The wide clinical spectrum and nigrostriatal dopaminergic damage in spinocerebellar ataxia type 6

Abstract

Spinocerebellar ataxia type 6 (SCA6) manifests a wide spectrum of non-cerebellar system involvements. The objective of this study was to examine the presence of nigrostriatal dopaminergic system derangement in SCA6. Eight patients with SCA6 who underwent a regular follow-up for at least 2 years participated in this study. A detailed neurological examination was performed and striatal dopamine transporter (DAT) was evaluated using [(99m)Tc]-TRODAT-1 SPECT. The main clinical feature of SCA6 was cerebellar ataxia with impaired eye movements. However, a wide spectrum of non-cerebellar system involvements, such as autonomic dysfunction, and pyramidal and extrapyramidal signs, was also observed. Two patients had bradykinesia. l-dopa was tried in one patient without benefit. Of the two patients with bradykinesia, DAT density was reduced to the Parkinson's disease (PD) range with a rostrocaudal gradient typical of PD in one patient (CAG repeats 13/22) and was mildly decreased in the other patient (12/25). Of the four patients without extrapyramidal signs, three (12/22, 11/25, 17/22) showed mild to severe reduction of DAT density and one (13/22) had a normal density. This study shows that SCA6 has a varying degree of nigrostriatal dopaminergic derangement. Two patients manifested mild bradykinesia, emphasising the need to screen for SCA6, even in patients with progressive ataxia and parkinsonism. Further histopathological studies would be helpful to determine the nigrostriatal dopaminergic damage in SCA6.

Evidence of Pre-Synaptic Dopaminergic Deficit in a Patient with a Novel Progranulin Mutation Presenting with Atypical Parkinsonism†

“…Alterations of dopamine synthesis along the nigrostriatal pathway due to degeneration of neurons of the substantia nigra is reflected by abnormal DAT-tracer uptake and has been demonstrated in various neurodegenerative disorders in which parkinsonism can be part of the clinical picture at different stages. These include SCA2, SCA 3, SCA6, and SCA17 [20][21][22], Cerebrotendinous Xanthomatosis [23], and early-onset dystonia-parkinsonism due to PLA2G6 mutations [24]; alterations of DAT-Scan have been shown in idiopathic REM sleep behavior disorder as well [25], and in fragile X-associated tremor ataxia syndrome [26]. Recently, O'Dowd and colleagues described a patient carrying a pathogenic C9Orf72 hexanucleotide expansion presenting with a complex phenotype including amyotrophic lateral sclerosis, FTD, and parkinsonism who also showed abnormal DAT-Scan [27].…”

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

“…PET tracers of nigrostriatal function including [ 18 F]-FDopa and ligands of striatal dopamine transporter as [ 11 C]d-MP and of D2 receptors as [ 11 C]-raclopride have been used for the same purposes with similar results to those obtained with SPECT tracers [1]. Notably, nigrostriatal dysfunction was observed in presymptomatic carriers of the SCA2, SCA3, SCA6, and SCA17 genes [1, 18, 20, 21]. …”

Dystonia and ataxia progression in spinocerebellar ataxias

“…The brain circuitry involved in dystonia has been reported in the cerebellum and its connection to the brainstem, cervical spinal cord, thalamus, and motor cortex [5,24–29]. Alternatively, dystonia might come from the extra-cerebellar regions, including basal ganglia, and the alterations of basal ganglia have been identified in SCAs based on the volumetric magnetic resonance imaging (MRI) studies [5], dopamine transporter scan studies [30], and postmortem pathological examination [31–33]. The presence of dystonia might indicate the preferential involvement of different cerebellar or extra-cerebellar circuits and thus represent different subtypes of respective SCAs.…”