ObjectiveThis study aims to investigate the clinical phenotype and genetic etiology of a case of Ververi–Brady syndrome (VBS) with infantile epileptic spasms syndrome (IESS) caused by a novel de novo variant in the QRICH1 gene.MethodsClinical data were retrospectively collected from a pediatric patient admitted to Hunan Children’s Hospital on July 28, 2025, due to intermittent nodding episodes for 10 days. Trio-based whole-exome sequencing (trio-WES) was performed for the proband and his parents. Candidate variants were validated by Sanger sequencing and assessed for pathogenicity. Relevant literature was reviewed to summarize genotype–phenotype correlations.ResultsThe patient, a 5-month-and-22-day-old male infant, presented with facial dysmorphism, global developmental delay, and IESS. After treatment with adrenocorticotropic hormone (ACTH) and vigabatrin, seizures were fully controlled and developmental outcomes improved. Trio-WES identified a novel heterozygous frameshift variant in the QRICH1 gene (NM_198880.3: c.1282dup, p. Gln428Profs*27), which was de novo and absent in both parents. According to the ACMG/AMP guidelines, this variant was classified as pathogenic (PVS1 + PS2 + PM2_Supporting). A literature review identified 11 relevant articles, encompassing a total of 46 patients (including the present case) with 41 distinct QRICH1 variants: 10 missense, 11 nonsense, 17 frameshift, and 3 splicing mutations. Common clinical features included developmental delay, nonspecific facial dysmorphism, hypotonia, autism spectrum disorder, epilepsy, and scoliosis.ConclusionQRICH1 variants underlie Ververi–Brady syndrome. Here we describe a patient with QRICH1-related Ververi–Brady syndrome presenting with IESS. Combined treatment with ACTH and vigabatrin was followed by seizure freedom, electroencephalographic (EEG) improvement, and developmental gains in this patient. This report expands the genotypic and phenotypic spectrum of the disorder.

Spinal muscular atrophy is the most common fatal neurogenetic disorder in infancy and early childhood, caused by insufficient expression of SMN protein due to mutations in the survival motor neuron 1 (SMN1) gene. In this study, we describe the SMN1 mutation spectrum in our SMA cohort and the clinical characteristics of 30 patients with SMN1 compound heterozygous mutations. We find the c.22_23insA hotspot mutation has a founder effect, and identify 6 novel SMN1 variants and verify the pathogenicity of these variants at molecular levels. This study proposes that SMA newborn screening should integrate RT-PCR, MLPA, and long-read sequencing to prevent missed diagnoses of compound heterozygous mutations. Furthermore, in the era of therapeutics, new clinical classification methods based on genetic characteristics are worthy of further exploration.

The albumin-globulin ratio (AGR) is a well-established marker of systemic infl-ammation. Whether AGR is associated with motor function outcomes or media-tes age-related muscle deterioration in Duchenne muscular dystrophy (DMD) re-mains unclear.In this retrospective cohort study, 201 children with DMD and 202 age- and sex-matched healthy controls were enrolled between January 2013 and December 2023. Logistic and Cox regression analyses were used to assess the impact of the AGR on muscle strength and treatment efficacy. Further me-diation and moderation analyses were conducted to investigate potential underl-ying mechanisms.A statistically significant difference in the AGR was observed between the DMD group and the control group(1.85 ± 0.31 vs. 2.13 ± 0.28, t = − 9.452, p < 0.001). Logistic regression analyses indicated that lower AGR significant-ly predicted higher Vignos scores at both baseline (adjusted odds ratio[OR] = 0.137, 95% confidence interval [CI]:0.018–0.946, p = 0.035) and follow-up (adjusted OR = 0.477, 95%CI:0.258–0.882, p = 0.018). Cox regression analysis further revea-led that a lower AGR was significantly associated with an increased risk of ambulatory loss (adjusted hazard ratio [HR] = 4.863, 95%CI: 2.182–9.935, p = 0.007). Mediation analyses showed that the associations between age and Vignos s-core (proportion mediated:11.38% at admission, 10.12% at follow-up) and bet-ween age and therapeutic efficacy (proportion mediated:8.96%) were partially mediated through AGR. Moreover, weight exerted a significant negative moder-ating effect on the relationship between age and AGR. Conclusion : AGR partially mediates the age-dependent motor functional decline in DMD and modulates therapeutic responses, body weight being a key regula-tor of AGR levels. AGR may represent a potential therapeutic target for inter-vention.

Abstract Objective To identify the clinical features of CASPR2 neurological autoimmunity in children and to strengthen the understanding of the disease for developing diagnosis and treatment strategies. Methods A multicenter retrospective analysis and prospective observation of CASPR2 autoimmunity in the past 7 years was conducted. Results Twenty-six anti-CASPR2-positive patients were enrolled in this study, including 25 with serum positivity and 3 with cerebrospinal fluid (CSF) positivity (2 patients with both serum and CSF positivity); 3 patients were co-positive with anti-NMDAR antibody and 1 was copositive with anti-GABABR antibody. Eleven patients (6 manifesting with refractory epilepsy, 4 manifesting with psychobehavioral abnormalities and 1 accompanied with germinoma) presented with low antibody titers, relatively normal MRI/EEG/CSF examinations, and poor response to immunotherapy and were thus considered false positive (42.3%). Fifteen patients were diagnosed with anti-CASPR2-related neurological autoimmunity: 10 with autoimmune encephalitis (including 2 manifested as Morvan syndrome and 1 whose condition was secondary to Japanese encephalitis), 4 with typical clinical features of autoimmune encephalopathy, and 1 with autoimmune cerebellitis. The most common symptoms included disorders of consciousness (10/15), fever (8/15), psychological symptoms/abnormal behaviors (8/15), sleep disorders (8/15), seizures (7/15), movement disorders (5/15), autonomic symptoms (5/15), peripheral nerve hyperexcitability/neuromyotonia (5/14) and weakness/hemiplegia (4/15). Brain MRI revealed abnormalities in 10 patients (66.7%). The most common sites of lesions were the cerebral cortex (6/15, widely distributed across the frontal, parietal, occipital and temporal lobes) and thalamus (5/15). Electroencephalography (EEG) recordings revealed a slow wave background in 13 patients (86.7%). Five of 15 patients showed elevated WBCs in the CSF, and 4 of 15 patients showed elevated protein levels in the CSF. Thirteen patients received immunotherapy (rituximab was adopted in 2 cases) and recovered well. Two patients received symptomatic treatment, and the recovery was slow and accompanied by emotional abnormalities and developmental delay. Conclusions CASPR2 autoantibody disease is not very rare in children and can occur in infancy. The most common clinical phenotypes of CASPR2-related autoimmunity were encephalitis phenotype, including Morvan syndrome and cerebellar ataxia. We also first reported a case of autoimmune encephalitis secondary to Japanese encephalitis. The prognosis of this disease is good, and rituximab can be used in patients who respond poorly to conventional immunotherapy. The high false-positive rate of anti-CASPR2 in refractory epilepsy and the psychobehavioral abnormalities needs to be explored further.

Background: The aim of the study was to identify the post-traumatic growth status and influencing factors of parents with children with Duchenne muscular dystrophy (DMD). Methods: We adopted a cross-section survey study. Between February and December 2022, 181 parents responded to the survey including a participants’ characteristics section, post-traumatic growth assessment scale, caregiver burden scale, and social support assessment scale. Multiple linear regression analysis was used to investigate influencing factors of post-traumatic growth. Results: The mean score of post-traumatic growth of parents was 56.66 (SD±18.67). Post-traumatic growth was positively correlated with social support (r=0.452, P<0.01) and negatively correlated with care burden (r=-0.207, P<0.01). Multiple linear regression showed that the child's age, course of disease, self-care ability, parent’s working condition, residence, education, number of children, and health status were the main influencing factors for the post-traumatic growth of parents (P<0.001). Conclusion: The post-traumatic growth of parents with children with DMD was at a moderate level. Healthcare professionals should pay attention to the psychological state of parents with children with this rare disease and promote post-traumatic growth through psychological mindfulness interventions, strengthening family and social support, and providing care knowledge and skills.

OBJECTIVE:To explore the clinical manifestations and genetic characteristics of a child with Leukoencephalopathy with ataxia (LKPAT) caused by a CLCN2 gene variant. METHODS:A retrospective analysis was conducted on the clinical data of a child admitted to Hunan Children's Hospital in June 2024 due to "intermittent convulsions for 13 days". Peripheral blood samples were collected from the child and his parents for whole exome sequencing, followed by Sanger sequencing validation and pathogenicity analysis of candidate variants. Literature searches were performed using the keywords "CLCN2 gene" "chloride channel-2" "leukoencephalopathy with ataxia/LKPAT" "leukoencephalopathy" in both Chinese and English on CNKI, Wanfang, and PubMed databases. The search time was set from the establishment of the databases to July 31, 2024. Childhood-onset LKPAT literature was screened and analyzed. This study was approved by the Medical Ethics Committee of Hunan Children's Hospital (Ethics No. HCHLL-2024-351). RESULTS:The child was a 7-month-and-26-day-old male infant born to consanguineous parents, presenting with epileptic seizures and borderline development. Cranial MRI revealed symmetrical long T2 signal shadows in the posterior limb of the internal capsule, cerebral peduncle, pons, and middle peduncle of the cerebellum. Video electroencephalogram (EEG) showed an abnormal childhood EEG with one focal seizure. Whole exome sequencing revealed a homozygous c.2201dup (p.Glu735Ter) variant in the CLCN2 gene of the child. Sanger sequencing confirmed that the variant was inherited from both parents. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), this variant was classified as pathogenic (PVS1+PM3_Supporting+PM2_Supporting). A total of 8 relevant literature were retrieved, together with the present case, 16 childhood-onset LKPAT patients were cumulatively reported, which consisted of 9 males and 7 females. Twelve CLCN2 gene variants were involved, including 2 nonsense variants, 3 missense variants, 7 frameshifting variants, 2 c.61dup variants, and 5 c.1709G>A variants. The initial symptoms of the 16 patients included headache, ataxia, epileptic seizures, spasticity, developmental delay, lower back pain, hearing impairment, and intention tremor. Three patients had onset of the disease before the age of one, of which 2 had epileptic seizures as the initial symptom. CONCLUSION:The homozygous variant CLCN2: c.2201dup (p.Glu735Ter) is considered the pathogenic cause of LKPAT in this child, marking the first childhood-onset case reported in China. Genetic testing has facilitated the diagnosis of childhood-onset LKPAT and expanded the spectrum of CLCN2 gene mutations.

Nusinersen was the first approved disease modifying therapy (DMT) for spinal muscular atrophy (SMA). Intrathecal administration of nusinersen enables drug delivery directly to the central nervous system, where the motor neurons are located. Per the package insert, individuals with SMA receive 4 loading doses of nusinersen followed by maintenance doses every 4 months thereafter. The aim of this analysis was to investigate the administration practices of and adherence to nusinersen in Chinese children with SMA. Data were analyzed from a longitudinal, multicenter registry enrolling children with 5q-SMA in China. Information on nusinersen administration, including administration date, care setting, use of sedation and general anesthesia, method of administration, and use of imaging guidance before administration, was collected both retrospectively and prospectively. Adherence rate was calculated at dose and participant level. A dose was considered adherent if the inter-dose interval (for dose-level) and interval from the first dose (for participant-level) followed the standard dosing regimen, with a grace period of ± 7 days for Dose 2 to 4 and ± 28 days thereafter. A total of 385 participants receiving nusinersen with a total of 2,415 doses were included in the study. The median (interquartile range) number of doses administered per participant was 6 (5–7). Over 99

AIM:To characterise spinal muscular atrophy (SMA) phenotypes, genetic profiles, and nusinersen efficacy in China. METHODS:In 133 SMA patients (age 6.38 ± 3.66 years), SMN1 mutations and SMN2 copy numbers were analysed by MLPA and sequencing. Motor function was longitudinally assessed using subtype-specific scales (CHOP-INTEND/HFMSE/RULM/6MWT) at baseline, 6, and 12 months post-nusinersen. RESULTS:Cohort distribution: type I 31.6% (42/133), II 42.1% (56/133), III 26.3% (35/133). Genetic profiling identified: SMN1 exon7 + 8 deletions (81.2%, 108/133); exon7-only deletions (15.0%, 20/133); and a novel c.884A>T; c.22dup mutation (0.8%). SMN2 copy number inversely correlated with clinical severity (p < 0.001). At 12 months, type I patients showed CHOP-INTEND improvement from 22.0 ± 10.7 to 34.4 ± 14.9 (Δ12.4 ± 8.7; all Δ ≥ 5); type II demonstrated HFMSE Δ3.6 ± 3.4 and RULM Δ3.4 ± 2.1 (1 ambulation milestone); type III exhibited 6MWT gains of 48.8 ± 35.1 m (Δrange 6.0-119.8) with concurrent RULM/HFMSE improvements. CONCLUSIONS:Nusinersen elicited clinically significant motor improvements across SMA subtypes, demonstrating the strongest functional gains in type I (56.4% CHOP-INTEND improvement). We report for the first time a rare case of SMN1 compound heterozygous double-site mutations (c.884A>T; c.22dup).

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder characterized primarily by progressive degeneration and necrosis of skeletal muscle, resulting from mutations in the Dystrophin gene. Patients with DMD typically present with progressive muscle weakness and atrophy during childhood. Currently, available treatment options for DMD remain limited and their efficacy is suboptimal. This review aims to provide a systematic overview of recent advances in therapeutic strategies for DMD, including an analysis of the mechanisms underlying various treatment approaches, outcomes from clinical trials, and their potential clinical applications, in order to inform and guide clinical decision-making.

Background:Methylmalonic acidemia (MMA) lacks specific clinical manifestations, often leading to misdiagnosis and underdiagnosis by clinicians. Methods:We retrospectively analyzed the clinical data of children with MMA admitted to the Department of Neurology, Hunan Children's Hospital, from April 2015 to February 2024. Results:A total of 9 children with MMA were included. The age at onset ranged from 1 month and 9 days to 8 years, with the time from onset to diagnosis extending up to 1 year and 2 months. Among them, 7 cases were early-onset and 2 were late-onset. Eight cases presented with neurological symptoms, including recurrent seizures, global developmental delay, mental and behavioral abnormalities, and disturbances of consciousness. One case was asymptomatic and confirmed via neonatal screening. Blood biochemistry showed elevated levels of lactic acid, homocysteine, ammonia, alanine aminotransferase, and glucose. All 9 patients received treatments such as vitamin B12 and L-carnitine to improve energy metabolism. Among them, seven achieved favorable clinical outcomes, while two had poor outcomes: one patient with MMACHA compound heterozygous variants (c.609G > A/p. Trp203* and c.658-660del/p. Lys220del*) died due to treatment failure, and the other experienced a poor outcome from delayed intervention. Conclusion:Early-onset MMA is more common, and its clinical manifestations are non-specific. Clinicians should be vigilant about genetic metabolic etiologies in patients with early-onset MMA characterized by recurrent seizures and developmental delay, late-onset MMA with mental and behavioral abnormalities or consciousness disturbances, and those with abnormal metabolic indicators. It is recommended to actively perform blood and urine tandem mass spectrometry and genetic analysis to confirm the diagnosis. The MMACHA c.658-660del (p. Lys220del*) variant may be associated with a poor prognosis in MMA patients.

BACKGROUND:Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, but comprehensive analyses of mutational patterns and clinical correlations remain limited. OBJECTIVE:To characterize the DMD mutational spectrum and its clinical implications in a large Asian cohort. METHODS & SETTINGS:A retrospective genetic analysis of 507 unrelated male DMD/Becker muscular dystrophy patients was conducted at Hunan Children's Hospital (2018-2021). Multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) were employed for comprehensive variant detection. Variants were classified per ACMG/AMP guidelines. RESULTS:Exon deletions predominated (64.9%), followed by small mutations (26.0%) and duplications (9.1%). Nonsense mutations were the most frequent small variant (16.0%). Domain analysis revealed mutations clustered in the Central Rod Domain (CRD; exons 45-55). The Carboxy-Terminal Domain (CTD) was associated with the most severe phenotype (earliest loss of ambulation, P < 0.05 vs. Actin-Binding Domain [ABD] or CRD). Exon 53 skipping was applicable in 39.39% of eligible patients. De novo mutations accounted for 7.9% (40/507) of cases. Epilepsy comorbidity occurred in 1.34% (6/448) of DMD patients. CONCLUSION:This study delineates the DMD mutational landscape in a Chinese cohort, highlighting domain-specific phenotypic severity (CTD > ABD > CRD) and identifying exon 53 as the primary therapeutic target for exon skipping. These findings enhance prognostic precision and guide targeted therapeutic strategies.

To better understand the variations in gut microbiota in children with different types of epilepsy. Thirty-seven children with epilepsy were included in the case group, which was further divided into focal (group A, n = 28) and generalized epilepsy groups (group B, n = 9) based on the origin and extent of the seizures. The focal epilepsy group was subdivided into the benign childhood epilepsy with centrotemporal spikes (BECT) (group C, n = 9) and non-BECT groups (group D, n = 19) based on the appearance of typical centrotemporal spikes or spike-wave complexes on the electroencephalogram (EEG). Additionally, 14 healthy children were selected as the control group (group E, n = 14). Significant differences were observed in the diversity and composition of gut microbiota between the case and control groups. At the genus level, the abundance of Megamonas (P = 0.001), Streptococcus (P<0.001), Romboutsia (P = 0.001), Bacteroides (P<0.05), and Escherichia/Shigella (P<0.05) was significantly higher in the focal epilepsy group than in the control group (0.027 vs. 0.00009, P = 0.001; 0.016 vs. 0.002, P<0.001; 0.013 vs. 0.002, P = 0.001; 0.030 vs. 0.002, P<0.05, respectively). Additionally, Escherichia/Shigella (P<0.05) was more abundant in the case group compared to the control group (0.033 vs. 0.002, P<0.05). Bacteroides (P<0.05) was more abundant in the control group than in the case group. Megamonas (P<0.001) and Collinsella (P<0.05) were significantly more prevalent in the BECT group than in the control group (0.034 vs. 0.00009, P<0.001; 0.014 vs. 0.001, P<0.05, respectively). In the non-BECT group, compared to the control group, Megamonas (P = 0.013), Streptococcus (P<0.001), Romboutsia (P = 0.001), and Escherichia/Shigella (P<0.05) were found in greater abundance (0.023 vs. 0.00009, P = 0.013; 0.018 vs. 0.002, P<0.001; 0.014 vs. 0.002, P = 0.001; 0.037 vs. 0.002, P<0.05, respectively). Though, there were no statistically significant differences in gut microbiota between the different types of epilepsy, the gut microbiota of children with epilepsy significantly differed from that of healthy controls. The increased abundance of Escherichia/Shigella may lead to the worsening of clinical phenotypes and poor prognosis, and it could be a candidate biomarker to identify the focal epilepsy or even non-benign childhood epilepsy with centrotemporal spikes, potentially providing new therapeutic targets for the future.

Background and purpose: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are neuromuscular diseases in children that resulted from mutations in the dystrophin gene. DMD stay in a high fatality rate, and currently, there is no specific medication or cure available. A comprehensive analysis of DMD gene mutations was conducted in patients with DMD/BMD to better understand the characteristics of the mutations and the intrinsic relationship between genotype and phenotype. The aim of this study is to improve the diagnosis and treatment efficacy of DMD/BMD by addressing the root cause of genetic mutations, thus providing a theoretical foundation for further development of exon skipping treatments. Methods: Between October 2018 and July 2021, a total of 507 DMD/BMD patients were collected from Hunan Provincial Children's Hospital. Initially, Multiplex Ligation-dependent Probe Amplification (MLPA) was employed to detect deletions and duplications in the 79 exons of the DMD gene. If negative, Next-Generation Sequencing (NGS) was used subsequently to identify point mutations. Finally, Sanger sequencing was utilized to confirm the identified point mutations. Results: Combined with MLPA, NGS and Sanger sequencing proved to be a cost-effective and high-efficient approach in providing gene diagnosis services for DMD/BMD patients. Among the 507 patients with DMD/BMD, the highest percentage of mutations observed was deletions in exons (64.9%), followed by point mutations (26.0%) and duplication mutations in exons (9.1%). The pathogenicity ratio of these mutations was P: LP: VUS=24.5:2.67:1. The hotspot regions of exon deletions in the DMD gene were primarily found in the distal exons in the range of 45-55 (79.64%), as well as in the proximal exons in the range of 2-20 (15.20%). The hotspot regions for exon duplications were concentrated in the proximal exons within the range of 3-9 (39.13%). Point mutations were distributed throughout the DMD gene, with the top four exons showing the highest mutation frequency being exon 22 with 9 mutations, exon 70 with 7 mutations, and exon 20 with 6 mutations. the top four exons with the highest mutation frequency are exon 22 with 9 mutations, exon 70 with 7 mutations, and exon 70 and exon 20 with 6 mutations, respectively. Additionally, 40 de novo mutations were identified in this study.

IntroductionThe cases of MOG-AD (MOG antibody-associated disorder) and anti-NMDAR encephalitis overlapping syndrome (MNOS) are rare, especially among pediatric patients, and their clinical understanding is limited. This study aimed to investigate the clinical manifestations, imaging findings, treatments, and prognosis of Chinese pediatric patients who tested positive for anti-NMDAR and MOG antibodies.MethodsThis retrospective study enrolled 10 MNOS pediatric patients, 50 MOG-AD (anti-NMDAR antibody-negative), and 81 anti-NMDAR encephalitis (MOG antibody-negative) pediatric patients who were admitted from July 2016 to June 2022 and used their clinical data for comparison.ResultsThe MNOS patients had a significantly lower incidence of psycho-behavioral abnormalities and involuntary movements than anti-NMDAR antibody (+)/MOG antibody (−) patients and had a significantly higher incidence of sleep disorders, seizures, and psycho-behavioral abnormalities than MOG antibody (+)/anti-NMDAR antibody (−) patients. The MNOS patients had a significantly higher incidence of MRI abnormalities than the anti-NMDAR antibody (+)/MOG antibody (−) patients, while there was no significant difference in the incidence between the MNOS patients and the MOG antibody (+)/anti-NMDAR antibody (−) patients. No significant difference was seen in the initial mRS score between the three groups of patients. The anti-NMDAR antibody (+)/MOG antibody (−) patients had a higher rate of admission to the ICU, a longer length of in-hospital stay, and a higher rate of introduction to second-line treatment than the other two groups of patients. No significant difference was seen in the mRS score at the last follow-up and in the disease recurrence rate between the three groups. All these patients respond well to immunosuppressive therapy.DiscussionIn the presence of psycho-behavioral abnormalities, sleep disorders, and frequent seizures in MOG-AD patients or demyelinating symptoms of the central nervous system or demyelinating lesions on head MRI in anti-NMDAR encephalitis patients, the coexistence of MOG and anti-NMDAR antibodies should be considered and would suggest a diagnosis of MNOS for these patients. Immunotherapy is effective among these patients and should be given possibly earlier.

Objective: Serum globulin is associated with inflammatory or immune disorders. However, it has not been established whether it is associated with myasthenia gravis (MG). We investigated the association between globulin with relapse and prognosis in children with MG. Methods: A cohort of 148 MG cases and 150 healthy children were retrospectively enrolled from January 2015 to December 2021. Multivariate logistic and Cox regression models were used to analyze the treatment outcomes and recurrence of case group, exploring the influence of globulin. Results: Compared with the control group, globulin levels in the MG group were slightly increased (t = 7.244, p < 0.001). After a mean follow-up of 2.25 +/- 1.05 years, 35 cases relapsed, with a relapse rate of 23.65%. Logistic regression analysis showed that globulin levels at admission [adjusted odds ratio (OR) = 1.233, 95% confidence interval (CI) 1.028-1.472, p = 0.018] were independent risk factors for relapse. Cox regression analysis confirmed that globulin levels at admission affects relapse-free time [adjusted hazard ratio (HR) = 0.552, 95% CI 0.357-0.852, p = 0.007]. Receiver operating characteristic curve determined 25.10 as the optimal cutoff value for globulin. Cox regression showed that high globulin levels (>25.10) at admission (adjusted HR = 0.607, 95% CI 0.383-0.961, p = 0.033) were independent risk factors for poor therapeutic outcomes at follow-up. Ordinal logistic regression showed that globulin affects the treatment plan (OR = 1.445, 95% CI 1.223-1.847, p = 0.014). Conclusions: Elevated globulin levels in children with MG on admission predicts a high relapse rate and poor long-term therapeutic efficacies.

ObjectiveThe mechanisms driving the progression of infantile spasms are not well understood. We aimed to investigate the changes and correlations of the gut microbiota, the hypothalamus–pituitary–adrenal (HPA) axis hormones, and the inflammatory cytokines in children with infantile spasms before and after treatment in order to provide a reference for future pathogenesis research.MethodsChildren with infantile spasms who were admitted to our hospital were recruited into the case group. The case group was divided into the pre-treatment group (group A, n = 14), the 2 weeks after treatment group (group B), and the 1 month after treatment group (group C). On the other hand, healthy children with the same sex ratio as the case group were recruited into the control group (group D, n = 14). Three stool and blood samples were collected before treatment, 2 weeks after treatment, and 1 month after treatment. The serum samples were analyzed using cytometric bead array (CBA), enzyme-linked immunosorbent assay (ELISA), and chemiluminescent immunoassay (CLIA) to measure the levels of HPA axis hormones and inflammatory cytokines. The collected stool samples were sequenced using 16S rDNA.ResultsThe pre-treatment group demonstrated elevated levels of corticotropin-releasing hormone (CRH), interleukin 2 (IL-2), IL-4, IL-6, and IL-17α, which decreased with treatment. The level of CRH was lower in the effective group than that in the ineffective group. Sutterellaceae was lower in the pre-treatment group than that in the control group. Lachnospiracea_incertae_sedis was positively associated with CRH concentration (p < 0.05). After treatment, Sutterellaceae was negatively associated with IL-2 and TNF-α (p < 0.05).ConclusionThis study found that imbalance of the gut microbiota may be involved in the pathogenesis of infantile spasms and is related to the response to adrenocorticotropic hormone (ACTH). Lachnospiraceae and Lachnospiracea_incertae_sedis might be involved in the disease onset. Sutterellaceae might have a link to children’s improved health.

OBJECTIVE:To evaluate the effectiveness and safety of nusinersen for the treatment of 5q-spinal muscular atrophy (SMA) among Chinese pediatric patients. METHODS:Using a longitudinal, multi-center registry, both prospective and retrospective data were collected from pediatric patients with 5q-SMA receiving nusinersen treatment across 18 centers in China. All patients fulfilling the eligibility criteria were included consecutively. Motor function outcomes were assessed post-treatment by SMA type. Safety profile was evaluated among patients starting nusinersen treatment post-enrollment. Descriptive analyses were used to report baseline characteristics, effectiveness, and safety results. RESULTS:As of March 2nd, 2023, 385 patients were included. Most patients demonstrated improvements or stability in motor function across all SMA types. Type II patients demonstrated mean changes [95% confidence interval (CI)] of 4.4 (3.4-5.4) and 4.1 (2.8-5.4) in Hammersmith Functional Motor Scale-Expanded (HFMSE), and 2.4 (1.7-3.1) and 2.3 (1.2-3.4) in Revised Upper Limb Module (RULM) scores at months 6 and 10. Type III patients exhibited mean changes (95% CI) of 3.9 (2.5-5.3) and 4.3 (2.6-6.0) in HFMSE, and 2.1 (1.2-3.0) and 1.5 (0.0-3.0) in RULM scores at months 6 and 10. Of the 132 patients, 62.9% experienced adverse events (AEs). Two patients experienced mild AEs (aseptic meningitis and myalgia) considered to be related to nusinersen by the investigator, with no sequelae. CONCLUSIONS:These data underscore the significance of nusinersen in Chinese pediatric patients with SMA regarding motor function improvement or stability, and support recommendations on nusinersen treatment by Chinese SMA guidelines and continuous coverage of nusinersen by basic medical insurance.

Background Congenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report a novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy. Methods A comprehensive strategy combining laser capture microdissection, proteomics and whole-exome sequencing was performed to identify the candidate genes. In addition, the available clinical data, myopathological changes, the findings of electrophysiological examinations and thigh muscle MRIs were also reviewed. A cellular model was established to assess the pathogenicity of the TUBA4A variant. Results We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in the TUBA4A (NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F mutant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model. Conclusion Our findings expanded the phenotypic and genetic manifestations of TUBA4A as well as tubulinopathies, and added a new type of congenital myopathy to be taken into consideration in the differential diagnosis.