A comprehensive review of Alport syndrome: definition, pathophysiology, clinical manifestations, and diagnostic considerations

Eunjeong Kang; Byung Hwa Park; Hajeong Lee; Hee Gyung Kang; Ji Hyun Kim; Ye Na Kim; Yeonsoon Jung; Hark Rim; Ho Sik Shin

doi:10.23876/j.krcp.24.065

Kidney Res Clin Pract > Epub ahead of print

Kang, Park, Lee, Kang, Kim, Kim, Jung, Rim, and Shin: A comprehensive review of Alport syndrome: definition, pathophysiology, clinical manifestations, and diagnostic considerations

Review Article

Kidney Research and Clinical Practice 2024;j.krcp.24.065.

Published online: September 26, 2024

DOI: https://doi.org/10.23876/j.krcp.24.065

A comprehensive review of Alport syndrome: definition, pathophysiology, clinical manifestations, and diagnostic considerations

Eunjeong Kang^1,^2,^*

, Byung Hwa Park^3,^4,^*

, Hajeong Lee²

, Hee Gyung Kang⁵

, Ji Hyun Kim⁶

, Ye Na Kim^3,⁴

, Yeonsoon Jung^3,⁴

, Hark Rim^3,⁴

, Ho Sik Shin^3,⁴

¹Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea

²Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea

³Renal Division, Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Republic of Korea

⁴Transplantation Research Institute, Kosin University College of Medicine, Busan, Republic of Korea

⁵Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea

⁶Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

Correspondence: Ho Sik Shin Renal Division, Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 49267, Republic of Korea. E-mail: shs@kosin.ac.kr

^*Eunjeong Kang and Byung Hwa Park contributed equally to this study as co-first authors.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial and No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted non-commercial use, distribution of the material without any modifications, and reproduction in any medium, provided the original works properly cited.

Abstract

Alport syndrome, a rare genetic disorder affecting around 1 in 50,000 individuals, primarily presents as microscopic hematuria and chronic kidney disease (CKD) with associated extrarenal complications. The Alport syndrome results from mutations in COL4A3, COL4A4, and COL4A5 genes, disrupting the formation of the α3–α4–α5 chain in the collagen IV network. The etiology involves X chromosome-related, autosomal dominant, autosomal recessive, and digenic inheritance patterns. The disease primarily manifests as kidney involvement, featuring persistent hematuria, proteinuria, and a progressive decline in renal function. Hearing loss, ocular abnormalities, and extrarenal manifestations further contribute to its complexity. Genotype-phenotype correlations are relatively evident, with distinct presentations in X-linked, autosomal recessive, and autosomal dominant cases. Diagnosis relies on urinalysis, histologic examination, and genetic testing with advancements in next-generation sequencing aiding identification. Although no specific treatment exists, early diagnosis improves outcomes, emphasizing the importance of genetic testing for prognosis and familial screening. The purpose of this review is to advance knowledge and enhance understanding of Alport syndrome.

Keywords: Alport syndrome, Diagnosis, Genetic kidney disease, Genetic testing, Pathophysiology

Introduction

Alport syndrome is a rare genetic disease that occurs sporadically due either to a mutation inherited from a parent or a mutation that was not present in the parent. It causes problems in the kidneys with progression to chronic kidney disease (CKD), and it can be accompanied by complications such as sensorineural or neurogenic hearing loss, phakic cones, and retinal macular spots (Fig. 1) [1]. Despite its rarity, Alport syndrome is the second-most frequent monogenic kidney disease, affecting around one in every 50,000 individuals. When the disease first occurs, nonspecific symptoms such as hematuria, proteinuria, and edema appear, making it difficult to differentiate the condition from other kidney diseases, so it might be misdiagnosed [2]. Because it is difficult to differentiate based on the patient’s symptoms and family history alone, testing for type IV collagen-related genes plays an important role in diagnosis. This review paper summarizes Alport syndrome to help diagnose patients in clinical settings.

Etiology and pathophysiology of Alport syndrome

The main cause of Alport syndrome is a mutation in the collagen IV gene as well as mutations in the COL4A3, COL4A4, and COL4A5 genes, which encode the α3–α4–α5 chain [2]. During the process of normal basement membrane formation, α3, α4, and α5 chains are expressed within the glomerular basement membrane (GBM) to form a collagen IV network, and the α5 chain forms an α5–α5–α6 network in the basement membrane beneath the epidermis (Fig. 2) [3–5]. Alport syndrome was discovered following the serendipitous observation that the ultrastructural lesions in the GBM characteristic of patients with Goodpasture syndrome did not bind to antibodies from patients with anti-GBM antibody disease (including Goodpasture syndrome) [2,6–9]. Alport syndrome is a mutation that disrupts the process of α3–α4–α5 chain formation in the GBM, which makes the GBM vulnerable to filtration pressure. As a result, the filtration of necessary substances in the body is not carried out properly, which leads to functional decline and progressive renal failure [10,11].

A Southern blot analysis study using the COL4A5 complementary DNA probe was conducted in male patients with a mutation in the COL4A5 gene on the X chromosome (i.e., X-linked inheritance), and the results confirmed that the α3 chain was not expressed in the GBM in four patients [5,12]. In addition, although the mechanism of X-linked Alport syndrome (XLAS) is still unclear, research has shown that, when an α5 mutation occurs, α3 and α4 are also not expressed [12,13]. Because gene transcription occurs in the renal cortex, the absence of α3, α4, and α5 chains in the basement membrane indicates that the COL4A3, COL4A4, and COL4A5 genes are not properly expressed; in other words, there is support for the hypothesis that abnormalities in the α5 chain can interfere with the formation of the α3 and α4 chains [14].

A collagen IV network generally forms the Bowman capsule and basement membrane of the glomeruli, distal tubules, and collecting ducts as well as the basement membrane of the cochlea and eye. When this chain mutation occurs, collagen IV network formation and basement membrane are damaged, resulting in hearing loss, macular spots, and other problems, such as Alport syndrome [4,5].

Recently, genetic defects in the α3–α4–α5 chain have been identified not only in patients with typical Alport syndrome but also in those with thin basement membrane disease, focal segmental glomerulosclerosis (FSGS), and CKD of an unknown cause. Therefore, a new classification method for type IV collagen-related diseases was recently proposed to eliminate ambiguity in clinical diagnosis and facilitate the early diagnosis and treatment of all patients with the possibility of progressive renal disease (Fig. 3) [10,11].

Inheritance and genetics of Alport syndrome

The new classification organizes the causes of Alport syndrome into the following four types: X chromosome-related, autosomal dominant (ADAS), autosomal recessive (ARAS), and digenic (Table 1) [15,16]. First, XLAS accounts for approximately 80% of all Alport syndrome cases. It arises from mutations in the COL4A5 gene on the X chromosome, which encodes the α5 chain of collagen IV. This kind of mutation was confirmed through animal model studies with a human nonsense mutation in the mouse COL4A5 gene [17]. Separately, its X-linked inheritance was confirmed through studies in an XLAS mouse model. Because the father passes on only the unaffected Y chromosome to his son, inheritance from father to son does not occur. However, a mother can pass the X chromosome associated with Alport syndrome on to her son. In most females with XLAS, half of their cells express the variant COL4A5 allele, while the remaining cells have heterozygous X chromosomes expressing the normal COL4A5 allele. As a result, Alport syndrome in female individuals presents with less severe clinical manifestations than Alport syndrome in male individuals (Fig. 4) [18,19]. Until recently, women carrying COL4A5 heterozygous mutations were labeled as “carriers.” While they were initially perceived as experiencing only a benign course of disease, in fact, 25% of these individuals develop CKD stage G5 over their lifetime. Consequently, the need for women with COL4A5 heterozygous mutations to be recognized as “patients” rather than merely benign “carriers” has been emphasized; thus, regular monitoring for proteinuria and kidney function is recommended for female Alport syndrome patients [1,20,21].

Autosomal recessive inheritance accounts for 10% to 15% of Alport syndrome cases and is caused by genetic defects in the COL4A3 or COL4A4 genes encoding the α3 (IV) chain (including the Goodpasture antigen) and α4 (IV) chain, respectively [22]. The prevalence rates are similar between males and females [22,23], and the clinical symptoms are almost identical to those seen in male individuals who develop XLAS [17–19]. Separately, autosomal dominant inheritance accounts for 20% to 30% of Alport syndrome cases. This phenomenon results from heterozygous mutations in the COL4A3 or COL4A4 genes and presents with a variety of clinical manifestations ranging from isolated microscopic hematuria to progression to end-stage renal disease [24].

Digenic inheritance is rare in Alport syndrome, but patients with coexisting mutations in COL4A3, COL4A4, and COL4A5 have been reported [25].

Clinical manifestations of Alport syndrome

Kidney involvement

The most crucial and invariable clinical manifestation of Alport syndrome is microscopic hematuria. Most male patients with Alport syndrome exhibit persistent microscopic hematuria, and they may also show transient gross hematuria typically in their early to mid-20s following upper respiratory infections [26]. Microhematuria is likely indicative of GBM thinning with focal ruptures due to deficient expression of the α3–α4–α5 (type IV) network.

Proteinuria generally does not manifest in the early years of life but does occur in male patients with XLAS and in both male and female patients with ARAS. Proteinuria is probable as a consequence of modified podocyte interactions with the abnormal GBM, while the deterioration of kidney function can be attributed to profibrotic processes occurring in both glomeruli and the tubulointerstitial compartment. This clinical feature, beginning as microalbuminuria, tends to increase progressively with advancement of the disease, leading to nephrotic syndrome in some cases. Proteinuria is recognized as a significant risk factor for the progression to CKD and end-stage kidney disease (ESKD), irrespective of the mode of inheritance of Alport syndrome.

Hypertension increases in frequency and severity with age, with male patients with XLAS experiencing hypertension more frequently than female ones. However, in ARAS, there is no sex-related difference in the development of hypertension.

Typically, the clinical course involves the initiation of recurrent microscopic hematuria, which later develops with proteinuria, accompanied by a gradual decline in kidney function, before eventually progressing to ESKD. The development of ESKD through renal impairment and CKD occurs before the age of 20 years in about 50% of male patients with XLAS and in both male and female patients with ARAS, necessitating the consideration of kidney replacement therapy [27–29].

Extrarenal manifestations

Deafness is a commonly observed but not universally present manifestation in Alport syndrome patients with kidney conditions. The onset of hearing loss in Alport syndrome is not congenital, typically becoming noticeable in late childhood to early adolescence in males with XLAS and in both males and females with ARAS. By the age of approximately 15 years, half of the males with XLAS experience hearing loss, which increases to 75% by 25 years and 90% by 40 years of age, respectively [27]. Women with XLAS, however, have a lower prevalence, with 10% affected by 40 years of age and around 20% affected by 60 years of age [29]. In ARAS, hearing loss is prevalent in approximately 40% to 66% of individuals, but it is less common in ADAS, affecting only 2% to 13% of these patients [30]. In certain families with Alport syndrome who have normal hearing, deafness may develop later and progress very gradually. Hearing deficits in individuals from families diagnosed with Alport syndrome are consistently accompanied by kidney involvement. The hearing impairment can only be diagnosed through audiometry, typically revealing a bilateral reduction in sensitivity tones within the 2,000 to 8,000-Hz range. In affected males, the hearing deficit progressively extends to include other frequencies, encompassing those relevant to conversational speech.

Ocular abnormalities are present in 30% to 40% of males with XLAS and approximately 15% of females with XLAS, respectively [27,29]. The occurrence of anterior lenticonus, characterized by a cone-shaped distortion of the anterior surface of the lens, is pathognomonic for Alport syndrome; its onset is observed in about 15% of males with XLAS and remains predominantly limited to Alport syndrome families with progression to ESKD before the age of 30 years and concurrent deafness [27,31]. Anterior lenticonus is not present at birth, instead typically manifesting during the second to third decade of life following CKD onset, and it is bilateral in 75% of patients. The patterns and occurrence of ocular abnormalities seem comparable between XLAS and ARAS, with ADAS patients rarely manifesting any such lesions [32,33]. A prevalent ocular manifestation of Alport syndrome is maculopathy, which is characterized by whitish or yellowish flecks or granulations distributed around the macula. This condition is prevalent in 50% to 60% of males with XLAS, in both males and females with ARAS, and in approximately 15% of females with XLAS [34]. This journal will feature a more comprehensive review on the histologic findings and extrarenal manifestations of Alport syndrome.

An association between Alport syndrome and leiomyomatosis of the esophagus and bronchi has been reported in more than 30 families to date. Females with this condition typically exhibit clitoral hypertrophy and genital leiomyomas, along with various clinical manifestations involving the labia and uterus. When leiomyomatosis is diagnosed concurrently, bilateral posterior subcapsular cataracts are frequently observed. Symptoms typically manifest in the later stages of childhood and may include dysphagia, postprandial vomiting, sternal and upper abdominal pain, recurrent bronchitis, respiratory distress, and stridor. However, the genotype-phenotype correlation in leiomyomatosis remains unclear [35,36].

Some males have been reported to exhibit arterial aneurysmal changes in the chest and abdominal aorta as well as smaller arterial vessels, although this phenomenon is relatively rare. Additionally, occurrences of ventricular septal defects and mitral valve prolapse have been observed in this subset of individuals [37].

Genotype-phenotype correlation of Alport syndrome

X-linked Alport syndrome

This type of Alport syndrome demonstrates a strong genotype-phenotype correlation. In XLAS males, microscopic hematuria is always present, often accompanied by proteinuria from an early age. The average age of progression to ESKD in this population is 40 years [27], although the definitive age varies with the type of mutation from 25 years for truncating mutations to 28 years for splicing mutations and 37 years for missense mutations [38]. Hearing loss typically occurs in late childhood, affecting approximately 90% of patients by the age of 40 years. Ocular manifestations associated with Alport syndrome, such as anterior lenticonus and posterior subcapsular cataracts, are less common compared to hearing loss. Early diagnosis and prompt use of renin-angiotensin-aldosterone blockade can delay the deterioration of kidney function, highlighting the importance of rapid diagnosis and treatment in XLAS males [27].

In female patients with XLAS, 98% exhibit hematuria, while about 73% show both proteinuria and hematuria, with the median age of initial proteinuria presentation reported to be 7 years old [39]. The proportion of these individuals reaching ESKD by the age of 40 years is 12%, with 65 years reported to be the median age of ESKD onset [29,39]. Although initially considered to lack a genotype-phenotype correlation, recent findings suggest that, in XLAS females, truncating mutations may lead to earlier onset of proteinuria [40,41] and a greater rate of progression to ESKD when compared to non-truncating mutations [42], indicating a potential genotype-phenotype correlation that warrants further research.

Autosomal recessive Alport syndrome

ARAS accounts for 15% of all Alport syndrome patients and arises due to mutations in the COL4A3 or COL4A4 genes through an autosomal recessive inheritance pattern [43]. In patients with this inheritance pattern, the disease manifests when an individual inherits two mutated genes, one from each parent. Consequently, if both parents are carriers, there is a 25% chance of disease occurrence in their offspring. Symptoms and signs tend to appear earlier and to be more severe in both males and females, with 62% of patients progressing to ESKD. The average age of ESKD onset in this group is reported to be about 21 years. Sensorineural hearing loss occurs in 64% of patients, while ocular manifestations are present in 17%. Prognosis tends to be worse in ARAS patients without missense mutations compared to those with such mutations [44].

Autosomal dominant Alport syndrome

Approximately 5% of Alport syndrome cases manifest as an autosomal dominant type, where the disease can occur due to a single mutation in either the COL4A3 or COL4A4 genes [43]. This form of Alport syndrome shows a more pronounced family history compared to ARAS, with a 50% chance of parents passing the syndrome to the next generation. Manifestations tend to be relatively milder in both males and females. To date, no definite genotype-phenotype correlation has been identified, and no significant differences have been noted according to sex, causative gene, or type of mutation. Microhematuria is present in 92% of ADAS patients, and kidney survival has been estimated to be 67 years [45].

Diagnosis and differential diagnosis of Alport syndrome

Urinalysis serves as an exceptionally effective screening method for Alport syndrome. Persistent microhematuria occurs in all males with XLAS and in both males and females with ARAS; thus, Alport syndrome should be considered in clinical practice when evaluating patients with persistent microscopic hematuria after excluding anatomical and structural abnormalities of the kidneys or urinary tract.

Notably, the level of suspicion increases when hematuria is concomitant with familial history, sensorineural hearing loss, or ocular abnormalities [46]. In pediatric cases, where performing a kidney biopsy may be more challenging compared to in adults, a detailed medical history should be obtained, especially when hematuria or proteinuria are isolated findings. However, the absence of a family history of hematuria or CKD does not exclude the possibility of Alport syndrome. De novo mutations are present in 12% of children with XLAS, while ARAS patients frequently have no family history of kidney disease [27]. Diagnosing Alport syndrome becomes challenging when there are no extrarenal manifestations or family history and proteinuria is predominant. Most effective strategies involve maintaining a heightened awareness of the possibility of the diagnosis.

The evaluation of individuals suspected to have Alport syndrome should encompass audiometry, an ophthalmological examination, and retinal imaging. Audiometry has proven valuable for both diagnostic purposes and for validating the necessity of hearing aids in patients suspected to have Alport syndrome, and it should be repeated as clinically warranted.

In cases with an absence of family history, it is advisable to contemplate a kidney biopsy to confirm the diagnosis of Alport syndrome (Fig. 5). When conducting a biopsy for diagnosis, electron microscopy is crucial. Pathognomonic findings in the GBM that signify Alport syndrome include its splitting and enlargement, along with podocyte effacement [47]. The pathologic diagnosis of Alport syndrome can be challenging and requires careful attention to avoid misdiagnosis [48]. In pediatric patients, kidney biopsy findings can vary significantly with age. It is important to note that performing a biopsy before the age of 4 years may result in the observation of a thin GBM, which could potentially lead to a misdiagnosis or underestimation of the severity of the disease. Therefore, caution is advised when interpreting biopsy results in this age group.

Despite careful investigation of the pedigree and the use of the full histologic evaluation, a definitive diagnosis of Alport syndrome may not be able to be established or the type of transmission may not be identifiable. Recent advancements in genetic diagnostic methods have improved accessibility, leading to the identification of genetic mutations related to Alport syndrome in patients with CKD who were previously undiagnosed or thought to have more common causes like diabetes or hypertension [11,49]. In these instances, whole-exome sequencing or next-generation sequencing gives information crucial for directing genetic counseling and assessing prognosis, although up to 10% of patients diagnosed with Alport syndrome based on clinical and pathological confirmation may harbor mutations that remain undetected through genetic testing [50]. However, genetic testing is the gold standard for diagnosing Alport syndrome, and it should be conducted in all patients with suspected or biopsy-confirmed Alport syndrome to determine the genotype and prognosis and to promote testing of at-risk family members.

In particular, the widespread adoption of next-generation sequencing has led to the reevaluation of numerous kidney disease cases, resulting in the reclassification of some patients as having Alport syndrome even when their symptoms do not consistently align with typical Alport syndrome manifestations. In a comprehensive analysis following whole-exome sequencing in a CKD population [49], 10% were identified to have genetic disease, with 30% of these cases being diagnosed as having Alport syndrome with COL4A mutations. Roughly 62% of these patients had previously been misdiagnosed with hypertensive nephropathy, steroid-resistant nephrotic syndrome, immunoglobulin A (IgA) nephropathy, or FSGS [51–54]. Particularly, COL4A mutations have emerged as the predominant cause in adult-onset FSGS, leading to up to 20% of familial FSGS cases. Finally, consideration of COL4A3–COL4A5 mutations in cases of CKD with unknown etiology is crucial. Current recommendations underscore the importance of categorizing FSGS or IgA nephropathy with pathogenic COL4A variants as Alport syndrome rather than an unrelated disease [55].

Conclusion

Progress in molecular genetics and clinical investigations in the last decade has enabled early identification and intervention in individuals with Alport syndrome. Additionally, histopathological diagnoses that differ from Alport syndrome cannot definitively rule out the presence of the disease, as some of these patients may carry disease-causing variants associated with it. Currently, there is no specific treatment for Alport syndrome. However, if the disease is diagnosed early, when patients are young, the prognosis can be improved by starting angiotensin-converting enzyme inhibitor treatment. A sodium-glucose cotransporter 2 inhibitor, bardoxolone, is another effective drug that can preserve renal function, but further research is needed, and its effectiveness is not enough to prevent the progression of Alport syndrome.

Given the current lack of a fundamental treatment for genes and gene-expression processes, we hope that this paper summarizing the etiology of Alport syndrome will promote research on necessary treatments in the future.

Notes

Conflicts of interest

All authors have no conflicts of interest to declare.

Data sharing statement

The data presented in this study are available from the corresponding author upon reasonable request.

Authors’ contributions

Conceptualization: EK, JHK, YNK

Supervision: HL, HGK, JHK, YNK, YJ, HR, HSS

Visualization: EK, BHP

Writing–original draft: EK, BHP, HSS

Writing–review & editing: EK, BHP, YNK, YJ, HR, HSS

All authors read and approved the final manuscript.

Figure 1.

Representative signs and symptoms of Alport syndrome.

Figure 2.

Types and composition of type IV collagen genes present on various chromosomes.

Figure 3.

Type IV collagen from gene to protein trimerization to disease.

ADAS, autosomal dominant Alport syndrome; AS, Alport syndrome; ARAS, autosomal recessive Alport syndrome; CAKUT, congenital anomalies of the kidney and urinary tract; XLAS, X-linked Alport syndrome.

Figure 4.

Factors that affect disease severity in AS.

ADAS, autosomal dominant Alport syndrome; AS, Alport syndrome; ARAS, autosomal recessive Alport syndrome; XLAS, X-linked Alport syndrome.

Figure 5.

Diagnostic approach for AS.

AS, Alport syndrome; RAAS, renin-angiotensin-aldosterone system; VUS, variant of uncertain significance.

Table 1.

Classification of Alport syndrome

Inheritance	Genetics	Risk of end-stage kidney disease
X-linked	Mutated COL4A5 gene in males	100%
X-linked	Females	Up to 25%
Autosomal recessive	Mutated COL4A3 or COL4A4 gene (homozygous or compound heterozygous)	100%
Autosomal dominant	Mutated COL4A3 or COL4A4 gene (single allele)	0%–50%
Autosomal dominant	Mutated COL4A3 or COL4A4 gene (single allele)	Risk factors: proteinuria, glomerular basement membrane lamellation, focal segmental glomerulosclerosis, hearing loss
Digenic	Mutated COL4A3 and COL4A4 genes in the trans position	Up to 100%
Digenic	Mutated COL4A3 and COL4A4 genes in the cis position	Up to 20%

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