Neurophysiological Characterization of Autosomal Dominant Spinocerebellar Ataxia 17

Abstract

Recently, trinucleotide expansion (critical limit 42±2) has been described in the TATA box binding protein gene in autosomal dominant spinocerebellar ataxia 17 (SCA 17, OMIM 600075). The clinical presentation is very variable with psychiatric disturbance, gait ataxia, dysarthria, bradykinesia and/or dystonia. We neurophysiologically characterized two families with SCA-17 using transcranial magnetic stimulation (TMS) and brain parenchyma sonography (BPS). The two families consisted of 14 individuals with genetically proven SCA-17 (trinucleotide expansion 45 to 54). 7 family members (4 male, mean age 44±9 years, mean disease duration 8±7 years) were characterized neurophysiologically. Our TMS measures comprised a routine investigation, the contralateral and ipsilateral silent period as well as analysis of short latency intracortical inhibition (PPI 3 ms) and facilitation (PPF 13 ms) using a paired-pulse paradigm. The echogenicity of several brain structures of the basal ganglia and the midbrain was investigated by BPS according to a standardized protocol. All patients showed a moderate to severe dementia and a wide spectrum of clinical symptoms including dyspraxia, atypical Parkinsonism as well as myoclonus, and ataxia in only one case. TMS revealed only one abnormal parameter with loss of PPF 13 ms in 6 patients. BPS demonstrated a reduced echogenicity of the brainstem raphe in all 7 individuals, a hyperechogenicity of the caudat nucleus in 5 patients (with correlation to the severity of dementia), and in all patients a dilatation of the IV. ventricle (7.4±1.9mm). Clinical features of SCA17 comprised a broad spectrum of more psychiatric and extrapyramidal symptoms than ataxia. A loss of short-latency intracortical facilitation measured by TMS was also reported previously in other types of SCA and may be the expression of a disturbed cerebello-thalamic-cortical connection. Hyperechogenicity of the caudate nucleus in the BPS was described also in other forms of dementia. The hypoechogenicity of the brainstem raphe, a serotonergic nucleus area, was described for patients with unipolar depression. Disturbances in the serotonergic system seem to play a role in patients with SCA suggesting that the hypoechogenicity of the brainstem raphe revealed by BPS may be of pathogenetic importance.