Alport syndrome is a rare genetic condition characterized by kidney disease, hearing impairment, and ocular abnormalities. It exhibits various inheritance patterns involving pathogenic variants in COL4A3, COL4A4, and COL4A5 genes. The phenotypes can range from isolated hematuria with a non-progressive or very slowly progressive course to progressive kidney disease with extrarenal abnormalities. Timely diagnosis of Alport syndrome facilitates the early and effective implementation of treatment, as well as genetic counseling. Here, we report the COL4A3 c.765G > A, p.((=)) mutation in three ethnically Azerbaijani, apparently unrelated, consanguineous families from the village of Algeti in the Marneuli region of Georgia. We speculate that this variant could represent a founder mutation within this population and recommend offering genetic testing to Algeti village residents with persistent hematuria.

Alport syndrome is a hereditary disorder caused by pathogenic variants in the COL4A gene, which can be inherited in an autosomal recessive, dominant, or X-linked pattern. In the Bukharian Jewish population, no founder pathogenic variant has been reported in COL4A4.
The cohort included 38 patients from 22 Bukharian Jewish families with suspected Alport syndrome who were referred the nephrogenetics clinic between 2012 and 2022. The study collected demographic, clinical, and genetic data from electronic medical records, which were used to evaluate the molecular basis of the disease using Sanger sequencing, and next-generation sequencing.
Molecular diagnosis was confirmed in 20/38 patients, with each patient having at least one of the three disease-causing COL4A4 variants detected: c.338GA (p.Gly1008Arg), and c.871-6T>C. In addition, two patients were obligate carriers. Overall, there were 17 heterozygotes, 2 compound heterozygotes, and 3 homozygotes. Each variant was detected in more than one unrelated family. All patients had hematuria with/without proteinuria at referral, and the youngest patient with proteinuria (age 5 years) was homozygous for the c.338G>A variant. End-stage renal disease was diagnosed in two patients at the age of 38 years, a compound heterozygote for c.338G>A and c.871-6T>C. Hearing deterioration was detected in three patients, the youngest aged 40 years, all of whom were heterozygous for c.338G>A.
This study unveils three novel disease-causing variants, c.3022G>A, c.871-6T>C, and c.338G>A, in the COL4A4 gene that are recurrent among Jews of Bukharian ancestry, and cause Alport syndrome in both dominant and recessive autosomal inheritance patterns.

UNASSIGNED: Loin pain hematuria syndrome (LPHS) is a rare clinical syndrome with a reported prevalence of 1 in 10,000. The syndrome is characterized by severe pain localized to the kidney in the absence of identifiable urinary tract disease. Because of an inadequate understanding of the pathophysiology of the disease, the goal of management has been limited to symptomatic pain management. Through detailed phenotype and genotype assessment we sought to identify possible underlying etiologies.
UNASSIGNED: We completed a chart review, ultrasound imaging, kidney biopsy, and type IV collagen (COL4A3, COL4A4, and COL4A5) gene sequencing in 14 patients with loin pain hematuria recruited from a single center.
UNASSIGNED: Red blood cells and red cell casts were observed within the tubules in 10 of 14 patients. The glomerular basement membrane (GBM) was normal in 11 patients and thickened in 1 patient. Staining for IgA kappa was present in 1 patient. C3 deposition without any inflammation was present in 7 patients. Arteriolar hyalinosis was present in 4 patients and endothelial cell injury was present in 6 patients. No pathogenic COL4A3, COL4A4, or COL4A5 variants were identified.
UNASSIGNED: Conventional histopathology and genetic testing for type IV collagen variants failed to identify the cause of hematuria in 14 patients with LPHS.

暂无摘要。

Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in the gene COL4A3, COL4A4, or COL4A5. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS).
Retrospective cohort study.
82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected.
A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families), whereas 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 (95% CI, 58-73) years, without significant differences across sex (P=0.8), causative genes (P=0.6), or type of variant (P=0.9). Microhematuria was the most common kidney manifestation (92.1%), and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of estimated glomerular filtration rate change was-1.46 (-1.66 to-1.26) mL/min/1.73m2 per year for the overall group, with no significant differences between ADAS genes (P=0.2).
The relatively small size of this series from a single country, potentially limiting generalizability.
Patients with ADAS have a wide spectrum of clinical presentations, ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.

In this issue, Matthews et al. provide a comprehensive review of published cohorts with heterozygous pathogenic variants in COL4A3 or COL4A4, documenting the wide spectrum of the disease. Due to the extreme phenotypes that patients with heterozygous pathogenic variants in COL4A3 or COL4A4 may show, the disease has been referred to in a variety of ways, including \'autosomal dominant Alport syndrome\', \'thin basement membrane disease\', \'thin basement membrane nephropathy\', \'familial benign hematuria\' and \'carriers of autosomal dominant Alport syndrome\'. This confusion over terminology has prevented nephrologists from being sufficiently aware of the relevance of the entity. Nowadays, however, next-generation sequencing facilitates the diagnosis and it is becoming a relatively frequent finding in haematuric-proteinuric nephropathies of unknown origin, even in non-familial cases. There is a need to raise awareness among nephrologists about the disease in order to improve diagnosis and provide better management for these patients.

Minimal change disease (MCD) is a main cause of the nephrotic syndrome. Thin basement membrane disease (TBMD) is another disease characterized by microscopic hematuria. The present case is a young adult female who presented with classic nephrotic syndrome, but she had microscopic hematuria as well. Hematuria can be part of MCD in 21% of patients, but in this case, histopathological diagnosis confirmed MCD with concurrent TBMD. This was reported only in two cases, up to our literature review. Using steroids resulted in nephrotic syndrome improvement, but microscopic hematuria has persisted, which is mostly related to TBMD rather than a primary part of MCD. Up to our knowledge, this is the first case report of MCD with concurrent TBMD in Arab countries.

A 21-year-old woman was referred to our hospital because of proteinuria and hematuria. She had occasional flank pain. A renal biopsy was performed and revealed a thin basement membrane. Therefore, she was diagnosed with thin basement membrane disease. However, the frequency of her flank pain increased. Since her left kidney was slightly larger than the right, nutcracker syndrome (NCS) was suspected. Renal vein ultrasonography and venography were performed, and NCS was confirmed. Her hematuria was multifactorial, and NCS can go unnoticed if there is a comorbidity that also causes hematuria.

We examined a group of 83 patients (57 children and 26 adults) with thin basement membrane disease and 17 patients with Alport syndrome. We compared the clinical data and, above all, the morphological patterns of both disease entities, with particular focus on not very advanced changes which might lead to a misdiagnosis due to the non-detection of the early stages of Alport syndrome.

We report a case of a 48-year-old male who presented with hematuria of at least 10 years, and has a daughter with hematuria as well. The patient has a history of degenerative hearing loss, decreased vision and cataract formation, but no diabetes, hypertension or proteinuria. A full serology and urology workup was negative for any abnormality. A kidney biopsy for the patient revealed a diagnosis of Alport syndrome but was unable to rule out thin basement membrane disease. The biopsy was inconclusive in making the diagnosis but the patient\'s clinical presentation led to the diagnosis of Alport syndrome. The patient\'s 10-year-old daughter also has hematuria with no clear etiology but now can subsequently be anticipatorily managed for Alport syndrome progression. Due to the rarity of the disease, diagnosis is often missed or delayed by primary care providers especially when no associated proteinuria has yet developed. This can lead to confusion and misdiagnosis with thin basement membrane disease, a generally benign hematuria without kidney failure progression. Additionally, biopsy can be inconclusive in these patients, relying on the physician\'s history and physical examination findings to diagnose. It is important to appropriately diagnose Alport syndrome not only to manage the patient\'s rate of kidney failure progression but also allow for a higher degree of suspicion, screening and intervention in the patient\'s family members. Both the inconclusive nature of kidney biopsies and the usefulness of diagnosis for family member screening are often overlooked in medical literature but are explored in this case.