Temporal retinal thinning might be an early diagnostic indicator in male pediatric X-linked Alport syndrome

AIM: To evaluate temporal retinal thinning changes in retinal layers using spectral-domain optical coherence tomography(SD-OCT) in pediatric X-linked Alport syndrome(XLAS) patients.METHODS: A retrospective case-control study. SDOCT scans of pediatric patients diagnosed with XLAS and age-and sex-matched healthy control participants were reviewed. Automated segmentation of SD-OCT scans was induced to analyze the retinal thickness(RT) of different layers. The temporal thinning index(TTI) was calculated for each layer and compared between the patients and the control group.RESULTS: Forty-three pediatric XLAS patients and 60 healthy controls were included. Temporal retinal thinning was present in 33 patients(76.74%), while 28 patients(65.11%) had severe pathological temporal retinal thinning and 5 patients(11.63%) had moderate thinning. The temporal inner sector RT(P<0.0001), the temporal outer sector RT(P<0.0001), and the nasal outer sector RT(P=0.0211) were significantly thinner in the XLAS male patients. The TTI of the total retina was significantly higher in the XLAS group than in the control group(P<0.0001). The TTI of the inner retina layers(P<0.0001), ganglion cell layer(P<0.0001), inner plexiform layer(P<0.0001), inner nuclear layer(P<0.0001), and outer nuclear layer(P<0.0001) were significantly higher in the XLAS group. The central RT of the XLAS group was significantly thinner than that of the control group(P<0.0001).CONCLUSION: Temporal retinal thinning appears early in XLAS patients, especially in male patients. The thinningis mainly caused by structural abnormalities of the inner retina. This suggests that temporal retinal thinning could be helpful for the early diagnosis and follow-up of XLAS with noninvasive SD-OCT examination.

Novel COL4A3 synonymous mutation causes Alport syndrome coexistent with immunoglobulin A nephropathy in a woman:A case report

BACKGROUND Alport syndrome(AS)is an inherited disease of the glomerular basement membrane caused by mutations in genes encodingα3,α4,orα5 chains of type IV collagen.It manifests with hematuria or proteinuria,which is often accompanied by hearing impairments and ocular abnormalities.Histopathologically,AS shows mesangial proliferation and sometimes incidental immunoglobulin A(IgA)deposition.Hematuria or proteinuria is also a common presentation in patients with IgA nephropathy that makes it difficult to differentially diagnose AS and IgA nephropathy solely based on these clinical and pathological features.CASE SUMMARY Herein,we present the case of a 59-year-old female patient who was admitted to our hospital with persistent microscopic hematuria and occasional proteinuria that had lasted for>2 years.This patient had a familial history of renal disease and was diagnosed with autosomal dominant AS(ADAS)and IgA nephropathy based on the findings of renal biopsy as well as genetic testing performed using whole-exome sequencing,which suggested that the patient carried a novel heterozygous variation(c.888G>A:p.Gln296Gln)in the COL4A3 gene that enriches the mutation spectrum of ADAS.The proband received an angiotensin receptor blocker therapy after a definitive diagnosis was established.After one year of therapy,a significant reduction in proteinuria was observed.The number of microscopic red blood cells per high-power field decreased to one-quarter of the baseline levels.Renal function also maintained well during the follow-up.CONCLUSION Our case highlights the significance of performing kidney biopsy and genetic testing in the diagnosis of AS and familial IgA nephropathy.

CNKSR2 mutation causes the X-linked epilepsy-aphasia syndrome:A case report and review of literature

The mutation in CNKSR2 leads to a broad spectrum of phenotypic variability and manifests as an X-linked intellectual disability. However, we reported that the male patient in this study not only had intellectual disability but also epileptic seizures. In addition, there were progressive language impairment, attention deficit hype-ractivity disorder and autism. Electroencephalograms showed continuous spike-and-wave during sleep. Genetic testing revealed a de novo mutation of the CNKSR2 gene(c.2185C >T, p.Arg729Ter) in the child that was not detected in the parents. Therefore, the child was diagnosed with X-linked epilepsy aphasia syndrome. Deletion of the CNKSR2 gene has been rarely reported in epilepsy aphasia syndrome, but no de novo mutation has been found in this gene. This report not only adds to the spectrum of epilepsy aphasia syndrome but also helps clinicians in diagnosis and genetic counseling.

X-linked recessive Kallmann syndrome:A case report

BACKGROUND Kallmann syndrome(KS),also known as hypogonadotropic hypogonadism(HH)or olfactory-gonadal dysplasia,is a genetic condition in which the primary symptom is a failure to begin puberty or a failure to fully complete it.It occurs in both males and females and has the additional symptoms of hypogonadism and almost invariably infertility.The condition has a low prevalence that is estimated to be 1 in 4000 for male HH cases overall and 1:50000 for KS.It is three to five times more common in males than females.Whether this is a true sex imbalance or a reflection of how difficult KS/HH is to diagnose correctly in males vs females has yet to be fully established.CASE SUMMARY This article reports a 26-year-old male presenting with delayed puberty.The synthetic decapeptide luteinizing hormone-releasing hormone stimulation test showed that the secretion levels of follicle-stimulating hormone and luteinizing hormone were delayed.The eigengenes commonly associated with idiopathic HH(IHH)were screened,and an X-linked recessive(KAL-1)mutation was found.His gonadotropin and testosterone levels increased significantly after pulsatile gonadotropin-releasing hormone(GnRH)subcutaneous therapy by pump.A relevant literature review on the recent advances in the diagnosis and treatment of KS and genetic counseling was conducted.CONCLUSION KS is caused by a KAL-1 mutation that follows an X-linked recessive inheritance pattern.Pulsatile GnRH subcutaneous therapy by pump was effective in this patient.

Early-onset refractory diarrhea due to immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome associated with a novel mutation in the FOXP3 gene: A case report

BACKGROUND Immune dysregulation,polyendocrinopthy,enteropathy,X-linked(IPEX)syndrome is a rare X-linked recessive disease caused by mutations in the forkhead box protein 3(FOXP3)gene,which is a master transcriptional regulator for the development and function of CD4+CD25+regulatory T(Treg)cells.The dysfunction of these cells leads to multiple system autoimmune diseases.We present a case of IPEX due to a mutation not reported in the literature before.CASE SUMMARY We report a male patient with IPEX syndrome who presented with refractory diarrhea and malabsorption leading to failure to thrive,as well as with hypothyroidism and nephrotic syndrome.Laboratory investigation showed increased total IgE and Treg cells,decreased free triiodothyronine(FT3)and free thyroxine(FT4),and proteinuria.Multiple dietary and supportive treatments were introduced but did not improve the diarrhea during his hospital stay.Ultimately,whole exome sequencing revealed that the patient was hemizygous for the exon 5,c.542G>A(p.Ser181Asn)mutation of the FOXP3 gene,which has not been previously reported.The patient remains on prednisone and euthyrox while awaiting hematopoietic stem cell transplantation at the time of the compilation of this case report.CONCLUSION We report a novel FOXP3 gene mutation involved in IPEX.A high level of suspicion should be maintained in an early-onset refractory diarrhea patient.

Identification of a novel COL4A5 mutation in the proband initially diagnosed as Ig AN from a Chinese family with X-linked Alport syndrome

Alport syndrome(AS) is a hereditary progressive nephropathy characterized by hematuria, ultrastructural lesions of the glomerular basement membrane, ocular lesions and sensorineural hearing loss. Germline mutations of COL4 A5 are associated with X-linked AS with an extreme phenotypic heterogeneity. Here, we investigated a Chinese family with Alport syndrome. The proband was a 9-year-old boy with hematuria and proteinuria. Based on the test results of renal biopsy and immunofluorescence,the proband was initially diagnosed as Ig A nephropathy and the treatment was recommended accordingly. Meanwhile, we found that the treatment outcome was poor. Therefore, for proper clinical diagnosis and appropriate treatment, targeted exome-based next-generation sequencing has been undertaken. We identified a novel hemizygous single nucleotide deletion c.1902 del A in COL4 A5 gene. Segregation analysis identified that this novel mutation is co-segregated among the affected family members but absent in unaffected family members. The clinical diagnosis of the proband was revised as AS accompanied by Ig A nephropathy,which has been rarely reported. Our findings demonstrated the significance of the application of Genetic screening, expanded the mutation spectrum of COL4 A5 associated AS patients with atypical renal phenotypes and provided a good lesson to be learned from our detour during the diagnosis.

Ocular manifestations of Alport syndrome

AIMTo analyze the clinical manifestation of Alport syndrome, especially the ocular features.

X-linked Charcot-Marie-Tooth disease after SARS-CoV-2 vaccination mimicked stroke-like episodes: A case report

BACKGROUND Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) vaccinations have been administered worldwide, with occasional reports of associated neurological complications. Specifically, the impact of vaccinations on individuals with Xlinked Charcot-Marie-Tooth disease type 1(CMTX1) is unclear. Patients with CMTX1 can have stroke-like episodes with posterior reversible encephalopathy syndrome on magnetic resonance imaging(MRI), although this is rare.CASE SUMMARY A 39-year-old man was admitted with episodic aphasia and dysphagia for 2 d. He received SARS-CoV-2 vaccination 39 d before admission. Physical examination showed pes cavus and reduced tendon reflexes. Brain MRI showed bilateral, symmetrical, restricted diffusion with T2 hyperintensities in the cerebral hemispheres. Nerve conduction studies revealed peripheral nerve damage. He was diagnosed with Charcot-Marie-Tooth disease, and a hemizygous mutation in the GJB1 gene on the X chromosome, known to be pathogenic for CMTX1, was identified. Initially, we suspected transient ischemic attack or demyelinating leukoencephalopathy. We initiated treatment with antithrombotic therapy and immunotherapy. At 1.5 mo after discharge, brain MRI showed complete resolution of lesions, with no recurrence.CONCLUSION SARS-CoV-2 vaccination could be a predisposing factor for CMTX1 and trigger a sudden presentation.

Searching for a treatment for Alport syndrome using mouse models

Alport syndrome （AS） is a hereditary nephritis caused by mutations in COL4A3, COL4A4 or COL4A5 encod-ing the type IV collagen α3, α4, and α5 chains, which are major components of the glomerular basement membrane. About 20 years have passed since COL4A3, COL4A4, and COL4A5 were identifed and the frst Al-port mouse model was developed using a knockout ap-proach. The phenotype of Alport mice is similar to that of Alport patients, including characteristic thickening and splitting of the glomerular basement membrane. Alport mice have been widely used to study the patho-genesis of AS and to develop effective therapies. In this review, the newer therapies for AS, such as pharma-cological interventions, genetic approaches and stem cell therapies, are discussed. Although some stem cell therapies have been demonstrated to slow the renal disease progression in Alport mice, these therapies demand continual refnement as research advances. In terms of the pharmacological drugs, angiotensin-con-verting enzyme inhibitors have been shown to be effec-tive in Alport mice. Novel therapies that can provide a better outcome or lead to a cure are still awaited.

Alport syndrome combined with lupus nephritis in a Chinese family:A case report

BACKGROUND Alport syndrome(ATS)is a rare hereditary disease caused by mutations in genes such as COL4A3,COL4A4,and COL4A5.ATS involves a spectrum of phenotypes ranging from isolated hematuria that is nonprogressive to progressive renal disease with extrarenal abnormalities.Although ATS can be combined with other diseases or syndromes,ATS combined with lupus nephritis has not been reported before.CASE SUMMARY A Chinese family with ATS was recruited for the current study.Clinical characteristics(including findings from renal biopsy)of ATS patients were collected from medical records,and potential causative genes were explored by whole-exome sequencing.A heterozygous substitution in intron 22 of COL4A3(NM_000091 c.2657-1G>A)was found in the patients,which was further confirmed by quantitative polymerase chain reaction.CONCLUSION Heterozygous substitution of a COL4A3 gene splice site was identified by wholeexome sequencing,revealing the molecular pathogenic basis of this disorder.In general,identification of pathogenic genes can help to fully understand the molecular mechanism of disease and facilitate precise treatment.

Keratoconus in a patient with Alport syndrome: A case report

BACKGROUND Known ocular manifestations of Alport syndrome include features such as anterior lenticonus and fleck retinopathy. Reports of keratoconus in such patients are limited. We report tomographic findings consistent with keratoconus in a patient with Alport syndrome.CASE SUMMARY A 52-year-old female was referred to our ophthalmology clinic with decreased vision and increased tearing. She was diagnosed with stage Ⅲ Alport syndrome two years prior. Upon examination she was found to have average keratometries of 48D bilaterally with tomographic evidence of keratoconus.CONCLUSION Although a rare presentation, concurrent Alport syndrome and keratoconus should be considered when reviewing the ocular health of Alport syndrome patients and appropriate management steps should be taken upon the diagnosis.

Speech,language,and hearing function in twins with Alport syndrome:A seven-year retrospective case report

Alport syndrome is an X-linked syndrome that results in nephritis, renal failure, sensorineural hearing loss, and eye deficits. As a result of sensorineural hearing loss, these individuals are likely to experience difficulties in the area of speech and language. While studies in the past have examined the speech and language characteristics of children with syndromic sensorineural hearing loss, to our knowledge there are no previous studies to have documented the speech and language characteristics of these children on a long-term basis. The current study addresses this limitation by reporting speech, language, hearing, and function of twin brothers with X-linked Alport syndrome across a seven-year period.Information was collected by examining the medical records of the participants as well as through a verbal interview with the participants' guardian. Results revealed that the participants' hearing abilities gradually deteriorated over the seven-year period which affected their speech and language development as well. The kidney function tests revealed significant presence of hematuria(blood in the urine) as well as proteinuria(protein in the urine) suggesting chronic kidney dysfunction. This longitudinal study demonstrates the functional relationship between the kidneys and the cochlea, although they appear to be independent of one another. As individuals with Alport syndrome exhibit systemic complications, interdisciplinary collaboration is essential among health care providers including audiologists, speech-language pathologists,nephrologists, and ophthalmologist to promote evidence-based practice.

Optic Disc Drusen in a Child Diagnosed with Alport Syndrome—Case Report

Optic disc drusen are eye abnormalities characterised by calcific degeneration affecting some axons of the optic nerve. Alport syndrome is a collagen IV related nephropathy with well-described pathognomonic ocular features. We present the case of a child who following series of investigations was found to have bilateral optic disc drusen, and eventually a further diagnosis of Alport syndrome confirmed. Literature is clear on the underlined aetiology responsible for both renal and extra renal abnormalities of Alport syndrome, which is not related to development of optic disc drusen. The case described makes it pertinent that not only the associated eye signs of Alport syndrome are monitored, but also early detection of other possible co-existing diseases that may influence outcomes.

Immunofluorescence study of type Ⅳ collagen α chains in epidermal base-ment membrane : application in diagnosis of X-linked Alport syndrome

Objective To detect the distribution of α5(Ⅳ) chain of collagen on the glomerular basement membrane (GBM) and epidermal basement membrane (EBM) in the Chinese Alport syndrome (AS) kindreds and to develop a simple diagnostic alternative method to electronic microscopy for diagnosis of AS. Methods Four male patients from 4 unrelated families manifested with hematuria, sensorineural hearing loss and had distinct family history. All patients had the characteristic AS pathologic changes by electron microscopy on their renal biopsy tissues. Three normal skin samples and 2 normal kidney samples were used as normal controls. Monoclonal antibody based IF test was performed to examine the α5(Ⅳ)NC1 domain in EBM of normal controls, X linked AS patients and their parents, and in GBM of normal controls and AS patients. Results In normal controls as well as the patients' fathers, all the monoclonal antibodies used in EBM and GBM staining showed positive reactions along basement membranes in a linear pattern. Characteristically, in AS patients there were negative reactions to monoclonal antibodies anti α5(Ⅳ)NC1 domain in EBM and anti α3 5(Ⅳ)NC1 domains in GBM. In patients' mothers, α5(Ⅳ) chain was distributed segmentally in EBM. Conclusion The staining of α5(Ⅳ) NC1 domain in EBM by IF can be used to diagnose patients and screen defect gene carriers of X linked AS.

母女同患紫癜性肾炎合并Alport综合征1家系报道

过敏性紫癜(henoch-schonlein purpura,HSP)又称IgA血管炎,是儿童常见的系统性血管炎疾病之一,本病多为自限性疾病、预后相对较好。HSP累及肾脏即为紫癜性肾炎(henoch schonlein purpura nephritis,HSPN),又称IgA血管炎肾炎,是儿科临床肾脏专业常见的继发性肾小球疾病之一[1-4]。

双基因Alport综合征研究进展

双基因Alport综合征特指在Alport综合征的3个致病基因(COL4A3、COL4A4和COL4A5)中存在两个不同基因的致病性变异,包括两种类型,其一为COL4A5合并COL4A3或COL4A4两个基因之一的致病性变异;其二为COL4A3和COL4A4两个基因的各一致病性变异。理论上,双基因Alport综合征的临床表型相对较单基因Alport综合征可能更重,特别是蛋白尿和肾功能异常的出现时间更早、程度更重,但需要多中心、大样本研究去证实。

Identification of micro RNAs and their target genes in Alport syndrome using deep sequencing of iPSCs samples

MicroRNAs （miRNAs） are a class of small RNA molecules that are implicated in post-transcriptional reg- ulation of gene expression during development. The discovery and understanding of miRNAs has revolutionized the traditional view of gene expression. Alport syndrome （AS） is an inherited disorder of type IV collagen, which most commonly leads to glomerulonephritis and kidney failure. Patients with AS inevitably reach end-stage renal disease and require renal replacement therapy, starting in young adulthood. In this study, Solexa sequencing was used to identify and quantitatively profile small RNAs from an AS family. We identified 30 known miRNAs that showed a sig- nificant change in expression between two individuals. Nineteen miRNAs were up-regulated and eleven were down-regulated. Forty-nine novel miRNAs showed significantly different levels of expression between two individuals. Gene target predictions for the miRNAs revealed that high ranking target genes were implicated in cell, cell part and cellular process categories. The purine metabolism pathway and mitogen-activated protein kinase （MAPK） signaling pathway were enriched by the largest number of target genes. These results strengthen the notion that miRNAs and their target genes are involved in AS and the data advance our understanding of miRNA function in the patho- genesis of AS.

一个Alport综合征家庭的临床特征及遗传病因学分析

目的分析一个Alport综合征家庭的临床特征及遗传学病因。方法选取2019年12月于南通大学附属医院耳鼻咽喉科门诊就诊的一个AS耳聋家庭(NT103),该家庭家系成员包括父母姐妹4例,其中姐姐为AS患者(Ⅱ-1),其余人临床表现均无异常。对Alport综合征家庭进行详尽临床资料的收集和评估;采用基于家庭为单位,结合定向捕获技术二代测序的策略分析测序结果;对可疑致病基因的变异位点进行家庭内Sanger测序验证,依据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)指南确定变异致病性。结果该Alport综合征家庭的先证者表现为持续性血尿伴感音神经性聋但无眼部异常。定向捕获及Sanger测序显示,患者(Ⅱ-1)携带COL4A3复合杂合错义突变,c.4793T>G,p.L1598R/c.4981C>T,p.R1661C分别来自父母双亲,且在家系其他成员中共分离。根据ACMG指南,该Alport综合征家庭先证者携带的COL4A3基因复合杂合突变位点,判定为疑似致病变异。结论本研究丰富了COL4A3临床表型谱及基因突变谱。此外,对于疑似Alport综合征的患者,提倡常规开展基因检测以实现Alport综合征患者的早期个体化精准诊治。

Alport综合征遗传学特征和诊治进展

Alport综合征是一类由Ⅳ型胶原基因突变所致的遗传性肾病,根据不同遗传方式分为X连锁Alport综合征、常染色体显性Alport综合征、常染色体隐性Alport综合征和双基因Alport综合征。临床表现具有异质性,从孤立性血尿或血尿伴蛋白尿到进行性肾功能衰竭,伴或不伴有肾外表现。该文综述Alport综合征的遗传学特征、生物标记物和治疗等相关研究进展,以期为该病的早期诊治和改善远期预后提供参考。

Alport综合征的诊治进展

Alport综合征是由COL4A3、COL4A4或COL4A5基因突变所致的遗传性肾脏疾病,主要表现为血尿、蛋白尿、听力损伤以及眼部病变。近十年来,随着基因检测技术在医学实践中的普及,更新了我们对于该病流行率及诊断方式的认知。尽管目前Alport综合征尚缺乏病因性治疗,但早期使用肾素-血管紧张素-醛固酮系统阻滞剂仍可以极大程度改善患者预后,并且多种新的治疗药物以及治疗方法正在研究阶段,将为患者带来新的希望。本文主要就Alport综合征的临床表现、诊断及治疗方面的最新进展做一综述,以期实现该病的早期诊治并优化患者的临床管理。