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We present clinical practice recommendations for the treatment of children with Alport syndrome who are not enrolled in clinical trials. Our goal is to promote early initiation of a standard therapeutic approach that will facilitate assessment of the safety and efficacy of the protocol. The treatment protocol is based on the reduction of proteinuri...
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Alport syndrome (AS) is a hereditary glomerulonephritis caused by COL4A3, COL4A4 or COL4A5 gene mutations and characterized by abnormalities of glomerular basement membranes (GBMs). Due to a lack of curative treatments, the condition proceeds to end-stage renal disease even in adolescents. Hampering drug discovery is the absence of effective in vit...
Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end‐stage kidney disease (ESKD). Monoallelic disease‐causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clini...
Alport syndrome is a hereditary kidney disease caused by mutations in the three genes encoding for collagen IV: COL4A3, COL4A4, and COL4A5. Several mouse models have been created for the study of this disease with variable phenotypic outcomes. This review is an up-to-date presentation of the current mouse models existing in the literature with a de...
Citations
... While the administration of the selective vasopressin V2 receptor (V2R) antagonist, tolvaptan, is considered the gold standard treatment for ADPKD [40,41], clinical practice recommendations for the treatment of individuals with AS encourage the early use of angiotensinconverting enzyme (ACE) inhibitors that have proven efficient to reduce lifetime risk for ESRD [42,43]. In addition, as discussed above, COL4A5 genotype data can suggest the renal prognosis and partially predict the timing of ESRD, thus guiding the timing and intensity of intervention [44]. On the other hand, according to current knowledge, kidney cysts in patients with COL4A3-5 pathogenic variants are generally asymptomatic and do not require specific treatment [16,30]. ...
Citation: Graziani, L.; Minotti, C.; Carriero, M.L.; Bengala, M.; Lai, S.; Terracciano, A.; Novelli, A.; Novelli, G. A Novel COL4A5 Pathogenic Variant Joins the Dots in a Family with a Synchronous Diagnosis of Alport Syndrome and Polycystic Kidney Disease. Genes 2024, 15, 597. Abstract: Alport Syndrome (AS) is the most common genetic glomerular disease, and it is caused by COL4A3, COL4A4, and COL4A5 pathogenic variants. The classic phenotypic spectrum associated with AS ranges from isolated hematuria to chronic kidney disease (CKD) with extrarenal abnormalities. Atypical presentation of the disorder is possible, and it can mislead the diagnosis. Polycystic kidney disease (PKD), which is most frequently associated with Autosomal Dominant PKD (ADPKD) due to PKD1 and PKD2 heterozygous variants, is emerging as a possible clinical manifestation in COL4A3-A5 patients. We describe a COL4A5 novel familial frameshift variant (NM_000495.5: c.1095dup p.(Leu366ValfsTer45)), which was associated with AS and PKD in the hemizygous proband, as well as with PKD, IgA glomerulonephritis and focal segmental glomerulosclerosis (FSGS) in the heterozygous mother. Establishing the diagnosis of AS can sometimes be difficult, especially in the context of misleading family history and atypical phenotypic features. This case study supports the emerging genotypic and phenotypic heterogeneity in COL4A3-A5-associated disorders, as well as the recently described association between PKD and collagen type IV (Col4) defects. We highlight the importance of the accurate phenotyping of all family members and the relevance of next-generation sequencing in the differential diagnosis of hereditary kidney disease.
... Renin-angiotensin-aldosterone system (RAAS) inhibitors have been considered the primary treatment for AS for nearly a decade. The AS Study Collaboration has recommended considering ACEIs for the treatment of microalbuminuria in children with XLAS who have a family history of early-stage CKD or harbor severe (deletion, nonsense, or splicing) mutations [25]. Recent guidelines recommend initiating ACEI therapy in XLAS at the time of diagnosis in men and at the onset of microalbuminuria in women [26]. ...
Background: Alport Syndrome (AS) is a genetic kidney disorder characterized by progressive kidney failure. It is often misdiagnosed as other kidney diseases due to its clinical phenotypic heterogeneity and the lack of specific clinical symptoms in early childhood.
Methods: This study retrospectively analyzed clinical data of 7 pediatric patients admitted to Xi'an Children's Hospital between 2016 and 2022 due to clinical manifestations of nephrotic syndrome.
Results: The 7 patients were from six families, and 4 patients had a family history of kidney disease. The median(IQR) age at presentation was 9.8 (7.8, 10.8) years and median follow-up was 4.4 (2.4–8.0) years.They all had hematuria, nephrotic proteinuria and hypoproteinemia. Kidney biopsy revealed focal segmental glomerulosclerosis (FSGS) on light microscopy. Among the patients, 8 pathogenic gene mutations were detected, 6 patients had mutations in the COL4A5gene. Furthermore, the mutations in 6 patients (85.7%) were severe.Treatment involved administering renin-angiotensin-aldosterone system (RAAS) inhibitors to all the patients starting from their first visit. Up to the present follow-up time, all the 7 patients exhibited varying degrees of reduction in proteinuria, with 1 of them experiencing kidney function decline, and 1 progressing to end-stage kidney disease (ESKD).
Conclusion: AS should be considered in patients co-exhibiting nephrotic syndrome and hematuria, especially those with a poor response to steroid therapy or with a family history of hematuria. Additionally, AS should be considered in the genetic diagnosis of patients with kidney pathology consistent with FSGS. The most common pathogenic gene in AS patients with nephrotic syndrome is the COL4A5 gene, and most of them have severe mutations.
... Disease management emphasizes reducing hematuria and proteinuria, ultimately delaying renal complications, while other ocular and auricular impairments are managed symptomatically. [7] With the aim of preserving vision and hearing capacity, as well as improving renal function, rejuvenating Ayurveda treatment was planned. This included Sarivadi Vati, Ashwagandha Churna, Rasayana Churna, Dashmoolarishta, Chandanasava, Maha Triphala Ghrita, Asanabilvadi Taila for Karna Pichu, and Anu Taila for Pratimarsha Nasya. ...
Alport syndrome is a genetically inheritable condition occurring due to alterations in the alpha-5 chain of type 4 collagen. This affects the cochlea in the inner ear, the eyes, and the basement membrane in the glomerulus. The prevalence of the disease is 1 in 50,000, with a higher incidence among males. According to Ayurveda, defects in Shukra (sperm) or Shonita (ovum) lead to the development of Adi Bala Pravritta Rogas (genetic disorders). Ayurveda literature contains certain references to ocular, auricular, and renal manifestations of genetic disorders. In this case, a patient presented with complaints of gradual, progressive, painless vision impairment in both eyes over the last 5–6 years along with gradual impaired hearing over the past year. Ocular examination revealed bilateral anterior lenticonus. The tuning fork test suggested sensorineural hearing loss in both ears. Urine routine and bio-microscopic analysis showed hematuria. Currently, there is no viable cure for Alport syndrome in modern science. This case study highlights the potential of the Ayurvedic medical system to slow the progression of the disease and enhance the patient’s quality of life through a holistic approach.
... Unlike patients in groups 2 and 3, most individuals in this group have only isolated microscopic hematuria associated with thin GBM without any high-risk features (such as proteinuria), putting them at a slightly increased risk of developing KF late in life. These are the patients whom Kashtan et al. [7] previously suggested should be made cognizant of this risk and to be proactive about monitoring and treatment according to expert recommendations [49,50]. A subset of these individuals will be parents or siblings of patients with ARAS and will be aware of the importance of maintaining kidney health. ...
Purpose of review
With the latest classification, variants in three collagen IV genes, COL4A3 , COL4A4 , and COL4A5 , represent the most prevalent genetic kidney disease in humans, exhibiting diverse, complex, and inconsistent clinical manifestations. This review breaks down the disease spectrum and genotype–phenotype correlations of kidney diseases linked to genetic variants in these genes and distinguishes “classic” Alport syndrome (AS) from the less severe nonsyndromic genetically related nephropathies that we suggest be called “Alport kidney diseases”.
Recent findings
Several research studies have focused on the genotype–phenotype correlation under the latest classification scheme of AS. The historic diagnoses of “benign familial hematuria” and “thin basement membrane nephropathy” linked to heterozygous variants in COL4A3 or COL4A4 are suggested to be obsolete, but instead classified as autosomal AS by recent expert consensus due to a significant risk of disease progression.
Summary
The concept of Alport kidney disease extends beyond classic AS. Patients carrying pathogenic variants in any one of the COL4A3/A4/A5 genes can have variable phenotypes ranging from completely normal/clinically unrecognizable, hematuria without or with proteinuria, or progression to chronic kidney disease and kidney failure, depending on sex, genotype, and interplays of other genetic as well as environmental factors.
... Treatment for ATS not only contributes to increased life expectancy but also improves the overall quality of life for affected individuals. Molecular con rmation of the diagnosis is crucial, primarily for preventive measures and to avoid unnecessary treatments, allowing for appropriate management such as kidney transplantation when necessary [45,[51][52][53]. ...
Background:
Alport syndrome is defined by the co-occurrence of hematuria, renal failure, and a family history of renal failure or hematuria. Pathogenic variants in COL4A3, COL4A4, and COL4A5 cause this phenotype. These genes code for the α3, α4, and α5 chains of collagen IV found in the kidneys, eyes, and cochlea. This explains the frequent association of extra-renal signs, such as bilateral sensorineural deafness and ocular abnormalities. Different modes of transmission have been reported. X-linked transmission is attributed to the pathogenic variants of COL4A5, while homozygous pathogenic variants of COL4A3 or COL4A4 lead to autosomal recessive inheritance. The digenic form occurs when a pathological variation in both COL4A3 and COL4A4coexist. Additionally, autosomal dominant inheritance can occur due to heterozygous pathogenic variants in COL4A3or COL4A4.
In this study, we investigated 45 patients with Alport syndrome from 11 Tunisian families to establish their clinical and genetic characteristics.
Methods:
Clinical data were collected retrospectively, and molecular analysis of COL4A3, A4,andA5 was performed. Among the 45 patients, whole-exome sequencing was performed on 11 individuals, with one patient selected from each family. All candidate pathogenic variations were validated by Sanger sequencing. Cascade screening in the family of each proband allowed us to expand the number of individuals tested to 53 to verify the presence of the pathogenic variant found in their family.
Results:
We identified 9 likely pathogenic variations among 11 index cases. Six were novel variations and three were known ones. Of these, five out of nine were in the COL4A3 gene, while four out of nine were found in the COL4A5 gene. Frame-shift, nonsense, missense, and alternative splicing variants were detected in our cohort. Most of these variants affected the Gly-XY codon.Thirty out of the 45 clinically identified siblings were tested and confirmed for Alport syndrome. Cascade screening then identified 3 additional affected individuals, along with 10 unaffected siblings and 10 unaffected parents.The mode of inheritance of Alport syndrome was autosomal recessive in 6 familiesand X-linked in 4 families.
Conclusions:
This study represents the first Tunisian screening of the mutational spectrum of Alport syndrome. It contributes new pathogenic variants to the literature and demonstrates that autosomal recessive inheritance of Alport syndrome is more frequent in the Tunisian population than the X-linked dominant form as reported in the literature.
... It is vital to maintain ideal blood pressure, which is typically achieved through the use of medications like ACE inhibitors or angiotensin 1 or 2 receptor blockers (ARBs). ACE inhibitor therapy has been proven effective in patients with proteinuria and well-preserved kidney function has been shown to suspend progression to renal failure [29]. Studies in animals with Alport syndrome have also confirmed that treatment that postpone the commencement of proteinuria or decrease its occurrence can extend kidney survival and prevent ESRD. ...
Alport syndrome is an genetic disorder that distresses the basement membrane of the kidneys and can also impact other organs, such as the cochlea of the inner ear and eyes. It is characterized by mutation causing abnormalities in the collagen within the basement membrane, which has a crucial role in the filtration process of the kidneys. These abnormalities lead to progressive kidney damage and often result in chronic kidney disease. In some cases of Alport syndrome, the abnormal collagen can also affect the cochlea in the inner ear, leading to sensorineural hearing loss. Additionally, changes in the ocular lens, named anterior lenticonus, can occur, causing vision problems. Alport syndrome can manifest differently among individuals, and its severity can vary. Some people may experience mild symptoms, while others may develop more severe kidney problems, including end-stage renal disease, which may need dialysis or kidney transplant. Treatment for Alport syndrome primarily focuses on managing its symptoms and complications. Regular monitoring of kidney function and blood pressure, along with medications to control hypertension, are crucial aspects of the management plan. In cases of severe kidney damage, kidney transplantation may be necessary. As with any medical condition, early detection and intervention can improve results and quality of life for persons with Alport syndrome. Therefore, if there is a family history of the disorder or any concerning symptoms, it is essential to seek medical attention promptly. Genetic testing can help confirm the diagnosis and identify affected family members, allowing for appropriate monitoring and management.
... The earlier angiotensinconverting-enzyme-inhibition starts in an affected child, the better the chances are of improving life quality and life expectancy. [9][10][11] Early diagnosis is therefore very important and was the ultimate target of our research into early BMs. However, finding BMs is also important for monitoring responses to therapy and for finding new therapeutic strategies. ...
Introduction
Alport syndrome (AS) is a hereditary type IV collagen disease. It starts shortly after birth, without clinical symptoms, and progresses to end-stage kidney disease early in life. The earlier therapy starts, the more effectively end-stage kidney disease can be delayed. Clearly then, to ensure preemptive therapy, early diagnosis is an essential prerequisite.
Methods
To provide early diagnosis, we searched for protein biomarkers (BMs) by mass spectrometry in dogs with AS stage 0. At this very early stage, we identified 74 candidate BMs. Of these, using commercial enzyme-linked immunosorbent assays (ELISAs), we evaluated 27 in dogs and 28 in children, 50 with AS and 104 healthy controls.
Results
Most BMs from blood appeared as fractions of multiple variants of the same protein, as shown by their chromatographic distribution before mass spectrometry. Blood samples showed only minor differences because ELISAs rarely detect disease-specific variants. However, in urine , several proteins, individually or in combination, were promising indicators of very early and preclinical kidney injury. The BMs with the highest sensitivity and specificity were collagen type XIII, hyaluronan binding protein 2 (HABP2), and complement C4 binding protein (C4BP).
Conclusion
We generated very strong candidate BMs by our approach of first examining preclinical AS in dogs and then validating these BMs in children at early stages of disease. These BMs might serve for screening purposes for AS before the onset of kidney damage and therefore allow preemptive therapy.
... Nephrotic range proteinuria and/or NS at presentation were associated with poor prognosis and in the kidney survival analysis of male patients, no significant difference was found in patients who received immunosuppressive therapy or not. In the literature, it was shown that RAAS inhibition has nephroprotective effects and may delay progression to CKD in patients with AS. 5,[12][13][14] Firstly, in 2004, Proesmans et al. 15 reported the 5 years results of enalapril treatment in a group of ten children with AS and stated that enalapril reduces urinary protein excretion and preserves glomerular filtration. Subsequently, Webb et al. 16 demonstrated that losartan reduced proteinuria significantly and was well tolerated after 12 weeks of treatment in a group of 15 children with AS. ...
Background. Alport syndrome (AS) is characterized by progressive kidney disease. There is increasing evidence that renin-angiotensin-aldosterone system (RAAS) inhibition delays chronic kidney disease (CKD) while the effectiveness of immunosuppressive (IS) therapy in AS is still uncertain. In this study, we aimed to analyze the outcomes of pediatric patients with X-linked AS (XLAS) who received RAAS inhibitors and IS therapy.
Methods. Seventy-four children with XLAS were included in this multicenter study. Demographic features, clinical and laboratory data, treatments, histopathological examinations, and genetic analyses were analyzed retrospectively.
Results. Among 74 children, 52 (70.2%) received RAAS inhibitors, 11 (14.9%) received RAAS inhibitors and IS, and 11 (14.9%) were followed up without treatment. During follow-up, glomerular filtration rate (GFR) decreased <60 ml/min/1.73 m2 in 7 (9.5%) of 74 patients (M/F=6/1). In male patients with XLAS, kidney survival was not different between RAAS and RAAS+IS groups (p=0.42). The rate of progression to CKD was significantly higher in patients with nephrotic range proteinuria and nephrotic syndrome (NS), respectively (p=0.006, p=0.05). The median age at the onset of RAAS inhibitors was significantly higher in male patients who progressed to CKD (13.9 vs 8.1 years, p=0.003).
Conclusions. RAAS inhibitors have beneficial effects on proteinuria and early initiation of therapy may delay the progression to CKD in children with XLAS. There was no significant difference between the RAAS and RAAS+IS groups in kidney survival. AS patients presenting with NS or nephrotic range proteinuria should be followed up more carefully considering the risk of early progression to CKD.
... Jedoch konnte in Registerstudien gezeigt werden, dass der Beginn der Niereninsuffizienz durch die Gabe von ACE-Hemmern deutlich verzögert werden kann und die Lebenserwartung steigt [12]. Auch die aktuellen "Alport Syndrome therapy guidelines" empfehlen inzwischen den Beginn einer ACE-Hemmer-Therapie bei Kindern ab 2 Jahre schon in frühen, oligosymptomatischen Stadien der Erkrankung [18]. ...
Background and objective:
Alport syndrome (AS) is a rare hereditary systemic disease that results in alterations of the kidneys, inner ear, and various structures of the eye. It is caused by mutations in one of the genes encoding collagen type IV. In recent years, new and innovative imaging techniques have added characteristics of ocular alterations in AS and provided new insights, including into the pathogenesis of the disease. The aim of this paper is to provide an overview of the current knowledge of ocular changes in AS, as well as to present the Alport ocular pass.
Method:
Narrative review article.
Results:
Ocular manifestations of AS include changes in the cornea, lens, and retina. Specifically, posterior polymorphic corneal dystrophy, anterior lenticonus (pathognomonic for AS), and various retinal changes have been described, which have been further characterized in recent years by newer imaging techniques. In particular, foveal changes in AS may present as both a thickened central retina in the context of foveal hypoplasia or a staircase-like thinning of the fovea. Both lesions could provide further insights into the role of type IV collagen in ocular structures.
Conclusion:
The AS can manifest in various structures of the eye. The staircase-like changes of the central retina in AS patients indicate the important role of collagen type IV in the homeostasis and regular function of the inner retinal layers. The often mild foveal hypoplasia may provide clues to the role of collagen type IV in retinal embryogenesis. While anterior lenticonus is pathognomonic for AS and can be treated easily by refractive lens exchange, the only option currently available for retinal alterations is close follow-up and, if necessary, treatment of systemic complications of AS.
... 4,5 Los varones con SALX progresan a enfermedad renal crónica terminal (ERCT) en la segunda o tercera década de vida, con complicaciones extrarrenales asociadas frecuentemente, como hipoacusia y manifestaciones oculares patognomónicas. 1,2,[4][5][6] El diagnóstico de SA se puede realizar por estudio genético molecular, biopsia cutánea o renal. 6 clínico amplio, heterogéneo y, en ocasiones, atípico-han generado dificultades en el reconocimiento y en el diagnóstico precoz de esta entidad. 2 Si bien no existe en el momento actual un tratamiento específico para el SA, la terapia bloqueadora del sistema renina-angiotensinaaldosterona puede enlentecer la progresión a ERCT, ya desde la edad pediátrica, en caso de proteinuria. ...
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.
