CYP27A1 mutation in a case of cerebrotendinous xanthomatosis: A case report

lNTRODUCTlON

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid deposition disorder characterized by systemic signs and neurological dysfunction[1]. CTX is a treatable genetic metabolic disease,and early diagnosis and treatment can delay the progression of the disease to a considerable extent[2].We report a case of CTX caused by mutations at two sites in

. This case report will help clinicians to better understand CTX and its presentation, leading to early diagnosis and treatment,thereby improving the quality of life of patients.

CASE PRESENTATlON

Chief complaints

A 38-year-old male was admitted to our hospital with a history of unabating postural instability and difficulty in walking for more than 30 years.

History of present illness

The patient was first brought for treatment at the age of 5 years. Clinical documentation at that time reported that the patient had exhibited unabating postural instability and difficulty in walking that did not improve with rest. He also exhibited cognitive impairment and irritability.

History of past illness

Since childhood, the patient experienced frequent episodes of chronic diarrhea lasting multiple weeks.At the age of 11 years, the patient underwent bilateral cataract surgery. At the age of 36 years, the patient presented with bilateral masses on the Achilles tendons coupled with thickening of the Achilles tendons.

合金中加入Cu元素后，Cu会以颗粒状化合物形式存在于铝基体之中或者固溶于铝基体，显著提高铝合金的强度和硬度，但会使铝合金的伸长率有所降低；Cu在Al-Si合金中会形成强化相 Al2Cu 及 Al4Mg6Cu4Si4，这两种强化相有助于提高合金的强度[6].在Si，Mg，Mn三种元素的质量分数分别为10%，0.1%，0.1%的条件下，铸态下不同Cu含量的合金显微组织如图7所示.由图7可知，随着Cu含量的增加，条片状Si相减少，细化程度得到明显改善，分布逐渐变得不均匀，大部分Si相呈现聚集倾向.

Personal and family history

The patient had no specific personal and family medical history.

精工是世界上唯一一家能够用单体表壳制造潜水表的制造商。整体式结构非常有价值，专为70年代末制作的水肺潜水表而设计（例如，最初的PloProf也采用整体式表壳），它代表着令人难以置信的特点---没有密封件（除了从表盘侧面外无法进入机心），完美的密封性和独特的设计。SLA025就继承了伟大原型的这一特点：采用厚重的单体不锈钢表壳，表径44.8毫米，厚15.7毫米 - 与原型相比略大一些。此外，该表壳还具有超硬涂层，具有更好的防刮性；而4点钟位置的表冠是典型的向原型致敬设计。

Physical examination

（四）强化生态环境保护能力保障体系。增强科技支撑，开展大气污染成因与治理、水体污染控制与治理、土壤污染防治等重点领域科技攻关，

Laboratory examinations

The main cause of CTX is sterol 27-hydroxylase deficiency caused by the mutation of

[3].

encodes sterol 27-hydroxylase and is the only gene known to be associated with CTX[4]. Sterol 27-hydroxylase is involved in the biosynthesis of primary bile acids, including cholic acid and CDCA[5]. Sterol 27-hydroxylase deficiency obstructs the synthesis of primary bile acids, which causes the accumulation of bile acid synthesis pathway intermediates and derivative metabolites such as cholesterol and cholestanol. These substances are easily deposited in various lipophilic tissues, and therefore, they are more common in the brain, lens, and tendons[6]. They can negatively influence the function of cellular calcium channels, destroy the stability of cell membranes, and initiate the apoptosis pathway[7].

Imaging examinations

Based on the patient's medical history, clinical manifestations, auxiliary examinations and gene sequencing results, the diagnosis of CTX was confirmed.

丁小慧才不相信许诺是那种人，她是认识许诺的。当初，许诺开着一个小加工厂，想跟丁小慧的爸爸谈合作，承包一个金属零件的制作。可是，他的技术水平有限，做出来的零件并不符合规范，丁爸爸一口回绝了他。许诺很固执，一次又一次拿着新样品上门，每次都比上次更好一点。最后那次，丁小慧看他满脸失望地下了楼，楼下一个模特般的女孩在等他，他克制着自己的失落，努力冲她笑。

Genetic testing

Based on the patient's medical history, clinical manifestations, and imaging analyses, it was unclear if CTX was involved, and gene sequencing was required to confirm the diagnosis. After informing the patient, the patient was eager to identify the underlying cause and had hopes for treatment; therefore he agreed to undergo gene sequencing analyses. Genomic DNA was extracted from the peripheral blood cells of the patient, and first-generation sequencing of the exon coding region of

revealed that the gene had a compound heterozygous mutation of c.380G＞A (Figure 3) and c.1563dupA (Figure 4).Further examination demonstrated that the mother and sister of the patient were carriers of the c.1563dupA mutation.

本研究还发现2015年MV野毒株组内遗传变异较小，而与疫苗株（A型）比较遗传变异较大。同时也发现有3例麻疹患者之前接种过麻疹疫苗，由于基因测序未发现沪191麻疹疫苗株，且前2例患者接种疫苗到发病时间较短，可能在接种前已经感染MV野毒株，最后1例考虑为免疫失败。冯燕等[15]研究显示，A基因型疫苗免疫后，对国外B、D型MV毒株侵袭的保护效果，要远远好于对我国的H1a流行株的保护。因此，MV野毒株核苷酸及氨基酸变异情况，是否会引起抗原性变化影响疫苗株保护效果，还有待进一步研究。

FlNAL DlAGNOSlS

Magnetic resonance imaging (MRI) (Figure 2A and B) of the brain showed T2-weighted and FLAIR imaging hyperintensity in the bilateral cerebellar dentate nuclei. Electroencephalography showed abnormal slow-wave activity, composed of θ and δ waves, bilaterally in the posterior regions. MRI(Figure 2C and D) of the right ankle indicated fusiform swelling and abnormal signals in the Achilles tendons.

TREATMENT

After the diagnosis of CTX, the patient was prescribed chenodeoxycholic acid (CDCA) at 250 mg three times per day and instructed to adhere to a low-cholesterol diet.

OUTCOME AND FOLLOW-UP

利用微信公众号开展实验室安全知识宣传、安全设施使用、事故案例分析和安全文化建设，此举突破了时空限制，可结合实验室实际情况和实验教学进程编写图文并茂、针对性强的信息资料，及时传送给学生，使学生能及时、持续地获取丰富的学习内容，激发学生的学习兴趣，时时保持实验安全的警惕性，从而达到更好的安全教育目的，这种方式也是传统的安全教育方法的有效补充[12]。

DlSCUSSlON

Blood lipid level examination revealed a total cholesterol concentration of 4.03 mmol/L (reference range: 2.60-5.20 mmol/L).

Currently, CTX is considered a rare disease, as are only a few hundred reported cases worldwide.However, we believe that this value is likely underestimated owing to the diversity of symptoms and the frequent delay in diagnosis. Consequently, the number of CTX cases is likely to be considerably far higher than that reported. The primary manifestations of CTX are infant-onset chronic refractory diarrhea, juvenile-onset bilateral cataracts, tendinous xanthomas, and progressive neurological dysfunction[8]. Neurophenotypes include ataxia, pyramidal tract signs, cognitive impairment, and peripheral neuropathy[8]. When the above symptoms are unexplained by common diseases at any age,the possibility of CTX should be considered, and further examinations should be performed. In the case of our patient, almost all the aforementioned symptoms occurred, although they varied in age at presentation. The constellation of symptoms observed in our patient caused us to consider CTX before other possible diseases.

There are no recognized diagnostic criteria for CTX; thus, clinicians must make their diagnoses based on medical history, family history, and clinical characteristics, following which the diagnosis must be confirmed by performing blood biochemistry tests, plasma cholesterol assessment, MRI, and gene sequencing. Our patient’s gene sequencing results showed two mutation sites in

: c.380G＞A located on exon 2 and c.1563dupA located on exon 9. Among these, the mutation site c.380G＞A has been reported previously[9], but the c.1563dupA mutation is novel and yet to be reported. As our patient possesses a known pathogenic mutation in

, we are currently unable to determine whether the new gene mutation is pathogenic; further research is needed to confirm the same. In addition, the biochemical diagnosis of CTX is based on the increase in serum cholestanol and urine bile alcohols levels[4]. The typical imaging findings indicating the prevalence of CTX include T2-weighted and FLAIR imaging hyperintensity in the dentate nucleus[10]. The current case supports the inclusion of high signal intensity of the two dentate nuclei on MRI as a typical feature of CTX[11]. The typical imaging manifestations of CTX are high signal in T2 weighted imaging and FLAIR imaging of dentate nucleus.

After 1 year of treatment, the patient felt that the symptoms of weakness in both lower limbs had improved slightly, but he did not report any additional changes. The patient reported no adverse reactions to CDCA.

In CTX treatment, there is currently no clear treatment plan, and the condition can be treated symptomatically based on the different clinical manifestations. Bile acid supplements, such as CDCA, provide a source of primary bile acids, which can inhibit the synthesis of bile acids through a negative feedback mechanism, thereby prevent the accumulation of cholesterol and cholestanol[12]. Consequently, early oral bile acid supplement treatment is recommended[13]. In addition, cataract extraction is common performed in these patients, and xanthoma can be surgically removed.

Our patient was prescribed CDCA replacement therapy. At a follow-up visit 6 months posttreatment, the symptoms of the patient had improved slightly. Based on previous studies, we understand that the clinical process of CTX is progressive[14]. Saussy

[14] compared three cases of CTX and concluded that early and uninterrupted treatment can delay progression of the disease, avert nervous system involvement, and improve the quality of life of patients. Once the neurological symptoms are completely determined, the therapeutic effect will be considerably reduced.

CONCLUSlON

Herein, we reported a case where first-generation sequencing of

was performed in a patient with CTX, leading to the detection of an unreported new mutation as well as a previously reported mutation. Consequently, this case provides new data for further examination of the pathogenesis of CTX and enriches the pathogenic mutational spectrum of

. In addition, the diagnosis of our patient helped him to receive genetic counseling and guidance regarding fertility. We hope that our case report enables other clinicians to more deeply understand the diagnosis and treatment of CTX, leading to early diagnoses and treatment and improved patient prognoses.

ACKNOWLEDGEMENTS

We would like to thank the patient and the patient’s family.

FOOTNOTES

Li ZR acquired patient information and prepared the manuscript; Zhou YL prepared the Figure; Jin Q and Xie YY checked the literature and proposed the idea of publishing this case study; Meng HM reviewed and edited the manuscript; and All authors read and approved the final manuscript.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

Informed consent was obtained from the patient. The participant consented to the submission of the case report to the Journal.

Neurological examination revealed gait ataxia, increased muscle tension in both lower limbs, bilateral hyperreflexia of the Achilles and knee tendons, a bilateral positive Babinski sign, and bilateral positive ankle clonus, indicating that the pyramidal tracts were damaged bilaterally. In addition, the patient also presented with arched feet and egg-sized, hard, painless lumps in both achilles tendons (Figure 1).

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Zhao-Ran Li 0000-0002-0048-8398; Yu-Ling Zhou 0000-0002-9155-111X; Qi Jin 0000-0002-5966-9118; Yin-Yin Xie 0000-0002-8749-2831; Hong-Mei Meng 0000-0001-6418-7300.

新时代深化司法鉴定制度改革不仅为司法鉴定管理制度改革提出新要求，也为探索司法鉴定监管模式提出了新任务。司法鉴定管理制度改革需要为司法配套措施改革提供引领和方向。基于时代的要求，开创司法鉴定监管的新模式需要考虑以下问题。

Ma YJ

A

我相信随着对混合式教学模式的深入研究和使用，它巨大的网络平台优势一定会得到更充分的利用，收到更好的教学效果。

Ma YJ

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