IntroductionLinear scleroderma en coup de sabre (ECDS) is a rare disorder that often involves the central nervous system (CNS), requiring systemic immunotherapy. This study characterizes the clinical and neuroimaging features as well as the long-term treatment outcomes of pediatric ECDS.MethodsPatients with ECDS and CNS involvement were enrolled. Clinical manifestations, cranial imaging, pathology, and immunotherapy responses were documented.ResultsSeven patients (6 females and 1 male) were included, with onset ages ranging from 1.8 to 13.5 years. Rash preceded neurological symptoms in five patients; seizures were the initial manifestation in the remaining two. Seizures were the most common neurological symptom (5/7), followed by dizziness (3/7), movement disorder (2/7), blurred vision (1/7), and headache (1/7). All exhibited ipsilateral supratentorial MRI abnormalities, exclusively on the left side and predominantly frontal. White matter lesions were observed in all patients, and cyst-like lesions were identified in four. Brain biopsy performed in two patients indicated vasculitis. All received systemic corticosteroids, either alone (2 cases) or combined with other agents (methotrexate in 5, mycophenolate mofetil in 3, IVIg in 3, tocilizumab in 2, and rituximab in 1). Over 6 months to 15 years of follow-up, neurological symptoms resolved in five patients. Skin lesions progressed in three patients, stabilized in two, and improved in two.ConclusionLinear scleroderma en coup de sabre with CNS involvement predominantly affects females and typically involves the left cerebral hemisphere. Characteristic brain MRI findings include ipsilateral supratentorial white matter abnormalities and cyst-like lesions. Combination therapy with systemic corticosteroids and methotrexate is recommended as first-line treatment, while tocilizumab may be beneficial for refractory cases.

BACKGROUND:Hereditary ataxias are genetically heterogeneous; however, despite major advances in next-generation sequencing technologies, 20%-54% of childhood-onset cases remain genetically undiagnosed. OBJECTIVE:To elucidate the genetic etiology of childhood-onset hereditary ataxia. METHODS:Oxford Nanopore long-read genome sequencing (LRS) was performed in two unrelated Chinese patients with clinically suspected childhood-onset hereditary ataxia. RESULTS:Both patients presented with childhood-onset, slowly progressive ataxia, accompanied by mild cognitive impairment. Brain magnetic resonance imaging demonstrated cerebellar atrophy, and electromyography showed neurogenic damage. Muscle biopsy revealed fiber-type grouping, indicative of neurogenic changes, with no evidence of primary myopathy. LRS detected pathogenic-length CGG repeat expansions (>100 repeats) in GIPC1, which were validated by repeat-primed polymerase chain reaction. CONCLUSIONS:These findings expand the phenotypic spectrum associated with GIPC1 CGG repeat expansion and define a novel subtype of childhood-onset hereditary ataxia accompanied by mild cognitive impairment and neurogenic involvement. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND AND OBJECTIVES:Natural history studies in Duchenne muscular dystrophy (DMD) can help to elucidate the trajectory of the disease, understand the importance of clinical milestones, and identify endpoints for clinical trials. We present data from a natural history study of DMD in Chinese individuals with a follow-up of up to 30 months. METHODS:This was a multicenter, prospective, single-cohort study in Chinese boys of any age with a confirmed diagnosis of DMD. Participants were allocated into one of three groups: Group 1 (ambulatory, < 6 years old); Group 2 (ambulatory, ≥ 6 years old); and Group 3 (non-ambulatory, any age). Endpoints included time to life-altering clinical milestones, North Star Ambulatory Assessment (NSAA; Groups 1 and 2), Performance of Upper Limb 2.0 (PUL2.0; Groups 2 and 3), pulmonary function (Groups 2 and 3), left ventricular ejection fraction (LVEF; Groups 2 and 3), and quality of life endpoints. RESULTS:312 participants were enrolled (Group 1, n = 99; Group 2, n = 177; Group 3, n = 36). Mean (SD) age at baseline in the total study population was 7.9 (3.4) years. Median (95% confidence interval) age at failure to walk in the total study population was 13.1 (12.5-14.1) years. Up to 30 months, NSAA total score deteriorated in Group 2 with no decline in Group 1. PUL 2.0 score declined in both Groups 2 and 3. Pulmonary function decreased in Groups 2 and 3 but to a greater extent in Group 3. Changes in LVEF were minimal. Quality of life deteriorated over time, particularly in Group 3. DISCUSSION:These data extend the 1-year findings from the same study and demonstrate the progression of DMD in Chinese individuals of differing age and ambulatory status. REGISTRATION INFORMATION:ClinicalTrials.gov identifier: NCT03760029.

BACKGROUND AND OBJECTIVE:To understand the prevalence and risk factors of acute symptomatic seizures (ASSs) and epilepsy in children with central nervous system inflammatory demyelinating diseases (CIDDs). METHODS:The cohort of children with CIDDs in pediatric department of Peking University First Hospital between January 2013 and June 2024 were followed up. We evaluated and compared the incidence of ASSs among patients with different CIDDs. The correlation between clinical information and the occurrence of ASS was further analyzed. The incidence of epilepsy was analyzed in patients with disease course longer than 1 year. RESULTS:Of 204 patients with CIDDs, 97 were female (47.5 %), and the age at onset was 6.75 (IQR: 4.50, 9.73) years, with a total of 598 attacks. Of 204 patients, 75 (36.8 %) experienced ASSs, and the incidence of ASSs were significantly higher in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (39/94, 41.5 %) and seronegative CIDDs (31/72, 43.1 %). Among 598 attacks, 143 (23.9 %) were accompanied by ASSs. ASSs were more likely to occur in attacks manifested as acute disseminated encephalomyelitis (ADEM) and cerebral cortical encephalitis (CCE) phenotypes. Fever (OR=0.453) and cortical involvement on brain MRI (OR=0.191) were independent risk factors for ASSs. Prevalence of epilepsy was 9.9 % (19/192). Patients with multiple demyelinating attacks were more likely to develop epilepsy. CONCLUSION:The incidence of ASS in children with CIDDs was 36.8 %, which was more common in children with MOGAD or seronegative CIDDs. ASSs were more likely to occur in attacks presented with ADEM and CCE. Prevalence of epilepsy was 9.9 %.

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by a deletion or variant of SHANK3. Patients with PMS typically present with global developmental delay, delayed or absent speech, intellectual disability, hypotonia, autism spectrum disorder, behavioral abnormalities, and minor specific dysmorphic features. The SRCAP variation is rare and may be associated with chromatin remodeling and neural development. The SRCAP and SHANK3 phenotypes display certain overlapping features, including impaired intellectual and delayed speech development as well as behavioral and psychiatric problems. We report the case of a young male with significant recurrent neuropsychiatric symptoms, developmental regression, and cerebrospinal fluid white blood cell 72/mm3. The diagnosis was consistent with antibody-negative autoimmune encephalitis; the patient improved after immunomodulatory treatment. Whole-exome sequencing identified two de novo pathogenic frameshift variants, one in SHANK3 and the other in SRCAP, with SRCAP being a chimeric variant. Both variants were novel and pathogenic according to the pathogenicity rating provided by the American College of Medical Genetics and Genomics.

Case presentationA girl aged 2 years and 5 months presented to the hospital with chief complaints of intermittent fever and weakness of the left limb for more than 1 month. The child had transient urticaria appearing on her face for 5 days. The inflammatory biomarkers were significantly increased. Brain MRI showed multiple ischemic lesions in the brain’s small vessels. The patient exhibited significant systemic inflammation and multiple vasculitis. Whole-exome sequencing showed c.1358A>G p. (Tyr453Cys) and c.1082-7T>A compound heterozygous variants in the adenosine deaminase 2 (ADA2) gene, of which the c.1082-7T>A variant has not been reported yet in previous literature. Peripheral blood mRNA reverse transcription-Sanger sequencing confirmed that this variant affected mRNA splicing, resulting in a frameshift with premature stop codon c.1083_1103del p. (Leu362Glnfs*45). Peripheral blood test suggested a significant decrease in ADA2 activity. Eventually, the patient was diagnosed with deficiency of adenosine deaminase 2 (DADA2). Her condition improved after treatment with etanercept. She had no more fevers, and no hemiplegia attacks were observed during the 3 years of follow-up.ConclusionFever and hemiplegia were the main manifestations in this patient, without typical rashes. DADA2 was finally confirmed by enzymology and genetic testing, and we believe this is the first reported case of the c.1082-7T>A intronic variant in DADA2, and the RNA studies conducted in this case have been pivotal in assessing its pathogenicity.

OBJECTIVE:To confirm the retention rate of ketogenic diet therapy (KDT) in children with drug-resistant epilepsy and identify its related factors through a cohort analysis. METHODS:This was a single-center cohort study. Baseline data were collected, and regular follow-up was conducted after KDT treatment. The retention rate of KDT at different time points was determined. Cox regression analyses and other statistical methods were used to identify the factors related to the retention rate. RESULTS:A total of 337 patients were included. 43.3% (146/337) of the patients had only spasms, 16.9% (57/337) had a genetic etiology, and 14.0% (47/337) had a structural etiology. Overall, 51.9% (175/337) of the patients were classified as having infantile epileptic spasm syndrome. The median age at KDT initiation was 33 months. 38.3% (129/337) of the patients responded to KDT. The retention rate of KDT at 3, 6, 12 and 24 months were 86.6% (292/337), 62.6% (211/337), 35.0% (118/337), and 20.2% (68/337), respectively. 9.9% (56/282) stopped the treatment due to unsatisfactory seizure control and 54.6% (154/282) stopped due to a non-response. The retention rate in patients who responded to KDT was relatively greater than that in patients who did not respond to KDT [HR: 4.714 (95% CI: 3.493, 6.362), p < 0.001]. The retention rate of KDT at 3 months was associated with seizure type and anti-seizure efficacy. The retention rate of KDT at 6 months was associated with seizure type, status epilepticus and anti-seizure efficacy. The retention rate of KDT at 12 and 24 months were both associated with anti-seizure efficacy. SIGNIFICANCE:Anti-seizure efficacy was the sole independent predictor of long-term retention. This large-scale cohort study advances the field by demonstrating the predominant role of efficacy in long-term adherence. The cohort size (N = 337), one of the largest reported, strengthens evidence that the long-term retention rate (>1 year) can be used as an important indicator to evaluate the efficacy of KDT, which is simple and reliable.

In order to solve the problems of white noise generated by data updates caused by dynamic changes in substation equipment and difficulty in identifying GIS equipment signals, a three-dimensional dynamic modeling method for substation GIS equipment based on an improved Res BiGRU model is proposed. The waveform image of the white noise signal is reconstructed by improving the depth residual network. Improved Bidirectional gated cyclic unit structure (BiGRUa), based on improved Res-BiGRU neural network, recognition GIS device signal recognition. Based on this, the 3D dynamic model of power transformation GIS equipment is established by 3D MAXS software, and the color of the 3D dynamic model of power transformation GIS equipment is processed by IHS algorithm to adjust the brightness, hue and saturation of the appearance of the 3D dynamic visual model of power transformation GIS equipment. The experimental results show that: The research method can get better modeling results. At different time, the proposed method can effectively simulate and visually detect the state of the GIS equipment, and the relative disturbance of the proposed method is lowest.

The delivery of a mini-dystrophin gene to skeletal muscles using recombinant adeno-associated virus serotype (AAV) holds great potential as a gene therapy for Duchenne muscular dystrophy (DMD). However, the presence of anti-AAV-neutralizing antibodies (NAbs) may impede the effectiveness of gene transduction. This study aimed to evaluate the prevalence of anti-AAV9 NAbs in Chinese patients with DMD, and to characterize the target population for an AAV gene therapy. A total of one hundred male patients with DMD were included in this study, and demographic and clinical data were collected. A blood specimen was obtained from each participant for the purpose of evaluating the existence of anti-AAV9 NAbs through a cell-based functional assay conducted at a central laboratory. A NAb titer exceeding 1:4 was considered positive. The positivity rates of anti-AAV9 NAb were compared among different subgroups. The median age of this DMD cohort was 8 years old, ranging from 3 to 15 years of age. Forty-two percent of patients tested positive for anti-AAV9 NAb. Notably, all samples from patients under 4 years of age tested negative, and the positivity rates of anti-AAV9 NAb differed significantly across the three age subgroups (<4 years old, >= 4 years old and <12 years old, and >= 12 years old, chi(2) = 7.221, p = 0.023). Further investigation into the living environment revealed a higher positivity rate of anti-AAV9 NAb in rural patients compared with urban patients (chi(2) = 3.923, p = 0.048). Moreover, the prevalence in patients from different cities/provinces varied greatly (chi(2) = 16.550, p = 0.003). There was no statistically significant difference in the positivity rate of NAb among subgroups of patients with different motor functions (ambulatory or nonambulatory) and different treatment strategies (taking or not taking glucocorticoid). In Chinese DMD patients, the prevalence of anti-AAV9 NAb was found to reach 42%. Moreover, the antibody-positive rate in children <4 years of age was low and revealed notable regional discrepancies.

BackgroundIntraneural perineurioma is a rare, benign slow-growing lesion that usually involves a single main trunk nerve during childhood and young adulthood. The treatment of intraneural perineurioma is still a subject of controversy, especially in fast-growing children. To date, there was no systemic analysis of intraneural perineurioma in children.MethodA case of Intraneural perineurioma affecting the left sciatic nerve with 2 years of follow-up was presented. A systematic review was performed on literature published before June 2023, focusing on intraneural perineurioma diagnosed at no older than 18 years old.ResultA 9-year-old boy presented with progressive left foot-drop and abnormal gait for 2 years. The electromyography and magnetic resonance neurography study confirmed neuropathy involving the left sciatic nerves and its branches. Pathological investigation of the left sural nerve confirmed the diagnosis of intraneural perineurioma. The boy received physical therapy, and the disease was stable during the 2 years of follow-up. Fifty-seven childhood cases were identified in literature. Five patients with oral intraneural perineurioma underwent excision of the mass with good outcomes. In the other 52 patients with peripheral nerve involvement, 25 of them received surgical treatment, with different outcomes according to different operations. Out of 33 cases with precise lesion sizes, the length of the lesion in patients without nerve resection was significantly longer than that in patients with nerve resection (12.86 ± 7.44 cm vs 4.57 ± 4.5 cm. p < 0.05).ConclusionsIntraneural perineuriomas are rare benign tumors with slow progression. The options for surgery should be cautiously considered in childhood patients with long segmental peripheral nerve involvement.

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.

Background Duchenne muscular dystrophy (DMD) is a disabling and life-threatening, X-linked recessive disorder caused by mutations in dystrophin. Natural history studies can inform the disease characteristics of DMD, and data from these studies can be used to plan and design clinical trials and as external controls for long-term studies. We report 12-month results from the largest natural history study of individuals with DMD in China receiving standard of care treatment.Methods This ongoing, multicentre, prospective, single-cohort study (ClinicalTrials.gov: NCT03760029) was conducted in Chinese male participants with DMD (ambulatory aged <6 years [Group 1; n = 99]; ambulatory aged >= 6 years [Group 2; n = 177], and non-ambulatory of any age [Group 3; n = 36]. The follow-up period is >24 months, with some participants followed for 30 months. The primary endpoint was time to clinical milestones due to DMD disease progression, and motor, pulmonary, and cardiac function. Secondary endpoints were quality of life (QoL) assessments.Findings Mean (standard deviation [SD]) age at screening was 3.4 (1.2), 8.6 (2.0), 12.3 (2.7) and 7.4 (3.5) years in Groups 1, 2, 3 and total respectively. Mean (SD) North Star Ambulatory Assessment (NSAA) total score at baseline was 21.2 (5.8) in Group 1, 19.5 (8.3) in Group 2 and 20.0 (7.7) in ambulatory total. Overall, the time to clinical milestones due to DMD disease progression was consistent with previous findings, in which loss of ambulation occurred at 13 years. There was a trend towards a decline over 12 months in NSAA and timed motor function from age 6 years, with the greatest reductions observed thereafter. There were no consistent trends in measures of QoL, although participants of any age generally had poorer outcomes at Month 12 versus their domain scores at baseline.Interpretation This study improves the understanding of DMD progression according to the current standards of care in the Chinese DMD population and may inform selected endpoints and patient populations in clinical trials.

Objective: To evaluate the efficacy and safety of rituximab in pediatric myasthenia gravis (MG). Methods: Case series study. The clinical manifestations, laboratory tests, treatment plans and prognosis of 27 pediatric MG patients treated with rituximab from June 2013 to June 2023 at Children's Medical Center of Peking University First Hospital were retrospectively collected. Results: There were 5 males and 22 females in 27 MG children. The onset age was 2.1 (1.6, 4.8) years, ranging from 8 months to 11 years. The clinical classification included 20 children (74%) of ocular MG and 7 children (26%) of generalized MG. Seventeen children (63%) had positive MG-related pathogenic antibodies, including 17 children of anti-AchR antibody and 1 of them also had anti-MuSK antibody. Rituximab was used as first-line immunosuppressant in 13 children, second-line immunosuppressant in 13 children and third-line immunosuppressant in 1 child. Immunosuppressants used before rituximab including 8 children of cyclosporine, 3 children of tacrolimus, 1 child of azathioprine, 1 child of mycophenolate mofetil and 1 child of cyclosporine combined with azathioprine. Rituximab was used for at least half a year with a follow-up period of more than 12 months. At the last follow-up after rituximab treatment, all children achieved improved or above, 14 children (52%) achieved complete stable remission, 7 children (26%) achieved pharmacologic remission, 1 child (4%) achieved minimal manifestations, and 5 children (18%) improved. After rituximab treatment, 27 children all could reduce the immunomodulation therapy and shorten the course of glucocorticoid therapy, and 22 children (81%) had stopped the glucocorticoid therapy. Among the 14 children with poor efficacy of other immunosuppressants, rituximab had complete stable remission of 7 children. The most common adverse reaction was respiratory infection (4 children (15%)). Only 2 children had allergic reaction to rituximab and got better after symptomatic treatment. Conclusions: Rituximab has good efficacy and tolerance in pediatric MG. Early application of rituximab can improve the prognosis and shorten the course of glucocorticoid treatment.

Substation as a power facility, the surrounding environment may have a variety of complex factors, such as strong electromagnetic field, strong electromagnetic interference, noise, dust and so on. These environmental factors may interfere with the positioning equipment and measuring instruments, affecting the accuracy of the measurement. Therefore, this paper proposes a high-precision positioning algorithm for substation live construction based on Beidou high-precision differential positioning. Neural network is introduced to monitor the abnormal position of substation voltage. Based on this, the Beidou high-precision differential positioning technology is used to realize the high-precision location of substation construction signal. The experimental results show that: For single electromagnetic interference and multi-electromagnetic interference, the research algorithm can realize the high-precision location of live construction position of substation, and the error is always less than 2m.

The TRNT1 gene encodes tRNA nucleotidyltransferase 1, which catalyzes the addition of cytosine-cytosine-adenosine (CCA) to the ends of cytoplasmic and mitochondrial tRNAs. The most common clinical phenotype associated with TRNT1 is autosomal recessive sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (SIFD). Muscle involvement has rarely been reported in TRNT1-related disorders. Here we report a Chinese patient with incomplete SIFD and hyperCKemia, and explored the skeletal muscle pathological changes. The patient was a 3-year-old boy with sensorineural hearing loss, sideroblastic anemia, and developmental delay since infancy. At the age of 11 months, significantly increased levels of creatine kinase were noted, accompanied by mild muscle weakness. Whole-exome sequencing revealed compound heterozygous variants of the TRNT1 gene, c.443C > T (p.Ala148Val) and c.692C > G (p.Ala231Gly), in the patient. Western blot showed a decreased expression of TRNT1 and cytochrome c oxidase subunit IV (COX IV) in the skeletal muscle of the patient. Electron microscopy observation of skeletal muscle pathology revealed abnormal mitochondria of various sizes and shapes, supporting a diagnosis of mitochondrial myopathy. The present case indicates that in addition to the classic SIFD phenotype, TRNT1 mutations can cause mitochondrial myopathy, a rare clinical phenotype of TRNT1-related disorders.

Background:LAMA2-related limb girdle muscular dystrophy (LGMD R23) is rare. The detailed clinical phenotypes and genetic information associated with LGMD R23 are unknown. Methods:We conducted a retrospective cross-sectional and longitudinal study on 19 LGMD R23 patients. Results:Normal early motor development was observed in 84.2% patients. Mild orthopedic complications were observed in 42.1% patients. 36.8% patients had seizures, which is unusually frequent in LGMD. Epilepsy was eventually diagnosed in 26.3% patients. 46.7% patients presented with motor neuropathy. Genetic analysis identified 29 pathogenic variants, with missense and frameshift variants being the most common. The mutant sites were mainly distributed in the N-terminal and G-like domains of laminin. The missense variants are distributed near the N-terminus (exons 3-11), whereas frameshift variants are distributed in exons 12-65. Five patients were diagnosed with epilepsy and all of them harbor at least one missense variants in exon 4. 71.4% variants of patients with motor neuropathy located in the LN domain. Conclusions:Missense variants in exon 4 maybe correlated with epilepsy and variants in the LN domain maybe correlated with motor neuropathy in Chinese patients. Our study expands the clinical and genetic spectrum caused by LAMA2 variations and provides novel genotype-phenotype correlations of LGMD R23.

This systematic review and meta-analysis aimed to evaluate the efficacy of vigabatrin (VGB) in treating infantile epileptic spasms syndrome (IESS). Databases of PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library were systematically searched. All the relevant randomized controlled trials (RCTs) and observational studies (OSs) of VGB for IESS were included and analyzed separately. The primary outcome was the cessation of epileptic spasms (ES). Five RCTs and nine OSs compared the efficacy of VGB vs hormonal monotherapy for IESS. Meta-analysis of the five RCTs showed that hormonal monotherapy was significantly better than VGB monotherapy (OR = 0.37, 95% CI = 0.20-0.67) for patients with new-onset IESS. Meta-analysis of the nine OSs agrees with the result from RCTs (OR = 0.61, 95% CI = 0.43-0.85). VGB was more effective in patients with TSC than in those with other etiologies (five OSs, OR = 5.59, 95% CI = 2.17-14.41). There was no significant difference in the efficiency of VGB combined with hormonal therapy vs hormonal monotherapy for IESS (two RCTs, OR = 0.75, 95% CI = 0.09-6.45). Hormonal monotherapy is better than VGB monotherapy for non-TSC-associated IESS. But for patients with IESS due to TSC, VGB is the first choice. VGB combined with hormone therapy does not definitely increase ES control rates compared with that of hormonal monotherapy.

Abstract Background Congenital myopathies are a group of rare neuromuscular diseases characterized by specific histopathological features. The relationship between the pathologies and the genetic causes is complex, and the prevalence of myopathy-causing genes varies among patients from different ethnic groups. The aim of the present study was to characterize congenital myopathies with infancy onset among patients registered at our institution. Method This retrospective study enrolled 56 patients based on the pathological and/or genetic diagnosis. Clinical, histopathological and genetic features of the patients were analysed with long-term follow-up. Results Twenty-six out of 43 patients who received next-generation sequencing had genetic confirmation, and RYR1 variations (12/26) were the most prevalent. Eighteen novel variations were identified in 6 disease-causing genes, including RYR1, NEB, TTN, TNNT1, DNM2 and ACTA1. Nemaline myopathy (17/55) was the most common histopathology. The onset ages ranged from birth to 1 year. Thirty-one patients were followed for 3.83 ± 3.05 years (ranging from 3 months to 11 years). No patient died before 1 year. Two patients died at 5 years and 8 years respectively. The motor abilities were stable or improved in 23 patients and deteriorated in 6 patients. Ten (10/31) patients developed respiratory involvement, and 9 patients (9/31) had mildly abnormal electrocardiograms and/or echocardiograms. Conclusion The severity of congenital myopathies in the neonatal/infantile period may vary in patients from different ethnic groups. More concern should be given to cardiac monitoring in patients with congenital myopathies even in those with static courses.

IntroductionNext generation sequencing results in an explosive identification of rare variants of RYR1, making the correlation between phenotype and genotype complicated. We analyzed the data of 33 patients with RYR1-related myopathy, attempting to elucidate correlations between phenotype, genotype, and protein structure of RyR1.MethodsClinical, histopathologic, and genetic data were evaluated, and variants were mapped to the cryo-EM RyR1 structure. The three-dimensional structure of the variant on RyR1 was analyzed.ResultsThe clinical spectrum was highly variable regardless of the mode of inheritance. Recessive variations were associated with more severe feeding problems and respiratory insufficiency in infancy (p < 0.05). Forty pathogenic and likely pathogenic variations were identified, and 14 of them were novel. Missense was the most common variation type regardless of inheritance mode. Arginine (15/45) was the most frequently involved residue. All but one dominant variation clustered in Pore forming and pVSD domains, while recessive variations enriched in Bsol (7/25) and SPRYs (6/25) domains. Analysis of the spatial structure of variants showed that dominant variants may impact RyR1 mainly by breaking down hydrogen or electrovalent bonds (10/21); recessive variants located in different domains may impact the function of RyR1 through different pathways. Variants located in RyR1 coupling sites (PY1&2 and the outermost of Bsol) may cause the most severe clinical manifestation.ConclusionClinical diversity of RYR1-related myopathy was impacted by the inheritance mode, variation type, and variant location. Dominant and recessive variants have different sensitive domains impacting the function of RyR1 through different pathways.