肌萎缩侧索硬化相关基因致痉挛性截瘫表型：临床、影像及遗传学分析

doi:10.3969/j.issn.1674-8115.2026.02.016

上海交通大学学报（医学版） ›› 2026, Vol. 46 ›› Issue (2): 256-264.doi: 10.3969/j.issn.1674-8115.2026.02.016

• 短篇论著 • 上一篇

肌萎缩侧索硬化相关基因致痉挛性截瘫表型：临床、影像及遗传学分析

程先茹¹^,²^,³, 曹煜雯²^,³, 田沃土²^,³, 曹立¹^,²^,³()

^1.安徽医科大学附属宿州医院神经内科，宿州 234000
^2.上海交通大学医学院附属第六人民医院神经内科，上海市神经系统罕见疾病生物样本库和精准诊断专业技术服务平台，上海 200233
^3.上海市第六人民医院海口骨科与糖尿病医院脑病中心，海口 570311

收稿日期:2025-10-16 接受日期:2025-11-21 出版日期:2026-02-28 发布日期:2026-02-28
通讯作者: 曹立，主任医师，博士；电子信箱：caoli2000@yeah.net。
基金资助:
国家自然科学基金(82371255,82201398,82071258);上海市优秀学术带头人项目(23XD1402500);上海市科技创新行动计划(23DZ2291500);上海市卫生健康领军人才(2022LJ011);医企融合创新成果转化专项(SHDC2022CRD037);上海市“医苑新星”青年医学人才培养资助计划青年医学人才类——专科项目[SHWSRS(2025)_071];上海市第六人民医院院级探索性临床研究项目(ynts202507);上海市卫生健康委员会卫生行业临床研究专项青年项目(151)

Spastic paraplegia phenotypes associated with amyotrophic lateral sclerosis-related genes: clinical, imaging and genetic analysis

Cheng Xianru¹^,²^,³, Cao Yuwen²^,³, Tian Wotu²^,³, Cao Li¹^,²^,³()

^1.Department of Neurology, Suzhou Hospital of Anhui Medical University, Suzhou 234000, China
^2.Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai 200233, China
^3.Neurological Disorder Center, Haikou Orthopedic and Diabetes Hospital of Shanghai Sixth People's Hospital, Haikou 570311, China

Received:2025-10-16 Accepted:2025-11-21 Online:2026-02-28 Published:2026-02-28
Contact: Cao Li, E-mail: caoli2000@yeah.net.
Supported by:
National Natural Science Foundation of China(82371255,82201398,82071258);Program for Shanghai Outstanding Academic Leaders(23XD1402500);Shanghai Science and Technology Innovation Action Plan(23DZ2291500);Program for Outstanding Medical Academic Leader of Shanghai(2022LJ011);Training Program for Research Physicians of Innovative Translational Ability(SHDC2022CRD037);Shanghai "Rising Stars of Medical Talents" Youth Development Program Youth Medical Talents-Specialist Program [SHWSRS(2025)_071];Exploratory Clinical Research Project of Shanghai Sixth People's Hospital(ynts202507);Shanghai Municipal Health Commission Clinical Research Youth Foundation(151)

摘要/Abstract

摘要：

目的·探析由肌萎缩侧索硬化（amyotrophic lateral sclerosis，ALS）相关基因所致的痉挛性截瘫（spastic paraplegia，SPG）表型的临床、影像和遗传学特征。方法·对2017年4月—2025年9月，上海交通大学医学院附属第六人民医院神经内科收治的5例由ALS相关基因所致SPG的家系进行详细的病史采集与影像学检查，并进行Sanger测序、家系共分离验证及表型分析。结果·5例先证者（男∶女=3∶2）平均发病年龄为（18.4±21.7）岁（1~51岁），平均病程为（12.8±13.3）年（3~33年）。体格检查提示，下肢肌张力增高（5/5）、下肢腱反射亢进（5/5）、髌阵挛（2/5）、踝阵挛（4/5）、下肢病理征阳性（4/5）、足畸形（2/5）。头颅MRI检查提示，2例患者存在异常，分别为例1的小脑和颈髓萎缩、例2的胼胝体压部出现少许异常信号。周围神经电生理检查提示，1例患者双下肢可见少量自发电位，且运动诱发电位显示中枢性损害。基因检测在5例患者中共检出肌萎缩侧索硬化2（amyotrophic lateral sclerosis 2，ALS2）、含缬酪肽蛋白（valosin-containing protein，VCP）、肌萎缩侧索硬化4（senataxin，SETX）、丝氨酸/苏氨酸蛋白激酶NEK1（never in mitosis gene A-related kinase 1，NEK1）等4个不同基因的致病性变异，其中新发现了ALS2基因的c.3527T>C（p.Met1176Thr）和c.1732T>C（p.Ser578Pro）2个变异。结论·分析了ALS相关基因所致的SPG患者的临床异质性和遗传学特征，为准确诊断和深入理解此类疾病提供临床依据。

关键词: 痉挛性截瘫, 肌萎缩侧索硬化, 肌萎缩侧索硬化2（ALS2）, 含缬酪肽蛋白（VCP）, 肌萎缩侧索硬化4（SETX）, 丝氨酸/苏氨酸蛋白激酶NEK1（NEK1）

Abstract:

Objective ·To analyze the clinical, imaging, and genetic characteristics of spastic paraplegia (SPG) phenotypes caused by amyotrophic lateral sclerosis (ALS)-related genes. Methods ·A total of 5 pedigrees with SPG caused by ALS-related genes, admitted to the Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, from April 2017 to September 2025, were included in the study. Detailed medical histories and imaging examinations were collected, and Sanger sequencing, family co-segregation verification, and phenotype analyses were performed. Results ·Among the 5 probands, the male-to-female ratio was 3:2. The average age at onset was (18.4±21.7) years (ranging from 1 to 51 years), and the average disease duration was (12.8±13.3) years (ranging from 3 to 33 years). Physical examination revealed increased muscle tone in the lower extremities in all patients (5/5), hyperreflexia in the lower extremities (5/5), patellar clonus in 2 patients (2/5), ankle clonus in 4 patients (4/5), positive pathological signs in the lower extremities in 4 patients (4/5), and foot deformities in 2 patients (2/5). Brain MRI examinations detected abnormalities in 2 patients, specifically cerebellar and cervical spinal cord atrophy in case 1, and a small number of abnormal signals in the splenium of the corpus callosum in case 2. Peripheral nerve electrophysiological examinations indicated that a small number of spontaneous potentials were observed in both lower extremities of 1 patient, and motor evoked potentials revealed central conduction impairment. Genetic testing identified pathogenic variants in 4 different genes, namely amyotrophic lateral sclerosis 2 (ALS2), valosin-containing protein (VCP), senataxin (SETX), and never in mitosis gene A-related kinase 1 (NEK1), in these 5 patients. Among them, 2 new variants, c.3527T>C (p.Met1176Thr) and c.1732T>C (p.Ser578Pro), were newly discovered in the ALS2 gene. Conclusion ·This article analyzes the clinical heterogeneity and genetic characteristics of SPG patients caused by ALS-related genes, providing clinical evidence for accurate diagnosis and in-depth understanding of such diseases.

Key words: spastic paraplegia, amyotrophic lateral sclerosis, ALS2, VCP, SETX, NEK1

中图分类号:

R774.8

程先茹, 曹煜雯, 田沃土, 曹立. 肌萎缩侧索硬化相关基因致痉挛性截瘫表型：临床、影像及遗传学分析[J]. 上海交通大学学报（医学版）, 2026, 46(2): 256-264.

Cheng Xianru, Cao Yuwen, Tian Wotu, Cao Li. Spastic paraplegia phenotypes associated with amyotrophic lateral sclerosis-related genes: clinical, imaging and genetic analysis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(2): 256-264.

图/表 3

表1 5例ALS相关基因致SPG患者临床及遗传学特征总结

Tab1 Summary of clinical and genetic characteristics of 5 patients with SPG due to ALS-related genes

Item		Case 1	Case 2	Case 3	Case 4	Case 5
Gender		Female	Male	Male	Female	Male
Age/year		29	6	63	4	54
Age at onset/year		9	1	30	1	51
Disease duration/year		29	5	33	3.25	3
Difficulty walking		+	+	+	+	+
Delayed motor development		+	+	-	+	-
Reduced vision		-	-	-	-	+
Difficulty swallowing		+	-	-	-	-
Epileptic seizure		+	-	-	-	-
Upper limbs	HT	-	-	-	-	-
	HR	-	-	-	-	-
	MS/grade	3	5	5	5	5
Lower limbs	HT	+	+	+	+	+
	HR	+	+	+	+	+
	MS/grade	3	5	5	4+	5
Ankle clonus		+	+	-	+	+
Patellar clonus		-	-	-	+	+
Foot deformity		+	+	-	-	-
Scissor gait		-	+	+	+	+
Babinski sign		+	-	+	+	+
Brain MRI		Cerebellar atrophy and cervical spinal cord atrophy	A little abnormal signal in the splenium of the corpus callosum	-	-	-
EMG		NA	NA	NA	-	A small amount of spontaneous potentials could be seen in both lower extremities, and the MEP of the right lower extremity revealed central conduction impairment
MMSE		NA	NA	27	NA	27
MoCA		NA	NA	22	NA	25
SPRS		NA	4	20	NA	23
Mutation type		Com Het	Het	Het	Com Het	Het
Gene mutation		ALS2 c.1804C>T (p.Arg602Cys), c.3527T>C (p.Met1176Thr)	SETX c.3631C>T (p.Arg1211Cys)	NEK1 c.3842A>G(p.Gln1281Arg)	ALS2 c.1732T>C (p.Ser578Pro)、 c.4832G>A (p.Arg1611Gln)	VCP c.476G>A(p.Arg159His)
ACMG		P(PVS1+PS4+PM1+PM2+PP3+PP4)/P(PS4+PM1+PM2+PM3+PP4)	P(PVS1+PS4+PM2+PP4)	P(PVS1+PS4+PM2+PP3+PP4)	P(PS4+PM1+PM2+PM3+PP3+PP4)/P(PVS1+PS4+PM1+PM2+PP3+PP4)	P(PVS1+PS1+PS4+PS3+PM2+PM5+PP1+PP2+PP3)

图1 5例ALS相关基因致SPG患者家系图、测序图、保守性分析和头颅MRINote： A. Case 1 (Ⅲ3) had compound heterozygous variants of c.1804C>T and c.3527T>C in the ALS2 gene. Her mother (Ⅱ2) was a heterozygous carrier of the same variants, while her father (Ⅱ1) was negative. Brain MRI showed cerebellar atrophy (red arrow) and cervical spinal cord atrophy (red triangle). B. Case 2 (Ⅱ2) had a heterozygous variant c.3631C>T in the SETX gene. His mother (Ⅰ2) was a heterozygous carrier of the same variant, while his father (Ⅰ1) was negative. C. Case 3 (Ⅱ3) had a heterozygous variant c.3842A>G in the NEK1 gene. His son (Ⅲ1) was a heterozygous carrier of the same variant. D. Case 4 (Ⅱ1) had compound heterozygous variants c.1732T>C (maternal) and c.4832G>A (paternal) in the ALS2 gene. E. Case 5 (Ⅱ2) had a heterozygous variant c.476G>A in the VCP gene. His brother (Ⅱ1) was a heterozygous patient with the same variant.

Fig 1 Pedigree diagrams, sequencing results, conservation analysis, and brain MRI of 5 patients with SPG associated with ALS-related genes

图2 基因结构域及变异位点示意图Note： At the gene loci, black indicates variants reported in the existing literature, while red denotes newly identified variants in this study. A. Amyotrophic lateral sclerosis 2 (ALS2) gene. RLD—RCC1-like domain; DH-PH—Dbl homology domain and Pleckstrin homology domain; MORN—membrane occupation and recognition nexus domain; VPS9—vacuolar protein-sorting 9 domain. B. Valosin-containing protein (VCP) gene. C. Senataxin (SETX) gene. D. Never in mitosis gene A-related kinase 1 (NEK1) gene; CC—coiled-coil domain.

Fig 2 Schematic diagram of gene domains and variant loci

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肌萎缩侧索硬化相关基因致痉挛性截瘫表型：临床、影像及遗传学分析

Spastic paraplegia phenotypes associated with amyotrophic lateral sclerosis-related genes: clinical, imaging and genetic analysis

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