References for this review were identified by searches of MEDLINE with the search terms “spinocerebellar ataxia”, “SCA1”, “SCA2”, “SCA3”, “MJD”, “SCA4”, “SCA5”, “SCA6”, “SCA7”, “SCA8”, “SCA10”, “SCA11”, “SCA12”, “SCA13”, “SCA14”, “SCA15”, “SCA16”, “SCA17”, “SCA18”, “SCA19”, “SCA21”, “SCA22”, “SCA23”, and “SCA25” and references from relevant articles. “Geneclinics reviews” (http://www.geneclinics.org) covering several of the search terms were assessed. Numerous articles were also
ReviewAutosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis
Section snippets
Prevalence and incidence
Epidemiological data about the prevalence of SCA are restricted to a few studies of isolated geographical regions, and most do not reflect the real occurrence of the disease. In general a prevalence of about three cases per 100 000 people is assumed, but this may be an underestimate.1, 2 As SCA are highly heterogeneous, the prevalence of specific subtypes varies between different ethnic and continental populations (figure 1).3, 4, 5, 6, 7, 8, 9, 10 Most recent data suggest that SCA3 is the
Genetic causes of SCA
24 autosomal dominant ataxias—SCA 1–8, 10–19, 21–23, and 25, dentatorubral-pallidoluysian atrophy (DRPLA), and ataxia caused by mutations in the gene that encodes fibroblast growth factor 14 (FGF14)—have been identified. In 12 of these disorders the genes involved and the underlying mutations are known (table 1). Six SCA subtypes (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) and DRPLA are caused by CAG trinucleotide repeat expansions in the respective genes. These expansions encode polyglutamine
Repeat instability and genetic testing
For SCA subtypes caused by repeat expansions, the age at onset is inversely correlated with repeat length (figure 3).16, 17, 18, 19 Thus small expansions are found in patients with late onset of symptoms. Small expansions that are sometimes close to the normal repeat range (SCA2, SCA6), may have reduced penetrance and may thus appear as sporadic disease without a family history. Indeed, we and others found repeat expansion in the genes associated with SCA2 and SCA6 in up to 8% of the patients
CAG repeat expansions
For most types of SCA caused by CAG repeat expansion in the coding region of a gene the functions of the affected proteins are still unknown; the exceptions are SCA6, which encodes the α1A-subunit of a P/Q-type calcium channel,25 and SCA17, which encodes TATA-box binding protein (TBP).26, 27 Except for the polyglutamine repeats, the affected proteins have no common sequences or domains. Therefore it is assumed that the pathogenesis is directly linked to the expanded polyglutamine stretch.28
Region-specific cell death in SCA
Cell-type-specific expression patterns of mutated genes do not explain region-specific cell death in different SCA subtypes. Interacting proteins might contribute to the selectivity of the neurodegenerative process. Only for two SCA subforms, SCA1 and SCA7, have matching candidates for the region specific to neuronal cell death been identified: the Leucine-rich acidic nuclear protein, LANP, interacting with ataxin 1 might explain neurodegeneration of Purkinje cells observed in patients with SCA1
Animal models of SCA
Why only specific neuronal cells are prone to cell death is unclear because most of the affected genes are expressed ubiquitously. Animal models are valuable tools to gain insights into the regional susceptibility of neurodegeneration in SCA. As naturally occurring animal models of repeat expansion diseases have not been described, numerous transgenic models have been generated in Caenorhabditis elegans,66 Drosophila, and mice.28
Mouse models have been generated for SCA1, SCA2, SCA3, SCA7, and
Clinical features of ataxias
SCA have a wide range of neurological symptoms including ataxia of gait, stance, and limbs, cerebellar dysarthria, oculomotor disturbances of cerebellar and supranuclear genesis, retinopathy, optic atrophy, spasticity, extra-pyramidal movement disorders, peripheral neuropathy, sphincter disturbances, cognitive impairment, and epilepsy. The clinical diagnosis of specific subtypes is complicated by the huge overlap of the phenotype between genetic subtypes and substantial variability of clinical
Neuropsychological features
Neuropsychological analyses revealed executive dysfunction as a common sign in SCA1. Additionally, mild deficits of verbal memory were found in SCA1, SCA2, and SCA3.94 In SCA2, dementia has been found in four of 17 patients (24%) according to Mini-Mental State Examination. Dementia is a common and prominent symptom in SCA17.16, 27, 106 Cognitive deficits of variable degree are also reported in patients with SCA12, SCA13, SCA19, and SCA21, as well as in patients with mutations in FGF14.
A study
Electrophysiology
Neurophysiological investigations in SCA are used to search for spreading of the disease to non-cerebellar systems and may serve as progression markers for clinical trials in the future. They are also of help to direct genetic testing. Most SCA subtypes show involvement of the peripheral nervous system. Sensory or sensorimotor neuropathy is found in about half of patients with SCA1, in 80% of patients with SCA2, and in 75% of patients with SCA3. In SCA6 up to 60% have mild sensorimotor
Neuroimaging in SCA
MRI is the imaging of choice in SCA. Brain MRI is useful in patients with spinocerebellar syndromes in order to exclude differential diagnoses such as multiple sclerosis and cerebrovascular disease or malignancy. MRI helps in the diagnosis of SCA, but it is not diagnostic and may be normal in the first years after onset of symptoms. Corresponding to neuropathological findings in hereditary ataxia, there are three fundamental patterns of degeneration on MRI: spinal atrophy, olivopontocerebellar
Morphological findings
Neuropathological studies of genetically defined SCA are scarce128 and rely, with a few exceptions, on autopsies of patients in end-stage disease. A summary of the morphological findings for the more common subtypes of SCA is given in table 3.129, 130, 131, 132, 133, 134, 135, 136, 137 Neuropathological findings match with clinical features in most systems; however, striking mismatch is seen—eg, between morphologically normal pyramidal tracts and prominent spasticity in the clinical picture of
DNA analysis in patients with ataxia
Genetic analyses should be directed according to the frequency of genetic subtypes in the relevant ethnic background (figure 1) and with regard to clinical features (table 4). A pragmatic approach is suggested in figure 5, which needs adaptation for local specialties like DRPLA in Japan. For neurologists, the proposed phenotypic classification by Harding102 who distinguished three types of autosomal dominant cerebellar ataxias (ADCA) might be useful. According to this classification, ADCA type
Therapeutic options
Today, there is no therapy to prevent neuronal cell death in ataxia or even to delay the age at onset. However, defining the genetic causes of the SCA subtypes might give some directions for the treatment of certain symptoms. For instance, SCA6 is caused by mutations in the α1A-subunit of the voltage-gated neuronal calcium channel, as is episodic ataxia type 2 and familial hemiplegic migraine. Increasing evidence supports the hypothesis that SCA6 is caused by impaired calcium flux into neurons.
Conclusions
Since the identification of the first CAG repeat-expansion underlying SCA1 in 1993147 more than 25 additional gene loci have been found to be responsible for autosomal dominant inherited forms of SCA. Further gene loci will be identified but will most likely be the cause of disease in just a few families. Overall, ataxias represent one of the most heterogeneous groups of diseases in neurology. Although a common pathogenetic mechanism has not yet been identified for SCA, new technologies such as
Search strategy and selection criteria
References (147)
- et al.
The hereditary adultonset ataxias in South Africa
J Neurol Sci
(2003) - et al.
A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]
Am J Hum Genet
(2003) - et al.
Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia
Am J Hum Genet
(2003) - et al.
Close associations between prevalences of dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations
Am J Hum Genet
(1998) - et al.
Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse
Cell
(1997) - et al.
Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo
Cell
(1997) - et al.
Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length
Neurobiol Dis
(1998) - et al.
Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3
Neuron
(1997) - et al.
Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice
Cell
(1998) - et al.
Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions
Cell
(1998)
Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila
Neuron
Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport
Neuron
Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract
J Biol Chem
Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1
Cell
Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice
Neuron
Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice
Neuron
Does tissue transglutaminase play a role in Huntington's disease?
Neurochem Int
PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning
Cell
Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7
Neuron
Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death
Neuron
The role of protein composition in specifying nuclear inclusion formation in polyglutamine disease
J Biol Chem
Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3
Am J Hum Genet
Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation
Am J Hum Genet
Hereditary ataxia overview
Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis
Neurology
Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1286 Japanese patients
Am J Med Genet
Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families
Neurology
Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG) n allele at the SCA17 locus
Arch Neurol
Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes?
Ann Neurol
Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds
Arch Neurol
Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation
Hum Genet
Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12
Nat Genet
Why is SCA12 different from other SCAs?
Cytogenet Genome Res
Do CTG expansions at the SCA8 locus cause ataxia?
Ann Neurol
Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17)
Ann Neurol
Intergenerational instability and marked anticipation in SCA-17
Neurology
SCA12 is a rare locus for autosomal dominant cerebellar ataxia: a study of an Indian family
Ann Neurol
SCA10 and ATTCT repeat expansion: clinical features and molecular aspects
Cytogenet Genome Res
Genetic background of apparently idiopathic sporadic cerebellar ataxia
Hum Genet
Mosaicism of the CAG repeat in CNS tissue in relation to age at death in spinocerebellar ataxia type 1 and Machado-Joseph disease patients
Am J Hum Genet
Very large (CAG) (n) DNA repeat expansions in the sperm of two spinocerebellar ataxia type 7 males
Hum Mol Genet
Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype
Neurology
Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel
Nat Genet
A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease?
Hum Mol Genet
SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein
Hum Mol Genet
Glutamine repeats and neurodegeneration
Annu Rev Neurosci
Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases
Proc Natl Acad Sci USA
Formation of polyglutamine inclusions in non-CNS tissue
Hum Mol Genet
Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions
Hum Mol Genet
Cited by (859)
White matter integrity assessment in spinocerebellar ataxia type 2 (SCA2) patients
2024, Clinical RadiologyExtreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias
2023, American Journal of Human GeneticsEvaluation of Cerebellar Ataxic Patients
2023, Neurologic ClinicsEarly-onset familial essential tremor is associated with nucleotide expansions of spinocerebellar ataxia in China
2024, Molecular Biology Reports