De novo DYNC1H1 mutation causes infantile developmental and epileptic encephalopathy with brain malformations

Abstract

Background:The human dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene encodes a large subunit of the cytoplasmic dynein complex. DYNC1H1 mutations are associated with various neurological diseases involving both the peripheral and central nervous systems. Methods: The clinical characteristics and genetic data of an infant carrying the de novo DYNC1H1 variant identified by trio exome sequencing were analyzed. Patients with epilepsy with DYNC1H1 mutations were summarized by reviewing the literature. Results: We first identified an infant presenting with epileptic spasms harboring a de novo missense mutation in DYNC1H1 (c.874C>T; p. Arg292Trp), once reported in an adult case, and further summarized another 54 patients with seizures or epilepsy caused by DYNC1H1 pathogenic variants in the literature. Refractory epilepsy, intellectual disability, and cortical developmental malformations are crucial characteristics of patients with developmental and epileptic encephalopathy (DEE) caused by DYNC1H1 variants. Notably, epileptic spasms in this case were resistant to multiple anti-seizure medications, corticosteroids, ketogenic diet, and vagus nerve stimulation treatment. The child also showed cortical gyrus malformation and global developmental delay. Conclusion: DYNC1H1 variants can cause infantile developmental and epileptic encephalopathy, in which Arg292Trp is a mutation hotspot of the DYNC1H1 gene. Epileptic seizures in this type of DYNC1H1-related DEE are mostly resistant to multiple antiepileptic strategies and need to explore optimized treatments.

Case report: Genotype and phenotype of DYNC1H1-related malformations of cortical development: a case report and literature review

“…Furthermore, Hoang et al found that the mutations with the strongest effects on dynein motility were associated with MCD in humans ( 56 ). The mutation detected in our patient (p.Arg292Trp) was previously reported by Benson et al ( 43 ), and a previous study reported that a female with this mutation had focal epilepsy (with onset between 13–18 months) and intellectual disability. A similar phenotype was observed in our patient in that she had early-onset epilepsy and severe intellectual disability.…”