脑腱黄瘤病伴腭肌阵挛的临床特征和CYP27A1基因复合杂合突变家系分析

Clinical features of cerebrotendinous xanthomatosis with complicated palatal myoclonus anda pedigree analysis of compound heterozygous mutation in CYP27A1 gene

目的分析脑腱黄瘤病的临床特点及CYP27A1基因复合杂合突变家系,旨在提高对该病的认识。方法对我中心2018年收治确诊的1例合并腭肌阵挛的脑腱黄瘤病患者临床资料,以及文献检索的25例中国籍患者的组织病理学及基因学特点进行分析。结果患者为20岁女性,总病程12年,白内障12年,行走不稳、构音不清1年,癫痫发作6个月,饮水呛咳5个月。简易精神状态检查(Mini-Mental State Examination,MMSE)评分21分;蒙特利尔认知评估量表(Montreal Cognitive Assessment,MoCA)评分18分。查体:左侧跟腱增粗,高弓足;构音不清;双侧腭肌持续阵挛;辨距不良;双侧掌颏反射阳性,双侧肱二头肌腱反射、膝腱反射亢进,双侧踝阵挛阳性。双侧Babinski征、Chaddock征阳性。头颅MRI显示:双侧脑室旁、双侧底节区、双侧小脑半球对称斑片状T1WI等、低信号,T2WI高信号;DWI呈低信号为主的混杂信号;FLAIR呈高信号;增强扫描未见异常强化;MRS显示病灶区域NNA峰减低,总胆固醇升高。跟腱活检玻璃样变的纤维组织。基因检测发现CYP27A1基因复合杂合变异,分别为5号外显子c.1016C>T(p.Thr339Met)及7号内含子c.1263+1G>A(IVS7-5),美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)变异评级均为致病性,均为国外已报道位点。结合文献复习该病平均发病年龄为(21.38±12.87)岁,平均确诊时间为(12.58±11.5)年。首发症状以跟腱肿物最多,神经系统表现有小脑性共济失调、锥体束征、癫痫发作、认知障碍、周围神经病变。头颅MRI异常表现多在小脑半球、齿状核、内囊及脑干等。多数可查到CYP27A1基因致病变异,最常见于2号外显子,其次为5号、1号、6号,包括复合杂合突变、纯合突变、缺失突变等。结论脑腱黄瘤病临床罕见,临床表现复杂多样,诊断依靠病理检查及基因检测。

Objective To investigate the clinical features of cerebrotendinous xanthomatosis and conduct a pedigree analysis of compound heterozygous mutation in the CYP27A1 gene,and improve the understandings of this disease.Methods An analysis was performed for the clinical data collected from one confirmed case with cerebrotendinous xanthomatosis complicated with palatal myoclonus who was admitted to our hospital in 2018,and the clinical features,laboratory examination,radiological examination,histopathological features,and genetic features of 25 Chinese patients who were identified by literature search.Results The patient was a 20 year-old woman with a history of cerebrotendinous xanthomatosis for 12 years,and she had cataract for 12 years,ataxia and dysarthria for 1 year,seizures for 6 months,and cough during drinking for 5 months.She had a Mini-Mental State Examination score of 21 and a Montreal Cognitive Assessment Mini-Mental State Examination score of 18.Physical examination showed the following results:thickening of the left calcaneal tendon and pes cavus;dysarthria;persistent bilateral palatal myoclonus;dysmetria;positive bilateral palmomental reflex;hyperactive bilateral biceps reflex and patellar tendon reflex and biceps tendon reflex;positive bilateral ankle clonus;positive bilateral Babinski and Chadock signs.Cranial MRI showed symmetric patchy isointensity and hypointensity on T1W1 and hyperintensity on T2W1 in bilateral paraventricular regions,bilateral basal ganglia,and bilateral cerebellar hemispheres;DWI showed mixed-intensity signals,mainly hypointensity;FLAIR showed hyperintensity;contrastenhanced scan showed no abnormal enhancement;magnetic resonance spectroscopy(MRS)showed a reduction in ased NNA peak and an increase in cholesterol in the lesion. Calcaneals tendon biopsy showed hyaline fibrous tissue. Genetic testing revealed twocompound heterozygous mutations in the CYP27A1 gene, i.e., c.1016C > T (p.Thr339Met) in exon 5 and c.1263+1G > A (IVS7-5) in intron 7, both of which were determined as pathogenic mutations based on ACMG mutation ratings and had been reportedabroad. With reference to literature review, the mean age of onset of this disease was 21.38±12.87 years, and the mean time fromonset to confirmed diagnosis was 12.58±11.5 years. Calcaneal tendon mass was the most common initial symptom, and neurologicalmanifestations included cerebellar ataxia, pyramidal signs, seizures, cognitive impairment, and peripheral neuropathy. Abnormalcranial MRI findings were mostly in the cerebellar hemisphere, dentate nucleus, internal capsule, and brain stem. Pathogenicmutations in the CYP27A1 gene were found in most patients, most common mutation in exon 2, followed by those in exons 5, 1,and 6, including compound heterozygous mutations, homozygous mutations, and deletion mutations. Conclusion Cerebrotendinousxanthomatosis is a rare disease in clinical practice, with complex and diverse clinical manifestations, and the diagnosis of this diseasemainly depends on pathological examination and genetic testing.