Alport Syndrome Research Articles

Hearing loss phenotypes in Alport syndrome: experience in a tertiary referral center

Hearing loss phenotypes in Alport syndrome: experience in a tertiary referral center

Natural History of Auditory Function in Patients with Alport Syndrome: A Case Series Study

Background: Alport syndrome (AS) is a genetic disorder characterized by progressive renal disease, ocular abnormalities, and sensorineural hearing loss. However, the audiological profile of patients with AS remains elusive. Thus, this study aims to evaluate the natural history of auditory function in patients with AS. Methods: Exome or targeted sequencing for deafness genes was performed to confirm the pathogenic variants in patients with AS. Results: We identified fifteen individuals with AS who carried pathogenic variants of COL4A3, COL4A4, or COL4A5. Among fifteen, twelve (80%) showed hematuria, and six (40%) showed proteinuria. The patients exhibited bilateral sensorineural hearing loss, which was progressive and symmetric. The hearing thresholds increased according to age and plateaued at the level of 53 dB HL, indicating the hearing loss did not reach the severe-to-moderate level. The auditory dysfunction showed a distinct natural history depending on the inheritance pattern, but there was no remarkable difference between males and females among X-linked AS. Conclusions: Auditory dysfunction in AS is progressive up to the level of moderate hearing loss. Precise auditory rehabilitation for patients with AS is warranted depending on the inheritance pattern and genetic predisposition.

Spontaneous rupture of anterior lenticonus in a patient with Alport syndrome

Spontaneous rupture of anterior lenticonus in a patient with Alport syndrome

COL4A5 intronic variants at 3rd-5th nucleotides cause Alport syndrome

COL4A5 intronic variants at 3rd-5th nucleotides cause Alport syndrome

Dyspnea and nocturnal cough due to esophageal diffuse leiomyomatosis in a girl with hematuria.

A 7-year-old girl with hematuria and clinical suspicion of Alport syndrome (AS) presented with dyspnea and nocturnal cough, initially diagnosed and treated as asthma. Despite inhaled corticosteroid therapy, her symptoms persisted, and spirometry indicated obstructive lung function without bronchodilator response. Chest CT revealed diffuse thickening of the esophageal wall, tracheal compression, with involvement of the gastric cardia, suggestive of diffuse leiomyomatosis. Subsequent genetic reanalysis confirmed the presence of a contiguous deletion of COL4A5 and COL4A6 genes, solidifying the diagnosis of AS. Diffuse leiomyomatosis, a rare benign neoplasm associated with AS, typically manifests as dysphagia, but in this case, it presented initially with asthma-like symptoms. This case emphasizes the importance of imaging when asthma treatment fails, particularly in patients with coexisting conditions of another system.

Clinical and Genetic characteristics of patients with Peripheral Retinal Fleck in Koreans.

To describe the clinical and genetic features of Korean patients with peripheral retinal flecks unrelated to aging. A retrospective analysis was conducted on the clinical characteristics of patients with symmetric peripheral retinal flecks. Age-related deposits such as reticular pseudodrusen were excluded, as well as secondary deposits related to intraocular inflammation, tumor, and drug toxicity. Multimodal imaging, electrophysiological examinations, and genetic testing were analyzed. A total of 10 patients (2 males and 8 females) with bilateral peripheral flecks were enrolled in this study. A mean age at diagnosis was 30.5±19.6 years (4-59 years). Within the 10 patients, 6 were genetically confirmed with monogenic retinal disorders. Biallelic pathogenic variants in RDH5 were found in 5 patients, and 1 patient was diagnosed with retinopathy related to Alport syndrome due to a pathogenic variant in COL4A5. Although not genetically confirmed, one case associated with nanophthalmos and another case showing chorioretinal mottling in a carrier of ocular albinism have been identified. In one patient, genetic testing also revealed unknown causes. The mean logMAR initial visual acuity was 0.12±0.18 and 0.07±0.18 in right and left eyes, respectively. Night blindness was reported by 4 patients (40%), with 3 showing decreased or delayed rod response in electroretinogram, particularly those with RDH5 mutations. Differences in the deposit layers and the patterns of flecks were observed on multimodal imaging. In the study population, we observed various causes and clinical differences in the retinal fleck patterns among Koreans, including RDH5-related fundus albipunctatus and Alport syndrome. Despite reports of night blindness symptoms in some cases, all patients demonstrated satisfactory corrected visual acuity.

Genetics in nephrology - any news?

While genetic kidney diseases were long regarded as a rare cause of kidney failure, it has been shown in recent years that they account for a relevant proportion of cases. In cohorts of kidney transplant recipients, a monogenic cause is found in up to 30% of cases. Identifying the genetic cause of kidney disease has become much easier thanks to technological advances in DNA sequencing. The focus has now shifted to understanding the significance of the findings and identifying diagnostic gaps. It is still not possible to clarify all CKD cases of unclear aetiology. Besides very effective generic treatments for monogenic kidney disease (e.g., ACE-inhibitor use in Alport Syndrome), increasing knowledge of the pathophysiology of genetic kidney diseases has led to a growing number of targeted therapies. These include the treatment of ADPKD with Tolvaptan, which has now been in use for 10 years. Recently, exciting, and completely new approaches have been added, such as the first siRNA therapies in nephrology for primary hyperoxaluria type 1, the targeted treatment of hyperphagia in Bardet-Biedl syndrome, the therapy of APOL1-associated kidney disease or the use of the HIF-2 antagonist Belzutifan for renal cell carcinoma associated with Von-Hippel-Lindau syndrome. The new possibilities in the treatment of patients with genetic kidney diseases have also clearly revealed deficits in current patient care. Centers of excellence with extensive experience in this area therefore play an important role in improving care. This also applies to the further training of colleagues in the field. In Germany, the National Action Alliance for People with Rare Diseases (NAMSE) and the nationwide establishment of - to date - 36 centers for rare diseases play an important role in this regard.

Investigation of exon skipping therapy in kidney organoids from Alport syndrome patients derived iPSCs.

Alport syndrome (AS) is a hereditary disease caused by mutations in the COL4A5 gene and leads to chronic kidney disease. Currently, no specific treatment has been developed. However, a recent study using AS-model mice demonstrated that the exon skipping method could partially rescue the symptoms. In this study, we evaluated the effects of the exon skipping method using kidney organoids generated from AS-patient-derived induced pluripotent stem cells (AS-iPSCs). We generated kidney organoids from AS-iPSCs, which exhibited nephron structures. As expected, the C-terminus of COL4A5 was not expressed in AS-organoids. Interestingly, anti-sense oligonucleotides restored the expression of the C-terminus of COL4A5 in vitro. Next, we transplanted AS-organoids into mice and evaluated glomerular basement membrane formation in vivo. We found that AS-organoids formed a lower slit diaphragm ratio compared to control organoids. Finally, we assessed the effects of exon skipping on transplanted organoids but observed minimum effects. These studies suggest that AS-iPSCs can generate kidney organoids lacking the C-terminus of COL4A5, and that exon skipping can induce its expression in vitro.

Correction: Finerenone and other future therapeutic options for Alport syndrome

Correction: Finerenone and other future therapeutic options for Alport syndrome

Slowly progressive autosomal dominant Alport Syndrome due to COL4A3 splicing variant.

Alport syndrome is a rare genetic kidney disease caused by variants in the COL4A3/A4/A5 genes. It's characterised by progressive kidney failure, though therapies targeting Renin-Angiotensin System can delay its progression. Additionally, extrarenal manifestations may sometimes coexist. Recent advances in genetic analysis and the necessity to better clarify genotype-phenotype correlations in affected patients raises the importance of detecting even cryptic splicing variants, lying in both canonical and non-canonical splice sites variants such as last exonic nucleotide variants. These variants, often, do not cause an amino acid change but alter the snRNP proteins binding. We studied a big Italian family with Alport syndrome showing a clear dominant pattern of transmission with younger family members having only haematuria and older individuals presenting with End-Stage Kidney Failure (ESKF). Kidney biopsy showed the typical disease hallmarks. We deeply mined the data for SNV and CNV through exome sequencing on DNA from both peripheral blood samples and patients' podocytes-lineage cells. We identified an already reported synonymous variant, c.765G>A (p.(Thr255Thr)), in the last exonic nucleotide of exon 13 of the COL4A3 gene. Employing the patient's podocytes we demonstrated that this variant results in exon skipping leading to an in-frame deletion of 28 amino acids without leaky effect. According to the pattern of transmission, to the kidney biopsy and to the exome data analysis we provided further evidence that autosomal dominant Alport syndrome is a well-defined clinical entity. We also confirmed the pathogenicity of the synonymous COL4A3 variant for the first time demonstrating its role in a dominant pattern of transmission.

Monogenic Kidney Diseases in Adults With Chronic Kidney Disease (CKD).

According to current evidence, every 10th to 11th adult with chronic kidney disease (CKD) has a monogenic disease of the kidney. This review is based on reported studies in which molecular genetic diagnostic techniques were used to investigate monogenic kidney diseases in adults with CKD. The studies were identified by a selective literature search using predefined criteria. In 12 selected studies, diagnostic variants of 179 different genes were identified in 1467 out of 6607 study participants with CKD (22.2%). More than 60% of these variants affected 8 genes (PKD1, PKD2, COL4A3, COL4A4, COL4A5, UMOD, MUC1, HNF1B). Three diseases are associated with these genes: autosomal dominant polycystic kidney disease (ADPKD), Alport syndrome, and autosomal dominant tubulo-interstitial kidney disease (ADTKD). Physicians treating patients with CKD should be alert to the presence of any red flags, such as onset at a young age, a positive family history, or hematuria of unknown cause. When a genetic etiology is suspected, a specialized work-up is indicated, often including a molecular genetic investigation. A positive genetic finding usually leads to a modification of the patient's specific diagnosis and/or treatment. Awareness of the high prevalence of monogenic kidney diseases in adults with CKD and alertness to their suggestive clinical features are crucial for the timely initiation of targeted diagnostic testing. The molecular genetic identification of these diseases is a prerequisite for appropriate patient management.

Aberrant serum-derived FN1 variants bind to integrin β1 on glomerular endothelial cells contributing to thin basement membrane nephropathy

The glomerular basement membrane (GBM) is a critical component of the glomerular filtration barrier (GFB), with its thickness directly influencing renal function. While a uniformly thinned GBM can cause hematuria while preserving normal renal function, this condition is typically diagnosed as thin basement membrane nephropathy (TBMN). However, the pathogenesis and potential progression to renal insufficiency of TBMN are not fully understood. In this study, we analyzed clinical cohorts presenting with microscopic hematuria who underwent genetic testing and identified five novel pathogenic FN1 mutations. Through bioinformatics analysis of these variants, expression localization analysis of GBM-related molecules in renal biopsies, and functional studies of the mutants, we found that these variants exhibited gain-of-function characteristics. This led to the excessive deposition of aberrant serum-derived FN1 variants on glomerular endothelial cells rather than cell-type-specific variants. The deposition competitively binds FN1 variants to Integrin β1, disrupting the interaction with Laminin α5β2γ1 and subsequently reducing the expression of key GBM components, resulting in TBMN. This study elucidated, for the first time, the genetic pathogenesis of TBMN caused by FN1 variants. It provides a crucial foundation for understanding the progression of renal dysfunction associated with simple hematuria, highlights the potential for targeted therapeutic strategies, and differentiates TBMN from early-stage Alport syndrome.

Matrix metalloproteinases in kidney homeostasis and diseases: an update.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with important roles in kidney homeostasis and pathology. While capable of collectively degrading each component of the extracellular matrix, MMPs also degrade nonmatrix substrates to regulate inflammation, epithelial plasticity, proliferation, apoptosis, and angiogenesis. More recently, intriguing mechanisms that directly alter podocyte biology have been described. There is now irrefutable evidence for MMP dysregulation in many types of kidney disease including acute kidney injury, diabetic and hypertensive nephropathy, polycystic kidney disease and Alport syndrome. This updated review will detail the complex biology of MMPs in kidney disease.

Alport syndrome: Expanding diagnosis and treatment

Alport syndrome (AS) is the second common monogenic cause of end-stage kidney disease (ESKD) worldwide and is caused by defective type 4 collagen due to pathogenic variants of COL4A3, COL4A4, or COL4A5. Type 4 collagen also exists in the eyes and ears, and thus ocular defects and hearing loss occur in AS. The understanding of AS has expanded over the past two decades due to greater availability of genetic testing and research on genotype-phenotype correlation. Patients previously diagnosed with idiopathic steroid resistant nephrotic syndrome or ESKD of unknown etiology may now be diagnosed as AS if pathogenic COL4A3-5 variants are identified. Some carriers of heterozygous COL4A3-5 variants may now be classified into females with X-linked AS or autosomal dominant AS, if there are typical pathologic changes in the glomerular basement membrane or if there is proteinuria and progression of kidney disease. Lastly, it has been recommended that renin-angiotensin-aldosterone system inhibition be started as soon as possible for selected AS patients for its long-term protective effect against kidney function deterioration. The purpose of this review is to introduce these important concepts to general pediatricians and pediatric nephrologists.

A Novel Deep Learning Approach for Analyzing Glomerular Basement Membrane Lesions in a Mouse Model of X-Linked Alport Syndrome

Alport syndrome is a rare kidney disease typically more severe in males due to its X-linked inheritance. However, female patients with heterozygous X-linked Alport syndrome (XLAS) can develop renal failure over time, necessitating accurate pathological assessment for effective therapy. A key pathological finding in female XLAS patients is the mosaic pattern of partial loss of α5 chains of type IV collagen. This study, using a mouse model of XLAS with a nonsense mutation (R471*) in the Col4a5 gene, analogous to human XLAS, aimed to examine the consistency of this pattern with the glomerular basement membrane (GBM) structure. A modified periodic acid-methenamine silver (PAMS) staining method was developed for clearer GBM visualization. The integrated images from COL4α5-stained fluorescence, PAMS, and low-vacuum scanning electron microscopy (LVSEM) into a single-slide section and applied supervised deep learning to predict GBM lesions. Results showed significant individual variability in urinary protein levels and histological lesions. Pathological parameters, including crescent formation, focal segmental glomerulosclerosis, and the COL4α5/α2 ratio, correlated with clinical parameters like urinary protein and plasma creatinine levels. Integrated LVSEM analysis revealed dense GBM regions corresponded to areas where COL4α5 was preserved, while coarse GBM (basket-weave lesions) occurred in COL4α5-deficient regions. These advanced techniques can enhance biopsy-based diagnosis of Alport syndrome and aid in developing AI diagnostic tools for diseases involving basement membrane lesions.

Oral L-lysine Treatment Ameliorates Proximal Tubular Damage in Mice with Alport Syndrome

Oral L-lysine Treatment Ameliorates Proximal Tubular Damage in Mice with Alport Syndrome

Impact of Glomerular Basement Membrane Stiffness on Podocyte Metabolism in Alport Syndrome

Impact of Glomerular Basement Membrane Stiffness on Podocyte Metabolism in Alport Syndrome

Towards a Translatable Model for Studying Therapeutic Efficacy in Alport Syndrome

Towards a Translatable Model for Studying Therapeutic Efficacy in Alport Syndrome

Dapagliflozin in Addition to Ramipril Ameliorates Kidney Disease Progression in Mice with Alport Syndrome

Dapagliflozin in Addition to Ramipril Ameliorates Kidney Disease Progression in Mice with Alport Syndrome

Urinary DKK3 as a Novel Biomarker for Kidney Function Decline in Children with Alport Syndrome

Urinary DKK3 as a Novel Biomarker for Kidney Function Decline in Children with Alport Syndrome