Clinical analysis of 173 pediatric patients with antibody-mediated autoimmune diseases of the central nervous system: a single-center cohort study.

Background: Antibody-mediated disorders of the central nervous system (CNS) have seen a gradual rise in their incidence and prevalence. This retrospective observational study aimed to investigate the clinical characteristics and short-term prognosis of children with antibody-mediated CNS autoimmune diseases at Hunan Children's Hospital. Methods: We collected the clinical data of 173 pediatric patients diagnosed with antibody-mediated CNS autoimmune diseases between June 2014 and June 2021 and analyzed their demographics, clinical features, imaging and laboratory data, treatment, and prognosis. Results: A total of 187 patients tested positive for anti-neural antibodies and 173 patients were finally diagnosed with antibody-mediated CNS autoimmune diseases after excluding the 14 false-positive cases through clinical phenotypic evaluation and follow-up of treatment outcomes. Of the 173 confirmed patients, 97 (56.06%) were positive for anti-NMDA-receptor antibody, 48 (27.75%) for anti-MOG antibody, 30 (17.34%) for anti-GFAP antibody, 5 (2.89%) for anti-CASPR2 antibody, 3 (1.73%) for anti-AQP4 antibody, 2 (1.16%) for anti-GABABR antibody, and 1 (0.58%) for anti-LGI1antibody. Anti-NMDAR encephalitis was the most commonly seen among the patients, followed by MOG antibody-associated disorders and autoimmune GFAP astrocytopathy. Psycho-behavioral abnormalities, seizures, involuntary movements, and speech disorder were the most common clinical presentations of anti-NMDAR encephalitis, while fever, headache, and disturbance of consciousness or vision were the most seen among patients with MOG antibody-associated disorders or autoimmune GFAP astrocytopathy. The coexistence of multiple anti-neural antibodies was detected in 13 patients, among which 6 cases had coexistent anti-NMDAR and anti-MOG antibodies (including 1 case with anti-GFAP antibody also), 3 cases had coexistent anti-NMDAR and anti-GFAP antibodies, 3 cases had coexistent anti-MOG and anti-GFAP antibodies, 1 case had coexistent anti-NMDAR and anti-CASPR2 antibodies, and 1 case had coexistent anti-GABABR and anti-CASPR2 antibodies. All the survivors were followed up for at least 12 months; 137 recovered completely, 33 had varying sequelae, and 3 died; 22 had one or more relapses. Conclusion: Antibody-mediated CNS autoimmune diseases occur in children of all ages. Most such pediatric patients have a good response to immunotherapy. Despite the low mortality rate, some survivors have a non-negligible risk of developing relapses.

Genetic analysis of developmental and epileptic encephalopathy caused by novel biallelic SZT2 gene mutations in three Chinese Han infants: a case series and literature review.

BACKGROUND: Developmental and epileptic encephalopathy (DEE) exhibits phenotypic and genetic heterogeneity. Biallelic variants of the SZT2 gene can lead to DEE18, of which few cases have been reported. This study aimed to analyze the potential pathogenic factors in three cases of DEE18. METHODS: Trio-whole exome sequencing and crystal structure simulation analysis were performed, along with a literature review of DEE18 cases. RESULTS: All three patients had compound heterozygous variants in the SZT2 gene (patient 1, c.2887A > G/c.7970G > A; patient 2, c.3508A > G/c.7936C > T; and patient 3, c.2489G > T/c.8640_8641insC). The variants were predicted to have structural effects on the protein. Particularly, c.3508A > G/p.Ser1170Gly may lead to impaired binding of SZT2 to GATOR1, potentially resulting in the overactivation of the mTORC1 signaling pathway, causing seizures. Through the literature review, we observed that 27 patients with DEE had different degrees of intellectual and developmental disorders (DDs), and the variants leading to protein truncation cause severe DD and refractory epilepsy. Therefore, the phenotypic severity of patients may be related to the residual activity of variant SZT2 protein. CONCLUSION: We provide recently developed knowledge on the DEE18 genotype-phenotype spectrum and suggest that gene detection is of great value for the accurate diagnosis of patients with early-onset epilepsy. Further research is required for the development of individualized interventions for patients with DEE.

Case Report: Compound Heterozygous Variants of SLC13A3 Identified in a Chinese Patient With Acute Reversible Leukoencephalopathy and α-Ketoglutarate Accumulation.

Background: SLC13A3 gene encodes the Na+/dicarboxylate cotransporter 3 (NaDC3), which locates on the plasma membrane and is mainly expressed in kidney, astrocytes and the choroid plexus. It imports four to six carbon dicarboxylates together with three Na+ ions into the cytosol. Nowadays, pathogenic variants of SLC13A3 gene were found to cause acute reversible leukoencephalopathy and α-ketoglutarate accumulation (ARLIAK) in patients. Here, we report two novel SLC13A3 variants c.185C>T (p.T62M) and c.331C>T (p.R111*) identified in a Chinese patient with ARLIAK. Case Presentation: The patient was a Chinese girl aged 13 years and 7 months old, who had acute, recurrent neurological deterioration during two febrile episodes. She presented with reversible leukoencephalopathy and increased urinary excretion of α-ketoglutarate. Genetic studies revealed compound heterozygous variants (c.185C>T, p.T62M, and c.331C>T, p.R111*) in SLC13A3, which had not been reported previously. Conclusions: These findings expand the variant spectrum of SLC13A3, providing the basis for the further study of this rare disease.

CNKSR2 gene mutation leads to Houge type of X-linked syndromic mental retardation: A case report and review of literature.

RATIONALE: Mutations of connector enhancer of kinase suppressor of Ras-2 (CNKSR2) gene were identified as the cause of Houge type of X-linked syndromic mental retardation. The mutations of CNKSR2 gene are rare, we reporta patient carrying a novel nonsense mutation of CNKSR2,c.625C > T(p.Gln209∗) and review the clinical features and mutations of CNKSR2 gene for this rare condition considering previous literature. PATIENT CONCERNS: We report a case of a 7-year and 5-month-old Chinese patient with clinical symptoms of intellectual disability, language defect, epilepsy and hyperactivity. Genetic study revealed a novel nonsense variant of CNKSR2, which has not been reported yet. DIAGNOSIS: According to clinical manifestations, genetic pattern and ACMG classification of mutation site as Class 1-cause disease, the patient was diagnosed as Houge type of X-linked syndromic mental retardation caused by CNKSR2 gene mutation. INTERVENTIONS: The patient was administrated with a gradual titration of valproic acid (VPA). OUTCOMES: On administration of valproic acid, he had no further seizures. LESSONS: This is the first time to report a nonsense variant in CNKSR2, c.625C > T(p.Gln209∗), this finding could expand the spectrum of CNKSR2 mutations and might also support the further study of Houge type of X-linked syndromic mental retardation.

A Chinese patient with developmental and epileptic encephalopathies (DEE) carrying a TRPM3 gene mutation: a paediatric case report.

BACKGROUND: Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of chronic encephalopathies characterized by epilepsy with comorbid intellectual disability that are frequently associated with de novo nonsynonymous coding variants in ion channels, cell-surface receptors, and other neuronally expressed genes. Mutations in TRPM3 were identified as the cause of DEE. We report a novel patient with DEE carrying a de novo missense mutation in TRPM3, p.(S1202T); this missense mutation has never been reported. CASE PRESENTATION: A 7-year and 2-month-old Chinese patient who had recurrent polymorphic seizures was clinically diagnosed with DEE. A de novo missense mutation in TRPM3, which has not yet been reported, was identified in this case. The patient had a clinical phenotype consistent with previous reports. CONCLUSIONS: These findings could expand the spectrum of TRPM3 mutations and might also support that de novo substitutions of TRPM3 are a cause of DEE.

[Effects of bacterial lysates and all trans-retinoic acid on airway inflammation in asthmatic mice].

OBJECTIVE: To observe the effects of bacterial lysates (OM-85BV) and all trans-retinoic acid (ATRA) on airway inflammation in asthmatic mice, and to investigate the immunoregulatory mechanism of OM-85BV and ATRA for airway inflammation in asthmatic mice. METHODS: Forty female BALB/c mice were randomly divided into five groups: normal control, model, OM-85BV, ATRA, and OM-85BV+ATRA. A bronchial asthma model was established by intraperitoneal injection of ovalbumin (OVA) for sensitization and aerosol challenge in all mice except those in the normal control group. On days 25-34, before aerosol challenge, the model, OM-85BV, ATRA, and OM-85BV+ATRA groups were given normal saline, OM-85BV, ATRA, and OM-85BV+ATRA respectively by gavage. Normal saline was used instead for sensitization, challenge, and pretreatment before challenge in the normal control group. These mice were anesthetized and dissected at 24-48 hours after the final challenge. Bronchoalveolar lavage fluid (BALF) was collected from the right lung to measure the levels of interleukin-10 (IL-10) and interleukin-17 (IL-17) by ELISA. The left lung was collected to observe histopathological changes by hematoxylin-eosin staining. The relative expression of ROR-γT mRNA was measured by quantitative real-time PCR. RESULTS: Compared with the normal control group, the model group showed contraction of the bronchial cavity, increased bronchial secretions, and a large number of infiltrating inflammatory cells around the bronchi and alveolar walls, as well as a significantly reduced level of IL-10 (P<0.05) and significantly increased levels of IL-17 and ROR-γT mRNA (P<0.05). Compared with the model group, the OM-85BV, ATRA, and OM-85BV+ATRA groups showed a significant reduction in infiltrating inflammatory cells around the bronchi and alveolar walls; the OM-85BV group showed a significant increase in the level of IL-10 in BALF (P<0.05) and significant reductions in the levels of IL-17 and ROR-γT mRNA (P<0.05); the ATRA group showed significant reductions in the levels of IL-17 and ROR-γT mRNA (P<0.05). Compared with the OM-85BV group, the OM-85BV+ATRA group had significantly increased relative expression of ROR-γT mRNA (P<0.05). Compared with the ATRA group, the OM-85BV+ATRA group had significantly increased levels of IL-10 and IL-17 in BALF (P<0.05). CONCLUSIONS: Both OM-85BV and ATRA can reduce respiratory inflammation in asthmatic mice. However, a combination of the two drugs does not have a better effect than them used alone.