Spinocerebellar ataxia 17: Inconsistency between phenotype and neuroimage findings.

Spinocerebellar ataxia 17 (SCA17) is an autosomal dominant neurodegenerative disease clinically characterized by the presence of cerebellar ataxia in combination with variable neurological symptoms. Here we report a Chinese SCA17 family which proband's clinical manifestation was inconsistent with the neuroimage findings.

Introduction

SCA17, a rare neurodegenerative disorder, is caused by a CAG trinucleotide expansion in the gene encoding TATA-box binding protein (TBP), which is a general transcription factor crucial for normal cellular function and development.[123] The cardinal features include cerebellar ataxia, cognitive decline, psychiatric symptoms, and Parkinsonism; with frequent occurrence of abnormal movements such as chorea or dystonia.[4] Here, we report a Chinese SCA17 family in which the proband's clinical manifestation was inconsistent with the neuroimage findings.

Case Report

A Chinese family including four affected individuals with ataxia syndrome spanning two generations, whose age of onset ranged from 39 to 55 years. The clinical characteristics were somewhat variable, but all patients showed one or more features of cerebellar ataxia, dysarthria, memory deterioration and character change. The proband, a 41-year-old male, was a bank clerk who initially noticed progressive memory deterioration at age 39 when he could not remember the names of his friends occasionally. And his speech became mildly slurred thereafter. The syndromes developed slowly, but the patient was sensitive to the disease because of his positive family history of ataxia. Then he presented to our outpatient clinic at age 40. His past history was negative for alcoholism and drug poisoning.

Neurological examination showed mild ataxia. The score of scale for the assessment and rating of ataxia (SARA) was 4 with abnormalities in four items including stance (1 point), speech disturbance (1 point), finger chase (1 point), and fast alternating hand movements (1 point). He stood in natural position steadily, and also able to stand with feet together without sway. But in tandem, he could not stand for 10 s. During conversation, we found his speech slightly slurring, but easy to understand. For finger chase, he presented with a little bit dysmetria, overshooting target below 2 cm in both sides. He could complete 10 cycles of fast alternating hand movements within 10 s, but slightly irregular in both sides. The mini-mental state examination (MMSE) was normal. His muscle strength, muscle tones, limb reflexes, sensory perception, and autonomic system were also normal. However, it is very interesting that comparing the mild phenotype, the magnetic resonance imaging (MRI) which was taken 1 year before his first visit showed noticeable cerebellar atrophy with moderate cerebral atrophy [Figure 1].

Figure 1

MRI scans of the proband. T2-weighted sagittal view (a) and T1-weighted axial view (b) showing marked cerebellar atrophy (arrow) accompanied by moderate cerebral atrophy (arrowhead)

The pathological CAG triplet repeat expansions of spinocerebellar ataxias (SCAs) including SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA)were analyzed by means of polymerase chain reaction (PCR), fragment analysis based on capillary electrophoresis, and clone sequencing. The results showed that the proband carried pathological allele of the TBP gene with 45 CAG repeats and normal allele with 36 repeats.

Discussion

SCA17 is a rare neurodegenerative disorder that belongs to the group commonly referred to as ‘polyglutaminopathies’. The normal CAG trinucleotide repeats range from 25 to 42, while observed pathogenic expansions range from 43 to 66.[5] A series of studies indicated the broad clinical spectrum of the disease, which most prevalent abnormalities include cerebellar ataxia and dementia at the onset of the disease.[4] However, reduced penetrance is known for alleles of 43-48 repeats.[67]

For the case in our study, because of the positive family history, he was quite sensitive to the disease at very early stage and came to our clinic. He just noted mild memory deterioration and speech slurring. The neurological examination based on SARA showed slightly abnormalities. The expanded allele of 45 triplets locates in the intermediate range. However, the MRI showed noticeable cerebellar atrophy with moderate cerebral atrophy. The interest of this case lies in the considerably mild phenotype and intermediate repeat size, which are not in accord with the MRI findings. Normally, for SCA17, the MRI findings seem to be associated with the disease course and the repeat length. After longer durations, the atrophy is always pronounced in the cerebellum.[1] Nielsen et al., reported a patient carrying with 43 CAG repeat presented with rapid cognitive decline, but the MRI scan revealed mild atrophy of the cerebellum.[8] The patients carrying with 55 CAG repeats presented in the third decade with obviously gait ataxia and dementia, whose MRI findings indicated diffuse cortical and cerebellar atrophy.[2] Compared to these affected individuals with full blown disease state, the case had mild phenotype, but the cerebellar atrophy was noticeable.

SCA17 is a very rare disorder and the phenotypic variation is therefore not fully described. Our case contributes to a more detailed characterization of clinical picture seen in the quite early stage of SCA17 and it highlights the need for precise clinical and neuroimaging examinations of the patients. The inconsistency between phenotype and the neuroimage findings of this case might suggest that the mechanism of neural compensation might exist.