成人脑型肾上腺脑白质营养不良的临床及遗传学特征

doi:10.3969/j.issn.1674-8115.2023.05.009

上海交通大学学报（医学版） ›› 2023, Vol. 43 ›› Issue (5): 592-599.doi: 10.3969/j.issn.1674-8115.2023.05.009

• 论著 · 临床研究 • 上一篇

成人脑型肾上腺脑白质营养不良的临床及遗传学特征

刘桃桃¹^,²(), 刘晓黎³, 邬静莹¹, 倪瑞隆¹^,², 张梦圆¹^,², 季杜欣¹, 张梅², 曹立¹^,²()

^1.上海交通大学医学院附属第六人民医院神经内科 200233
^2.安徽理工大学第一附属医院神经内科，淮南 232001
^3.上海市奉贤区中心医院神经内科，上海 201400

收稿日期:2023-02-03 接受日期:2023-05-06 出版日期:2023-05-28 发布日期:2023-07-11
通讯作者: 曹立 E-mail:liutt@rjlab.cn;caoli2000@yeah.net
作者简介:刘桃桃（1991—），女，硕士生；电子信箱：liutt@rjlab.cn。
基金资助:
国家自然科学基金(81870889)

Clinical and genetic characteristics of adult cerebral adrenoleukodystrophy

LIU Taotao¹^,²(), LIU Xiaoli³, WU Jingying¹, NI Ruilong¹^,², ZHANG Mengyuan¹^,², JI Duxin¹, ZHANG Mei², CAO Li¹^,²()

^1.Department of Neurology, Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
^2.Department of Neurology, The First Affiliated Hospital of Anhui University of Science and Technology, Huainan 232001, China
^3.Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai 201400, China

Received:2023-02-03 Accepted:2023-05-06 Online:2023-05-28 Published:2023-07-11
Contact: CAO Li E-mail:liutt@rjlab.cn;caoli2000@yeah.net
Supported by:
National Natural Science Foundation of China(81870889)

摘要/Abstract

摘要：

目的·探究成人脑型肾上腺脑白质营养不良（adult cerebral adrenoleukodystrophy，ACALD）患者的临床及遗传学特点。方法·收集2018年6月至2022年9月在上海交通大学医学院附属第六人民医院就诊的8例ACALD患者的临床资料，包括发病年龄、病程、家族史、现病史及详细的体格检查等结果。影像学检查包括头颅及颈、胸椎磁共振成像（magnetic resonance imaging，MRI）。实验室检测包括血清极长链脂肪酸（very-long-chain fatty acids，VLCFA）、肾上腺皮质功能及基因检测。使用简易精神状态检查量表（Mini-Mental State Examination，MMSE）及蒙特利尔认知评估量表（Montreal Cognitive Assessment，Moca）评估患者的认知功能。结果·共纳入8例ACALD患者，均为男性，发病年龄（32.75±5.80）岁（23~40岁），病程4~59个月。患者首发症状差异较大，其中3例患者表现为记忆力下降、认知功能障碍，2例表现为脾气暴躁、易怒、性格改变，1例表现为精神、行为异常，1例表现为构音不清、共济失调，1例表现为持续性头晕、枕部麻木、失眠。5例患者头发稀疏，4例皮肤色素沉着。患者均有多发性脑白质脱髓鞘病灶，以顶枕叶及胼胝体压部等后部白质脱髓鞘模式最常见；3例头颅增强MRI显示部分病灶斑片状强化；2例患者磁共振波谱成像检查均提示胆碱（Cho）峰升高，N-乙酰基天门冬氨酸（NAA）峰减低。6例患者接受血清VLCFA检查，均表现为C26、C24/C22及C26/C22水平升高；7例患者进行肾上腺皮质功能检测，其中6例出现肾上腺皮质功能减退。6例患者有认知功能受损，其中4例患者MMSE及MoCA评分下降，2例患者因严重的认知障碍不能配合评估。共发现8种ABCD1基因突变，其中c.1750delC（p.H584Tfs*52）及c.160_170delACGCAGGAGGC（p.T54Lfs*137）为新发现的突变。结论·ACALD首发症状多样，以记忆力下降及认知功能障碍最常见。白质脱髓鞘常累及顶枕叶、胼胝体压部，影像学异常早于明显的神经系统症状。头发稀疏、皮肤色素沉着是该病重要特征。血清VLCFA升高及肾上腺皮质功能减退是特征性实验室指标异常。ABCD1基因的错义突变常见，1号和6号外显子是中国人热点突变外显子。

关键词: 肾上腺脑白质营养不良, 遗传性疾病, X连锁, 认知障碍, 脱髓鞘疾病, 肾上腺功能减退

Abstract:

Objective ·To summarize and analyze the clinical and genetic characteristics of adult cerebral adrenoleukodystrophy(ACALD ). Methods ·The data of eight patients with ACALD who attended the Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine from June 2018 to September 2022 were collected and comprehensively analyzed. Clinical data included age at onset, duration of disease, family history, present history and physical examination. Imaging examinations included magnetic resonance imaging (MRI) of the cranial, cervical spine and thoracic spine. Laboratory tests included serum very-long-chain fatty acids (VLCFA), adrenal cortical function and genetic test. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (Moca) were used to assess patients′ cognitive function. Results ·A total of 8 male patients with ACALD were included in this study. Ageat onset ranged from 23 to 40 years old with an average age of (32.75±5.80) years, and the disease duration ranged from 4 to 59 months. Patients′ first symptoms were highly variable. Three patients showed memory loss and cognitive dysfunction, two showed irritability and personality change, one showed mental and behavioral abnormalities, one showed dysarthria and ataxia, and one showed persistent dizziness, occipital numbness and insomnia. All the patients had multiple white matter demyelination lesions, and white matter demyelination in parietal occipital lobe and posterior corpus callosum was the most common. Enhancement MRI showed patchy Gd-enhancement of partial lesions in three cases. In two patients, magnetic resonance spectroscopy showed that choline (Cho) peak increased and N-acetyl-aspartate (NAA) peak decreased. Serum VLCFA levels of C26, C24/C22 and C26/C22 were elevated in six patients who underwent serum VLCFA examination. Seven patients underwent adrenal cortical function testing, of which six experienced adrenal cortical dysfunction. Six patients were cognitively impaired, four of whom had decreased MMSE and MoCA scores, and two of whom were unable to cooperate with the assessment due to severe cognitive impairment. Eight different ABCD1 gene mutations were identified, among which c.1750delC (p.H584Tfs*52) and c.160_170delACGCAGGAGGC (p.T54Lfs*137) were novel mutations. Conclusion ·The initial symptoms of ACALD vary, among which memory loss and cognitive dysfunction are the most common. White matter demyelination lesions in the parietal and corpus callosum pressure are the most common, and imaging abnormalities precede neurological symptoms. The clinical features of the disease are hair thinning and skin pigmentation, and the biochemical features are elevated serum VLCFA and adrenal insufficiency. Missense mutations are more common in the ABCD1 gene, and exons 1 and 6 are the hot mutant exons in Chinese.

Key words: adrenoleukodystrophy(ACALD), genetic diseases, X-linked, cognition disorders, demyelinating diseases, adrenal insufficiency

中图分类号:

R742.3

刘桃桃, 刘晓黎, 邬静莹, 倪瑞隆, 张梦圆, 季杜欣, 张梅, 曹立. 成人脑型肾上腺脑白质营养不良的临床及遗传学特征[J]. 上海交通大学学报（医学版）, 2023, 43(5): 592-599.

LIU Taotao, LIU Xiaoli, WU Jingying, NI Ruilong, ZHANG Mengyuan, JI Duxin, ZHANG Mei, CAO Li. Clinical and genetic characteristics of adult cerebral adrenoleukodystrophy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(5): 592-599.

图/表 4

表1 ACALD患者基本信息、临床特征及实验室指标

Tab 1 General information， and clinical and biochemical characteristics of ACALD patients

Items	P1	P2	P3	P4	P5	P6	P7	P8
Age of onset/Years	27	23	40	37	34	30	33	38
Disease duration/Months	12	4	59	31	5	4	8	16
First symptoms	Memory and cognitive decline	Dizziness with occipital numbness, insomnia	Mental and behavioral abnormalities	Dysarthria and ataxia	Bad temper, personality change	Memory and cognitive decline	Memory decline	Bad temper, personality change
MMSE/MoCA	21/17	ND	NA	ND	21/16	14/9	23/16	NA
VLCFA
C26(≤1.30 nmol/mL)	5.71	ND	3.94	ND	3.77	3.03	3.28	3.38
C24/C22(≤1.39)	1.89	ND	1.50	ND	1.46	1.77	1.76	1.95
C26/C22(≤0.023)	0.132	ND	0.065	ND	0.077	0.068	0.070	0.073
Adrenal insufficiency
Cortisol levels	↓	ND	↓	↓	N	N	↓	↓
ACTH	↑	ND	↑	↑	N	↑	↑	↑
Protein content in cerebrospinal fluid	1.00 g/L	N	0.47 g/L	0.47 g/L	N	ND	ND	ND
Mutation information
Exon	8	10	6	7	1	1	6	3
Nucleotide mutations	c.1817C>T	c.2135G>A	c.1559T>C	c.1750delC	c.323C>T	c.160_170delACGCAGGAGGC	c.1534G>A	c.1202G>A
Amino acid variants	S606L	R712H	L520P	H584Tfs*52	S108L	T54Lfs*137	G512S	R401Q
ACMG	Pathogenic	VUS	VUS	Pathogenic	Pathogenic	Pathogenic	Pathogenic	Pathogenic
Reported phenotypes	CCALD^[3],AMN^[4],AO^[5]	NB^[6]	NB^[6]	‒	CCALD^[7],AO^[8], AMN^[9], Olivo-ponto-cerebellar^[10]	‒	CCALD^[11],AMN^[12],ACALD^[11],AO^[13],Female^[14]	CCALD^[7],AMN^[15],ACALD^[16],NB^[6]AO^[17], Female carrier^[18]

图1 ACALD患者头颅MRINote： A. Advanced ACALD patient (P3), extensive and diffuse distribution of white matter lesions with typical butterfly wing-like changes. B. Olivopontocerebellar ACALD patient (P4), white matter demyelinating lesions involving the bilateral cerebellar hemispheres and brainstem. C. Early stage ACALD patient (P5), white matter demyelinating lesions involving the posterior horn of the lateral ventricle and the corpus callosum. D. Rapidly progressive ACALD patient (P8), white matter demyelination lesions involving the anterior horn of the lateral ventricle and the anterior part of the white matter in the frontotemporal lobe. Some lesions showed patchy enhancement on the T1 enhanced sequence (D1, white arrow). Patients with ACALD had bilateral symmetrical cerebral white matter demyelinating lesions with low signal in T1 sequences (white arrows in A1-C1) and high signal in FLAIR sequences (red arrows in A2-D2).

Fig 1 Cranial MRI of ACALD patients

图2 ACALD患者 ABCD1 基因突变示意图Note： Red indicates new mutations reported in this study. Black indicates previously reported mutations.

Fig 2 Schematic diagram of ABCD1 gene mutation in ACALD patients

图3 患者家系图及Sanger测序图Note： A. Pedigree of patient P4. B. The proband P4 was Hemizygous for c.1750delC, and his mother was Heterozygous at this site (red arrow). C. Pedigree of patient P6. D. The proband P6 was Hemizygous for c.160_170delACGCAGGAGGC, and his elder sister was Heterozygous at this site (red arrow). The rest of the family refused to have blood drawn, so the genetic results were not verified.

Fig 3 Pedigree and Sanger sequencing of ACALD patients

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成人脑型肾上腺脑白质营养不良的临床及遗传学特征

Clinical and genetic characteristics of adult cerebral adrenoleukodystrophy

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