De novo DDX3X variants account for 1%-3% of intellectual disability (ID) in females and have been occasionally reported in males. Here, we report a female patient with severe ID and various other features, including epilepsy, movement disorders, behavior problems, sleep disturbance, precocious puberty, dysmorphic features, and hippocampus atrophy. With the use of family-based exome sequencing, we identified a de novo pathogenic variant (c.1745dupG/p.S583 *) in the DDX3X gene. However, our patient did not present hypotonia, which is considered a frequent clinical manifestation associated with DDX3X variants. While hand stereotypies and sleep disturbance have been occasionally associated with the DDX3X spectrum, hippocampus atrophy has not been reported in patients with DDX3X-related ID. The investigation further expands the phenotype spectrum for DDX3X variants with syndromic intellectual disability, which might help to improve the understanding of DDX3X-related intellectual disability or developmental delay.

BackgroundThe Clinical Assessment Scale for Autoimmune Encephalitis (CASE), a new scale used for rating the severity of autoimmune encephalitis (AE), has demonstrated good validity and reliability in adults with AE, but there is a shortage of data on its performance in children with AE. This study aimed to assess the reliability and validity of the CASE in a cohort of children with AE.MethodsForty-seven pediatric inpatients with AE who visited Guizhou Provincial People’s Hospital between January 1, 2017, and October 31, 2021, were enrolled in the study. The CASE and mRS scores were obtained through a review of detailed medical records from the Health Information System by two pediatric neurologists. Finally, the performance of the CASE in this pediatric AE cohort was analyzed.ResultsThe results showed that anti-NMDA receptor encephalitis was the most common (61.70%) type of AE in children. The most common clinical manifestations were language problems (85.1%), psychiatric symptoms (80.9%), and dyskinesia/dystonia (78.7%). The CASE had good item reliability and interevaluator reliability; the Cronbach’s alpha value of the total score was 0.825, and the intraclass correlation (ICC) was 0.980. The Cronbach’s alpha value by item ranged from 0.16 to 0.406; items 1 and 9 had the lowest and highest Cronbach’s alpha values, respectively. The criterion validity between CASE and mRS total scores, as quantified by Pearson correlation, was 0.459, indicating slight to good criterion validity. The area under the curve (AUC) was 0.992 (95% confidence interval: 0.974-1.00). A cutoff value of 14 was selected to determine whether a patient needed admission to the ICU; this cutoff had a sensitivity of 100% and a specificity of 92%. The changes in EEG, MRI, and antibody titers were not related to the severity of AE. A CASE score cutoff of 9 was selected to indicate whether second-line treatment would be needed.ConclusionThe CASE has good reliability and validity in children with AE; however, some items of the CASE may not apply to this population. Thus, an in-depth study of the CASE is needed in children with AE.

Dopa-responsive dystonia (DRD) comprises a group of rare but treatable dystonias that exhibit diurnal fluctuation. The GCH1 gene encodes GTP cyclohydrolase-1 (GTPCH-І), a protein that catalyzes the first rate-limiting step of tetrahydrobiopterin biosynthesis. Pathogenic variants in GCH1 are the most common causes of DRD. However, the autosomal recessive form of DRD caused by biallelic GCH1 variants is very rare. Homozygous GCH1 variants have been associated with two clinically distinct human diseases: hyperphenylalaninemia, and DRD with or without hyperphenylalaninemia. Here, we describe one patient who presented during infancy with severe truncal hypotonia and motor developmental regression but without diurnal fluctuation and hyperphenylalaninemia. Treatment with levodopa/carbidopa resulted in the complete and persistent remission of clinical symptoms without any side effects. This was accompanied by age-appropriate neurological development during follow-up. A homozygous GCH1 variant (c.604G>A/p.V202I) was identified in the patient. To our knowledge, this is the first Chinese case of DRD caused by a homozygous GCH1 variant, thus expanding the spectrum of DRD phenotypes. Autosomal recessive DRD that is associated with homozygous GCH1 variants should be considered in patients with severe truncal hypotonia, with or without diurnal fluctuation, even if there is an absence of limb dystonia and hyperphenylalaninemia.