Summary Cerebellar ataxias with autosomal dominant transmission are rare, but identification of the associated genes has provided insight into the mechanisms that could underlie other forms of genetic or non-genetic ataxias. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes complex multisystemic neurological deficits. The designation of the loci, SCA for spinocerebellar ataxia, indicates the involvement of at least two systems: the spinal cord and the cerebellum. 11 of 18 known genes are caused by repeat expansions in the corresponding proteins, sharing the same mutational mechanism. All other SCAs are caused by either conventional mutations or large rearrangements in genes with different functions, including glutamate signalling (SCA5/ SPTBN2 ) and calcium signalling (SCA15/16/ ITPR1 ), channel function (SCA13/ KCNC3 , SCA14/ PRKCG , SCA27/ FGF14 ), tau regulation (SCA11/ TTBK2 ), and mitochondrial activity (SCA28/ AFG3L2 ) or RNA alteration (SCA31/ BEAN-TK2 ). The diversity of underlying mechanisms that give rise to the dominant cerebellar ataxias need to be taken into account to identify therapeutic targets.

Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond

Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease

Background: All spinocerebellar ataxias (SCAs) are rare diseases. SCA1, 2, 3 and 6 are the four most common SCAs, all caused by expanded polyglutamine-coding CAG repeats. Their pathomechanisms are becoming increasingly clear and well-designed clinical trials will be needed. Methods: To characterize the clinical manifestations of spinocerebellar ataxia (SCA) 1, 2, 3 and 6 and their natural histories in the United States (US), we conducted a prospective multicenter study utilized a protocol identical to the European consortium study, using the Scale for the Assessment and Rating of Ataxia (SARA) score as the primary outcome, with follow-ups every 6 months up to 2 years. Results: We enrolled 345 patients (60 SCA1, 75 SCA2, 138 SCA3 and 72 SCA6) at 12 US centers. SCA6 patients had a significantly later onset, and SCA2 patients showed greater upper-body ataxia than patients with the remaining SCAs. The annual increase of SARA score was greater in SCA1 patients (mean ± SE: 1.61 ± 0.41) than in SCA2 (0.71 ± 0.31), SCA3 (0.65 ± 0.24) and SCA6 (0.87 ± 0.28) patients (p = 0.049). The functional stage also worsened faster in SCA1 than in SCA2, 3 and 6 (p = 0.002). Conclusions: The proportions of different SCA patients in US differ from those in the European consortium study, but as in the European patients, SCA1 progress faster than those with SCA2, 3 and 6. Later onset in SCA6 and greater upper body ataxia in SCA2 were noted. We conclude that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies.

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Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; A prospective observational study

Spinocerebellar ataxia type 6 (SCA6) is a devastating midlife-onset autosomal dominant motor control disease with no known treatment. Using a hyper-expanded polyglutamine (84Q) knock-in mouse, we found that cerebellar Purkinje cell firing precision was degraded in heterozygous (SCA684Q/+) mice at 19 months when motor deficits are observed. Similar alterations in firing precision and motor control were observed at disease onset at 7 months in homozygous (SCA684Q/84Q) mice, as well as a reduction in firing rate. We further found that chronic administration of the FDA-approved drug 4-aminopyridine (4-AP), which targets potassium channels, alleviated motor coordination deficits and restored cerebellar Purkinje cell firing precision to wildtype (WT) levels in SCA684Q/84Q mice both in acute slices and in vivo. These results provide a novel therapeutic approach for treating ataxic symptoms associated with SCA6.

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4-aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6.

Systematic perturbations in motor adaptation tasks are primarily countered by learning from sensory-prediction errors, with secondary contributions from other learning processes. Despite the availability of these additional processes, particularly the use of explicit re-aiming to counteract observed target errors, patients with cerebellar degeneration are surprisingly unable to compensate for their sensory-prediction error deficits by spontaneously switching to another learning mechanism. We hypothesized that if the nature of the task was changed-by allowing vision of the hand, which eliminates sensory-prediction errors-patients could be induced to preferentially adopt aiming strategies to solve visuomotor rotations. To test this, we first developed a novel visuomotor rotation paradigm that provides participants with vision of their hand in addition to the cursor, effectively setting the sensory-prediction error signal to zero. We demonstrated in younger healthy control subjects that this promotes a switch to strategic re-aiming based on target errors. We then showed that with vision of the hand, patients with cerebellar degeneration could also switch to an aiming strategy in response to visuomotor rotations, performing similarly to age-matched participants (older controls). Moreover, patients could retrieve their learned aiming solution after vision of the hand was removed (although they could not improve beyond what they retrieved), and retain it for at least 1 year. Both patients and older controls, however, exhibited impaired overall adaptation performance compared to younger healthy controls (age 18-33 years), likely due to age-related reductions in spatial and working memory. Patients also failed to generalize, i.e. they were unable to adopt analogous aiming strategies in response to novel rotations. Hence, there appears to be an inescapable obligatory dependence on sensory-prediction error-based learning-even when this system is impaired in patients with cerebellar disease. The persistence of sensory-prediction error-based learning effectively suppresses a switch to target error-based learning, which perhaps explains the unexpectedly poor performance by patients with cerebellar degeneration in visuomotor adaptation tasks.

Can patients with cerebellar disease switch learning mechanisms to reduce their adaptation deficits

We report a 39-year-old woman with spinocerebellar ataxia type 6. She presented with ataxia and a 3-year history of progressive ataxia and recurrent falls. There was no relevant family history. Genetic tests revealed an expanded allele of 24 CAG repeats at the spinocerebellar ataxia type 6 locus. This appears to be the first case reported in Hong Kong. As genetic testing becomes more widely available and clinical awareness increases, more such patients are expected to be diagnosed.

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B Sheng

Papers

Spinocerebellar ataxia type 6.