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-contro...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.展开更多
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 ...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.展开更多
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 disab...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.展开更多
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 co...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.展开更多
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 ...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.展开更多
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...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.展开更多
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 vacci...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.展开更多
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...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.展开更多
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 consist...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.展开更多
Alport syndrome(AS) is a hereditary nephritis caused by mutations in COL4A3,COL4A4 or COL4A5 encoding the type IV collagen α3,α4,and α5 chains,which are major components of the glomerular basement membrane.About 20...Alport syndrome(AS) is a hereditary nephritis caused by mutations in COL4A3,COL4A4 or COL4A5 encoding 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 identified and the first Alport mouse model was developed using a knockout approach.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 pathogenesis of AS and to develop effective therapies.In this review,the newer therapies for AS,such as pharmacological interventions,genetic approaches and stem cell therapies,are discussed.Although some stem cel therapies have been demonstrated to slow the rena disease progression in Alport mice,these therapies demand continual refinement as research advances.In terms of the pharmacological drugs,angiotensin-converting enzyme inhibitors have been shown to be effective in Alport mice.Novel therapies that can provide a better outcome or lead to a cure are still awaited.展开更多
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 dif...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.展开更多
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 fea...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.展开更多
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 d...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.展开更多
文摘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.
基金Supported by The Major Project of Zhejiang Administration of Traditional Chinese Medicine,No.2020ZZ008.
文摘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.
基金Supported by Jining Medical University,No.JYP201740
文摘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.
基金Supported by the National Natural Science Foundation of China,No.81860265the Special Foundation for Discipline Leaders of High-level Health Technical Talents in Yunnan Province,No.D-2018035。
文摘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.
文摘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.
基金supported by the Key Research and Development Program of Hunan Province in China (2018SK2139)
文摘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.
基金Supported by Shenzhen Science and Technology Project,No. SGLH20180628161804465The Clinical Research Project of The First Affiliated Hospital of Shenzhen University,No. 20203357035 and No. 20223357021。
文摘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.
基金Supported by the Science and Technology Bureau of Jiulongpo District in Chongqing,No.2019-02-027-D.
文摘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.
文摘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.
文摘Alport syndrome(AS) is a hereditary nephritis caused by mutations in COL4A3,COL4A4 or COL4A5 encoding 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 identified and the first Alport mouse model was developed using a knockout approach.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 pathogenesis of AS and to develop effective therapies.In this review,the newer therapies for AS,such as pharmacological interventions,genetic approaches and stem cell therapies,are discussed.Although some stem cel therapies have been demonstrated to slow the rena disease progression in Alport mice,these therapies demand continual refinement as research advances.In terms of the pharmacological drugs,angiotensin-converting enzyme inhibitors have been shown to be effective in Alport mice.Novel therapies that can provide a better outcome or lead to a cure are still awaited.
文摘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.
文摘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.
文摘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.