Shiwei Yang

Background: Danon disease is an X-linked disorder caused by variants in the lysosome-associated membrane protein-2 (LAMP2) gene located on Xq24. Due to its inheritance in an X-chromosome dominant manner, males typically experience more severe manifestations than females.Method: The whole exome sequencing was conducted on a cohort of 218 children diagnosed with hypertrophic cardiomyopathy; four children with hypertrophic cardiomyopathy carrying the LAMP2 variants were diagnosed at our centre. Variants in the LAMP2 gene were summarised, and their pathogenicity and conservation were analysed using bioinformatics methods. A retrospective analysis of genotype-phenotype associations was also conducted in conjunction with previously reported cases.Results: Four patients with Danon disease were diagnosed in our single centre by gene sequencing; they all presented with myocardial hypertrophy as the initial manifestation. Both male patients manifested symptoms from infancy, while disease onset in the two female cases occurred below the average age reported for females. Through gene sequencing, a total of four variants were identified in these four patients, including one splicing variant: c.865-1G>C, one loss of heterozygosity variant: loss1 exon:4-9), one frameshift variant: c.973delG(p.(L325Wfs×21)), and one stop codon variant: c.467T>G(p.(L156*)).Conclusion: This study identified four patients with LAMP2 gene variants, thereby enriching the documented genetic landscape of LAMP2-associated disorders. Bioinformatics analyses corroborated the pathogenicity of these variants. Additionally, we emphasised that women with suspected Danon disease should be thoroughly evaluated, and the possibility of implantable cardioverter defibrillator implantation and heart transplantation should be considered and discussed as early as possible.

Background: Numerous studies have shown that patent foramen ovale (PFO) is closely associated with migraine and PFO closure can significantly relieve migraine in adults. However, there are limited data on children. Therefore, this study aims to investigate the role of percutaneous PFO closure in children with PFO and severe migraine, thereby providing theoretical evidence for performing this procedure in the pediatric population. Methods: In this study, we conducted a retrospective analysis of the clinical data from 46 children with PFO and severe migraine admitted to our hospital between September 2021 and October 2023 and assessed the relief of migraine after percutaneous PFO closure. Results: All 46 children with PFO had severe migraine preoperatively. The PFO was determined by transthoracic echocardiography (TTE) and right heart contrast echocardiography suggested the presence of a significant right-to-left shunt (RLS). No residual shunt and complications were observed in all the children after intervention. Before PFO closure, every child experienced repeated migraines. Follow-up data for all patients were obtained by telephone, WeChat, or outpatient visits at 1, 6, 12, and 24 months after PFO closure. The migraine was significantly alleviated in 43 children, while three others experienced no change. There was a significant reduction in the frequency, duration, Visual Analogue Scale (VAS) score and Headache Impact Test-6 (HIT-6) score after PFO closure. Conclusions: Percutaneous PFO closure may be considered for children with PFO and severe migraine who have not responded to other treatments, after excluding other headache causes. In some children, this procedure may significantly improve headache symptoms.

Desminopathy is a rare heritable cardiac and skeletal muscle disease caused by variants in the DES gene, which encodes the primary muscle-specific intermediate filament protein, known as desmin. Childhood-onset is commonly associated with severe early-onset myopathy and early death. Here, we reported an 11-year-old Chinese girl presenting with complete atrioventricular block and cardiomyopathy, without skeletal muscle involvement. Genetic analysis identified a de novo variant (c.152C > T/p.Ser51Phe) in the DES gene.

Mitochondrial antiviral signaling (MAVS) was first discovered as an activator of NF-κB and IRF3 in response to viral infection in 2005. As a key innate immune adapter that acts as an ‘on/off’ switch in immune signaling against most RNA viruses. Upon interaction with RIG-I, MAVS aggregates to activate downstream signaling pathway. The MAVS gene, located on chromosome 20p13, encodes a 540-amino acid protein that located in the outer membrane of mitochondria. MAVS protein was ubiquitously expressed with higher levels in heart, skeletal muscle, liver, placenta and peripheral blood leukocytes. Recent studies have reported MAVS to be associated with various conditions including cancers, systemic lupus erythematosus, kidney disease, and cardiovascular disease. This article provides a comprehensive summary and description of MAVS research in cardiac disease, encompassing structure, expression, protein-protein interactions, modifications, as well as the role of MAVS in heart disease. It is aimed to establish a scientific foundation for the identification of potential therapeutic target.

This study aimed to develop a novel scoring system utilizing circulating interleukin (IL) levels to predict resistance to intravenous immunoglobulin (IVIG) in Chinese patients with Kawasaki disease (KD). We further compared this scoring system against six previously established scoring methods to evaluate its predictive performance. A retrospective analysis was conducted on KD patients who were treated at the cardiovascular medical ward of our institution from January 2020 to December 2022. Six scoring systems (Egami, Formosa, Harada, Kobayashi, Lan and Yang) were analyzed, and a new scoring system was developed based on our data. In our study, 521 KD patients were recruited, 42 of whom (8.06%) were identified as resistant to IVIG. Our study indicated that IVIG-resistant KD patients were at an increased risk for the development of coronary arterial lesions (CALs) (P = 0.001). The evaluation of IVIG resistance using various scoring systems revealed differing levels of sensitivity and specificity, as follows: Egami (38.10% and 88.52%), Formosa (95.24% and 41.13%), Harada (78.57% and 43.22%), Kobayashi (66.67% and 74.95%), Lan (66.67% and 73.49%), and Yang (69.05% and 77.24%). Our novel scoring system utilizing sIL-2R demonstrated the highest sensitivity and specificity of 69.29% and 83.91%, respectively, and calibration curves indicated a favorable predictive accuracy of the model. Our newly developed scoring system utilizing sIL-2R demonstrated superior predictive performance in identifying IVIG resistance among Chinese patients with KD.

Pathogenic mutations in mitochondrial DNA cause severe and often lethal multi-system symptoms in primary mitochondrial defects. However, effective therapies for these defects are still lacking. Strategies such as employing mitochondrially targeted restriction enzymes or programmable nucleases to shift the ratio of heteroplasmic mutations and allotopic expression of mitochondrial protein-coding genes have limitations in treating mitochondrial homoplasmic mutations, especially in non-coding genes. Here, we conduct a proof of concept study applying a screened DdCBE pair to correct the homoplasmic m.A4300G mutation in induced pluripotent stem cells derived from a patient with hypertrophic cardiomyopathy. We achieve efficient G4300A correction with limited off-target editing, and successfully restore mitochondrial function in corrected induced pluripotent stem cell clones. Our study demonstrates the feasibility of using DdCBE to treat primary mitochondrial defects caused by homoplasmic pathogenic mitochondrial DNA mutations.

Generalized arterial calcification of infancy (GACI) is a rare genetic disease characterized by arterial calcifications or stenoses and hypertension. GACI is caused by mutations in the ENPP1 or ABCC6 genes, and it often causes intrauterine or early infancy death. Here, we report a case of rare GACI caused by a homozygous variation in ENPP1, in a Chinese infant initially presenting with hypertension. The proband was an 8-month-old boy with in utero tricuspid valve calcification, presenting with hypertension at birth. Enhanced computed tomography revealed extensive arterial calcification. Genetic testing identified a homozygous variation in ENPP1 (c.783C > G p.Y261X), which led to the diagnosis of GACI. This mutation has been reported in only three Chinese patients, which all initially presented with hypophosphatemic rickets rather than GACI. This case enriches the clinical and genetic spectrum of ENPP1 mutations and reminds us that GACI should be considered in an infant presenting with hypertension and extensive arterial calcification, and that genetic testing should be performed.