Long-term auditory monitoring in children with Alport syndrome based on different degrees of renal injury / 临床耳鼻咽喉头颈外科杂志

Objective:To investigate long-term auditory changes and characteristics of Alport syndrome（AS） patients with different degrees of renal injury. Methods:Retrospectively analyzing clinical data of patients diagnosed AS from January 2007 to September 2022, including renal pathology, genetic detection and hearing examination. A long-term follow-up focusing on hearing and renal function was conducted. Results:This study included 70 AS patients, of which 33（25 males, 8 females, aged 3.4-27.8 years） were followed up, resulting in a loss rate of 52.9%.The follow-up period ranged from 1.1to 15.8 years, with 16 patients followed-up for over 10 years. During the follow-up, 10 patients presenting with hearing abnormalities at the time of diagnosis of AS had progressive hearing loss, and 3 patients with new hearing abnormalities were followed up, which appeared at 5-6 years of disease course. All of which were sensorineural deafness. While only 3 patients with hearing abnormalities among 13 patients received hearing aid intervention. Of these patients,7 developed end-stage renal disease（ESRD）, predominantly males （6/7）. The rate of long-term hearing loss was significantly different between ESRD group and non-ESRD group（P=0.013）. There was no correlation between the progression of renal disease and long-term hearing level（P>0.05）. kidney biopsies from 28 patients revealed varying degrees of podocyte lesion and uneven thickness of basement membrane. The severity of podocyte lesion was correlated with the rate of long-term hearing loss（P=0.048）, and there was no correlation with the severity of hearing loss（P>0.05）. Among 11 cases, theCOL4A5mutationwas most common （8 out of 11）, but there was no significant correlation between the mutation type and hearing phenotype（P>0.05）. Conclusion:AS patients exhibit progressive hearing loss with significant heterogeneity over the long-term.. THearing loss is more likely to occur 5-6 years into the disease course. Hearing abnormalities are closely related to renal disease status, kidney tissue pathology, and gene mutations, emphasizing the need for vigilant long-term hearing follow-up and early intervention.

Bilateral giant full thickness macular holes: an infrequent manifestation of alport syndrome

Purpose: To report a case of Alport syndrome presenting with bilateral giant full-thickness macular holes, hypertensive chorioretinopathy, and exudative retinal detachment. Case Report: A 20 year-old man, a known case of Alport syndrome on hemodialysis, was referred to our clinic with bilateral vision loss initiated about 10 years prior to presentation, which exacerbated in the month prior to our visit. Bilateral large full-thickness macular holes, hypertensive chorioretinopathy, and exudative retinal detachment were detected in fundus examination. The patient had previous genetic counseling confirming the diagnosis of Alport syndrome. During follow-up, macular holes were covered with a thick epiretinal membrane and visual acuity decreased progressively in two weeks. Pars plana vitrectomy was performed in the right eye. Two weeks following surgery, the macular hole was closed and visual acuity improved significantly. Conclusion: Bilateral giant full-thickness macular holes are uncommon presentations of Alport syndrome. The retinal findings may be caused by an inefficient type IV collagen presenting in the Bruch's membrane and in the internal limiting membrane. Pars plana vitrectomy can be considered to repair macular holes in these patients.

COL4A5 genotypes and clinical characteristics of children with Alport syndrome / 中国当代儿科杂志

OBJECTIVES@#To investigate the genotypes of the pathogenic gene COL4A5 and the characteristics of clinical phenotypes in children with Alport syndrome (AS).@*METHODS@#A retrospective analysis was performed for the genetic testing results and clinical data of 19 AS children with COL4A5 gene mutations.@*RESULTS@#Among the 19 children with AS caused by COL4A5 gene mutations, 1 (5%) carried a new mutation of the COL4A5 gene, i.e., c.3372A>G(p.P1124=) and presented with AS coexisting with IgA vasculitis nephritis; 3 children (16%) had large fragment deletion of the COL4A5 gene, among whom 2 children (case 7 had a new mutation site of loss51-53) had gross hematuria and albuminuria at the onset, and 1 child (case 13 had a new mutation site of loss3-53) only had microscopic hematuria, while the other 15 children (79%) had common clinical phenotypes of AS, among whom 7 carried new mutations of the COL4A5 gene. Among all 19 children, 3 children (16%) who carried COL4A5 gene mutations also had COL4A4 gene mutations, and 1 child (5%) had COL4A3 gene mutations. Among these children with double gene mutations, 2 had gross hematuria and proteinuria at the onset.@*CONCLUSIONS@#This study expands the genotype and phenotype spectrums of the pathogenic gene COL4A5 for AS. Children with large fragment deletion of the COL4A5 gene or double gene mutations of COL4A5 with COL4A3 or COL4A4 tend to have more serious clinical manifestations.

Genetic testing and prenatal diagnosis for two Chinese pedigrees affected with Alport syndrome due to variants of COL4A5 gene / 中华医学遗传学杂志

OBJECTIVE@#To analysis variants of COL4A5 gene in two Chinese pedigrees affected with Alport syndrome (AS) and provide prenatal diagnosis for them.@*METHODS@#Two unrelated ethnic Han Chinese pedigrees who had visited the First Affiliated Hospital of Zhengzhou University respectively in September 2018 and January 2020 were selected as the study subjects. Clinical data were collected, and genomic DNA was extracted from peripheral venous blood and amniotic fluid samples for genetic testing. Following next generation sequencing, candidate variants of the COL4A5 gene were verified by Sanger sequencing and bioinformatic analysis. The gender of the fetuses was determined by the presence of sex-determining region on Y (SRY).@*RESULTS@#Genetic testing revealed that the proband and a fetus from pedigree 1 had both harbored a c.2723G>A (p.Gly908Glu) variant in exon 32 of the COL4A5 gene, whilst the proband and a fetus from pedigree 2 had both harbored a c.3817G>A (p.Gly1273Asp) variant in exon 44 of the COL4A5 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as likely pathogenic (PP2+PM2_Supporting). Following exclusion of maternal contamination, PCR amplification of the SRY region indicated that both fetuses were males.@*CONCLUSION@#The c.2723G>A (p.Gly908Glu) and c.3817G>A (p.Gly1273Asp) variants of the COL4A5 gene probably underlay the AS in the two pedigrees. Detection of the SRY region can reliably identify the fetal sex, which is conducive to the prenatal diagnosis. Above results have also enriched the mutational spectrum of the COL4A5 gene and provided a reference for correlating the genotype and phenotype of the AS.

Clinical and genetic analysis of a child with X-linked dominant Alport syndrome / 中华医学遗传学杂志

OBJECTIVE@#To investigate the clinical features and genetic variant of a child with X-linked dominant Alport syndrome (XLAS).@*METHODS@#A child who had presented at the First Affiliated Hospital of Zhengzhou University in May 2019 was selected as the study subject. Clinical data of the child was collected. Next generation sequencing (NGS) was carried out for the child. Candidate variants were validated by Sanger sequencing of his family members.@*RESULTS@#The child, a 12-year-old boy, had mainly manifested gross hematuria, proteinuria, nephrotic syndrome, and progressive renal impairment in conjunct with hearing loss. Kidney biopsy has revealed uneven glomerular basement membrane thickness. DNA sequencing revealed that the child and his mother have both carried a heterozygous c.2632G>A (p.G878R) variant of the COL4A5 gene, for which his father and brother were of the wild type. This variant was unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was classified as pathogenic (PS1+PM1+PM2_Supporting+PP3).@*CONCLUSION@#The maternally derived hemizygous c.2632G>A (p.G878R) variant of the COL4A5 gene probably underlay the XLAS in this child. Above finding has enriched the mutational spectrum of the COL4A5 gene.

Genetic analysis and in vitro validation of a case of Alport syndrome due to a splicing variant of COL4A5 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a patient with Alport syndrome (AS) and confirm the existence of a splicing variant.@*METHODS@#An AS patient diagnosed at the Affiliated Hospital of Inner Mongolia Medical University on January 8, 2021 for significant proteinuria and occult hematuria was selected as the study subject. Clinical data was collected. Peripheral blood samples were collected for the extraction of genomic DNA. Whole exome sequencing and Sanger sequencing were carried out to identify potential genetic variants. An in vitro experiment was also conducted to verify the abnormal mRNA splicing. Bioinformatic software was used to analyze the conservation of amino acids of the variant sites and simulate the 3D structure of the variant collagen IV protein. Immunofluorescence and immunohistochemistry were carried out on renal tissues from the patient to confirm the presence of AS kidney injury.@*RESULTS@#The patient, a 21-year-old male, had a 24-hour urine protein of 3.53 g/24 h, which fulfilled the diagnostic criteria for proteinuria. His blood uric acid has also increased to 491 μmol/L. DNA sequencing revealed that he has harbored a c.835-9T>A splice variant of the COL4A5 gene, which was not found in either of his parents. In vitro experiment confirmed that the variant has removed 57 bp from the exon 15 of the mRNA of the COL4A5 gene. The deletion may cause loss of amino acid residues from positions 279 to 297, which in turn may affect the stability of the secondary structure of the α5 chain encoded by the COL4A5 gene. The amino acids are conserved across various species. The result of homology modeling indicated that the trimerization of Col-IV with the mutated α5 chain could be achieved, however, the 3D structure was severely distorted. The AS kidney damage was confirmed through immunofluorescence assays. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.835-9T>A variant was classified as likely pathogenic (PVS1_Moderate+PS3_Moderate+PM2_Supporting+PS2+PP3+PP4).@*CONCLUSION@#The c.835-9T>A variant of the COL4A5 gene probably underlay the AS in this patient. In vitro experiment has confirmed the abnormal splicing caused by the variant. Histopathological examination of the kidney tissue has provided in vivo evidence for its pathogenicity. Above finding has expanded the mutational spectrum of the COL4A5 gene.

Genetic analysis of a patient with Alport syndrome due to compound heterozygous variants of COL4A4 gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and genetic characteristics of a patient with Alport syndrome.@*METHODS@#A patient with Alport syndrome who had visited the First Affiliated Hospital of Zhengzhou University in November 2020 was selected as the study subject. Clinical data of the patient were collected. High-throughput sequencing was carried out to detect potential variant of the COL4A3, COL4A4 and COL4A5 genes, and Sanger sequencing was carried out for verification of candidate variants in the family.@*RESULTS@#The main clinical manifestations of the patient included hematuria, proteinuria, and impaired hearing. Audiometric testing suggested symmetrical cochlear sensory neural hearing loss on both sides. Renal biopsy revealed mild mesangial proliferative glomerulonephritis. Genetic testing revealed that the patient has harbored compound heterozygous variants of the COL4A4 gene, namely c.940G>A (p.Gly314Ser) and c.3773G>A (p.Gly1258Asp), which were respectively inherited from her father and mother. Neither variant has been reported before, and were predicted to be pathogenic based on the guidelines from the American College of Medical Genetics and Genomics.@*CONCLUSION@#The c.940G>A (p.Gly314Ser) and c.3773G>A (p.Gly1258Asp) compound heterozygous variants of the COL4A4 gene probably underlay the Alport syndrome in this patient. Above finding has enriched the mutational spectrum of the COL4A4 gene.

Short-term efficacy of dapagliflozin in children with hereditary proteinuric kidney disease / 中华儿科杂志

Objective: To explore the short-term efficacy and safety of dapagliflozin in children with hereditary proteinuric kidney disease. Methods: This was a prospective cohort study. From August 2020 to December 2021, 23 children with hereditary kidney disease from Children's Hospital of Fudan University were enrolled. Patients received dapagliflozin 5 mg/d (weight≤30 kg) or initial dose 5 mg/d for 1 week, then 10 mg/d (weight>30 kg) and the dose of angiotensin converting enzyme inhibitors was stable during treatment. Clinical data including demographic parameters, primary diagnosis, estimated glomerular filtration rate (eGFR), 24 h proteinuria and characteristics in the follow-up were collected. The primary outcome was the change in 24 h proteinuria at 12 (±2) weeks, secondary outcomes included changes of 24 h proteinuria at 24 (±2) weeks, eGFR at both 12 (±2) and 24 (±2) weeks. The data were analysed by using mixed linear model. Results: Totally 23 patients were enrolled, including 16 males and 7 females. The age was (10.8±2.9) years. The primary diseases were Alport syndrome (12 cases), Dent disease (5 cases), proteinuria (4 cases), and focal segmental glomerulosclerosis (2 cases) respectively. Primary outcome showed that 24 h proteinuria decreased from baseline at 12 (±2) weeks during treatment (1.75 (1.46, 2.20) vs. 1.84 (1.14, 2.54) g/m2, P<0.05). Secondary outcomes showed that there was no significant difference in 24 h urine protein at 24 (±2) weeks (P>0.05). eGFR decreased slightly at 12 (±2) weeks ((107±21) vs. (112±28) ml/(min·1.73m2), P<0.05), and there was no significant difference at 24 (±2) weeks (P>0.05). Serum albumin increased at 12 (±2) and 24 (±2) weeks following the treatment ((39±8) vs. (37±8) g/L, (38±7) vs. (37±8) g/L, both P<0.05). No hypoglycemia event was reported during the treatment. Conclusion: The dapagliflozin had therapeutic effects on decreasing proteinuria and increasing serum albumin in short-term treatment in children with hereditary proteinuric kidney disease, no hypoglycemia or serious adverse events were observed.

Fenotipos inesperados en el síndrome de Alport: la necesidad del estudio genético / Unexpected phenotypes in Alport syndrome: the need for genetic testing

El diagnóstico del síndrome de Alport supone un reto en la edadpediátrica, debido a la ausencia de fenotipos clínicos esperados de la enfermedad, su clásica caracterización de entidad rara y la práctica muy restringida de biopsias renales con análisis rutinario de la muestra por microscopía electrónica durante la infancia. Se presentan las características clínicas y genéticas de 6 pacientes pediátricos (4 mujeres) diagnosticados de síndromede Alport en dos centros hospitalarios entre 2018 y 2021. Todos los pacientes presentaron un debut clínico claramente diferente y ninguno presentó complicaciones auditivas nioftalmológicas. La mitad carecía de antecedentes familiares de enfermedad renal crónica. Ninguna biopsia renal realizada confirmó el diagnóstico. Todos los pacientes fueron confirmadosgenéticamente y fueron el caso índice del estudio familiar. Esta serie ilustra la presencia de fenotipos clínicos inesperados en el síndrome de Alport y refleja la necesidad de incorporar el estudio genético para su diagnóstico.

The diagnosis of Alport syndrome is a challenge in the pediatric age, due to the absence of expected clinical phenotypes of the disease, its classic characterization of a rare disease and the very restricted practice of renal biopsies with routine analysis of the sample by electron microscopy during infancy. The clinical and genetic characteristics of 6 pediatric patients (4 women) diagnosed with Alport syndrome in two hospital centers between 2018 and 2021 are reported. All patients presented a clearly different clinical debut and none presented auditory or ophthalmological complications. Half had no family history of chronic kidney disease. No kidney biopsy performed confirmed the diagnosis. All patients were genetically confirmed and were the index case in the family study. This series illustrates the presence of unexpected clinical phenotypes in Alport syndrome and reflects the need for the incorporation of the genetic study for its diagnosis.

Analysis of genetic variant in a child with autosomal recessive Alport syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pedigree affected with Alport syndrome.@*METHODS@#Next generation sequencing and Sanger sequencing was applied to detect potential variants of the COL4A3, COL4A4 and COL4A5 genes among members from the pedigree and 100 unrelated healthy controls.@*RESULTS@#The proband and his twin brother were found to carry two novel variants, namely c.4953G>A and c.4623C>A, of the COL4A4 gene, which were respectively inherited from her father and mother. The same variants were not detected among the 100 healthy controls and medical literature. Based on the guidelines of the American College of Medical Genetics and Genomics, both the c.4953G>A and c.4623C>A variants were predicted to be pathogenic (PVS1+PM2_supporting+PP1).@*CONCLUSION@#The c.4953G>A and c.4623C>A variants of the COLA4A gene probably underlay the Alport syndrome in this pedigree. Above finding has enriched the spectrum of COLA4A gene variants.

Genetic and clinical analysis of a pedigree affected with X-linked dominant Alport syndrome due to a novel variant of COL4A5 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with X-linked hereditary Alport syndrome.@*METHODS@#Next generation sequencing was carried out for the pedigree. Candidate variant was validated by Sanger sequencing. Pathological changes of renal basement membrane and expression of COL4A5 protein were analyzed by renal biopsy and immunofluorescence assay, respectively.@*RESULTS@#All patients from the pedigree manifested progressive renal damage, gross hematuria, proteinuria and nephrotic syndrome. Renal biopsy of the proband revealed thickening of the basement membrane. No expression of the COL4A5 gene was detected by immunofluorescence. High-throughput sequencing and Sanger sequencing indicated that the proband has carried a c.3706delC (p.1236Pfs*69) variant in exon 41 of the COL4A5 gene. The same variant was also found in his mother and two brothers whom were similarly affected.@*CONCLUSION@#The novel c.3706delC (p.1236Pfs*69) variant of the COL4A5 gene probably underlay the pathogenesis of X-linked hereditary Alport syndrome in this pedigree. Above findings have enriched the spectrum of COL4A5 gene variants and provided a basis for the diagnosis and genetic counseling for the pedigree.

Optical coherence tomography angiography findings in patients with Alport syndrome / Alterações encontradas na angiografia por tomografia de coerência óptica (OCT-A) em pacientes com síndrome de Alport

ABSTRACT Purpose: To describe the findings on optical coherence tomography angiography associated with Alport syndrome. Methods: Descriptive study from a referral ophthalmology service (Hospital Evangélico de Vila Velha, Brazil). Patients diagnosed with Alport syndrome were included. Results: The study group consisted of four patients (one female and three males) diagnosed with Alport syndrome. Visual acuity in the worst eye was between 20/40 and 20/60. All male patients had anterior lenticonus on biomicroscopy. The observed retinal findings included dots and flecks and pigmentary changes in the macula. On optical coherence tomography angiography, the inner retinal layers of all patients displayed thinning (especially in the temporal quadrant of the macula) and an increase in the foveal avascular zone. A thick choroid was observed in both eyes of the two youngest patients. Conclusions: In patients with Alport syndrome, the inner retinal layers suffer changes due to type IV collagen mutations. Optical coherence tomography angiography makes it possible to visualize and document these findings, making it a useful tool in the detection of early retinal findings associated with Alport syndrome.

RESUMO Objetivos: Descrever os achados na angiografia por tomografia de coerência óptica associada à síndrome de Alport. Métodos: Estudo descritivo de um serviço de referência em Oftalmologia (Hospital Evangélico de Vila Velha, Brasil). Os pacientes diagnosticados com síndrome de Alport, foram incluídos. Resultados: O grupo de estudo foi composto por quatro pacientes (um feminino e três homens) com diagnóstico de síndrome de Alport. A acuidade visual no pior olho estava entre 20/40 a 20/60. Todos os pacientes do sexo masculino apresentaram lenticone anterior à biomiscroscopia. Os achados da retina observados incluíram pontos e manchas e alterações pigmentares na mácula. Na angiotomografia de coerência óptica, as camadas internas da retina de todos os pacientes apresentaram afinamento (especialmente na região temporal da mácula) e aumento da zona avascular foveal. Uma coroide espessa foi observada em ambos os olhos dos dois pacientes mais jovens. Conclusões: Em pacientes com síndrome de Alport, as camadas internas da retina sofrem alterações devido à mutação do colágeno tipo IV. A angiotomografia de coerência óptica permite visualizar esses achados, tornando-o uma ferramenta útil na detecção de achados iniciais da retina associados à síndrome de Alport.

Nefritis intersticial aguda inducida por rifampicina en un paciente con tuberculosis pulmonar / Rifampicin-induced acute interstitial nephritis in a patient with pulmonary tuberculosis

La tuberculosis (TB) constituye un grave problema de salud en el mundo y está relacionada con problemáticas sociales que dificultan su control y erradicación como la pobreza, la marginalidad y el hacinamiento. Aunque la toxicidad hepática por rifampicina es bien conocida, la nefrotoxicidad es una complicación poco frecuente y grave del tratamiento antituberculosis. El deterioro de la función renal, determinado por nefritis tubulointersticial aguda o necrosis tubular aguda o ambos, por lo general aparece en pacientes que reciben tratamiento intermitente; no obstante, algunos autores han informado casos ocurridos durante la terapia continua con rifampicina.Con frecuencia la lesión renal aguda inducida por rifampicina tiene un curso favorable con tratamiento y una recuperación completa de la función renal en un lapso de tres meses. El siguiente reporte describe un paciente en tratamiento por TB Pulmonar, que desarrolló toxicidad renal inducida por rifampicina

Una nueva variante del gen COL4A4 (c.1856G> A). De un caso de glomeruloesclerosis focal y segmentaria a una familia con síndrome de Alport / A novel COL4A4 gene variant (c.1856G>A): from a focal segmental glomerulosclerosis case to a family with Alport syndrome

El síndrome de Alport (SA), también conocido como nefritis hereditaria, es una forma progresiva hereditaria de enfermedad glomerular que a menudo se asocia con pérdida auditiva neurosensorial y anomalías oculares. Es causada por mutaciones en los genes que codifican varios miembros de las proteínas de colágeno del tipo IV, que se hallan en las membranas basales principalmente. Los análisis genéticos de las familias afectadas han identificado cuatro modos diferentes de transmisión en pacientes con síndrome de Alport. La forma del síndrome ligada al X surge a partir de mutaciones de COL4A5 y COL4A6 en el cromosoma X, mientras que las formas autosómicas resutan de defectos genéticos tanto en el gen COL4A3 como en el COL4A4, en el cromosoma 2q35-37. Las formas digénicas incluyen pacientes con mutaciones coexistentes en COL4A3, COL4A4 y COL4A5. El resultado clínico a largo plazo en pacientes con SA con mutaciones heterocigotas de COL4A3/A4es generalmente impredecible. La glomeruloesclerosis focal y segmentaria suele desarrollarse en el SA clásico en etapas posteriores y se presenta predominantemente con proteinuria asociada con hematuria. En el caso índice presentado en este informe, a un hombre de 26 años se le realizó una biopsia de riñón debido a una proteinuria nefrótica y una hematuria microscópica acompañada de una función renal alterada. Se le diagnosticó glomeruloesclerosis focal y segmentaria. Debido a que tenía una pérdida auditiva progresiva desde el inicio del estudio, se le realizó un estudio genético de mutaciones en los genes COL4A3 y COL4A4. Se detectó una nueva mutación en el gen COL4A4 (c.1804-7T> C).Debido a que sus padres tenían un matrimonio consanguíneo, el resto de la familia fue sometida a estudio para la misma variante. Sus padres y su hermana fueron heterocigotos y homocigota para la misma variante, respectivamente. En este estudio, se demostró la existencia de una familia con síndrome de Alport con una nueva mutación en el gen COL4A4 (c.1856G> A) que, según sabemos, es el primer caso reportado.

Alport syndrome, also known as hereditary nephritis, is an inherited progressive form of glomerular disease that is often associated with sensorineural hearing loss and ocular abnormalities. It is caused by mutations in genes encoding several members of type IV colagen proteins primarily found in basement membranes. Genetic analyses of affected families have identified four different modes of transmission in patients with Alport syndrome. X-linked form of the syndrome arises from mutations of COL4A5 and COL4A6 on chromosome X, whereas autosomal forms result from genetic defects in either the COL4A3 or COL4A4 genes at chromosome 2q35-37. Digenic forms include patients with coexisting mutations in COL4A3, COL4A4, and COL4A5. The long-term clinical outcome in AS patients with heterozygous COL4A3/A4 mutations is generally unpredictable. Focal segmental glomerulosclerosis usually develops in classical AS at later stages and presents predominantly with proteinuria associated with hematuria. The index case presented in this report, a 26-year-old man, had kidney biopsy because of nephrotic proteinuria and microscopic hematuria accompanied by impaired renal function. He diagnosed focal segmental glomerulosclerosis. As he had progressive hearing loss since chidhood we conducted a genetic study for mutations in COL4A3 and COL4A4 genes. A novel mutation in COL4A4 gene (c.1804-7T>C) was detected. As his parents had consanguineous marriage we investigated the rest of the family for the same variant. His parents, and his sister were found to be heterozygote, and homozygote for the same variant, respectively. In this report we demonstrated an Alport syndrome family with a novel mutation in COL4A4 gene (c.1856G>A) that has been first reported to our best knowledge.

Repercusiones oculares del Síndrome de Alport: A propósito de dos casos / Alport syndrome. Report of two cases

Alport syndrome is an inherited progressive form of glomerular disease that is often associated with sensorineural hearing loss and ocular abnormalities. We report two men with Alport syndrome. Both had chronic kidney disease and consulted for long-term loss of visual acuity. One had auditory abnormalities. On the ophthalmological examination, both had anterior lenticonus and one had dot or fleck retinopathy. Those findings are described in up to 50% and 70% of men with X-linked Alport syndrome, respectively. Both patients had a family history of Alport syndrome or suggestive signs and symptoms.

Clinical and genetic diagnosis of a pedigree affected with autosomal recessive Alport syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a child with chronic kidney disease featuring renal shrinkage and creatinine increase.@*METHODS@#Peripheral venous blood samples were taken from the child, his brother and two parents and subjected to whole exome sequencing. Suspected mutations were verified by Sanger sequencing. Bioinformatic analysis was carried out to predict the influence of mutations on the structure and function of the protein product.@*RESULTS@#High-throughput and Sanger sequencing revealed that the child has carried compound heterozygous mutations of the COL4A4 gene, namely c.4550T>G in exon 47 (inherited from his mother) and c.199C>T in exon 5 (inherited from his father). Neither mutation was reported previously. Bioinformatic analysis showed that both mutations have located in highly conserved regions. The same mutations were not found in his brother.@*CONCLUSION@#The compound heterozygous c.4550T>G and c.199C>T mutations probably underlie the disease in this child. The findings have enriched the mutation spectrum of the COL4A4 gene.

Advances in research on gene and cell therapy for type IV collagen related hereditary kidney diseases / 中华医学遗传学杂志

Type IV collagen is a component of the extracellular matrix in the basement membrane. Abnormal secretion or assembly of type IV collagen may lead to kidney lesions resulting in numerous nephropathy symptoms, e.g., Alport syndrome, thin basement membrane nephropathy, and focal segmental glomerulosclerosis. Treatment for type IV collagen-related nephropathy includes drugs, kidney transplantation, gene and cell therapy. However, drugs are not always effective, and kidney transplantation is hindered by the shortage of donors. Moreover, basement membrane nephritis often occurs after kidney transplantation. Therefore, gene and cell therapy probably is the most promising treatment for type IV collagen related nephropathies.

Genetic diagnosis of Alport syndrome / 소아과

No abstract available.

De novo mutations in COL4A5 identified by whole exome sequencing in 2 girls with Alport syndrome in Korea / 소아과

Alport syndrome (ATS) is an inherited glomerular disease caused by mutations in one of the type IV collagen novel chains (α3, α4, and α5). ATS is characterized by persistent microscopic hematuria that starts during infancy, eventually leading to either progressive nephritis or end-stage renal disease. There are 3 known genetic forms of ATS, namely X-linked ATS, autosomal recessive ATS, and autosomal dominant ATS. About 80% of patients with ATS have X-linked ATS, which is caused by mutations in the type IV collagen α5 chain gene, COL4A5. Although an 80% mutation detection rate is observed in men with X-linked ATS, some difficulties do exist in the genetic diagnosis of ATS. Most mutations are point mutations without hotspots in the COL4A3, COL4A4, and COL4A5 genes. Further, there are insufficient data on the detection of COL4A3 and COL4A4 mutations for their comparison between patients with autosomal recessive or dominant ATS. Therefore, diagnosis of ATS in female patients with no apparent family history can be challenging. Therefore, in this study, we used whole-exome sequencing (WES) to identify mutations in type IV collagen in 2 girls with glomerular basement membrane structural changes suspected to be associated with ATS; these patients had no relevant family history. Our results revealed de novo c.4688G>A (p.Arg1563Gln) and c.2714G>A (p.Gly905Asp) mutations in COL4A5. Therefore, we suggest that WES is an effective approach to obtain genetic information in ATS, particularly in female patients without a relevant family history, to detect unexpected DNA variations.

Analysis of Alport syndrome induced by type IV collagen alpha 5 gene mutation in two families / 浙江大学学报·医学版

OBJECTIVE@#To investigate genetic characteristics of Alport syndrome.@*METHODS@#High-throughput sequencing-based whole exome sequencing was performed in two patients with recurrent unexplained abnormal urinalysis. The pathogenicity of the genetic variations, type of Mendelian genetics, and clinical phenotypes were analysed, and the disease-cause mutations were confirmed in the family members using Sanger sequencing.@*RESULTS@#Two heterozygous splice site mutations of gene c.2147-2A > T (IVS27) and c.646-2A > G (IVS11) (NM_033380) were found in patients of the two families, which showed a co-segregation association with the affected members of the families.@*CONCLUSIONS@#Alport syndrome is mainly inherited from direct female patients, and prenatal genetic screening based on amniotic fluid testing can effectively prevent birth defects in patients with a family history of this characteristic phenotype.