Ikeda, Yoshio

Jackson, Mandy

Kawarabayashi, Takeshi

Kimura, Tamaki

Matsubara, Etsuro

Miki, Yasuo

Monai, Natsuki

Seino, Yusuke

Shoji, Mikio

Suzuki, Chieko

Tomiyama, Masahiko

Wakasaya, Yasuhito

Watanabe, Mitsunori

Yamamoto-Watanabe, Yukiko

Internal Medicine

English

Soong BW, Paulson HL

Koide R, Kobayashi S, Shimohata T,

Nakamura K, Jeong SY, Uchihara T, e

Toyoshima Y, Yamada M, Onodera O, e

Fujigasaki H, Martin JJ, De Deyn PP

Oda M, Maruyama H, Komure O, et al

Kwee RM, Kwee TC

Maclullich AM, Wardlaw JM, Ferguson

Loy CT, Sweeney MG, Davis MB, et al

Bruni AC, Takahashi-Fujigasaki J, M

Gunther P, Storch A, Schwarz J, et

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A Small Trinucleotide Expansion in the TBP Gene Gives Rise to a Sporadic Case of SCA17 with Abnormal Putaminal Findings on MRI

A Japanese woman developed gait disturbances at 25 years of age, and subsequently underwent gradual changes in her personality. By the age of 42, she showed clear signs of dementia and cerebellar ataxia, and displayed behavioral abnormalities, choreic movements and hyperreflexia. The findings of MRI not only showed cerebellar and cerebral atrophy, but also revealed putaminal rim hyperintensity on T2-weighted images. We identified a heterozygously expanded CAG/CAA repeat (45/36) within the TATA-binding protein gene, leading to a diagnosis of SCA17. These results show that a 45 CAG/CAA repeat is pathological, giving rise to early-onset SCA17.</p

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2179˘ CASE REPORT ˘A Small Trinucleotide Expansion in the TBP Gene GivesRise to a Sporadic Case of SCA17 with AbnormalPutaminal Findings on MRIMitsunori Watanabe1, Natsuki Monai1, Mandy Jackson2, Yukiko Yamamoto-Watanabe1,Yoshio Ikeda3, Chieko Suzuki1, Masahiko Tomiyama1, Takeshi Kawarabayashi1,Tamaki Kimura1, Yusuke Seino1, Yasuhito Wakasaya1, Yasuo Miki1, Etsuro Matsubara1and Mikio Shoji1AbstractA Japanese woman developed gait disturbances at 25 years of age, and subsequently underwent gradualchanges in her personality. By the age of 42, she showed clear signs of dementia and cerebellar ataxia, anddisplayed behavioral abnormalities, choreic movements and hyperreflexia. The findings of MRI not onlyshowed cerebellar and cerebral atrophy, but also revealed putaminal rim hyperintensity on T2-weighted im-ages. We identified a heterozygously expanded CAG/CAA repeat (45/36) within the TATA-binding proteingene, leading to a diagnosis of SCA17. These results show that a 45 CAG/CAA repeat is pathological, givingrise to early-onset SCA17.Key words: SCA17, CAG/CAA repeat, TATA-binding protein, putaminal rim hyperintensity(Inter Med 47: 2179-2182, 2008)(DOI: 10.2169/internalmedicine.47.1499)IntroductionMore than twenty genomic loci have been associated withautosomal dominant spinocerebellar ataxias (ADCAs)(Search OMIM for SCA, URL http://www.ncbi.nlm.nih.gov/) and the genes involved have been identified for thir-teen subtypes (1). Of these, a number result from CAGtrinucleotide expansions resulting in the expression of pro-teins with abnormally long poly-glutamine tracts, which ap-pear to be associated with neuronal cell death by a toxicgain-of-function mechanism. Spinocerebellar ataxia type 17(SCA17) is caused by the expansion of a CAG/CAA repeatwithin the TATA-binding protein (TBP) gene (2-4). SCA17is characterized by cerebellar ataxia, choreic movements,dystonia, parkinsonism, dementia and epilepsy (2-4). Here,we report a Japanese patient with SCA17 having a shortCAG/CAA repeat expansion, and discuss the putaminal find-ings obtained from MRI.Abbreviations: SCA17: spinocerebellar ataxia 17,T B P :TATA-binding protein, ADCA: autosomal dominant spi-nocerebellar ataxiaCase ReportA Japanese woman developed gait disturbances at the ageof 25 and cerebellar atrophy was evident when a MRI scanwas carried out nine years later. By the age of 42, sheshowed dementia, truncal and limb ataxia, choreic move-ments in neck, truncal body, and all of her limbs, hyperre-flexia, and decreased vibratory sense. Her younger sisterwas healthy, and her healthy parents were not consanguine-ous and there is no previous history of similar neurologicaldiseases in the family.̍Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki,̎Centre for Neuroscience,University of Edinburgh, Edinburgh, UK and̏Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University, OkayamaReceived for publication July 11, 2008; Accepted for publication September 6, 2008Correspondence to Dr. Mitsunori Watanabe, miwata36@cc.hirosaki-u.ac.jpInter Med 47: 2179-2182, 2008 DOI: 10.2169/internalmedicine.47.14992180F i g u r e   1 .  F i n d i n g s   o n   T 1 - w e i g h t e d   MR I   d i s p l a y e d   s e v e r e   c e r e b e l l a r   a t r o p h y   ( A ) ,   a n d   d i f f u s e  c e r e b r a l   a t r o p h y   a n d   d i l a t e d   t h i r d   v e n t r i c l e   ( B ) .The patient was alert and cooperative, but cognitively im-paired, obtaining a score of 16 in a Mini-Mental Sate Ex-amination. Her verbal, performance, and full-scale scores ofWechsler Adult Intelligence Scale-Third Edition were 50, 47and 44, respectively. She showed behavioral abnormalitiesby continuing to use stairs despite severe truncal ataxia. Ex-amination of the optic fundi showed no abnormal findingssuch as sclerotic changes.The findings of MRI showed cerebellar atrophy, diffusecerebral atrophy, dilated third ventricle (Fig. 1) although thebrainstem was relatively preserved, and no cross sign wasdetected in the pons. The findings also displayed symmetri-cal putaminal rim hyperintensity on T2-weighted and T2*-weighted images (Fig. 2). The putaminal rim lesions showedlow intensity on the T1-weighted image, and on FLAIR im-age, the low intensity area was surrounded by isointensity(Fig. 2D). Similar putaminal rim intensities were observedin the same regions from the MRI performed previously, atthe age of 34 years (Fig. 2E and F). However, the cerebellarand cerebral atrophy, and dilated third ventricle were morepronounced in the MRI carried out at the age of 42. Shehad no history of smoking, hypertension, hypercholestremia,or diabetes mellitus.Blood samples were obtained from the patient with in-formed consent and genomic DNA was extracted by thestandard method. SCA1, SCA2, SCA3, SCA6, DRPLA andHuntington’s disease were ruled out genetically. We ampli-fied the genomic region of the TATA-binding protein (TBP)gene containing CAG/CAA repeats by polymerase chain re-action (PCR) as described previously (5), and subcloned andsequenced the PCR products using the TA vector (Invitro-gen, Carlsbad, CA). The patient was found to possess a het-erozygously expanded CAG/CAA repeats (45/36) in theTBP gene, leading to a diagnosis of SCA17. The configura-tions of the CAG/CAA repeats were (CAG)3(CAA)3(CAG)6CAACAGCAA ( CAG ) 28 CAACAG, and ( CAG ) 3 (C A A)3(CAG)9CAACAGCAA(CAG)16CAACAG, respectively. In asimilar fashion the TBP gene of her mother was analyzed,revealing that she had 39/36 repeats; (CAG)3(CAA)3(CAG)9CAACAGCAA(CAG)19CAACAG and (CAG)3(CAA)3(CAG)9CAACAGCAA(CAG)16CAACAG. We were unable to ge-netically examine her father.DiscussionThe present case was genetically diagnosed with SCA17as she possessed a small CAG/CAA repeat expansion (45repeats) within the TBP gene. She developed the disease ata relatively young age (25 years) and displayed typical clini-cal features of SCA17 such as personality change, dementia,choreic movements, cerebellar signs and hyperreflexia. Aprevious study of eight Japanese SCA17 cases revealed that44 repeats can be pathogenic, but also suggested that with44-47 repeats the disease may not be fully penetrant (6).The configuration of the mother’s CAG/CAA repeats sug-gests that the disease allele of the patient originates from herfather, however he could not be genetically examined and sowe do not know whether he may have possessed the ex-panded repeat and was asymptomatic or he possessed an in-termediate allele that became expanded through paternaltransmission. These results confirm that a shorter repeat ex-pansion can give rise to SCA17.The findings of MRI in the present case also showedsymmetrical putaminal rim hyperintensity on the T2-weighted image as well as cerebellar atrophy and diffusecerebral atrophy. These lesions were also detected when shewas 34 years of age, and displayed low intensity on the T1-weighted image. On the FLAIR image, the low intensity ar-eas were surrounded by isointensity. These MRI findingscould result from enlarged periventricular or Virchow-Robin(VR) spaces (7), which become increasingly common withage, and are often associated with hypertension, cerebral ar-Inter Med 47: 2179-2182, 2008 DOI: 10.2169/internalmedicine.47.14992181F i g u r e   2 .  S y mme t r i c a l   h y p e r i n t e n s e   a r e a s   w e r e   o b s e r v e d   i n   t h e   b i l a t e r a l   p u t a mi n a l   r i ms   o n   t h e  T 2 - w e i g h t e d   ( w h i t e   a r r o w s   i n   A   a n d   E )   a n d   T 2 * - w e i g h t e d   i ma g e s   ( B ) .   T h e   l e s i o n s   a r e   r e c o g n i z e d  a s   l o w   i n t e n s i t y   o n   t h e   T 1 - w i e g h t e d   i ma g e s   ( C   a n d   F )   a n d   a s   l o w   i n t e n s i t y   s u r r o u n d e d   b y   i s o i n t e n -s i t y   o n   t h e   F L A I R   i ma g e s   ( D ) .   MR I   p e r f o r me d   a t   3 4   y e a r s   o f   a g e   ( E   a n d   F ) .teriosclerosis and diabetes (7, 8). However, the present casehad none of these risk factors for the VR spaces, and she al-ready showed a putaminal abnormality at the age of 34, sug-gesting that the observed putaminal lesions are not due toVR spaces. Loy et al also reported putaminal rim hyperin-tensity on T2-weighted images in SCA17 (9) but furtherstudies are required to confirm that these abnormal putami-nal findings are specific to SCA17 and determine whetherthey may be related to the neuropsychiatric abnormalities (7,8) and/or basal ganglia pathology observed in SCA17 pa-tients (3-5, 10, 11).AcknowledgementThe authors thank Drs. Masayuki Baba, Kazuya Kannari andAkira Arai for their kind help. This study was supported byGrants-in Aid for Primary Amyloidosis Research Committee (MYamada), from the Ministry of Health, Labor and Welfare of Ja-pan, by Grants-in Aid for Scientific Research (B) (19390233),and by the grant provided by Sapporo Biocluster “Bio-S”, theKnowledge Cluster Initiative of the MEXT.Inter Med 47: 2179-2182, 2008 DOI: 10.2169/internalmedicine.47.14992182References1. Soong BW, Paulson HL. Spinocerebellar ataxias: an update. CurrOpin Neurol 20: 438-446, 2007.2. Koide R, Kobayashi S, Shimohata T, et al. A neurological diseasecaused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum MolGenet 8: 2047-2053, 1999.3. Nakamura K, Jeong SY, Uchihara T, et al. SCA17, a novelautosomal dominant cerebellar ataxia caused by an expandedpolyglutamine in TATA-binding protein. Hum Mol Genet 10:1441-1448, 2001.4. Toyoshima Y, Yamada M, Onodera O, et al. SCA17 homozygoteshowing Huntington’s disease-like phenotype. Ann Neurol 55:281-286, 2004.5. Fujigasaki H, Martin JJ, De Deyn PP, et al. CAG repeat expansionin the TATA box-binding protein gene causes autosomal dominantcerebellar ataxia. Brain 124: 1939-1947, 2001.6. Oda M, Maruyama H, Komure O, et al. Possible reduced pene-trance of expansion of 44 to 47 CAG/CAA repeats in the TATA-binding protein gene in spinocerebellar ataxia type 17. Arch Neu-rol 61: 209-212, 2004.7. Kwee RM, Kwee TC. Virchow-Robin spaces at MR imaging. Ra-diographics 27: 1071-1086, 2007.8. Maclullich AM, Wardlaw JM, Ferguson KJ, Starr JM, Seckl JR,Deary IJ. Enlarged perivascular spaces are associated with cogni-tive function in healthy elderly men. J Neurol Neurosurg Psychia-try 75: 1519-1523, 2004.9. Loy CT, Sweeney MG, Davis MB, et al. Spinocerebellar ataxiatype 17: extension of phenotype with putaminal rim hyperintensityon magnetic resonance imaging. Mov Disord 20: 1521-1523,2005.10. Bruni AC, Takahashi-Fujigasaki J, Maltecca F, et al. Behavioraldisorder, dementia, ataxia, and rigidity in a large family withTATA box-binding protein mutation. Arch Neurol 61: 1314-1320,2004.11. Gunther P, Storch A, Schwarz J, et al. Basal ganglia involvementof a patient with SCA 17--a new form of autosomal dominant spi-nocerebellar ataxia. J Neurol 251: 896-897, 2004.⡥ 2008 The Japanese Society of Internal Medicinehttp://www.naika.or.jp/imindex.html

A neurological disease caused by an expanded CAG trinucleotide repeat in the TATAbinding protein gene: a new polyglutamine disease?

Basal ganglia involvement of a patient with SCA 17--a new form of autosomal dominant spinocerebellar ataxia.

Behavioral disorder, dementia, ataxia, and rigidity in a large family with TATA box-binding protein mutation.

CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia.

Enlarged perivascular spaces are associated with cognitive function in healthy elderly men.

Kwee TC. Virchow-Robin spaces at MR imaging.

Possible reduced penetrance of expansion of 44 to 47 CAG/CAA repeats in the TATAbinding protein gene in spinocerebellar ataxia type 17.

SCA17 homozygote showing Huntington’s disease-like phenotype.

SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein.

Spinocerebellar ataxia type 17: extension of phenotype with putaminal rim hyperintensity on magnetic resonance imaging.

Spinocerebellar ataxias: an update.

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A Small Trinucleotide Expansion in the TBP Gene Gives Rise to a Sporadic Case of SCA17 with Abnormal Putaminal Findings on MRI

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