Eur. J. Psychiat. Vol. 30, N.° 1, (79-89)2016

Keywords: Cerebrotendinous xanthomatosis;Sterol 27-hydroxylase; CYP27A1.

Cerebrotendinous xanthomatosis with bradyphreniaand psychiatric disorders: a case with 18F-FDG PETimaging and a literature review

Shimeng Yua

Rong Dengb,*Yang Tanc

Yunjian Zhangc,*a Department of Neurology, Affiliated Hospital

of Xinyang Vocational and Technical College,411 Gongqu Road, Xinyang 464000

b Department of Neurology, JingmenHospital of Traditional Chinese Medicine,15 Baimiao Road, Jingmen 448000

c Department of Neurology, Union Hospital,Tongji Medical College, HuazhongUniversity of Science and Technology,1277 Jiefang Avenue, Wuhan 430022

CHINA

ABSTRACT – Background and Objectives: Cerebrotendinous xanthomatosis (CTX) is arare autosomal recessive lipid-storage disease caused by mutations in the CYP27A1. Thepurpose of this study is to determine the clinical characteristics, neuroimaging and muta-tion detect in a family with CTX systematically.

Methods: Collecting history materials and detecting the routine clinical biochemicaltests and imaging examination, and for the first time taking the whole body positron emis-sion tomography (PET)-CT examination for probed in the world to research abnormal me-tabolism activities in CTX. To observe the effect of treatment with chenodeoxycholic acid(CDCA) and stains before and after the intervention, using serum lipid level detection andneuropsychological evaluation. Genetic testing was carried out to screen the nine exonsand exon-intron boundaries about 200-300bq of CYP27A1.

Results: A 37-year-old woman with typical clinical characteristics of CTX. Magneticresonance imaging (MRI) of brain showed bilateral lesions in the dentate nucleus of thecerebellum, then, PET images revealed multiple abnormal hypermetabolism areas at distaltendon, and multifocal areas of hypometabolism in bilateral sides of cerebellar hemi-spheres, the frontal lobe and temporal lobe. Histopathology reveals accumulation of xan-thoma cells and dispersed lipid crystal clefts in xanthomas. In genetic analysis, it shownan insertion of cytosine (77-78insC) located in the first exon of CYP27A1 in the proband.

Conclusions: We found that a Chinese patient presented a typical clinical feature ofCTX along with clear correlation on both structural and functional imaging had a novelmutation in the CYP27A1 gene.

Received: 16 June 2015Revised: 15 October 2015Accepted: 24 November 2015

80 SHIMENG YU ET AL.

Introduction

Cerebrotendinous xanthomatosis (CTX) isa rare autosomal recessive neurometabolicdisease caused by mutation in CYP27A1 genelocated on chromosome 2q33-qter, leading toincreased deposition of cholesterol and cho -lestanol in multiple tissues, especially in theAchilles tendon and central nervous system1-3.Deficiency of sterol 27-hydroxylase leads tothe reduced production of CDCA, subse-quently resulted in the upregulation of cho-lesterol 7α-hydroxylase (CYP7A1). Mo re -over, upregulation of this rate-limiting en zymein the classic bile acid pathway results in theelevated level of 7α-Hydoxy-4-cho les ten-3-one, an efficient precursor to choles ta nol4.There are no consensus data on the preva-lence of CTX, the previous estimated inci-dence is 3-5/100,000 worldwide. CTX couldpresent at any age and its prevalence may bemuch higher than previously recognized5. Bi-lateral Achilles tendon xanthomas, early-onsetcataracts and neurological symptoms such asdementia and cerebellar ataxia are typical triadof CTX6. Imaging studies have a significantrole in prompt diagnosis. MRI and cerebellarmagnetic resonance spectroscopic (MRS)imaging demonstrated abnormal structu -ral/metabolic changes in brains of the CTXpatients7,8. Single photon emission computedtomography (SPECT) imaging of CTX casesshowed presynaptic do pa minergic deficit as-sociated with asymmetric parkinsonismsymptom9,10. However PET analysis of CTXis rarely reported. Several hundred of con-firmed cases and 50 different mutations of theCYP27A1 gene have been reported world-wide Since Van Bogaert reported the first pa-tient in 193711. In this study, we describe theclinical characteristics, pathology, whole bo -dy PET-CT neuroimaging and one novel mu-tation of the CYP27A1 gene in a Chinese fa -mily with CTX.

Case presentation

History

A 37-year-old female presented with gaitdifficulty and psychiatric disorders was ad-mitted to the hospital. Her history was ob-tained from her husband. When she was 17,bilateral Achilles tendon masses and pro-gressively unsteady gait were found. Becauseit didn’t significantly affect her life, she didnot go to see a doctor. The Achilles tendonmasses gradually increased in size over theyears. Then, when she became 35 years old,she couldn’t even do simple household works.She had slight bradyphrenia, spastic gait,mild dysarthria, psychiatric disorders suchas emotional instability and lack of motiva-tion. She often tried to hide some trivial itemsand kept seeking to ensure their safety. Shehad personality changes such as forced laugh-ter or crying. She had poor appetite, ea sy fa -tigability, and pessimistic thinking. She wasdiagnosed as dysthymic disorder and re-ceived treatment with fluoxetine (40 mg/d)and olanzapine (5 mg/d), the antidepressanttherapy played an effective role in her psychi-atric manifestations but did not change intel-ligence and cognition evaluation. She re-ceived surgical excision of bilateral tendonswellings since the age of 37. Tendon xan-thoma was diagnosed by needle biopsy of theswelling of Achilles tendon. After surgical ex-cision of the bilateral tendon xanthomatosis,her shuffling gait alleviated without improve-ment of mental retardation and behavioral dis-order. Her mother had bilateral cataract andeyelid xanthoma, and her son had a history ofseizures. Her other family history was unre-markable.

Clinical and laboratoryexaminations

Neurologic examination revealed pes ca vus,ankle clonus, bilateral deep tendon hyperre -

flexia and positive Babinski sign. Laboratoryexamination of blood uncovered hyperlipi-daemia: Triglyceride was 5.11 mmol/L (<5.11 mmol/L), cholesterol 6.54 mmol/L (3.2-5.2 mmol/L), high density lipoprotein cho-lesterol (HDL-C) 1.96 mmol/L (1.29-1.55mmol/L), and low density lipoprotein cho-lesterol (LDL-C) 3.79 mmol/L (2.7-3.1mmol/L), normal serum lactate 1.52 mmol/L(0.50-2.20 mmol/L). Her plasma cholestanollevel was 2843 g/dL (n.v 300-360 g/dL).Other routine blood tests (C-reactive protein,parathyroid hormone, thyroid function, rheu -matoid immune markers and tumor mark-ers) were unremarkable. Dual-energy X-rayabsorptiometry of the posteroanterior lumbarspine (L1–L4), femoral neck and total hip un-covered decreased bone mineral density(BMD) (range 0.612-0.976 g/cm2), whichrevealed the existence of osteoporosis in thepatient. Mild abnormal electroencephalog-raphy (diffuse slow waves in bilateral hemi-spheres) and somatosensory evoked potential(SEP) (prolonged latencies in N35, P45 andN60 waves) were detected. Electrophysio-logical conduction parameters of peripheralnerve were normal. Mini-mental state exam-ination (MMSE) score = 20/30 and MontrealCognitive Assessment (MoCA) Beijing Ver-sion score = 19/30. P300 latency period was293ms. The mental status examination sho -wed depressed and anxiety mood. An abdo -minal ultrasound revealed multiple chole-cystic polyps; the biggest one was 7×6 mm.

MRI and PET/CT neuroimagingand histopathology

Magnetic resonance imaging (MRI) of bi-lateral ankle showed fusiform thickening andheterogeneous signals (Fig. 1A). Histopathol-ogy of the tendon mass showed an accumula-tion of xanthoma cells and multiple, dispersedlipid crystal clefts (Fig. 1B). Positron emissiontomography (PET) with 18F-2-deoxy-2-flu-oro-glucose (18F-FDG) revealed abnormally

high radioactivity in Achilles tendons and ad-jacent regions (maximum standardized uptakevalues of 8.7-13.6) (Fig. 1C-D). Brain MRI re-vealed T2-weighted hyperintensities in thedentate nuclei, cerebellar hemispheres, andbasal ganglion (Fig. 1E-F). PET also revealedhypometabolism in the cerebral lobes (espe-cially the frontal and temporal lobe) and cere-bellar hemisphere (Fig. 1G-H). The differenceof brain metabolic changes between the CTXpatient and normal people was remarkable(Supplemental materials).

Genetic analysis

Written informed consent was obtainedfrom her family. Ethics committee in Unionhospital approved this research protocol.Blood samples were obtained from the pa-tient with CTX. Genomic DNA was extractedfrom peripheral blood leukocytes accordingto standard procedures. The sequence infor-mation of the CYP27A1 was obtained fromNCBI database. CYP27A1 gene is located onchromosome 2, 43.62 kb in total. Nine exonsof the CYP27A1 and intron adjacent regionsabout 200-300bq were amplified by poly-merase chain reaction (PCR). The primerswere designed with Primer 5. For example,exon1: Forward5’ TCGCTCCGAACTGAC -TCCG 3’, Reverse 5’ GCAGCCTTCAC TTT -CTGTCCAAC3’; exon2:5’GCCTCCAA-CATACACCTCAACG3’, Reverse5’TTATCCACCTGCCTGCCCT3’; exon3-5: For-ward5’CATAGAGGCTTATCTTTGT-GCTGT3’,Reverse5’ AACTGGTTCAGGTTGGGAGC 3’; exon6-8: Forward5’ CT-CATACACCCTCCCATTACTG 3’, Rever -se5’ ACACTCCTACCCTGTGCCTC 3’;exon9: Forward5’TACTCCTCGCAAGGGTGA3’, Reverse5’CCTCAGATGCTGGGTAGTCA 3’. The DNA sequences were ana-lyzed directly (Bio Miao Biological, Beijing,China). The genetic analysis showed an in-sertion of cytosine (c.-359_-358insC) locatedin the first exon of CYP27A1

CEREBROTENDINOUS XANTHOMATOSIS WITH BRADYPHRENIA AND PSYCHIATRIC... 81

82 SHIMENG YU ET AL.

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Treatment and follow-up

Medications included olanzapine (5mg/d),atorvastatin (20mg/d), donepezil (5mg/d), vi-tamin D (800IU/d) and chenodeoxycholicacid (750mg/d). The blood lipid level of thepatient and cholestanol concentration de-creased after treatment for one month. MoCAscore raised from 19 to 23. MMSE score in-creased from 20 to 22.

Discussion

Cerebrotendinous xanthomatosis (CTX)is a rare inherited lipid-storage disease, withan estimated prevalence of 3-5/100,000 peo-ple worldwide2, and is especially rare in Chi-nese population. Patients with inherited CTXlack sterol 27-hydroxylase (CYP27A1) andusually presents with diverse non-neurologicmanifestations (ie, juvenile cataracts, chronicdiarrhea, premature arteriosclerosis, osteo-porosis, respiratory insufficiency and cardiacsymptoms), and neurological dysfunction,such as dementia, cerebellar syndrome, epi -lepsy, pyramidal signs, peripheral neuropathyand myopathy6.

In this study, we described a patient with aconfirmed diagnosis of CTX characterized bya typical manifestation with bilateral Achillestendon xanthomas and neuropsychologicalsymptoms. The patient in our study didn’thave early non-neurologic dysfunction suchas early-onset cataract, chronic diarrhea andneonatal cholestatic jaundice mentioned inthe literature during her infancy12, but didhave some symptoms such as osteoporosis,Achilles tendon xanthomas and cognitive de-cline. This case also showed some behavio -ral changes that have seldom been reported inthe literature. CTX is a lipid metabolic dis-ease with multi-system involvement, pre-

dominantly brain, tendon, lung and liver13. Ka -wabata et al. uncovered accumulation of foa -my and giant cells with cholestanol in bron -choalveolar lavage fluids and lung bio psy ofCTX patients, which demonstrated lungswere apparently involved in CTX14.

Psychiatric manifestations in the CTX arerare and non-specific, and often lead to sig-nificant diagnostic and treatment delay15. Leeet al. reported three siblings with CTX withpsychiatric disorders such as long-term de-pressed mood, irritability, insomnia and pes-simistic thinking. However, the effectivetreatments for physical manifestations ofCTX did not have an effect on the IQ tests ofthe patients16, which is similar to our study.Early recognition of the psychiatric symp-toms of CTX is important because both thepsychiatric and neurological symptoms re-spond to treatment with CDCA17.

Elevated plasma 5 alpha-cholestanol con-centration detected by gas chromatography-mass spectrometry (GC-MS) is a biomarker inCTX patients18. Plasma cholestanol levelsalong with SEP assessment could support asensitive index of improved biochemical andneurological function before and after drugtreatment. It can also be used to distinguishCTX from other lipid-storage disorders likesitosterolemia and familial hypercholes-terolemia which share similar clinical featuressuch as xanthomas and cardiac disease19. Ho -wever a retrospective review involving twenty-five patients revealed that cholestanol levelsdidn’t correlate with clinical presentation,severity or response to therapy20.

MRI revealed involvement of the dentatenucleus, adjacent cerebellar and periventric-ular white matter hyperintensities6. Gray mat-ter and whiter matter volume correlated clo -sely with neuropsychological results arediffusely decreased in CTX patients21. Seve -ral previous MR spectroscopic study dis-

CEREBROTENDINOUS XANTHOMATOSIS WITH BRADYPHRENIA AND PSYCHIATRIC... 83

closed increased lactate and lipid peaks, anddiffuse decreased N-acetylaspartate (NAA)peaks in the FLAIR-hypointense lesion7,22.SPECT/CT imaging revealed regional cere-bral blood flow (rCBF) changes in multiplebrain lobes before and after therapy, whichmight be an useful tool to follow the therapyresponse in CTX patients23. SPECT imagingusing special photographic developer (eg,99mTc-sestamibi, 123I -FP-CIT) could assessthe mitochondrial status and presynapticdopaminergic function of CTX9,24. Howeverthe whole body PET analysis of CTX israrely reported. 18F-FDG PET/CT imaging inour study revealed multiple abnormal meta -bolism areas at quadriceps tendons and Achi -lles tendons, multifocal areas of hypometab-olism in bilateral cerebellar hemisphere, thefrontal lobe and temporal lobe. The brainmetabolism changes were correlating wellwith the patient’s clinical status (cognitive de-cline, behavior changes, cerebellar symp-toms and pyramidal signs).

The CYP27A1 gene had been firstly repor -ted to be associated with CTX Since 1991(1).Various mutation types included deletion(14%), insertion (2%), splice site mutation(18%), missense (approximately 45%) andnonsense mutations (approximately 20%) inall nine exons of CYP27A1 have been detec -ted11. 50% of mutations in CYP27A1 weredetected in the region of exons 6-8, 16% inexon 2, and 14% in exon 425. Mutation inexon 1 is rare. An insertion of cytosine loca -ted in the section start of the first exon ofCYP27A1 (77-78insC) was detected in ourstudy. It is important to note that none of theCYP27A1 gene mutations could be associ-ated with any special symptom, clinical fea-ture, onset age or prognosis20.

The mean age of onset in the living CTXpatients is 19, an average age on diagnosis is35 years (range 23-44) and a diagnostic delayof 16 years (range 2-34)20. In our study, thepatient was diagnosed with CTX at the age of37 years. Early detection and diagnosis ofCTX is crucial, for early and long-term treat-ment of CTX with CDCA (750mg/d) and itcould improve neurological symptoms andeven reverse the progression of CTX6. Thepotential mechanisms maybe that CDCAgiven exogenously inhibits the bile acid syn-thesis by negative feed back and further pre-vents accumulation of cholestanol in tissuesby normalizing cholestanol concentration26.Unfortunately, we conjugate ursodeoxycholicacid (UDCA) therapy with symptomatic treat-ment to cure the patient because CDCA isn’tavailable in china. Fortunately, the CTX pa-tient didn’t exacerbate in the follow-up withthe above medication. We also revealed thatearly detection and intervention may correctthe abnormal lipid metabolism and possiblyarrest the progression of CTX.

There are so many clinical researches aboutCTX, but the basic animal research aboutthe pathogenesis of CTX is still weak. It is in-teresting that the sterol 27-hydroxylase geneknock out doesn’t lead to formation of xan-thomas in tendons and brain of the knockout mice27. Although some accumulations ofcholestanol were detected in female mice,this accumulation is unremarkable and is notaccompanied by accumulation of cholesterol.The specific mechanism for the differencebetween CTX patients and the mouse modelis unclear. The relationship between the de-position of cholestanol and the developmentof xanthomas deserves further study and asuitable animal model for cerebrotendinousxanthomatosis is still lacking.

84 SHIMENG YU ET AL.

CEREBROTENDINOUS XANTHOMATOSIS WITH BRADYPHRENIA AND PSYCHIATRIC... 85

Figu

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86 SHIMENG YU ET AL.

Figure 2. Compare the PET of the low limb between normal people (A) and the patient with CTX (B, C) in coronal section.PET imaging uncover abnormal soft tissues thickening at CT window in coronal section between normal people (A)

and the patient with CTX (B), and unven 18F-FDG radioactive distribution in Achilles tendons andadjacent regions (SUVmax 8.7-13.6) at PET/fusion windows in the patient with CTX (C).

CEREBROTENDINOUS XANTHOMATOSIS WITH BRADYPHRENIA AND PSYCHIATRIC... 87

Figu

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Conclusions

We found that a Chinese patient presenteda typical clinical feature of CTX along withclear correlation on both structural and func-tional imaging had a novel mutation in theCYP27A1 gene. It is firstly whole body 18F-FDG PET/CT imaging report about CTX inthe world.

Acknowledgements

The authors want to express their gratitudeto the patients and her families for partici-pating in this research.

Consent

Written informed consent was obtainedfrom the patient or their relative for publica-tion of study.

Competing interests

The authors declare that they have no com-peting interests.

Authors ̓contributions

Shimeng Yu wrote the paper and revised themanuscript. Rong Deng collected the bloodand tissue samples for study. Yang Tan per-formed the genetic analysis. Yunjian Zhangdesigned the experiment and final approval ofthe revision. All authors have read and ap-proved the final manuscript.

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* Corresponding author:Yunjian ZhangDepartment of NeurologyUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyChinaE-mail: zhangyunjian66@126.com

Rong DengDepartment of NeurologyJingmen Hospital of Traditional Chinese Medicine15 Baimiao Road, Jingmen 448000ChinaE-mail: 37701640@qq.com

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