GAMT基因变异导致脑肌酸缺乏综合征2型临床特征及预后研究

doi:10.12372/jcp.2024.24e0300

Abstract

Abstract:

Objective To analyse the clinical features, imaging characteristics and prognosis of patients diagnosed with cerebral creatine deficiency syndrome type 2 (CCDS2) caused by variations in the guanidinoacetate methyltransferase (GAMT) gene. Methods To retrospectively analyse the clinical data of five patients diagnosed with CCDS2 due to GAMT gene mutations from January 2016 to March 2024. The analysis focused on the age of disease onset, clinical symptoms, laboratory findings, treatment approaches, and prognosis. Results There were 3 males and 2 females, age of onset 1.5 (1.0-1.5) years old, all patients presented with developmental delay and seizures, with 4 cases exhibiting drug-refractory epilepsy and 3 cases also showing autistic-like behaviors. Brain magnetic resonance spectroscopy (MRS) showed a significant decrease in cerebral creatine peaks in all 5 cases, and 2 cases showed abnormal signals in the brainstem with or without basal ganglia on brain magnetic resonance imaging (MRI). In all patients, blood or urine creatine metabolism tests showed a significant decrease in creatine and an increase in guanidinoacetate. Four patients received treatment with creatine supplementation and guanidinoacetate-lowering therapy, resulting in complete seizure control after 2 weeks to 10 months, discontinuation of anti-seizure medications, and varying degrees of improvement in motor and speech development. Conclusion CCDS2 due to variants in the GAMT gene usually presents with developmental delay with drug refractory epilepsy, partly combined with autistic-like behavior, and lacks specificity. Brain MRS and creatine metabolite testing may aid in genetic diagnosis, and treatment with creatine supplementation and guanidinoacetate lowering may be effective in controlling seizures and improving prognosis.

Key words: cerebral creatine deficiency syndromes, intellectual disabilities, guanidinoacetate methyltransferase, guanidinoacetate, refractory epilepsy

YANG Lei, FANG Fang, SONG Tianyu, XU Chaolong. A clinical and prognosis study of five patients with cerebral creatine deficiency syndrome 2 caused by GAMT gene mutations[J].Journal of Clinical Pediatrics, 2024, 42(12): 1039-1046.

Figures/Tables 6

患儿	性别	年龄	临床表现	头颅影像学检查	基因	代谢检查	治疗	预后
1^[8]	男	3岁	轻度发育迟缓、热性惊厥	脑白质发育异常、胼胝体发育异常；脑Cr↓	c.412C>T IVS4-1G>A	/	肌酸400 mg/（kg·d）	随访3月无惊厥发作
2^[9]	男	8岁	发育迟缓、癫痫、肌张力低	/	c.403G>A c.520T>C	GAA↑、Cr↓、游离肉碱↓、尿甲苯胺蓝3+	肌酸4g/d，左卡尼汀1g/d	随访1年无癫痫发作
3^[9]	女	4.5岁	发育迟缓	双侧苍白球异常信号	c.134G>A c.316C>T	GAA↑、Cr↓、Hcy?	肌酸2g/d，左卡尼汀1g/d	随访1月后可扶走
4^[9]	女	6.5岁	发育迟缓、癫痫、运动障碍	头MRI正常	c.491dup c.403G>A	GAA↑、Cr↓、尿酰基肉碱和多种有机酸升高	肌酸3g/d，左卡尼汀1g/d	治疗5月无癫痫发作
5^[9]	男	4.5岁	发育迟缓、孤独症样行为	/	c.181G>A c.158_181+7del	GAA↑、Cr↓	肌酸2g/d，左卡尼汀1g/d	治疗6月行为、脾气、语言有改善
6^[9]	女	2岁	发育落后、难治性癫痫	/	c.444_448del c.520T>C	GAA↑、Cr↓、酰基肉碱升高，尿多种有机酸升高	肌酸1.5g/d，左卡尼汀1g/d	治疗3年无癫痫发作
7^[10]	女	4岁	中度发育落后、癫痫、肌张力低、说2-3字	脑白质异常信号；脑Cr↓	c.564G>T c.491dupG	GAA↑、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访10年发育正常，治疗2年后无癫痫发作
8^[10]	女	20月龄	重度发育落后、无主动语言、癫痫	脑外间隙宽；脑Cr↓	c.289delC c.392-1G>C	GAA正常、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访2年运动、社交语言有改善，癫痫发作可药物控制
9^[10]	女	4岁	重度发育落后、无语言、癫痫	胼胝体薄；脑Cr↓	c.328-1G>A c.403G>A	GAA↑、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访2年运动、社交、语言有改善，癫痫治疗1年后无发作
10^[10]	女	6岁	中度发育落后、说2-3个字、难治性癫痫	脑白质异常信号；脑Cr?	c.328-1G>A c.114C>T	GAA↑、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访3年运动、社交语言改善，治疗2年后癫痫无发作
11^[10]	男	3岁	中度发育落后、说1-2个字	头MRI正常；脑Cr↓	c.328-2A>G c.115 A>G	GAA↑、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访7个月运动、语言、社交改善
12^[10]	男	1岁	轻度发育落后、说1-2个字	头MRI正常；脑Cr↓	/	GAA↑、Cr↓	肌酸400mg/（kg·d），鸟氨酸300~400mg/（kg·d），低蛋白饮食	随访7个月运动、语言、社交改善
13^[11]	女	3岁	发育落后、难治性癫痫	头MRI正常	c.491 dupG c.403G>A	/	肌酸300mg/（kg·d），鸟氨酸300~400mg/（kg·d）	随访4月运动语言改善不明显，治疗2月后癫痫发作控制

References 16

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项目	例1	例2	例3	例4	例5
性别	男	男	男	女	女
起病年龄	8月龄	1.5岁	2岁	1岁	1.5岁
确诊年龄	9月龄	10岁	8岁	7岁	5岁
随访年龄	8岁	15岁	14岁	14岁	13岁
临床表现
运动发育落后	+	+	+	+	+
语言发育迟缓	+	+	+	+	+
孤独症样行为	-	+	-	+	+
癫痫发作	点头发作（肌阵挛可能）、全身强直阵挛发作	强直发作，不典型失神、肌阵挛	全身强直阵挛发作、不典型失神、肌阵挛	跌倒发作（肌阵挛可能）、全身强直阵挛发作	肌阵挛
EEG	9月龄正常	各导联可见高-极高波幅尖波、尖慢波发放	全导频发广泛性高-极高波幅不规则慢波夹杂少量尖棘波，双枕及后颞导联频发棘波、尖波、尖棘慢波	广泛高波幅慢波夹杂多灶性尖棘波	慢波活动增加，广泛多灶性痫样放电
抗癫痫药物	VPA	VPA，LEV	PHT，LEV，VPA	TPM，LEV	TPM，LEV，PB
头颅MRI	双侧苍白球和脑桥背侧对称性长T1长T2信号	正常	正常	正常	脑干背侧可见长T1长T2信号
头颅MRS	Cr降低	Cr降低	Cr降低	Cr降低	Cr降低
代谢检查*
血肌酐	/	9.1 μmol/L	18.6 μmol/L	7.7 μmol/L	8.5 μmol/L
尿肌酸	0.012 mmol/L	0.002 mmol/mmolCrn	0.002 mmol/mmolCrn	0.003 mmol/mmolCrn	0.003 mmol/mmolCrn
尿GAA	1.192 mmol/L	2.168 mmol/mmolCrn	0.744 mmol/mmolCrn	1.575 mmol/mmolCrn	1.374 mmol/mmolCrn
尿肌酐	0.802 mmol/L	/	/	/	/
尿GAA/肌酐	1.486	/	/	/	/
治疗后血肌酐	/	40.2μmol/L	42.0μmol/L	/	/
治疗后尿肌酸	/	3.624 mmol/mmolCrn	0.553 mmol/mmolCrn	/	/
治疗后尿GAA	/	0.368 mmol/mmolCrn	0.428 mmol/mmolCrn	/	/

患儿	核苷酸变异	氨基酸变异	来源	致病性	ACMG评级
例1	c.194T>C	p.L65P	父源	临床意义未明	PM2_Supporting+PP3
	c.467C>A	p.A156D	母源	临床意义未明	PM2_Supporting+PP3+PS3_Supporting
例2	c.158_181+7 del	splicing	父源	致病	PVS1+PM2_Supporting+PM3_Supporting
	c.158_181+7 del	splicing	母源	致病	PVS1+PM2_Supporting+PM3_Supporting
例3	c.418_419delTC	p.S140Gfs*50	父源	疑似致病	PVS1+PM2_Supporting
	c.212T>G	p.M71R	母源	临床意义未明	PM3+PM2_Supporting+PP3
例4	c.328-1G>A	splicing	父源	致病	PVS1+PM2_Supporting+PM3_Supporting
	c.328-1G>A	splicing	母源	致病	PVS1+PM2_Supporting+PM3_Supporting
例5	c.328-1G>A	splicing	父源	致病	PVS1+PM2_Supporting+PM3_Supporting
	c.328-1G>A	splicing	母源	致病	PVS1+PM2_Supporting+PM3_Supporting

A clinical and prognosis study of five patients with cerebral creatine deficiency syndrome 2 caused by GAMT gene mutations

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