Background

The DYNC1H1 gene encodes the heavy chain of cytoplasmic dynein 1, a core structure of the cytoplasmic dynein complex. Dominant DYNC1H1 mutations are implicated in Charcot–Marie–Tooth disease, axonal, type 20, spinal muscular atrophy, lower extremity-predominant 1, and autosomal dominant mental retardation 13 with neuronal migration defects. We report two patients with DYNC1H1 mutations who had intractable epilepsy and intellectual disability (ID), one with and one without pachygyria.

Case reports

Patient 1 had severe ID. At the age of 2 months, she presented myoclonic seizures and tonic seizures, and later experienced atonic seizures and focal impaired-awareness seizures (FIAS). EEG showed slow waves in right central areas during myoclonic seizures. Brain MRI revealed pachygyria, predominantly in the occipital lobe. After callosal transection her atonic seizures disappeared, but FIAS remained. Patient 2 was diagnosed with autism spectrum disorder (ASD) and severe ID. At the age of 7 years, he presented generalized tonic–clonic seizures, myoclonic seizures, and FIAS. Interictal EEG showed generalized spike-and-wave complexes, predominantly in the left frontal area. Brain MRI was unremarkable. Exome sequencing revealed novel de novo mutations in DYNC1H1: c.4691A > T, p.(Glu1564Val) in Patient 1 and c.12536 T > C, p.(Leu4179Ser) in Patient 2.

Conclusions

DYNC1H1 comprises a stem, stalk, and six AAA domains. Patient 2 is the second report of an AAA6 domain mutation without malformations of cortical development. The p.(Gly4072Ser) mutation in the AAA6 domain was also reported in a patient with ASD. It may be that the AAA6 domain has little effect on neuronal movement of DYNC1H1 along microtubules.

中文翻译：

---

DYNC1H1突变合并难治性癫痫2例

背景

DYNC1H1基因编码细胞质动力蛋白 1 的重链，这是细胞质动力蛋白复合物的核心结构。显性DYNC1H1突变与 Charcot–Marie–Tooth 病、轴突、20 型、脊髓性肌萎缩症、下肢显性 1 和常染色体显性智力发育迟缓 13 与神经元迁移缺陷有关。我们报告了两名患有难治性癫痫和智力障碍 (ID)的DYNC1H1突变患者，一名患有脑回症，一名没有脑回。

病例报告

患者 1 患有严重的 ID。在 2 个月大时，她出现了肌阵挛性癫痫发作和强直性癫痫发作，随后出现了失张力性癫痫发作和局灶性意识障碍癫痫发作 (FIAS)。脑电图在肌阵挛发作期间在右中央区域显示慢波。脑 MRI 显示脑回肿大，主要位于枕叶。胼胝体横断后，她的失张力发作消失了，但 FIAS 仍然存在。患者 2 被诊断患有自闭症谱系障碍 (ASD) 和严重的 ID。7 岁时，他出现全身强直-阵挛发作、肌阵挛发作和 FIAS。发作间期脑电图显示广泛的棘波复合物，主要在左侧额叶区域。脑部核磁共振检查无异常。外显子组测序揭示了DYNC1H1中的新从头突变：患者 1 中的 c.4691A > T, p.(Glu1564Val) 和患者 2 中的 c.12536 T > C, p.(Leu4179Ser)。

结论

DYNC1H1 包含一个茎、茎和六个 AAA 结构域。患者 2 是没有皮质发育畸形的 AAA6 域突变的第二份报告。AAA6 结构域中的 p.(Gly4072Ser) 突变也被报道在患有 ASD 的患者中。可能是 AAA6 域对 DYNC1H1 沿微管的神经元运动几乎没有影响。