Here we report on a patient who was referred to the hospital due to rapid cognitive decline. Due to the severe cognitive impairment and rapid progression, the patient was initially suspected of Creutzfeldt-Jakob disease or a paraneoplastic syndrome. Cerebellar symptoms were not predominant in the clinical picture, but the MRI scan revealed mild atrophy of the cerebellar hemispheres and vermis, and reduced metabolism in the cerebellum visualized by a FDG-PET scan supported the suspicion that the diagnosis should be sought within the cerebellar disorders. The family history revealed a high prevalence of apparently different neurodegenerative disorders based on clinical diagnoses. Considering the phenotypic overlap of many neurodegenerative disorders, this family history was suggestive of a dominantly inherited disorder. Molecular genetic analyses revealed that the proband suffered from SCA17 and that he inherited the disease causing mutation through the maternal line. Diverse phenotypes resembling both HD, Alzheimer’s disease and Parkinson’s disease have previously been reported in patients with short expansions in the TBP
]. Hence, it is highly likely that the mother’s and the mother’s brother’s diagnoses of multiple sclerosis and Parkinson’s disease, respectively, are incorrect, and that the neurological disorders described in this family represent an example of the broad phenotypic variation of SCA17. Unfortunately, only the proband was available for clinical examination, and the family disease history is based solely on information provided by the proband’s wife.
Cloning of the proband’s alleles of the TBP
gene showed only marginal expansion of the disease causing CAG/CAA repeat with a length of 43. Considering that alleles with repeat lengths of 42–48 have previously been reported to cause disease with reduced penetrance [5
] and that repeat lengths in the shorter end of this range usually cause mild disease progression [5
], our case is interesting because of the rapid deterioration observed.
Neuropathology has shown both cerebellar and basal ganglia involvement in SCA17 [14
], and dopaminergic cell loss has been documented by reduced tracer uptake with SPECT-I123 FP-CIT [14
] and Fluoro-dopa PET [16
]. Such basal ganglia involvement has not been reported to correlate with symptoms of parkinsonism [17
], but it has been suggested to be a function of the severity of the disease with normal uptake of I123 FP-CIT and Fluoro-dopa in pre-clinical stages [14
]. Furthermore, basal ganglia involvement has been suggested to be associated with putaminal rim hyperintensity signal on T2 MRI in other cases [6
], and voxel based morphometry has indicated an increased involvement of basal ganglia as the disease progresses [20
]. The proband exhibited a rapid and severe decline in cognitive function suggesting an advanced stage of disease, and involvement of the basal ganglia would therefore not have been surprising. However, only slightly decreased metabolism in the left caudate nucleus was observed by the 18
F-FDG-PET-scan and we did not see any involvement of basal ganglia on MRI or SPECT-I123 FP-CIT, which emphasizes the heterogeneity of phenotypic presentation and pathology.
The current case emphasizes that diagnosing of neurodegenerative disorders remains a considerable challenge due to the phenotypic overlap, and it shows that the clinical manifestations and the disease course can be different from the classic description of the individual disorders. SCA17 is a very rare disorder and the phenotypic variation is therefore not fully described. Our case contributes to a more detailed characterization of the highly variable clinical picture seen in SCA17, and it highlights the need for a careful clinical and paraclinical examination of patients displaying symptoms of early onset neurodegeneration to enable precise diagnosing on which further counseling and initiation of treatment modalities can be based.