents in the second and third decades of life with
Whaley et al. Orphanet Journal of Rare Diseases 2011, 6:33
Page 6 of 13
symptomatic disease onset ranging from 13 to 27 years
. Initially this syndrome was described in an Ameri-
can-Irish family and has been linked to chromosome
7q22-q23 . The responsible gene mutation has not
been identified. Both SCA3 and SCA4 are also asso-
ciated with a peripheral neuropathy.
Spinocerebellar Ataxia type 19 (SCA19) and
Spinocerebellar Ataxia type 22 (SCA22)
SCA19 is a syndrome identified in a Dutch kindred in
2001. SCA19 presents in the third decade of life with
symptomatic disease onset ranging from 10 to 46 years.
The phenotype is characterized by mild cerebellar
ataxia, cognitive impairment, low scores on the Wiscon-
sin Card Sorting Test, myoclonus, and postural tremor
. Linkage to chromosome 1p21-q21 has been pro-
posed; however, the gene mutation has not been identi-
SCA22 was reported in a Chinese pedigree in 2003.
SCA22 symptomatic disease onset overlaps significantly
with symptomatic disease onset of SCA19 but with
more narrow range of 35 to 46 years. Clinical features
usually include only cerebellar signs. Occasionally
hyporeflexia is present. Linkage to chromosome 1p21-
q23 has been made , but Schelhaas et al. hypothe-
sized that SCA19 and SCA22 share the same genetic
Spinocerebellar Ataxia type 20 (SCA20)
SCA20 is a syndrome identified in a pedigree of Anglo-
Celtic origin in 2004 . A cerebellar dysarthria is
typically the initial manifestation. However, most of the
affected persons also exhibit palatal tremor and spasmo-
dic dysphonia. Head CT shows the dentate calcifica-
tions. The age of symptomatic disease onset ranges
from 19 to 64 years (mean age; 46.5years). SCA20 has
been linked to chromosome 11q12.2-11q12.3  over-
lapping with locus for SCA5, though clinical features
differ between SCA5 and SCA20. SCA5 belongs to
ADCA Type III and represents a “pure” ataxia syndrome
with on average earlier age of symptomatic disease onset
ranging from 14 to 50 years) [106,107]. Since the causa-
tive gene is unknown, it may well be that after discovery
of such gene SCA20 and SCA5 may be indeed geneti-
cally proven to be the same disorder as it has already
occurred with SCA16 and SCA15 (discussed above).
Spinocerebellar Ataxia type 21 (SCA21)
Identified only in a French kindred, SCA21 causes
slowly progressive cerebellar ataxia, mild cognitive
impairment, postural and/or resting tremor, bradykine-
sia, and rigidity [108,109]. Age of onset is 17.4 years and
is relatively earlier than for most ADCA Type I SCAs.
The parkinsonism was not responsive to L-dopa .
MRI revealed cerebellar and brainstem atrophy. SCA21
maps to chromosome 7p21.3-p15.1 ; however, the
gene and gene mutation has not been identified. Indivi-
duals in successive generations tend to have earlier ages
of onset .
Spinocerebellar Ataxia type 23 (SCA23)
SCA23 has been identified only in one Dutch family.
SCA23 is characterized by gait ataxia, dysarthria, slowed
saccades, ocular dysmetria, Babinski signs and hyperre-
flexia . Individuals with SCA23 have an age of
onset from 43 and 56 years. SCA23 maps to chromo-
some region 20p13-12.3 . The clinical features,
head MRI, and neuropathological findings are indistin-
guishable from other SCA subtypes.
Spinocerebellar Ataxia type 25 (SCA25)
Identified in a French kindred, SCA25 is characterized
by cerebellar ataxia and prominent sensory neuropathy
. The clinical features vary widely from sensory
neuropathy with little cerebellar ataxia to cerebellar
ataxia with little sensory neuropathy. Some patients
exhibit gastrointestinal dysfunction such as vomiting
and abdominal pain as initial symptom. Digestion pro-
blems can be persistent. Scoliosis and urinary problems
(nycturia or urinary urgency). Head MRI shows severe
global cerebellar atrophy like in SCA5 and SCA6. The
age of onset ranges from 1 to 39 years . SCA25
maps to chromosome 2p15-p21 . Repeat expansion
detection failed to identify CAG repeat expansion.
Spinocerebellar Ataxia type 27 (SCA27)
SCA27 was described in a Dutch family with early onset
tremor, dyskinesia, and slowly progressive cerebellar
ataxia associated with a mutation in the fibroblast
growth factor 14 (FGF14) gene on chromosome 13q34
. The mutation in this family was missense muta-
tion; however, since then a frameshift mutation in the
FGF14 gene has been described in an individual with a
familial ataxia  and the mechanism of neurodegen-
eration resulting from this mutation is unknown.
Spinocerebellar Ataxia type 28 (SCA28)
SCA28 is characterized by juvenile onset slowly progres-
sive cerebellar ataxia due to Purkinje cell degeneration.
Some persons show cognitive impairment . And in
more advanced stages of the syndrome, ophthalmopar-
esis, slowed saccades, ptosis and pyramidal signs were
reported . The mean age of symptom onset was
19.5 years in the original kindred. Additional kindreds
were found only in Europe [114,115]. SCA28 accounts
for approximately 1.5% of all European ADCA patients
. The candidate disease locus was identified on
chromosome 18p11.22-q11.2 . Recently missense
Whaley et al. Orphanet Journal of Rare Diseases 2011, 6:33
Page 7 of 13
mutation in the ATPase family gene 3-like 2 (AFG3L2)
has been discovered. AFG3L2 is a component of the
conserved matrix ATPase associated with diverse cellu-
lar activities (m-AAA) metalloprotease complex involved
in the maintenance of the mitochondrial proteome 
and highly expressed in Purkinje cells. The mutation
impairs cytochrome c oxidase activity and impairs the
Dentatorubral Pallidoluysian Atrophy (DRPLA)
DRPLA occurs with highest frequency in the Japanese
population (0.2 to 0.7/100,000) . A few cases were
reported from European countries [119-125], North
America  and recently from Turkey . The age
of disease onset ranges from 1 to 60 years (mean age is
28.8 years) [119,123]. Patients with earlier onset (below
20 years of age) tend to show myoclonus epilepsy and
mental retardation. Patients with late onset (over 40
years of age) tend to present with cerebellar ataxia,
choreoathetosis and dementia . Clinical features
and the age of onset are significantly correlated with the
size of CAG repeats . DRPLA is characterized by
prominent anticipation. Head MRI shows atrophy of
cerebellum, brainstem, cerebrum and high signal has
been shown in periventricular white matter .
Unstable expansion of a CAG repeats in the B37 has
been demonstrated on chromosome 12p13.31 .
And that repeats product an abnormal protein called
atrophin 1, which is widely expressed in neurons .
We believe the Harding classification of ataxia syn-
dromes to three major categories, ADCA Type I, ADCA
Type II, and ADCA Type III is still helpful to the clini-
cians taking care of patients presented with SCA pheno-
types. In this review we describe the progress in
understanding of clinical and pathological phenotypes,
and progress in molecular genetic studies related to the
ADCA Type I. Further progress in molecular genetic
studies will clarify future classifications of these disor-
ders as already indicated in our review (for examples see
SCA16 and SCA15). Table 3 lists the known genetic
characteristics of the ADCA Type I.
For the clinician, a strategy based on Harding’s classi-
fication of SCA disorders is important to aid in narrow-
ing the diagnostic possibilities. Although genetic testing
is the only means of distinguishing in certainty between
genotypes, Harding’s classification can aid the clinician
in developing a genetic molecular testing strategy. Like-
wise, the vast clinical variability among these syndromes
impedes a specific bedside diagnosis; however, knowl-
edge of the clinical characteristics that commonly are
associated with each syndrome may streamline the
selection of genetic testing. From the standpoint of pre-
valence, world distribution, and costs a molecular
genetic testing for ADCA Type I such as SCA1 - SCA3,
SCA8, SCA14, and SCA17 should be considered first. If
negative further molecular genetic testing for SCA4,
SCA10, SCA12, SCA13, SCA18, and SCA27 can be
Table 3 Genetic Characteristics of ADCA type 1
ADCA Gene/Gene productGene LocusRepeat
SCA12 SCA12(PPP2R2B)/Serine/threonine protein phosphatase 2A, 55 kDA regulatory subunit B, beta
SCA13 SCA13/KCNC3 (encodes for a voltage-gated potassium channel)
SCA16 SCA16/contactin 4?
SCA17 TBP/TATA-box binding protein
SCA27 FGF14/FGF 14
ADCA = autosomal dominant cerebellar ataxia; SCA = spinocerebellar ataxia; PPP2R2B = protein phosphatase 2, regulatory subunit B, beta isoform; KCNC3 =
Potassium voltage-gated channel subfamily C member 3; TBP = TATA box binding protein; TATA = thymine adenosine thymine adenosine; FGF14 = fibroblast
growth factor 14
Whaley et al. Orphanet Journal of Rare Diseases 2011, 6:33
Page 8 of 13
undertaken. The clinical phenotype may be also used to
guide the selection of molecular genetic tests. For exam-
ple a molecular genetic testing for SCA1, SCA3, SCA 4,
SCA8, SCA18 and SCA25 should be considered for an
individual with cerebellar ataxia and peripheral neuropa-
thy. Phenotype characterized by a combination of ataxia
and epilepsy may indicate need for molecular genetic
testing for SCA10, SCA17 and DRPLA. The presence of
ataxia and cognitive impairment may suggest the initial
selection of molecular genetic studies to SCA1 -, SCA2,
SCA13, SCA15/16, SCA17, SCA19, SCA21 and DRPLA.
The presence of extrapyramidal sign occurring in SCA2,
SCA3, SCA12, SCA15/16, SCA17, SCA21, SCA27, and
DRPLA may lead to selection of genetic studies indica-
tive for these disorders. A unique clinical or radiological
feature such as action tremor present in SCA12 or den-
tate calcification seen on head CT in SCA20 may nar-
row selection of available genetic tests substantially
reducing the cost of deriving to diagnosis. Exclusion of
treatable and/or structural causes of cerebellar ataxia is
mandatory. Neuroimaging studies and routine labora-
tory testing specifically required to exclude the condi-
tions in the differential diagnosis of cerebellar ataxia
should be directed by the history and physical
Unfortunately, no curative therapies have been discov-
ered, though speech and physical therapy, mechanical
aids for gait, and symptomatic management of pain and
depression can help improve functioning and overall
quality of life. Genetic testing is expensive and may not
be indicated in many instances where the diagnosis of a
neurodegenerative cause is not in question. For affected
individuals of child bearing age or where family plan-
ning decision making is requested, genetic counseling is
essential. Recently, some massively parallel sequencing
methods have become available which enable us to
screen of thousands of loci for genetic signatures simul-
taneously. And the methods can reduce the cost and
increase the throughput of genomic sequencing .
So genetic testing will be less costly and more widely
available in the near future.
At this time, the ADCA Type I are no different than
most any neurodegenerative syndrome in that the
pathophysiology remains uncertain and no curative
treatments have been discovered. In the future, more
mutations and kindreds with cerebellar ataxia will be
discovered and the ADCA type I group will grow, more
knowledge of the pathophysiology will mount, and even-
tually treatments will be forthcoming.
ZKW is partially funded by NIH NINDS (R01 NS057567, 1RC2 NS070276, P50
NS 072187), Mayo Clinic Florida Research Committee CR and Collaborative
programs (MCF Activity #90052018 and #90052030); Dystonia Medical
Research Foundation, Carl Edward Bolch, Jr. and Susan Bass Bolch Gift (MCF
Activity #90052031/PAU #90052) grants.
1Tri State Mountain Neurology 105 Woodlawn Dr Johnson City, TN, USA,
37604.2Mayo Clinic Jacksonville Department of Neurology 4500 San Pablo
Rd Jacksonville, FL, USA, 32224.
NRW created the 1stdraft of the manuscript that was critically revised by SF.
ZKW critically reviewed it.
All authors have read and approved the final manuscript.
The authors declare that they have no competing interests.
Received: 7 July 2009 Accepted: 28 May 2011 Published: 28 May 2011
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Cite this article as: Whaley et al.: Autosomal dominant cerebellar ataxia
type I: A review of the phenotypic and genotypic characteristics.
Orphanet Journal of Rare Diseases 2011 6:33.
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