8例儿童异染性脑白质营养不良临床表型、遗传学分析及异基因造血干细胞移植疗效观察

doi:10.12372/jcp.2025.25e0117

临床儿科杂志 ›› 2025, Vol. 43 ›› Issue (10): 734-741.doi: 10.12372/jcp.2025.25e0117

8例儿童异染性脑白质营养不良临床表型、遗传学分析及异基因造血干细胞移植疗效观察

胡佳悦¹, 应令雯²^,³, 常国营¹^,²^,³, 李娟²^,³, 杨帆¹, 王翠锦⁴, 郁婷婷³^,⁵, 姚如恩³^,⁵, 罗成娟⁶(), 王秀敏¹^,²^,³()

1.临床研究病区上海交通大学医学院附属上海儿童医学中心（上海 200127）
2.内分泌遗传代谢科上海交通大学医学院附属上海儿童医学中心（上海 200127）
3.上海市罕见病临床研究中心上海交通大学医学院附属上海儿童医学中心（上海 200127）
4.神经内科上海交通大学医学院附属上海儿童医学中心（上海 200127）
5.遗传分子诊断科上海交通大学医学院附属上海儿童医学中心（上海 200127）
6.造血干细胞移植科上海交通大学医学院附属上海儿童医学中心（上海 200127）

收稿日期:2025-02-17 录用日期:2025-05-26 出版日期:2025-10-15 发布日期:2025-09-29
通讯作者: 罗成娟,王秀敏 E-mail:luochengjuan@scmc.com.cn;wangxiumin1019@126.com
基金资助:
上海市卫生健康委员会2024年医疗服务与保障能力提升（国家临床重点专科建设）项目(10000015Z155080000004);科技部国家重点研发计划生育健康及妇女儿童健康保障项目(2023YFC2706305)

Clinical phenotypes, genetic analysis and allogeneic hematopoietic stem cell transplantation efficacy of 8 children with metachromatic leukodystrophy

HU Jiayue¹, YING Lingwen²^,³, CHANG Guoying¹^,²^,³, LI Juan²^,³, YANG Fan¹, WANG Cuijin⁴, YU Tingting³^,⁵, YAO Ruen³^,⁵, LUO Chengjuan⁶(), Wang Xiumin¹^,²^,³()

1. Department of Clinical Research Ward, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
2. Department of Endocrinology and Metabolism, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
3. Shanghai Rare Disease Clinical Research Center, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
4. Department of Neurology, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
5. Department of Genetic and Molecular Diagnosis, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
6. Department of Blood and Marrow Transplantation Ceuter, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China

Received:2025-02-17 Accepted:2025-05-26 Published:2025-10-15 Online:2025-09-29
Contact: LUO Chengjuan, Wang Xiumin E-mail:luochengjuan@scmc.com.cn;wangxiumin1019@126.com

摘要/Abstract

摘要：

目的分析8例异染性脑白质营养不良（MLD）患儿的临床特征和基因变异，探讨了基因型与临床表型的相关性及异基因造血干细胞移植（allo-HSCT）的疗效。方法研究收集了2013年至2024年的患儿资料，通过全外显子组测序确诊，发现所有患儿均有发育迟缓等表现，确诊年龄1岁3个月至9岁6个月。结果根据起病年龄和临床表现，4例为晚婴型，2例死亡；4例为青少年型，生存率100%。基因测序显示ARSA基因的复合杂合变异，共15种突变，其中3种为首次报道，均为有害变异。3例患儿接受了allo-HSCT治疗，均存活但症状有进展。结论 MLD主要表现为中枢神经系统损害，需结合临床表现、ARSA酶活性及基因检测确诊。早期诊断和治疗对改善预后至关重要，allo-HSCT可提高生存率，但疗效有限。

关键词: 异染性脑白质营养不良, ARSA基因, 溶酶体贮积病, 异基因造血干细胞移植

Abstract:

Objective To analyze the clinical characteristics and genetic variations in 8 children with metachromatic leukodystrophy (MLD), and to explore the correlation between genotype and clinical phenotype as well as the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods The study collected data from children diagnosed between 2013 and 2024, confirmed through whole exome sequencing, and found that all children had symptoms such as developmental delay, with ages at diagnosis ranging from 1 year and 3 months to 9 years and 6 months. Results Based on the age of onset and clinical manifestations, 4 cases were late infantile type, with 2 deaths; 4 cases were juvenile type, with a survival rate of 100%. Genetic sequencing revealed compound heterozygous variations in the ARSA gene, a total of 15 mutations, of which 3 were newly reported and all were deleterious variations. Three children received allo-HSCT treatment and all survived but with progression of symptoms. Conclusion MLD mainly manifests as central nervous system damage, and diagnosis should be confirmed in combination with clinical manifestations, ARSA enzyme activity, and genetic testing. Early diagnosis and treatment are crucial for improving prognosis, and allo-HSCT can increase survival rates, but the therapeutic effect is limited.

Key words: metachromatic leukodystrophy, ARSA gene, lysosomal storage disease, allogeneic hematopoietic stem cell transplantation

中图分类号:

胡佳悦, 应令雯, 常国营, 李娟, 杨帆, 王翠锦, 郁婷婷, 姚如恩, 罗成娟, 王秀敏. 8例儿童异染性脑白质营养不良临床表型、遗传学分析及异基因造血干细胞移植疗效观察[J]. 临床儿科杂志, 2025, 43(10): 734-741.

HU Jiayue, YING Lingwen, CHANG Guoying, LI Juan, YANG Fan, WANG Cuijin, YU Tingting, YAO Ruen, LUO Chengjuan, Wang Xiumin. Clinical phenotypes, genetic analysis and allogeneic hematopoietic stem cell transplantation efficacy of 8 children with metachromatic leukodystrophy[J]. Journal of Clinical Pediatrics, 2025, 43(10): 734-741.

图/表 3

表1

8例患儿临床资料"

病例	性别	发病年龄 /岁	确诊年龄 /岁	家族史	分型	主要临床表现	ARSA酶活性 /nmol·17h^－1 ·mg^－1	脑电图结果	头颅MRI结果	随访情况
P1	男	0.75	1.25	无	晚婴型	下肢无力，行走困难	未做	异常脑电图	移植前：两侧脑室周围、两侧半卵圆中心白质信号异常移植后1年：脑室周围异常信号较移植前范围缩小	目前5岁，移植后2年，肌张力升高，不会抬头，不能独坐，不能独站，进食正常，口齿欠清，会说5、6字交流
P2	男	7	7	有	青少年型	头颅MRI异常信号	7.97	中度异常脑电图	两侧脑室旁、额顶叶、胼胝体大片状对称性信号异常	目前8岁10个月，生活尚能自理，听力受损，现佩戴助听器，可自行进食，智力落后
P3	女	6	7.33	无	青少年型	注意力不集中，智力落后	未做	中度异常动态脑电图	脑白质发育不良	现11岁，有癫痫发作，就读特殊学校，生活尚可自理
P4	男	1.83	2	有	晚婴型	行走困难，容易摔倒	未做	异常脑电图，癫痫样放电	脑室周围及皮质下白质对称性脱髓鞘	目前3岁4个月，全身瘫痪，鼻饲，癫痫频繁发作PICU住院治疗中
P5	女	6.08	6.08	无	青少年型	智力落后	5.92	异常脑电图，失神癫痫	移植前：两侧大脑半球白质、胼胝体弥漫性异常信号移植后1年：白质异常信号较移植前范围缩小	目前7岁3个月，移植后1年，走路不稳，智力下降
P6	男	2.5	3.25	无	晚婴型	行走困难	未做	未做	脑白质病变，考虑髓鞘形成不良性疾病	家长放弃，已去世
P7	女	9.08	9.5	无	青少年型	走路不稳，智力落后	6.84	异常脑电图	双侧脑白质弥漫性脱髓鞘改变	目前17岁10个月，移植后7年，基本生活自理，走路不稳，智力下降，语速慢
P8	女	2.25	3	无	晚婴型	行走困难	未做	未做	双侧侧脑室旁脑白质区对称性异常信号影	家长放弃，已去世

表1

表2

图1

参考文献 28

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病例	分型	基因	核苷酸改变	氨基酸改变	ACMG致病性评估	变异来源	是否为新发现突变
P1	晚婴型	ARSA	c.465G>A c.960G>A	p. Gln155Gln p.Trp320*	可能致病性可能致病性	父亲母亲	否否
P2	青少年型	ARSA	c.418C>G c.370G>A	p.His140Asp p.Gly124Ser	可能致病性致病性	父亲母亲	否否
P3	青少年型	ARSA	c.412C>G c.488G>A	p.Pro138Ala p.Cys163Tyr	可能致病性可能致病性	父亲母亲	是是
P4	晚婴型	ARSA	c.925G>A c.465G>A	p.Glu309Lys p.Gln155Gln	致病性致病性	父亲母亲	否否
P5	青少年型	ARSA	c.737G>A c.1136C>T	p.Arg246His p.Pro379Leu	致病性致病性	父亲母亲	否否
P6	晚婴型	ARSA	c.449C>T c.1421delT	p.Pro150Leu p.Phe474Serfs*46	致病性致病性	母亲父亲	否是
P7	青少年型	ARSA	c.257G>A c.581C>G	p.Arg86Gln p.Pro194Arg	致病性致病性	母亲父亲	否否
P8	晚婴型	ARSA	c.302G>T c.827C>T	p.Gly101Val p.Thr276Met	致病性可能致病性	父亲母亲	否否

8例儿童异染性脑白质营养不良临床表型、遗传学分析及异基因造血干细胞移植疗效观察

Clinical phenotypes, genetic analysis and allogeneic hematopoietic stem cell transplantation efficacy of 8 children with metachromatic leukodystrophy

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