To report novel causal mutations, expanded clinical phenotypes, and clinical management of DNA methyltransferase 1 (DNMT1)-complex disorder.

Neurophysiologic testing, imaging, and genetic findings were summarized in clinical context for 5 cases with DNMT1-complex disorder.

We identified 2 novel DNMT1 mutations (p.E510K and p.P1546A) by whole-exome sequencing (WES). Case 1 (p.E510K) presented with childhood ataxia, treatment-refractory seizures, and rapid cognitive decline in his 50s. Case 2 also had childhood onset and presented with seizures, language regression, hearing loss, narcolepsy with cataplexy symptoms, optic atrophy, sensory neuropathy, and hypogammaglobulinemia requiring IV immunoglobulin. Case 2 (p.P1546A) was identified with a de novo and the first mutation residing outside the targeting sequence domain. Case 3 (p.A570V) had paralytic asymmetric onset attacks triggered by emotionality and lasting sometimes for weeks. Neuropsychological testing showed executive dysfunction localizing to frontosubcortical and frontoparietal structures. He gradually developed left predominant brain atrophy. MRI showed T2 hyperintense lesions that enhanced on T1 postgadolinium images, and brain PET showed hypometabolism in atrophied regions. Case 4 (p.T497P) underwent left cochlear implant, resulting in significant hearing improvements at all tested frequencies (250–6,000 Hz). Case 5 (p.Y511H) had profound gait ataxia with posterior column atrophy of the spinal cord and abnormal evoked potentials primarily affecting the fasciculus gracilis.

Broader application of WES further expands genotype-phenotype correlations of DNMT1-complex disorder. Two mutations are identified with early childhood onsets. The expanded new phenotypes include asymmetric brain hemiatrophy with parenchymal gadolinium enhancement, spinal cord atrophy, prolonged cataplectic spells, and hypogammaglobulinemia. Hearing loss treatment by cochlear implantation is helpful and should be considered.

报告新的因果突变、扩展的临床表型和 DNA 甲基转移酶 1 (DNMT1) 复杂疾病的临床管理。

在临床背景下总结了 5 例 DNMT1 复杂疾病病例的神经生理学测试、影像学和遗传发现。

我们通过全外显子组测序 (WES) 鉴定了 2 个新的 DNMT1 突变（p.E510K 和 p.P1546A）。病例 1 (p.E510K) 在 50 多岁时出现儿童共济失调、难治性癫痫发作和认知快速下降。病例 2 也有儿童期发病，并出现癫痫、语言退化、听力丧失、伴有猝倒症状的发作性睡病、视神经萎缩、感觉神经病和需要静脉注射免疫球蛋白的低丙种球蛋白血症。案例 2 (p.P1546A) 被鉴定为从头突变，并且第一个突变位于靶向序列域之外。病例 3 (p.A570V) 因情绪激动而出现麻痹性不对称发作，有时会持续数周。神经心理学测试显示执行功能障碍定位于额皮质下和额顶叶结构。他逐渐发展为左侧主要脑萎缩。MRI 显示 T2 高信号病变，在 T1 钆后图像上增强，脑 PET 显示萎缩区域的低代谢。案例 4 (p.T497P) 接受了左侧人工耳蜗植入，在所有测试频率 (250–6,000 Hz) 下都显着改善了听力。病例 5 (p.Y511H) 有严重的步态共济失调伴脊髓后柱萎缩和主要影响股薄束的异常诱发电位。

WES 的更广泛应用进一步扩展了 DNMT1 复杂疾病的基因型-表型相关性。两个突变被确定为儿童早期发病。扩展的新表型包括不对称性脑缺血伴实质钆增强、脊髓萎缩、长期猝倒发作和低丙种球蛋白血症。通过人工耳蜗植入治疗听力损失是有帮助的，应予以考虑。