Chapter 226

## Abstract

1. The dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurologic disorders characterized by variable degrees of degeneration of the cerebellum, spinocerebellar tracts, and brain stem neurons. The inter- and intrafamilial variability of clinicopathologic findings hampered the classification of this group of diseases until the 1990s, during which the discovery of the genetic bases of many of the SCAs provided a means of distinguishing among them.

2. The mutational locus has been mapped for 10 SCAs: spinocerebellar ataxia 1, 2, etc. [disease in Roman font and gene in italics] (SCA1, SCA2), Machado-Joseph disease (MJD)/SCA3 (sometimes referred to here simply as SCA3), SCA4, SCA5, SCA6, SCA7, SCA8, SCA10, and dentatorubropallidoluysian atrophy (DRPLA). The clinical features shared among these SCAs are ataxia, dysarthria, and eventual bulbar dysfunction. Variable features include ophthalmoparesis (common in SCA1, 2, 3, and 7); hyporeflexia (common in SCA2 and 4); dementia (more frequent in SCA2 and common in DRPLA); dystonia and rigidity (occasional in SCA1 and common in MJD/SCA3); choreoathetosis and myoclonus (common in DRPLA); spasticity (SCA1, 3, and DRPLA); bulging eyes and fasciculations (MJD/SCA3); neuropathy (most common in SCA4 but can be seen in SCA1, 2, and 3); seizures (common in SCA10 and DRPLA); and macular degeneration and extraneuronal involvement (unique to SCA7). Neuroimaging studies demonstrate cerebellar atrophy in SCA1, 2, 3, 6, 7, and DRPLA; cortical atrophy in SCA2, 7, and DRPLA; and brain stem atrophy in SCA1, 2, 3, 7, and DRPLA. Calcification of the basal ganglia and leukodystrophic changes occur in DRPLA. Nerve conduction abnormalities occur in SCA1, 2, and 3, and are most common in SCA4. Visual evoked potentials are abnormal in SCA7, and the EEG is abnormal in DRPLA. Purkinje cell and dentate neuron degeneration is severe in SCA1, 2, 6, 7, and DRPLA, but modest in MJD/SCA3. Degeneration of the inferior olive is common in SCA1, 2, 6, and 7. Loss of brain stem neurons is common in SCA1, 2, 3, 6, and DRPLA. Basal ganglia degeneration is pronounced in DRPLA and variable in MJD/SCA3. Macular degeneration and hypomyelination of the optic tract are unique to SCA7.

3. The mutational basis of SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPLA is the expansion of a translated trinucleotide (CAG) repeat that encodes for a polyglutamine tract in the relevant protein. SCA8 is caused by expansion of a CTA/CTG repeat that does not appear to be translated. Expanded disease alleles typically contain 34 to 84 CAG repeats in SCA1, 2, 3, and DRPLA. In SCA6, the pathogenic range is 21 to 33, and in SCA7 it is 35 to 306. For SCA8 the expanded range varies from 110 to 130 in kindreds with established linkage to the SCA8 locus, but has been found to exceed 575 repeats in some affected patients.

4. The gene products mutated in most of the SCAs—ataxin-1, ataxin-2, ataxin-3, ataxin-7, and atrophin-1—are novel proteins of unknown function. The gene product mutated in SCA6 is the α1A voltage-gated calcium channel (CACN1A1). The distribution of the proteins varies: ataxin-1 is predominantly nuclear in neurons, but cytoplasmic in peripheral cells. Ataxin-7 is a nuclear protein; ataxin-2, ataxin-3, atrophin-1, and CACN1A1 are cytoplasmic. In affected neurons, ataxin-1, ataxin-3, ataxin-7, and atrophin-1 aggregate in single large nuclear inclusions that stain positively for ubiquitin. Ataxin-2 does not form nuclear aggregates but appears to accumulate in the cytoplasm of affected neurons. The translation of the mutant proteins and their altered subcellular distribution support the hypothesis that the pathogenesis is mediated at the protein level.

5. The dynamic nature of the mutations in the SCAs (the expansion of unstable trinucleotide repeats) explains a clinical feature common to this group of diseases: genetic anticipation. The intergenerational repeat instability frequently leads to further expansion, particularly when paternally inherited, leading to earlier onset and more severe clinical course. In each of these diseases, there is an inverse correlation between the number of the repeats and the age of onset. However, the age of onset for a certain expanded range varies, depending on the protein context. Small expansions in CACN1A1 cause neuronal degeneration, whereas larger expansions are required to promote the other SCAs. Similarly sized expanded alleles appear to produce an earlier age of onset in SCA2 than in SCA1, DRPLA, or MJD/SCA3. Very large expansions in excess of 200 repeats have been seen in SCA7, and these typically lead to a severe infantile phenotype that involves nonneuronal tissues (e.g., the heart) as well.

6. The mutations identified to date account for approximately 65 to 70 percent of all dominantly inherited ataxias. The prevalence of the various SCAs varies considerably among different populations. MJD/SCA3 appears to be the most prevalent disease in all ethnic groups, accounting for 25 to 35 percent of all dominant ataxias. In Caucasians, SCA1 and SCA2 are the second most common diseases, whereas in Japan DRPLA and SCA6 are more prevalent. SCA7 is reasonably common, accounting for at least 10 percent of all dominant ataxias. There is a close association between the prevalence of the different SCAs and the frequencies of large normal alleles in various ethnic populations.

7. Pathogeneses of the SCAs share two features: the expansion of the polyglutamine tract and accumulation of the mutant protein. The data point to a gain-of-function mechanism whereby the mutant protein becomes toxic to neurons. Studies of transgenic animal models support such a mechanism and demonstrate that neuronal dysfunction rather than neuronal death precedes the clinical phenotype. The SCA1 mouse model also demonstrates that nuclear localization of ataxin-1 is necessary for the pathogenesis to occur, and visible aggregation of ataxin-1 is not essential to initiate SCA1 pathogenesis. Studies in cell culture demonstrate that the 40-kDa heat-shock proteins, respectively (Hsp40) chaperone human DnaJ-2/Homosapien DnaJ (HDJ-2/HSDJ) decreases the size and frequency of ataxin-1 and ataxin-3 aggregates, supporting the hypothesis that protein misfolding is involved in the aggregation of mutant protein with expanded polyglutamine tracts.

8. The selective degeneration of only a subset of neurons in each of the SCAs, despite widespread expression of the disease-causing gene, remains to be explained. Possible factors include different levels of expression and/or processing of the mutant polyglutamine proteins in various cell types and protein-protein interactions with cell-specific proteins. In the case of SCA1, for example, the temporal and cellular expression patterns and subcellular distribution of the leucine-rich acidic nuclear protein (LANP) parallel that of ataxin-1; that LANP interacts more strongly with mutant than normal ataxin-1 suggests that it may play a role in SCA1 pathogenesis.

9. Now that the gene products for several SCAs are in hand and knowledge about the fate of the mutant proteins is rapidly accumulating, the possibility of identifying proteins and/or compounds that could modulate the course of the diseases and slow their progression is not far-fetched.

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