<i>MTHFR</i>基因复合杂合突变致高同型半胱氨酸血症并发育性癫痫性脑病一例并文献复习

doi:10.3969/j.issn.1672-6731.2025.10.012

摘要/Abstract

摘要：

目的: 探讨MTHFR基因变异致高同型半胱氨酸血症与发育性癫痫性脑病的临床关联及干预策略。方法与结果: 女性患儿，2岁5个月，以婴儿痉挛症发病，视频脑电图呈现高度失律，逐渐进展为广泛性多灶性放电伴强直阵挛发作的Lennox-Gastaut综合征；头部MRI检查提示髓鞘化延迟和脑白质软化；基因检测显示MTHFR基因c.154C > T（p.Arg52X）和c.889T > C（p.Tyr297His）复合杂合突变，分别源自其母亲[c.154C > T（p.Arg52X）]和父亲[c.889T > C（p.Tyr297His）]，导致血清同型半胱氨酸水平达161 μmol/L。经联合抗癫痫发作药物、甜菜碱和B族维生素治疗后，同型半胱氨酸水平降至70 μmol/L，发作减少，但神经发育落后仍持续存在。结论: 新型MTHFR基因复合杂合突变[c.154C > T（p.Arg52X）和c.889T > C（p.Tyr297His）]拓展了MTHFR基因突变谱，通过叶酸代谢障碍诱发重度高同型半胱氨酸血症和发育性癫痫性脑病，提示早期代谢干预对改善预后的重要性。

关键词: 高同种半胱氨酸血症, 癫痫, 痉挛，婴儿, 5，10-亚甲基四氢叶酸还原酶（FADH2）, 基因, 突变, 杂合子

Abstract:

Objective: To investigate the clinical correlation between hyperhomocysteinemia caused by MTHFR gene mutation and developmental epileptic encephalopathy (DEE), as well as the corresponding intervention strategies. Methods and Results: A female child, aged 2 years and 5 months, presented with infantile spasm (IS) as the initial symptom. Video electroencephalography (VEEG) showed highly irregular, which progressively evolved into generalized multifocal discharges consistent with Lennox-Gastaut syndrome (LGS), accompanied by tonic clonic seizure. MRI showed delayed myelination and leukomalacia. Genetic testing showed the compound heterozygous mutations in the MTHFR gene: c. 154C > T (p. Arg52X) and c. 889T > C (p. Tyr297His). These were inherited from her mother [c. 154C > T (p. Arg52X)] and father [c.889T > C (p.Tyr297His)]. This genetic testing resulted in severely elevated serum homocysteine level of 161 μmol/L. Following treatment with a combination of antiepileptic seizure medication (ASM), betaine and B vitamins, the homocysteine level decreased to 70 μmol/L and seizure frequency was reduced. However, significant neurodevelopmental delay persisted. Conclusions: The novel compound heterozygous mutations of MTHFR gene [c. 154C > T (p. Arg52X) and c. 889T > C (p. Tyr297His)] expand the spectrum of known MTHFR gene mutation. These mutations disrupt folate metabolism, leading to severe hyperhomocysteinemia and DEE. This case underscores the critical importance of early metabolic intervention for improving clinical outcomes.

Key words: Hyperhomocysteinemia, Epilepsy, Spasms, infantile, 5, 10-Methylenetetrahydrofolate reductase (FADH2), Genes, Mutation, Heterozygote

杜雅坤, 王丽辉, 李焱, 陈芳, 东蕾, 孙素真. MTHFR基因复合杂合突变致高同型半胱氨酸血症并发育性癫痫性脑病一例并文献复习[J]. 中国现代神经疾病杂志, 2025, 25(10): 957-965.

Ya-kun DU, Li-hui WANG, Yan LI, Fang CHEN, Lei DONG, Su-zhen SUN. Hyperhomocysteinemia complicated with developmental epileptic encephalopathy caused by compound heterozygous mutations of MTHFR gene: one case report and literature review[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2025, 25(10): 957-965.

https://journal11.magtechjournal.com/cjcnn/CN/Y2025/V25/I10/957

图/表 6

图 1 患儿4个月时头部MRI检查所见 1a 横断面T₂WI显示，双侧额叶皮质下点片状高信号影（箭头所示） 1b 矢状位T₁WI显示，双侧额叶皮质下点片状低信号影（箭头所示） 1c 横断面T₂WI显示，双侧额颞部蛛网膜下腔间隙增宽（箭头所示） 1d 横断面T₁WI显示，左侧额部少量硬膜下血肿（箭头所示）

Figure 1 Head MRI findings at 4 months of age in the child Axial T₂WI showed subcortical patchy hyperintensity in bilateral frontal lobes (arrow indicates, Panel 1a). Sagittal T₁WI showed subcortical patchy hypointensity in bilateral frontal lobes (arrow indicates, Panel 1b). Axial T₂WI showed widened subarachnoid cavity in both frontal and temporal lobes (arrow indicates, Panel 1c). Axial T₁WI showed a small amount of subdural hematoma in the left frontal lobe (arrow indicates, Panel 1d).

图 2 患儿首次入院后（2岁5个月）头部MRI检查所见 2a 横断面T₂WI显示，双侧额叶高信号范围增大（箭头所示） 2b 冠状位T₂WI显示，双侧额叶高信号范围有所增大（箭头所示） 2c 横断面T₂WI显示，双侧侧脑室周围白质软化（箭头所示），双侧额颞部蛛网膜下腔间隙、脑沟增宽 2d 矢状位T₁WI显示胼胝体发育不良，胼胝体干和压部细薄（箭头所示）

Figure 2 Head MRI findings of the child at first admission (2 years and 5 months old) Axial T₂WI showed the range of hyperintensity in bilateral frontal lobes was increased (arrow indicates, Panel 2a). Coronal T₂WI (Panel 2b) and axial T₂WI (Panel 2c) showed periventricular leukomalacia in the bilateral lateral ventricle (arrows indicate), and widened subarachnoid cavity and sulcus in the bilateral frontal and temporal lobes. Sagittal T₁WI showed dysplasia of the corpus callosum, with the genu and splenium of the corpus callosum being thin and fragile (arrows indicate, Panel 2d).

图 3 患儿首次入院后视频脑电图所见 3a 发作间期清醒期不典型高度失律，即大量广泛性多灶性高至极高波幅的1.50 ~ 2.50 Hz棘慢复合波、尖慢复合波和δ慢波连续发放 3b 发作间期睡眠期不典型高度失律，即大量广泛性多灶性高至极高波幅的1.50 ~ 2.50 Hz棘慢复合波、尖慢复合波和δ慢波连续发放 3c 清醒期多次痉挛发作，可见广泛性正向电压偏转，随后中至高波幅的0.50 ~ 1.00 Hz慢波复合低波幅快节律，同步肌电图持续爆发2 ~ 3 s 3d 清醒期多次痉挛发作，可见广泛性中至高波幅的0.50 ~ 1.00 Hz慢波复合低波幅快节律

Figure 3 VEEG findings of the child at first admission During the interictal phase, the awake period (Panel 3a) and the sleep period (Panel 3b) were atypical and highly irregular, a large number of extensive and multifocal high- extremely high amplitudes of 1.50-2.50 Hz, spiky and slow wave complex, sharp and slow wave complex and δ slow wave were continuously emitted. There were multiple spasm seizure in the awake period with generalized forward voltage deflection, followed by medium-high amplitude 0.50-1.00 Hz slow wave combined with low amplitude fast rhythm, and synchronous electromyography burst for 2-3 s (Panel 3c). There were multiple spasm seizure in the awake period, and generalized medium-high amplitude 0.50-1.00 Hz slow wave combined with low amplitude fast rhythm (Panel 3d).

图 4 Sanger测序所见 4a 患儿存在MTHFR基因c.154C > T（p.Arg52X）杂合突变（箭头所示） 4b 患儿存在MTHFR基因c.889T > C（p.Tyr297His）杂合突变（箭头所示） 4c 患儿之母携带MTHFR基因c.154C > T（p.Arg52X）杂合突变（箭头所示） 4d 患儿之父携带MTHFR基因c.889T > C（p.Tyr297His）杂合突变（箭头所示）

Figure 4 Sanger sequencing findings The child had MTHFR gene c. 154C > T (p. Arg52X) heterozygous mutation (arrow indicates, Panel 4a) and c.889T > C (p.Tyr297His) heterozygous mutation (arrow indicates, Panel 4b). Her mother carried MTHFR gene c.154C > T (p.Arg52X) heterozygous mutation (arrow indicates, Panel 4c). Her father carried MTHFR gene c.889T > C (p. Tyr297His) heterozygous mutation (arrow indicates, Panel 4d).

图 5 患儿再次入院后（5岁7个月）视频脑电图所见 5a 发作间期清醒期和睡眠期广泛性2 ~ 3 Hz的中至高波幅慢波、尖慢复合波发放，以额颞区为著 5b 发作间期清醒期和睡眠期双侧额颞枕区低至高波幅棘波、尖波、棘慢复合波、尖慢复合波连续发放，以后颞区为著 5c 清醒期多次强直阵挛发作，表现为广泛性中波幅多相慢波阵发，跟随短暂性正向电压偏转和广泛性低波幅快节律阵发，同步肌电爆发10 s 5d 清醒期多次痉挛发作，表现为广泛性中波幅多相慢波阵发，跟随短暂性正向电压偏转和广泛性低波幅快节律阵发，同步肌电爆发2 s

Figure 5 VEEG findings of the child at the second admission (5 years and 7 months old) Interictal phase showed during the awake period and the sleep period, there were extensive continuous discontinuations of 2-3 Hz medium-high amplitude slow wave and sharp and slow wave complex, with a focus on the frontal and temporal regions (Panel 5a). Interictal phase showed during the awake period and the sleep period, low - high amplitude spike wave, sharp wave, spike and slow wave complex and sharp and slow wave complex were continuously emitted in the bilateral frontal, temporal and occipital regions, with a focus on the posterior temporal region (Panel 5b). During the awake period, multiple tonic clonic seizure, manifested as the generalized medium amplitude multiphase slow wave burst, followed by the brief forward voltage deflection and a generalized low-amplitude fast rhythm burst, synchronous electromyography burst for 10 s (Panel 5c). During the awake period, multiple spasm seizure, manifested as generalized multiphase slow wave burst of medium amplitude, followed by a brief forward voltage deflection and a generalized low-amplitude fast rhythm burst, synchronous electromyography burst for 2 s (Panel 5d).

表 1 7例MTHFR基因变异致高同型半胱氨酸血症并发育性癫痫性脑病患儿的临床特征

Table 1. Clinical features of 7 cases of hyperhomocysteinemia with DEE caused by MTHFR gene mutation

序号	文献来源	性别	年龄	临床表现	发作形式	血清Hcy（μmol/L）	脑电图	MRI表现	MTHFR基因变异	治疗	预后
1	Cappuccio等^[15]（2014）	女性	18个月	吸吮不良、肌张力低下、小头畸形、嗜睡、智力运动发育迟缓	痉挛发作	180.85	高度失律	广泛脑白质异常，胼胝体细薄，脑发育不良	c.547C > T（p.Arg183Ter）和c.1013T > C（p.Met338Thr）	多种抗癫痫发作药物、甜菜碱、叶酸	发作控制
2	Cappuccio等^[15]（2014）	男性	1个月	吸吮不良、肌张力低下、小头畸形、嗜睡、智力运动发育迟缓	痉挛发作进展为全面性强直-阵挛发作	—（低甲硫氨酸，伴同型半胱氨酸尿）	高度失律	脑萎缩，脑室扩张	c.547C > T（p.Arg183Ter）和c.1013T > C（p.Met338Thr）	—	7个月死亡
3	Cappuccio等^[15]（2014）	女性	10个月	吸吮不良、肌张力低下、小头畸形、嗜睡、智力运动发育迟缓	痉挛发作	180.85	高度失律	严重脑萎缩，脑白质异常，胼胝体细薄	c.547C > T（p.Arg183Ter）和c.1013T > C（p.Met338Thr）	多种抗癫痫发作药物	发作控制，反复感染
4	Prasad等^[20]（2011）	女性	9岁	喂养困难、小头畸形、智力运动发育停滞	痉挛发作，多种全面性发作	71.00	高度失律	脑白质异常信号，髓鞘化延迟	c.677C > T（p.Ala222Val）和c.1298A > C（p.Glu429Ala）	多种抗癫痫发作药物、ACTH、甜菜碱等，胼胝体切开术	骨折，失能，发作控制欠佳
5	Tonetti等^[21]（2000）	男性	22个月	智力运动发育迟缓、孤独症	痉挛发作	22.00	高度失律	—	c.677C > T（p.Ala222Val）和c.1081C > T（p.Arg361Cys）	多种抗癫痫发作药物、甲基叶酸、甜菜碱等	发育落后，发作控制
6	邓劼等^[22]（2020）	女性	28 d	吸吮不良、智力运动发育迟缓	痉挛发作，局灶性发作	> 13.50	爆发-抑制	髓鞘化延迟，胼胝体细薄	c.677C > T（p.Ala222Val）和c.152G > A（p.Arg51Gln）	多种抗癫痫发作药物	失访
7	本文病例	女性	2岁	喂养困难、小头畸形、智力运动发育落后	痉挛发作进展为强直阵挛发作	161.00	高度失律	髓鞘化延迟，脑白质软化	c.154C > T（p.Arg52X）和c.889T > C（p.Tyr297His）	多种抗癫痫发作药物、甜菜碱、B族维生素	发作减少

表 1 7例MTHFR基因变异致高同型半胱氨酸血症并发育性癫痫性脑病患儿的临床特征

Table 1. Clinical features of 7 cases of hyperhomocysteinemia with DEE caused by MTHFR gene mutation

序号	文献来源	性别	年龄	临床表现	发作形式	血清Hcy（μmol/L）	脑电图	MRI表现	MTHFR基因变异	治疗	预后
1	Cappuccio等^[15]（2014）	女性	18个月	吸吮不良、肌张力低下、小头畸形、嗜睡、智力运动发育迟缓	痉挛发作	180.85	高度失律	广泛脑白质异常，胼胝体细薄，脑发育不良	c.547C > T（p.Arg183Ter）和c.1013T > C（p.Met338Thr）	多种抗癫痫发作药物、甜菜碱、叶酸	发作控制
2	Cappuccio等^[15]（2014）	男性	1个月	吸吮不良、肌张力低下、小头畸形、嗜睡、智力运动发育迟缓	痉挛发作进展为全面性强直-阵挛发作	—（低甲硫氨酸，伴同型半胱氨酸尿）	高度失律	脑萎缩，脑室扩张	c.547C > T（p.Arg183Ter）和c.1013T > C（p.Met338Thr）	—	7个月死亡
3	Cappuccio等^[15]（2014）	女性	10个月	吸吮不良、肌张力低下、小头畸形、嗜睡、智力运动发育迟缓	痉挛发作	180.85	高度失律	严重脑萎缩，脑白质异常，胼胝体细薄	c.547C > T（p.Arg183Ter）和c.1013T > C（p.Met338Thr）	多种抗癫痫发作药物	发作控制，反复感染
4	Prasad等^[20]（2011）	女性	9岁	喂养困难、小头畸形、智力运动发育停滞	痉挛发作，多种全面性发作	71.00	高度失律	脑白质异常信号，髓鞘化延迟	c.677C > T（p.Ala222Val）和c.1298A > C（p.Glu429Ala）	多种抗癫痫发作药物、ACTH、甜菜碱等，胼胝体切开术	骨折，失能，发作控制欠佳
5	Tonetti等^[21]（2000）	男性	22个月	智力运动发育迟缓、孤独症	痉挛发作	22.00	高度失律	—	c.677C > T（p.Ala222Val）和c.1081C > T（p.Arg361Cys）	多种抗癫痫发作药物、甲基叶酸、甜菜碱等	发育落后，发作控制
6	邓劼等^[22]（2020）	女性	28 d	吸吮不良、智力运动发育迟缓	痉挛发作，局灶性发作	> 13.50	爆发-抑制	髓鞘化延迟，胼胝体细薄	c.677C > T（p.Ala222Val）和c.152G > A（p.Arg51Gln）	多种抗癫痫发作药物	失访
7	本文病例	女性	2岁	喂养困难、小头畸形、智力运动发育落后	痉挛发作进展为强直阵挛发作	161.00	高度失律	髓鞘化延迟，脑白质软化	c.154C > T（p.Arg52X）和c.889T > C（p.Tyr297His）	多种抗癫痫发作药物、甜菜碱、B族维生素	发作减少

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Hyperhomocysteinemia complicated with developmental epileptic encephalopathy caused by compound heterozygous mutations of MTHFR gene: one case report and literature review

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