References for the Review were identified through searches of PubMed from 1996, to June, 2010, by use of the following search terms: “spinocerebellar ataxia” OR “autosomal dominant cerebellar ataxia” OR “SCA”. Only papers published in English were considered. Studies were selected on the basis of relevance as judged by the author.
ReviewAutosomal dominant cerebellar ataxias: polyglutamine expansions and beyond
Introduction
The autosomal dominant cerebellar ataxias (ADCAs) are a rare cause of cerebellar ataxia. Most cases of cerebellar ataxia are sporadic, and diagnostic work-up remains a challenge.1, 2 The ADCAs, referred to as spinocerebellar ataxias (SCAs) in genetic nomenclature, are a group of inherited neurological disorders that are clinically and genetically very heterogeneous. They are progressive neurodegenerative diseases that are characterised by cerebellar ataxia, resulting in unsteady gait, clumsiness, and dysarthria. The cerebellar syndrome is often associated with other neurological signs such as pyramidal or extrapyramidal signs, ophthalmoplegia, and cognitive impairment.3 Onset is usually during the third or fourth decade of life, but can occur in childhood or old age. Atrophy of the cerebellum and brainstem are most often the prominent features, but other structures can be affected, leading to a substantial range of phenotypes.4
ADCAs were thought to be exclusively due to expansions of coding CAG repeats, as in the genes that underlie SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, and DRPLA (dentatorubro-pallidoluysian atrophy)—the so-called polyglutamine expansion SCAs. The polyglutamine expansion SCAs share a mutational mechanism with other polyglutamine expansion diseases, such as Huntington disease5 and spinal bulbar muscular atropy,6 and perhaps a pathogenic process, even though most of the proteins involved in polyglutamine expansion diseases have unknown or unrelated functions.7 These disorders manifest above a threshold of CAG repeats that varies depending on the gene. When large and uninterrupted, the CAG repeats are unstable on transmission and result mostly in expansions, particularly during paternal transmissions.8, 9 Correlations between phenotype and genotype in the polyglutamine expansion SCAs have shown that differences in repeat size contribute to variation in disease progression and severity and to some of the clinical differences between patients. The same pathogenetic mechanism applies to SCA subtypes caused by more recently discovered expansions in non-coding regions of genes for SCA10, SCA12, and SCA31—the so-called non-coding-expansion SCAs. The discovery of conventional mutations in some patients with ADCA—the conventional mutation SCAs—in addition to those with dynamic repeats, expands the variety of pathophysiological causes of ADCAs (table 1). Therefore, the different forms of dominantly inherited SCAs, which can no longer be grouped together as polyglutamine expansion disorders, need to be distinguished. This Review will focus on the clinical features of SCAs caused by polyglutamine expansions, non-coding expansions, and rare conventional mutations in SCA genes, and similarities and differences in the phenotypes and underlying pathophysiology between these SCA subtypes will be discussed.
Section snippets
Epidemiology of ADCA subtypes
Between one and three per 100 000 Europeans have ADCA. Polyglutamine expansion SCAs are more frequent than are other forms of SCA, and SCA3 is the most frequent subtype.8 A mean of 44% (SD 25, ranging from 1% to 90% depending on geographical origin) of ADCA cases are still unaccounted for by the genes tested in many series (webappendix). However, in most series, only genes for SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 were tested. There are founder effects in the genes for SCA2 (40/100 000 cases)
Polyglutamine expansion SCAs
The polyglutamine expansion SCAs caused by translated CAG repeat expansions are the most well studied group of ADCAs. They share the same mutation, a CAG repeat, which manifests above a threshold of CAG repeats that varies according to the gene—usually above 37–40 repeats, but repeats are much smaller in the gene for SCA6 (>19)28 and much larger for SCA3 (>51).29
Non-coding expansion SCAs
In addition to the CAG repeat expansions, untranslated expansions can cause disease through a gain of function mechanism, triggered by the accumulation of transcripts containing expanded CUG or CCUG repeats. A gain in RNA function might have a role, but other mechanisms have also been proposed.58
SCA8 was the first ADCA caused by an untranslated CTG expansion to be described.59 The phenotype is cerebellar ataxia with mild gait spasticity and global cerebellar atrophy.60, 61 Bidirectional
Conventional mutation SCAs
The fastest growing group of known ADCAs is those attributable to conventional, often private, mutations in the associated genes. Screening of these genes is costly and time consuming. Furthermore, interpretion of the identified change and proof of its pathogenicity can be difficult. Only a few families have been identified with some of these mutations, so correlations between phenotype and genotype are difficult to generate.
In 1994, the gene for SCA5 was assigned to the centromeric region of
Clinical features
ADCAs caused by conventional mutations (SCA5, SCA11, SCA13, SCA14, SCA15/16, SCA20, SCA27, and SCA28) are less frequent than are polyglutamine expansion ADCAs.20 The overall phenotype of patients with conventional mutations differs from that of patients with polyglutamine expansions (table 3). Polyglutamine expansion SCAs can lead to substantial neurological dysfunction and are fatal, whereas lifespan is healthy in patients with conventional mutation SCAs. Onset is most often in childhood, but
Conclusions
When should a patient with progressive cerebellar ataxia be tested for SCAs? The patient should have a family history of the disease before genes associated with ADCAs are tested. Repeat expansions in SCA1, SCA2, and SCA3 cause about 40–80% of autosomal dominant cerebellar ataxias, depending on the population (webappendix). These expansions can be searched for in sporadic cases, especially if the family history is unknown (eg, if the patient is adopted), the parents died before reaching the age
Search strategy and selection criteria
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