Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.

Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo in mice. We first constructed Mef2cL35P heterozygous mice. Male heterozygous mice exhibited hyperactivity, repetitive behavior and social abnormalities. We then programmed AeCBE to edit the mutated C·G base pairs of Mef2c in the mouse brain through the intravenous injection of blood-brain barrier-crossing adeno-associated virus. This treatment successfully restored Mef2c protein levels in several brain regions and reversed the behavioral abnormalities in Mef2c-mutant mice. Our work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.

NEXMIF variants are associated with epilepsy with or without intellectual disability.

OBJECTIVES: Variants in NEXMIF had been reported associated with intellectual disability (ID) without epilepsy or developmental epileptic encephalopathy (DEE). It is unkown whether NEXMIF variants are associated with epilepsy without ID. This study aims to explore the phenotypic spectrum of NEXMIF and the genotype-phenotype correlations. MATERIALS AND METHODS: Trio-based whole-exome sequencing was performed in patients with epilepsy. Previously reported NEXMIF variants were systematically reviewed to analyze the genotype-phenotype correlations. RESULTS: Six variants were identified in seven unrelated cases with epilepsy, including two de novo null variants and four hemizygous missense variants. The two de novo variants were absent in all populations of gnomAD and four hemizygous missense variants were absent in male controls of gnomAD. The two patients with de novo null variants exhibited severe developmental epileptic encephalopathy. While, the patients with hemizygous missense variants had mild focal epilepsy with favorable outcome. Analysis of previously reported cases revealed that males with missense variants presented significantly higher percentage of normal intellectual development and later onset age of seizure than those with null variants, indicating a genotype-phenotype correlation. CONCLUSION: This study suggested that NEXMIF variants were potentially associated with pure epilepsy with or without intellectual disability. The spectrum of epileptic phenotypes ranged from the mild epilepsy to severe developmental epileptic encephalopathy, where the epileptic phenotypes variability are potentially associated with patients' gender and variant type.

Clinical and EEG characteristics analysis of autoimmune encephalitis in children with positive and negative anti-N-methyl- D-aspartate receptor antibodies.

BACKGROUND: Autoimmune encephalitis is complex and varied, but it is a curable disease. However, the diagnosis and treatment of children with Autoimmune encephalitis remains challenging. Therefore, we conducted this study to analyze the clinical features, electroencephalogram (EEG) characteristics, treatment and prognosis of autoimmune encephalitis in children with negative and positive anti-N-methyl-D-aspartate receptor (NMDAR) antibody. METHODS: From January 2015 to January 2017, 28 child patients with autoimmune encephalitis were hospitalized in the Neural Ward of the Children's Medical Center, Qilu Hospital of Shandong University. Inclusion criteria were based on the diagnostic criteria for autoimmune encephalitis published in Lancet Neurology in 2016. The clinical, EEG and imaging data were summarized. The clinical features, treatment regimen, follow-up and prognosis were also analyzed. RESULTS: Among these 28 child patients, 10 patients had positive anti-NMDAR antibody, while 18 patients had negative anti-NMDAR antibody. The clinical manifestations, EEG findings and seizures were similar (P>0.05) between these two groups. All 28 child patients were treated with methylprednisolone shock and human immunoglobulin. The response to immunotherapy was similar between these two groups (P>0.05). CONCLUSIONS: The clinical manifestation of autoimmune encephalitis is complex and varied, but it is a curable disease. Immunotherapy should be considered as soon as possible, with or without autoantibodies. Most of the child patients had a good prognosis, while some of them had the sequelae of epilepsy, mild mental symptoms, and dyskinesia. It is necessary to improve the understanding of autoimmune encephalitis with/without positive antibodies, and make diagnosis and treatment as soon as possible, in order to improve the prognosis.

Radiologic features of Castleman's disease involving the renal sinus: A case report and review of the literature.

BACKGROUND: We present a rare case of plasma cell type of Castleman's disease (CD) involving only the right renal sinus in a 65-year-old woman with a duplex collecting system (DCS). CASE SUMMARY: The patient presented with a right renal sinus lesion after renal ultrasonography. Subsequent abdominal enhanced computed tomography (CT) and magnetic resonance imaging (MRI) of the kidneys showed DCS and a soft tissue mass with mild enhancement at the lower right renal sinus. The lesion was suspected to be a malignant renal pelvic carcinoma. Hence, the patient underwent a right radical nephrectomy. Histological examination revealed hyperplastic lymphoid follicles in the renal sinus. A detailed review of the patient's CT and MRI images and a literature review suggested that the lesion was hypointense on T2-weighted images and hyperintense on diffusion-weighted image manifestations, and showed mild enhancement, which distinguished the plasma cell type of CD from many other renal sinus lesions. Furthermore, peripelvic soft tissue masses with a smooth internal surface of the renal pelvis were on imaging findings, which suggests that the urinary tract epithelial system is invulnerable and can be used to differentiate the plasma cell type of CD from malignant lymphoma with a focally growth pattern to some extent. CONCLUSION: Preoperative diagnosis is often difficult in such cases, as plasma cell type of CD involving only the right kidney is exceedingly rare. However, heightened awareness of this disease entity and its radiographic presentations may alert one to consider this diagnosis.