The Pathogenic Role of Low Range Repeats in SCA17.
BACKGROUND
SCA17 is an autosomal dominant cerebellar ataxia with expansion of the CAG/CAA trinucleotide repeats in the TATA-binding protein (TBP) gene. SCA17 can have various clinical presentations including parkinsonism, ataxia, chorea and dystonia. SCA17 is diagnosed by detecting the expanded CAG repeats in the TBP gene; however, in the literature, pathologic repeat numbers as low as 41 overlap with normal repeat numbers.


METHODS
The subjects in this study included patients with involuntary movement disorders such as cerebellar ataxia, parkinsonism, chorea and dystonia who visited Seoul National University Hospital between Jan. 2006 and Apr. 2014 and were screened for SCA17. Those who were diagnosed with other genetic diseases or nondegenerative diseases were excluded. DNA from healthy subjects who did not have a family history of parkinsonism, ataxia, psychiatric symptoms, chorea or dystonia served as the control. In total, 5242 chromosomes from 2099 patients and 522 normal controls were analyzed.


RESULTS
The total number of patients included in the analysis was 2099 (parkinsonism, 1706; ataxia, 345; chorea, 37; and dystonia, 11). In the normal control, up to 44 repeats were found. In the 44 repeat group, there were 7 (0.3%) patients and 1 (0.2%) normal control. In 43 repeat group, there were 8 (0.4%) patients and 2 (0.4%) normal controls. In the 42 repeat group, there were 16 (0.8%) patients and 3 (0.6%) normal controls. In 41 repeat group, there were 48 (2.3%) patients and 8 (1.5%) normal controls. Considering the overlaps and non-significant differences in allelic frequencies between the patients and the normal controls with low-expansions, we could not determine a definitive cutoff value for the pathologic CAG repeat number of SCA17.


CONCLUSIONS
Because the statistical analysis between the normal controls and patients with low range expansions failed to show any differences so far, we must consider that clinical cases with low range expansions could be idiopathic movement disorders showing coincidental CAG/CAA expansions. Thus, we need to reconsider the pathologic role of low range expansions (41-42). Long term follow up and comprehensive investigations using autopsy and imaging studies in patients and controls with low range expansions are necessary to determine the cutoff value for the pathologic CAG repeat number of SCA17.
Department of Neurology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Jung Hwan
JH
Shin
Department of Neurology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Hyeyoung
H
Park
Department of Neurology, Myongi Hospital, Goyang, Republic of Korea.
Gwan Hee
GH
Ehm
Department of Neurology, Eulji General Hospital, Eulji University, Seoul, South Korea.
Woong Woo
WW
Lee
Department of Neurology, Ewha Womans University School of Medicine and Ewha Medical Research Institute, Seoul, Republic of Korea.
Ji Young
JY
Yun
Department of Neurology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea.
Young Eun
YE
Kim
Department of Neurology, Seoul National University Boramae Hospital, Seoul, South Korea.
Jee-Young
JY
Lee
Department of Neurology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Han-Joon
HJ
Kim
Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Jong-Min
JM
Kim
Department of Neurology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Beom Seok
BS
Jeon
Department of Laboratory medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Sung-Sup
SS
Park
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D020820:Dyskinesias / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D035181:TATA-Box Binding Protein / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
D035181:TATA-Box Binding Protein; C509817:TBP protein, human