Objective:To explore the genetic etiology and clinical outcome of a child with co-morbid progressive IgA nephropathy and COQ8B-associated glomerulopathy. Methods:A child who was admitted to Peking University First Hospital on March 2, 2021 was selected as the study subject. Genomic DNA was extracted from peripheral blood samples from the child and his parents and sister. Whole exome sequencing was carried out, and candidate variant was verified by Sanger sequencing. This study was approved by Medical Ethics Committee of the Peking University First Hospital (Ethics No. 2016[1029]).Results:The child, a 7-year-old boy who had developed proteinuria 8 months before, was diagnosed with IgA nephropathy (M1E1S1T1C1). With steroid, cyclophosphamide, cyclosporine and angiotensin-converting enzyme inhibitor therapy, partial remission of proteinuria was achieved. However, his serum creatinine level had increased from 53.8 mol/L at the onset of disease to 86.7 mol/L after 3.9 years, along with massive proteinuria. Kidney biopsy still indicated IgA nephropathy (M0E0S1T0C0). The child was found to harbor a homozygous c. 737G>A (p.Ser246Asn) missense variant of the COQ8B gene, for which his parents and sister were heterozygous carriers. The variant was predicted to be pathogenic (PS1+ PM2_Supporting+ PM3+ PP3+ PP4) based on the guidelines from the American College of Medical Genetics and Genomics. The child was treated with high-dose coenzyme Q10 in combination with steroid and/or mycophenolate mofetil, though his serum creatinine level still increased to 286 mol/L after 7.3 years, which conformed to a chronic kidney disorder with glomerular filtration rate category of G3b. Conclusion:The homozygous c.737G>A missense variants of the COQ8B gene probably underlay the progressive kidney dysfunction in this child. For children with IgA nephropathy presenting with atypical clinical manifestations, unsatisfactory therapeutic effect, and/or early onset of kidney function decline, coexistence of other diseases should be suspected.

End-stage liver diseases,such as cirrhosis and liver cancer caused by hepatitis B,are often combined with hepatic encephalopathy(HE);ammonia poisoning is posited as one of its main pathogenesis mechanisms.Ammonia is closely related to autophagy,but the molecular mechanism of ammonia's regulatory effect on autophagy in HE remains unclear.Sialylation is an essential form of glycosylation.In the nervous system,abnormal sialylation affects various physiological processes,such as neural development and synapse formation.ST3 β-galactoside α2,3-sialyltransferase 6(ST3GAL6)is one of the significant glycosyltransferases responsible for adding α2,3-linked sialic acid to substrates and generating glycan structures.We found that the expression of ST3GAL6 was upregulated in the brains of mice with HE and in astrocytes after ammonia induction,and the expression levels of α2,3-sialylated glycans and autophagy-related proteins microtubule-associated protein light chain 3(LC3)and Beclin-1 were upregulated in ammonia-induced astrocytes.These findings suggest that ST3GAL6 is related to autophagy in HE.Therefore,we aimed to determine the regulatory relationship between ST3GAL6 and autophagy.We found that silencing ST3GAL6 and blocking or degrading α2,3-sialylated glycans by way of Maackia amurensis lectin-Ⅱ(MAL-Ⅱ)and neuraminidase can inhibit autophagy.In addition,silencing the expression of ST3GAL6 can downregulate the expression of heat shock protein β8(HSPB8)and Bcl2-associated athanogene 3(BAG3).Notably,the overexpression of HSPB8 partially restored the reduced autophagy levels caused by silencing ST3GAL6 expression.Our results indicate that ST3GAL6 regulates autophagy through the HSPB8-BAG3 complex.

Background::While type 2 diabetes mellitus (T2DM) is considered a putative causal risk factor for coronary artery disease (CAD), the intrinsic link underlying T2DM and CAD is not fully understood. We aimed to highlight the importance of integrated care targeting both diseases by investigating the phenotypic and genetic relationships between T2DM and CAD.Methods::We evaluated phenotypic associations using data from the United Kingdom Biobank ( N = 472,050). We investigated genetic relationships by leveraging genomic data conducted in European ancestry for T2DM, with and without adjustment for body mass index (BMI) (T2DM: Ncase/ Ncontrol = 74,124/824,006; T2DM adjusted for BMI [T2DM adjBMI]: Ncase/ Ncontrol = 50,409/523,897) and for CAD ( Ncase/ Ncontrol = 181,522/984,168). We performed additional analyses using genomic data conducted in multiancestry individuals for T2DM ( Ncase/ Ncontrol = 180,834/1,159,055). Results::Observational analysis suggested a bidirectional relationship between T2DM and CAD (T2DM→CAD: hazard ratio [HR] = 2.12, 95% confidence interval [CI]: 2.01–2.24; CAD→T2DM: HR = 1.72, 95% CI: 1.63–1.81). A positive overall genetic correlation between T2DM and CAD was observed ( rg = 0.39, P = 1.43 × 10 -75), which was largely independent of BMI (T2DM adjBMI–CAD: rg = 0.31, P = 1.20 × 10 –36). This was corroborated by six local signals, among which 9p21.3 showed the strongest genetic correlation. Cross-trait meta-analysis replicated 101 previously reported loci and discovered six novel pleiotropic loci. Mendelian randomization analysis supported a bidirectional causal relationship (T2DM→CAD: odds ratio [OR] = 1.13, 95% CI: 1.11-1.16; CAD→T2DM: OR = 1.12, 95% CI: 1.07-1.18), which was confirmed in multiancestry individuals (T2DM→CAD: OR = 1.13, 95% CI: 1.10-1.16; CAD→T2DM: OR = 1.08, 95% CI: 1.04-1.13). This bidirectional relationship was significantly mediated by systolic blood pressure and intake of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, with mediation proportions of 54.1% (95% CI: 24.9-83.4%) and 90.4% (95% CI: 29.3-151.5%), respectively. Conclusion::Our observational and genetic analyses demonstrated an intrinsic bidirectional relationship between T2DM and CAD and clarified the biological mechanisms underlying this relationship.

Objective:To analyze clinical data of 3 children with LMX1B-associated disease characterized by asymptomatic glomerular proteinuria, thus improving the recognition of asymptomatic proteinuria with genetic causes. Methods:Three patients with LMX1B-associated disease presented with prominent asymptomatic proteinuria diagnosed by the next-generation sequencing in Department of Pediatrics, Peking University First Hospital from April 2014 to October 2017 were included in this study.Clinical data, including renal and extrarenal manifestations, renal biopsy, and family history, were collected and retrospectively analyzed. Results:All 3 children were girls, the age of onset were 2 years, 1 year, and 4 years, respectively, and the diagnosis age were 11 years, 5 years and 6 years, respectively.All of them had glomerular proteinuria, and nephrotic-level proteinuria occurred in one patient.Microscopic hematuria was found in 2 patients.All of them had normal renal function.Only one patient underwent renal biopsy.Electron microscopy of the first time of biopsy revealed segmental thinning of the glomerular basement membrane.Re-biopsy 4 years later showed irregular thickening of the glomerular basement membrane, moth-eaten appearance and collagen fibrillar material deposition.No abnormalities of nails, limbs and joints were observed by physical examination.Two patients had a family history of renal disease.Conclusions:Genetic factors should be considered in children with obscure onset asymptomatic proteinuria without definite clinical causes.Genetic testing can help diagnose and guide treatment as early as possible.

OBJECTIVE: To explore the genetic etiology and clinical outcome of a child with steroid-resistant nephrotic syndrome and diffuse mesangial sclerosis. METHODS: Genomic DNA was extracted from peripheral blood leukocytes of the proband and his parents. Targeted capture - next generation sequencing and Sanger sequencing were carried out. Candidate variant was verified by segregation analysis in his family. RESULTS: A heterozygous missense variant of the TRPC6 gene, namely c.325G>A (p.Gly109Ser), was detected in the proband. The same variant was not detected in either parent. According to the guidelines for the interpretation of sequence variants developed by American College of Medical Genetics and Genomics, the variant was predicted as pathogenic. CONCLUSION The missense variant of the TRPC6 gene probably underlay the diffuse mesangial sclerosis in this patient. Above finding has expanded the phenotypic spectrum of the TRPC6 gene.
Child ; Genomics ; Humans ; Mutation, Missense ; Nephrotic Syndrome/genetics* ; Sclerosis ; TRPC6 Cation Channel/genetics*

Objectives:To summarize the clinical and genetic characteristics of the patients with isolated methylmalonic acidemia and investigate the strategies for the diagnosis, treatment and prevention.Methods:Three hundred and fourteen patients (180 males, 134 females) with isolated methylmalonic acidemia were ascertained from 26 provinces or cities across the mainland of China during January 1998 to March 2020. Genetic analysis was performed by Sanger sequencing, gene panel sequencing, whole exome sequencing, multiplex ligation-dependent probe amplification or quantitative PCR. According to the age of onset, the patients were divided to early-onset group (≤12 months of age) and the late-onset group (>12 months of age). They were treated by cobalamin, L-carnitine and (or) special diet and symptomatic treatment. Statistical analysis was done using Chi-square test.Results:Fifty-eight of 314 (18.5%) patients were detected by Newborn screening using liquid chromatography tandem mass spectrometry. Five cases (1.6%) had a postmortem diagnosis. Two hundred and fifty-one patients (79.9%) were clinically diagnosed with an age of onset ranged from 3 hours after birth to 18 years. One hundred and fifty-nine patients (71.0%) belonged to early-onset groups, 65 patients (29.0%) belonged to the late-onset group. The most common symptoms were metabolic crises, psychomotor retardation, epilepsy, anemia and multiple organ damage. Metabolic acidosis and anemia were more common in early-onset patients than that in late-onset patients (20.8%(33/159) vs. 9.2% (6/65), 34.6% (55/159) vs. 16.9% (11/165), χ 2=4.261, 6.930, P=0.039, 0.008). Genetic tests were performed for 236 patients (75.2%), 96.2%(227/236) had molecular confirmation. One hundred and twenty-seven variants were identified in seven genes (MMUT, MMAA, MMAB, MMADHC, SUCLG1, SUCLA2, and MCEE), of which 49 were novel. The mut type, caused by the deficiency of methylmalonyl-CoA mutase, was the most common ( n=211, 93%) cause of this condition. c.729_730insTT, c.1106G>A and c.914T>C were the three most frequent mutations in MMUT gene. The frequency of c.914T>C in early-onset patients was significantly higher than that in late-onset patients (8.3% (18/216) vs. 1.6% (1/64), χ 2=3.859, P=0.037). Metabolic crisis was more frequent in mut type than the other types (72.6% (114/157) vs. 3/13, χ 2=13.729, P=0.001),developmental delay and hypotonia were less frequent in mut type (38.2% (60/157) vs. 9/13, 25.5% (40/157) vs. 8/13, χ 2=4.789, 7.705, P=0.030, 0.006). Of the 58 patients identified by newborn screening, 44 patients (75.9%) who were treated from asymptomatic phase developed normally whereas 14 patients (24.1%) who received treatment after developing symptoms exhibited varying degrees of psychomotor retardation. Conclusions:The characteristics of phenotypes and genotypes among Chinese patients with isolated methylmalonic acidemia were analyzed. Expanded the mutation spectrum of the associated genes. Because of the complex clinical manifestations and severe early onset of isolated methylmalonic acidemia, Newborn screening is crucial for early diagnosis and improvement of prognosis. MMUT gene is recommended for carrier screening as an effort to move the test earlier as a part of the primary prevention of birth defects.

Objective To explore the clinical characteristics, diagnosis and treatment of refractory hypertension caused by renal artery fibromuscular dysplasia (FMD) in children. Method The clinical data of a child with refractory hypertension caused by FMD were retrospectively analyzed. Results A boy, with onset at age of 4 years, had significantly increased blood pressure and decreased serum potassium. His renin and angiotensin levels were significantly elevated. The boy was diagnosed with renovascular hypertension by color Doppler ultrasonography, enhanced thoracoabdominal CT and vascular reconstruction. Oral administration of a variety of antihypertensive drugs is not effective. The child was finally diagnosed of refractory hypertension caused by FMD using renal angiography. The child was not suitable for surgery. After adjusting the antihypertensive drugs, the blood pressure of the child tended to be stable. The boy received continuous follow-up for 8 years. The antihypertensive regimen was adjusted annually and blood pressure fluctuations and target organ damage were dynamically assessed. Conclusion Children with FMD caused renal vascular hypertension may have no specific manifestations in the early stage. The drug treatment is preferred, and surgical treatment may be considered.

Objective To explore the etiology and prognosis of Dent disease combined with renal failure in children. Methods The clinical data of 2 children with Dent disease combined with renal failure from January 2014 to December 2016 were analyzed and the related literature was reviewed. Results Both of them were male, with the age of 8 and 10 years old respectively. Their renal functions were normal, and no renal calcification. Both of them had the history of upper respiratory tract virus infections within 1 week before the onset of renal failure. In case 1, acute phase (10 days) renal biopsy showed combined with acute tubulointerstitial nephritis, and his renal function recovered completely after glucocorticoids treatment. In case 2, renal biopsy at 6 months in course of disease showed the combined with subacute tubulointerstitial nephritis, and his renal function was improved partly after glucocorticoids treatment. Conclusions For children with Dent disease combined with acute renal failure, especially with upper respiratory tract virus infections and other inducement, renal biopsy should be early performed to exclude the possibility of acute tubulointerstitial nephritis, so that the treatment can be timely conducted and the prognosis can be improved.

Objective To analyze the characteristics and to evaluate the application of quantitative CT spectral parameters in patients with suspected lung cancer.Methods One hundred and thirty two patients with occupying lesions of the lung underwent chest plain and two-phase contrast enhanced CT scan with gemstone spectral imaging (GSI) mode.The CT images of patients with confirmed lung cancer by pathological evidence were analyzed with GSI viewer.Optimal energy value supplying optimal contrast-tonoise ratio (CNR) was recorded.The CT values of lesions at 40 keV,70 keY and optimal energy level were measured.Spectral curve slope at different intervals of 40-70 keV,40-100 keV and 40-140 keV was computed.Effective atomic number (Zeff),iodine concentration (IC) and water concentration (WC) were measured and analyzed by statistical methods.Results Sixty six patients with confirmed lung cancer were included in the analysis.The optimal energy values for optimal CNR on plain scan,arterial phase and venous phase were (63.09±5.33) keV,(52.65±6.44) keV and (54.06±5.53) keV,respectively.The difference of CT values at different energy levels on each scan phase was statistically significant (F=4.561,P=0.025).The spectral curve slope values among three different energy intervals were significantly different (F=2.137,P＜0.001).The differences of the slope between arterial phase and venous phase at same energy interval were not significant (40-70 keY:t=1.165,P=0.248;40-100 keV:t=1.102,P=0.274;40-140 keV:t=1.118,P=0.268).Zeff on plain scan,arterial phase and venous phase was 7.73±0.14,8.35±0.37 and 8.39±0.30,respectively.There was positive correlation between IC and Zeff on enhanced phase (arterial phase:r=0.998,P＜0.001;venous phase:r=0.998,P＜0.001).Conclusion CT spectral imaging can supply the optimal energy value for optimal CNR.CT value at optimal energy level and spectral curve slope at 40-140 keV are suitable for analysis.IC and Zeff can be used jointly in evaluation of patients with suspected lung cancer.

Objective To study the influence of continuous blood purification(CBP) on cardiac out-put of pediatric patients using bioreactance. Methods Patients underwent CBP in PICU and nephrology ward from March 2014 were prospectively enrolled after approval by ethics committee. CBP therapies were all performed by Fresenius Medical Care hemodialysis machine. Cardiac output values were obtained using the non-invasive cardiac output monitoring ( NICOM) device ( Cheetah Medical). Blood pressure, heart rate, cardiac index(CI) and stroke volume index(SVI) were recorded before the therapy,at the beginning of ther-apy,during the course of therapy,and at the end of each therapy. Results Twenty-one pediatric patients (from 1. 0 year to 15. 5 years) were recruited and 69 treatments were recorded from March 2014 to Decem-ber 2016. The basic CI was 3. 4 (2. 4,6. 1) L/(min·m2),basic SVI was 43 (26,75) ml/(m2·beat). Dur-ing the beginning of therapy,mean arterial pressure(MAP),CI and SVI all dropped from the baseline ( P<0. 001),whereas heart rate increased. During the course of CBP,CI and SVI (were both recorded every 4 hours) kept on dropping and stayed at a relatively lower level. Course CI was 3. 0 (2. 4,4. 6) L/(min·m2) and course SVI was 28 (21,57) ml/(m2·beat). At the end of therapy,CI was 3. 4 (2. 5,5. 3) L/(min· m2),with no significant difference from the baseline CI (P＝0. 073). However,the SVI at the end of therapy was 35 (25,67) ml/(m2·beat),higher than the course SVI but still lower than the basic SVI,the differences were statistically significant ( P<0. 05). Conclusion CI and SVI continue to decline at the beginning of CBP treatment and remain at a lower level throughout the course of treatment. After the therapy, CI has returned to the basic level whereas SVI has not recovered.