A report of 1 case with hereditary diffuse leukoencephalopathy with spheroids (HDLS) due to a new mutation of colony-stimulating factor 1 receptor (CSF1R)

XIE Lejing; CHEN Chunchun; MA Ying; ZHU Feiqi

doi:10.3969/j.issn.2096-5516.2020.03.006

Chinese Journal of Alzheimer's Disease and Related Disorders >

2020 , Vol. 3 >Issue 3: 195 - 198

DOI: https://doi.org/10.3969/j.issn.2096-5516.2020.03.006

A report of 1 case with hereditary diffuse leukoencephalopathy with spheroids (HDLS) due to a new mutation of colony-stimulating factor 1 receptor (CSF1R)

XIE Lejing ¹ ,
CHEN Chunchun ²^,³ ,
MA Ying ² ,
ZHU Feiqi ^,²^,³

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1 Department of General practice, Luohu People’s Hosptial, Shenzhen, 518001
2 Geriatric Cognitive Impairment ward of Department of Neurology / geriatric branch of Shenzhen Luohu District People's Hospital, Shenzhen 518001
3 Department of Cardiology, Luohu District People's Hospital, Shenzhen 518001

Received date: 2020-06-05

Revised date: 2020-06-17

Online published: 2020-09-25

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Abstract

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare disease, which is very easy to be misdiagnosis as Alzheimer’s disease, frontotemporal demention, Parkinson’s syndrome, multiple sclerosis, depression and ischemic stroke etc.. The progress of HDLS is very quick and its prognosis is very severe. The etiology of HDLS is the mutation of colony stimulating factor 1 receptor gene in exon 12~22. At present, only a few cases of HDLS have been reported in China. Here we reported a case with HDLS who was a 68 year old female. At the age of 58, she began to have memory decline and movement discordance. She had been once diagnosed with Alzheimer’s disease and accepted the treatments of donepezil and memantine. Her disease continued to progress. In the fifth year, she began to have generalized seizures and accepted the treatment of sodium valproate. In the 7th year, she suffered with aphasia, walking disability, bedridden, family unknown, urinary incontinence, etc. In January 2020, due to frequent seizures, she were hospitalized in Luohu People’s Hospital. We found that her bilateral cerebral hemispheres had symmetrical abnormal signals and atrophy of white matter, enlargement of lateral ventricle and atrophy of brain by the brain magnetic resonance image (MRI). It was confirmed that she has a mutation in exon 3 of CSF1R (c.220G> A (guanine> adenine), p.A74T (alanine> threonine)) by whole exon gene sequencing. According to HGMDpro database, this mutation has not been reported. At present, her parents are still alive at the age of 90, without family history of dementia, and the siblings and children are healthy. However, the family refuses to detect the gene. The mutation of CSF1R gene in her immediate relatives is unclear, so she may be a HDLS patient caused by the mutation of exon 3 gene of CSF1R. It had been reported that the treatment of allogeneic hematopoietic stem cell transplantation is effective for the improvement and stability of HDLS, so it is very important to improve the understanding of the disease and carry out allogeneic hematopoietic stem cell transplantation as soon as possible to improve the prognosis of patients.

Key words： Hereditary Diffuse Leukoencephalopathy with Spheroids; Colony Stimulating Factor 1 Receptor Gene; Exon 3

Cite this article

XIE Lejing , CHEN Chunchun , MA Ying , ZHU Feiqi . A report of 1 case with hereditary diffuse leukoencephalopathy with spheroids (HDLS) due to a new mutation of colony-stimulating factor 1 receptor (CSF1R)[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2020 , 3(3) : 195 -198 . DOI: 10.3969/j.issn.2096-5516.2020.03.006

伴球状体遗传性弥漫性白质脑病(hereditary diffuse leukoencephalopathy with spheroids, HDLS ) 是临床罕见疾病,国内只有个案报道,我们收治1例经过全外显子测序确诊的病例,为集落刺激因子受体-1 （colony stimulating factor 1 receptor gene, CSF1R）基因3号外显子新发突变,资料完整,为了提高对本病的认识,现报道如下：

1 临床资料

患者女性,68岁,2020年1月1日因“记忆力减退10年,间断抽搐4年,加重2个月”入院。现病史：患者家属代诉患者于2010年无明显原因出现记忆力减退,以近期记忆力减退为主,事情转身即忘记,呈进行性加重,并出现四肢动作不协调,偶有走失,逐渐丧失生活自理能力,出现穿衣服顺序颠倒, 2011年10月曾在罗湖区人民医院神经内科门诊诊断为“阿尔茨海默病”,予以多奈哌齐(安理申)5毫克/天口服至2014年,病情无明显改善,并且进行性加重,出现学习能力下降,对周围事情失去兴趣,生活能力越来越差,2014年开始予以美金刚片10 mg, bid服用至2018年,患者病情一直未见明显改善,2015年5月患者突发神志丧失,四肢抽搐,牙关紧闭,口吐白沫,双眼上翻,持续约2~3分钟,予以德巴金片0.5 mg, bid,后仍间断反复发作,2017年一次抽搐发作后患者出现语言功能丧失和行走不能,逐渐不认识家人,偶有肢体轻微抽搐,2月前患者家属发现患者双上肢抽搐次数增加,不伴口吐白沫和牙关紧闭,每次持续20~30分钟,可自行停止,一直服用德巴金片0.5 mg, bid,遂来我院住院。入院时患者饮食正常,偶有呛咳,夜间睡眠差,大便正常,小便失禁,用尿不湿。既往史：有高脂血症病史,无高血压病、糖尿病、冠心病和哮喘病史,否认肝炎和结核病史。无脑外伤、输血和手术病史。无药物及食物过敏史。个人史：出生于广东省梅州市,长期在深圳工作生活,无疫区疫水和接触史,无食生鱼片史,无烟酒嗜好,无冶游史和吸毒史。父母目前90岁仍健在,无痴呆家族史,兄妹及子女健康。入院查体：T 36.4℃,BP 146/80 mmHg, P 94次/分,R 20次/分。发育正常,营养中等,心肺腹未见明显异常,缄默状态,四肢肌张力增高和屈曲,双下肢病理征阳性。入院查脑电图：异常脑电图,弥漫性慢波活动为主。心脏彩超：主动脉硬化,主动脉瓣退行性改变,未见明显节段性室壁运动异常,左室舒张功能减退,左室收缩功能正常。血管彩超：双下肢动脉粥样硬化及斑块形成,双侧颈动脉粥样硬化及左侧斑块形成,双侧椎动脉阻力指数增高,右侧锁骨下动脉起始处斑块形成。血常规、肝肾功能和甲状腺功能均正常,免疫球蛋白：IgG 24.4 g/L(正常范围：8.6~17.4 g/L)明显升高,余IgA、IgM、C3和C4均正常。头颅MRI发现双侧大脑半球广泛对称性脑白质变性和萎缩、侧脑室扩大(图1),患者血标本送北京金准基因科技有限公司进行全外显子测序发现患者为CSF1R基因3号外显子c.220G> A（鸟嘌呤>腺嘌呤）,导致氨基酸改变p.A74T（丙氨酸>苏氨酸）（图2）根据HGMDpro数据库报道情况：该突变位点c:220G> A未见报道）。其APOE基因3/3型,未发现APP、PS-1和PS-2基因突变。

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图1 2020年1月份头颅MRI-T2序列

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图2 （全外显子测序结果：CSF1R基因3号外显子存在c.220G> A, chr5-149460417p.A74T突变）

2 讨论

HDLS 是一种罕见的成年起病的常染色体显性遗传的白质脑病。临床表现多样,主要表现为进行性认知功能障碍、性格改变、精神异常、运动障碍和癫痫等,容易误诊为额颞叶痴呆、阿尔茨海默病、抑郁症、多发性硬化、脑常染色体显性动脉病变伴皮质下梗死和白质脑病（cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL）、帕金森综合征甚至脑梗死^[1-2]。发病年龄15~78岁,多在40~50岁发病,平均发病年龄43岁,平均生存期约6.8年^[1⇓-3]。目前认为HDLS发病率被严重低估,有研究显示HDLS约占成人白质脑病的10%。病理学特征为：广泛脑白质脱髓鞘和轴突球样体^[1]。其磁共振特征为：早期表现为双侧、非对称性、片状脑白质异常信号,以额叶或额顶叶显著,累及深部脑白质和皮质脑室周围白质纤维束,亦可见皮质脊髓束受累,弥漫性脑萎缩和脑室扩大,伴胼胝体发育不良和异常信号;随着病情进展,病灶逐渐融合呈片状,并呈对称性分布;但是一般不累及皮质下U型纤维、脑干和小脑皮质^[3]。

2012年该病的致病基因被确定为CSF1R基因突变所致。CSF1R是一种完整的跨膜糖蛋白,由含有5个免疫球蛋白样结构域的细胞外配体结合部分、1个跨膜结构域和 1个胞内酪氨酸激酶结构域三部分组成,其基因突变位点集中在12号至22号外显子,属于高度保守的酪氨酸激酶结构域。CSF1R基因对单核巨噬细胞和小胶质细胞生成、增殖和分化发挥重要作用^[4]。部分未发现CSF1R基因的HDLS患者可能为烯丙基转移tRNA合成酶2（alanyl-transfer (t)RNA synthetase 2, AARS2）基因突变所致,AARS2基因突变导致的HDLS跟CSF1R基因突变的临床表现、影像学改变和神经病理改变非常相似,只是在所有女性患者当中卵巢功能早衰是一个显著特征^[5]。

2018年欧洲神经病学杂志发表了HDLS的诊断标准,尤其对CADASIL的鉴别诊断具有很高的敏感性。一、其核心特征包括：（1）发病年龄≤60岁;（2）至少具备以下2种临床症状和体征：a）认知损伤或精神症状;b）锥体束征;c）帕金森病症状;d）癫痫发作;（3）常染色体显性遗传或散发病例;（4）头部 CT或MRI: a）双侧脑白质病变;b）胼胝体变薄;（5）排除导致脑白质病变的其他原因,包括血管性痴呆、多发性硬化和脑白质营养不良（如肾上腺脑白质营养不良、Krabbe病、异染性脑白质营养不良）等。二、排除性发现包括：（1）发病年龄≤10岁;（2）除癫痫外,中风样发作超过两次;（3）突出的周围神经病变。三、支持性发现包括：（1）临床表现或认知功能评价提示额叶功能障碍;（2）病情进展迅速（发病5年内卧床）; （3）头部CT显示脑白质斑点状微小钙化灶;（4）神经病理发现符合遗传性弥漫性白质脑病合并轴索球样变。根据上述特征可以分为：1）确定的诊断,即满足核心特征（2、3和4 a）,并且存在CSF1R基因的突变;2）很可能的诊断,即满足核心特征（（1）-（5））但未行基因检测;3）可能的诊断,即满足核心特征中的2a、3和4a,但未行基因检测^[6]。尽管以上标准将HDLS病理改变限制在中枢神经脱髓鞘和轴突变性,但是也有HDLS显著累及视神经和周围神经的病例报道,中山大学第三附属医院神经内科陆正齐教授团队发表1例30岁女性,以进行性下肢无力、步态不稳和视力障碍起病的病例,视神经、光学相干断层扫描、视觉诱发电位和视野均发现明显异常,基因检测为CSF1R第18号外显子突变^[7]。意大利报道1例35岁男性HDLS患者,为19号外显子突变,肌电图显示感觉运动神经轴突变性,以运动神经为主^[8]。

该患者58岁时开始出现近期记忆力下降,伴随行动障碍,后出现痴呆和癫痫发作,曾被诊断为“阿尔茨海默病”,予以多奈哌齐和美金刚治疗无明显疗效。发病10年后才通过基因全外显子测序发现CSF1R基因3号外显子c.220G> A（鸟嘌呤>腺嘌呤,导致氨基酸改变p.A74T（丙氨酸>苏氨酸）。该患者的临床症状特点、发病过程及头颅磁共振广泛的脑白质脱髓鞘和萎缩均符合HDLS,但是其CSF1R基因突变的位点是3号外显子,属于含有5个免疫球蛋白样结构域的细胞外配体结合部分,不是导致HDLS疾病CSF1R基因突变的热点外显子12~22号外显子,但是2016年北京宣武医院贾建平教授团队报道1例散发性HDLS病例的CSF1R突变位点为2号外显子和3号内含子(C.49G> T)之间外显子剪接供体位点的杂合突变^[9]。CSF1R基因12号外显子前的基因突变位点报道很少,但是含有5个免疫球蛋白样结构域的细胞外配体结合部分基因突变可能影响CSF1R蛋白的定位和在细胞膜表面的定位。该患者父母近90岁,目前均健在,其兄弟姊妹均无类似发病,由于该患者家属成员拒绝完善基因检测,因此无法了解该患者直系亲属的CSF1R基因情况。尽管HDLS通常为常染色体显性遗传,但是HDLS也有散发病例,以及携带CSF1R基因杂合突变,但是并不发病的病例^[10]。还有CSF1R基因从头突变导致HDLS的病例,成红江等报道1例26岁女性患者,其父母和弟弟CSF1R基因检测正常,但是该患者为CSF1R基因19号外显子杂合突变^[11]。例如华西医院神经科曾报道1例24岁HDLS患者,该患者的母亲携带同样的CSF1R基因突变位点,但是该患者母亲无发病,并且头颅MRI正常^[12]。最近国内另有1例29岁女性HDLS患者,其父亲携带同一CSF1R基因突变位点,但是也并未发病^[13]。并且CSF1R基因同一位点突变的临床表现也差异很大^[14⇓-16],因此CSF1R基因突变导致HDLS的机制非常复杂,需要进一步研究。

2016年Brain杂志和2019年JNNP杂志均报道了采用异体造血干细胞移植治疗HDLS取得成功的个案报道,分别随访15年和3年,异体造血干细胞移植治疗HDLS可以长期保持HDLS患者病情的稳定和好转^[16-17]。有研究显示HDLS患者血浆和脑脊液中神经丝轻链蛋白显著升高,是HDLS的生物标志物^[18]。由于HDLS患者通常病情进展较迅速,预后极差,因此早期正确诊断,及早采用异体造血干细胞移植治疗可能显著改善HDLS的预后。

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