成年肾上腺脑白质营养不良患者临床及遗传分析

王梦文; 伍楚君; 张在强

doi:10.12376/j.issn.2097-0501.2022.02.006

成年肾上腺脑白质营养不良患者临床及遗传分析

doi: 10.12376/j.issn.2097-0501.2022.02.006

1.
福建医科大学附属第一医院神经内科，福州 350005
2.
首都医科大学附属北京天坛医院神经内科，北京 100050

详细信息

通信作者:
张在强，E-mail：ttyy0142011@126.com

中图分类号: R58
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出版历程
- 收稿日期: 2022-03-04
- 录用日期: 2022-03-18
- 网络出版日期: 2022-06-02

Clinical and Genetic Analysis of Adrenoleukodystrophy in Adults

1.
Department of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
2.
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China

More Information

Corresponding author: ZHANG Zaiqiang, E-mail: ttyy0142011@126.com

摘要

摘要: 目的总结分析成年肾上腺脑白质营养不良(ALD)患者的临床及遗传特点。方法纳入2016年5月至2021年4月于首都医科大学附属北京天坛医院就诊的18例明确诊断为ALD的成年患者，对其临床表型、影像学特点及基因检测结果进行综合分析。结果 18例患者根据临床分型可分为肾上腺脊髓神经型(AMN)6例(33%)、AMN合并脑型2例(11%)、成人脑型(ACALD)5例(28%)、儿童脑型(CCALD) 2例(11%)、青少年脑型(AdolCALD)1例(6%)及小脑型2例(11%)。所有患者的极长链脂肪酸(VLCFA)均出现不同程度的升高。AMN患者均以成年期起病的双下肢僵硬无力为首发及主要表现，并可进展为脑型，临床表现明显加重并出现脑内的脱髓鞘病灶；脑型ALD中成人脑型较为常见，突出表现为精神行为异常、认知障碍及运动功能下降，颅脑MRI表现为对称性额顶叶或顶枕叶白质病变，伴或不伴病灶边缘强化；小脑型患者以小脑性共济失调为主要表现，影像学特点为对称性小脑齿状核累及。18例患者来自18个家系，基因分析结果提示突变类型最常见为错义突变(10/18，55%)，其次是移码突变(7/18，39%)和剪切位点突变(1/18，6%)。其中5个突变为新发突变，均为移码突变。结论成年ALD患者中以肾上腺脊髓神经型最为常见，脑型中成人脑型并不少见，小脑型患者占有一定比率，应予以重视。
- 肾上腺脑白质营养不良 /
- 成年患者 /
- 基因型 /
- 表型
Abstract: Objective Adrenoleukodystrophy (ALD) is the most common peroxisomal diseases with high clinical and genetic heterogeneity. Our study is to analyze the phenotype and genotype characteristics of adult patients with ALD. Methods A total of 18 adult patients with ALD admitted to Beijing Tiantan Hospital from May 2016 to April 2021 were recruited, and their clinical manifestations, imaging features, and genetic results were comprehensively analyzed. Results Among 18 patients, 6(33%) patients were diagnosed as adrenomyeloneuropathy (AMN), 2(11%) were cerebral AMN, 5(28%) were adult cerebral ALD (ACALD), 2(11%) were childhood cerebral ALD (CCALD), 1(6%) were adolescent cerebral ALD (AdolALD), and 2(11%) were cerebellar variant of ALD. AMN patients presented with adult-onset stiffness and weakness of lower limbs as the initial and main symptoms, and can developed additional cerebral demyelination; In the case of cerebral ALD, ACALD is more common than CCALD and AdolALD. The prominent manifestations were psychiatric disorders, cognitive, and motor impairment. The imaging features were predominantly occipitoparietal involvement or predominantly frontal involvement with or without contrast enhancement marginal to the demyelinated areas; cerebellar ataxia is the main manifestation in patients with cerebellar variant, and the imaging feature was symmetrical involvement of the cerebellar dentate nucleus. Genetically, the most common mutation type was missense mutation (10/18, 55.6%), followed by frameshift mutation (7/18, 38.9%), and splice site mutation (1/18, 5.6%). Moreover, we found five novo mutations, all of which were frameshift mutations. Conclusions AMN is the most common subtype of adult patients with ALD. ACALD is common among the cerebral ALD. The proportion of cerebellar variant might have been underestimated.
- Adrenoleukodystrophy /
- Adult patients /
- Phenotype /
- Genotype
注释:

作者贡献：王梦文：采集数据、数据统计与分析、文章撰写; 伍楚君：采集数据、分析解释数据; 张在强：研究设计、指导及对文章的知识性内容作批评性审阅。

利益冲突：所有作者均声明不存在利益冲突。

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图 1 X连锁肾上腺脑白质营养不良的脑MRI特点

A.AMN合并脑型：双侧额叶及右顶叶弥漫性白质病灶在T₂WI上显示高信号，增强后可见不规则强化，弥散加权成像(DWI)上显示双侧病灶明显高信号，CT上可见病灶内点状钙化; B.成人脑型：双侧顶枕叶弥漫性白质病灶在T₁WI上显示低信号，在T₂WI上显示高信号，增强后未见强化，DWI上显示双侧病灶边缘线状高信号; C.成人脑型：双侧额叶弥漫性白质病灶在T₁WI上显示低信号，在T₂WI上显示高信号，增强后可见病灶边缘线状强化，DWI上显示双侧病灶边缘线状高信号; D.小脑型：T₂WI显示双侧小脑齿状核高信号，大脑皮层未累及，DWI上显示双侧小脑病灶边缘线状高信号

Figure 1. Brain MRI features of X-linked adrenoleukodystrophy

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表 1 18例成年期ALD患者的临床及遗传特点

Table 1. Clinical and genetic characteristics of 18 adult ALD patients

编号	发病年龄(岁)	首发表现	其他表现	肾上腺皮质功能	ABCD1基因突变	分型
P1	28	双下肢无力	痉挛性截瘫	正常	c.253_254insC	AMN
P2	27	双下肢僵硬无力	痉挛性截瘫，周围神经损害，二便障碍	正常	c.346G＞C	AMN
P3	25	步态异常	痉挛性截瘫，二便障碍，性功能障碍	异常	c.1028G＞A	AMN
P4	25	行走不稳	轻度认知障碍，痉挛性截瘫，周围神经损害，二便障碍	正常	c.1202G＞A	AMN
P5	25	行走不稳	痉挛性截瘫，共济失调，周围神经损害	正常	c.1552C＞T	AMN
P6	25	双下肢僵硬	痉挛性截瘫	异常	c.1978C＞T	AMN
P7	23	行走不稳	痉挛性截瘫，认知障碍，二便障碍	正常	c.1214_1216delCGT	AMN合并脑型
P8	38	下肢无力	认知障碍，精神异常，痉挛性四肢瘫，周围神经损害，二便失禁	异常	c.1488+1G＞A	AMN合并脑型
P9	40	认知障碍	精神异常，痉挛性截瘫，二便障碍	异常	c.290_299delA CTCGGCCGC	ACALD
P10	43	精神行为异常	认知障碍，小脑性共济失调，痉挛性四肢瘫，尿失禁	正常	c.422C＞T	ACALD
P11	34	精神异常	认知障碍，癫痫发作，痉挛性四肢瘫，小脑性共济失调，周围神经损害，二便障碍	正常	c.423_431dupCCTCCCTGC	ACALD
P12	30	认知障碍	痉挛性四肢瘫，小脑性共济失调，周围神经损害	异常	c.848A＞G	ACALD
P13	42	精神行为异常	认知障碍，命名困难	正常	c.1804A＞T	ACALD
P14	7	运动能力下降	认知障碍，癫痫发作，精神异常，小脑性共济失调	异常	c.24delG	CCALD
P15	9	癫痫发作	认知障碍，精神异常，失用，小脑性共济失调，痉挛性截瘫	正常	c.1876G＞A	CCALD
P16	12	癫痫发作	认知障碍，精神异常，痉挛性四肢瘫，周围神经损害	正常	c.1209_1214del	AdolCALD
P17	30	构音障碍，吞咽困难，饮水呛咳	小脑性共济失调，痉挛性截瘫	正常	c.1252C＞T	小脑型
P18	20	行走不稳	构音障碍，痉挛性截瘫，共济失调，周围神经损害	正常	c.1390C＞T	小脑型

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