Elsevier

The Lancet Neurology

Volume 3, Issue 5, May 2004, Pages 291-304
The Lancet Neurology

Review
Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis

https://doi.org/10.1016/S1474-4422(04)00737-9Get rights and content

Summary

Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.

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 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

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