Alport Syndrome

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2021-01-18

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Genes

COL4A3, COL4A5, COL4A4, MYH9, COL4A6, MFF-DT, ACE, REN, ACSL4, ACE2, DDR1, IGAN1, CHP1, TG, TGFB1, TRPC6, VHL, ZNF185, PIEZO1, AMMECR1, CLCN5, SOSTDC1, B3GAT1, ZEB1, INF2, COQ8B, CFHR5, RHOV, MIR21, MIB1, PAX3, STAT3, CASR, CYP24A1, EGF, EGFR, FCGRT, CFH, HLA-DRB1, IGBP1, LAMA5, LOXL2, LRPAP1, MITF, MKI67, MMP3, MMP9, AGT, NPHP1, PAX2, ACVR2A

Drugs

5'-A, Bardoxolone methyl, Single stranded, chemically modified oligonucleotide that binds to and inhibits the function of micro RNA-21

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Summary

Clinical characteristics.

In Alport syndrome (AS) a spectrum of phenotypes ranging from progressive renal disease with extrarenal abnormalities to isolated hematuria with a non-progressive or very slowly progressive course is observed. Approximately two thirds of AS is X-linked (XLAS); approximately 15% is autosomal recessive (ARAS), and approximately 20% is autosomal dominant (ADAS). In the absence of treatment, renal disease progresses from microscopic hematuria (microhematuria) to proteinuria, progressive renal insufficiency, and end-stage renal disease (ESRD) in all males with XLAS, and in all males and females with ARAS. Progressive sensorineural hearing loss (SNHL) is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In individuals with ADAS, ESRD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare.

Diagnosis/testing.

The diagnosis of Alport syndrome is established in a proband with a pathogenic variant(s) in COL4A3, COL4A4, or COL4A5 identified on molecular genetic testing.

Management.

Treatment of manifestations: Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to delay onset of ESRD; routine treatment of hypertension; renal transplantation for ESRD. Potential living related donors must be evaluated carefully to avoid nephrectomy in an affected individual. Routine treatment of SNHL and cataracts; surgical intervention for symptomatic leiomyomas.

Agents/circumstances to avoid: Protection of corneas from minor trauma in those with recurrent corneal erosions. Minimize exposure to loud noise.

Surveillance: Follow up of all individuals with Alport syndrome with a nephrologist every six to 12 months; monthly monitoring of at-risk transplant recipients for development of anti-glomerular basement membrane antibody-mediated glomerulonephritis for the first year post transplant; audiologic evaluation of children every one to two years beginning at age six to seven years; monitoring for ocular abnormalities; evaluation for aortic dilation (for males with XLAS).

Evaluation of relatives at risk: Evaluate at-risk family members either by urinalysis or, if the pathogenic variant(s) in the family are known, by molecular genetic testing.

Genetic counseling.

Three modes of inheritance are recognized for Alport syndrome: X-linked, autosomal recessive, and autosomal dominant.

In families with X-linked inheritance, mothers heterozygous for a COL4A5 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy; sons who inherit the pathogenic variant will be affected with Alport syndrome and will eventually develop ESRD and, in most cases, deafness; daughters who inherit the pathogenic variant will typically have asymptomatic hematuria but may have more severe renal disease. Affected males will pass the pathogenic variant to all of their daughters and none of their sons.
In families with autosomal recessive inheritance, the parents of an affected child are obligate heterozygotes and carry one pathogenic variant; at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier who may or may not be symptomatic, and a 25% chance of being unaffected and not a carrier.
In families with autosomal dominant inheritance, each child of an affected individual has a 50% chance of inheriting the pathogenic variant and being affected.
In rare Alport families with digenic inheritance (pathogenic variants in two or more of the COL4A3, COL4A4, and COL4A5 genes), transmission patterns may not conform to mendelian expectations.

Molecular genetic testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if the pathogenic variant(s) in the family are known.

Diagnosis

Alport syndrome is a familial renal disorder caused by pathogenic variants in COL4A3, COL4A4, and COL4A5 that result in abnormalities of the collagen IV α345 network of basement membranes [Kashtan et al 2018]. Alport syndrome can be transmitted in an X-linked (XLAS), autosomal dominant (ADAS), or autosomal recessive (ARAS) pattern. The spectrum of renal involvement ranges from isolated, non-progressive hematuria to progressive nephropathy characterized by hematuria, proteinuria, and chronic kidney disease (CKD) and end-stage renal disease (ESRD). Affected individuals often have sensorineural hearing loss and characteristic ocular abnormalities. Rare individuals have associated aortic disease or diffuse leiomyomatosis.

This definition differs from previous iterations in that it classifies individuals with isolated hematuria and heterozygous pathogenic variants in COL4A3 and COL4A4 as having ADAS, rather than so-called "thin basement membrane nephropathy." For the argument in favor of this approach see Kashtan et al [2018]; for the counterargument see Savige [2018]. The goals of this approach are:

To encourage establishment of specific diagnoses in individuals with persistent glomerular hematuria with molecular confirmation whenever possible;
To facilitate surveillance of individuals with pathogenic variants in COL4A3, COL4A4, and COL4A5 for evidence of renal disease progression;
To promote early initiation of therapy to delay or prevent ESRD; and
To improve identification of affected family members.

Suggestive Findings

Alport syndrome should be suspected in an individual with the following clinical and pedigree features [Kashtan 2004].

Renal

Hematuria. 100% of affected males and more than 90% of affected females with XLAS have microhematuria (blood in the urine detectable only by microscope); 100% of males and females with ARAS have hematuria. Episodic gross hematuria is not unusual. Most individuals with ADAS have hematuria, although it may be intermittent.
Proteinuria, hypertension, and renal insufficiency develop with advancing age in all males with XLAS and in all males and females with ARAS. Proteinuria is frequent in ADAS, especially with advancing age, and affected individuals may exhibit progressive renal disease. Pathogenic variants in COL4 genes are not unusual in adult patients with proteinuria and renal biopsy findings of focal segmental glomerulosclerosis.

Cochlear

Bilateral high-frequency sensorineural hearing loss (SNHL) typically becomes apparent by audiometry in late childhood or early adolescence in males with XLAS and in males and females with ARAS.
In XLAS, SNHL eventually develops in 80%-90% of affected males as well as in some affected females; the incidence of SNHL in males and females with ARAS is probably similar to that in males with XLAS.
In some families with XLAS and in ADAS, SNHL may not be detectable until well into adulthood.

Ocular

Anterior lenticonus is pathognomonic of Alport syndrome. It occurs in 15%-20% of those with XLAS or ARAS and typically becomes apparent in late adolescence or early adulthood.
Perimacular flecks occur in approximately 30% of individuals with Alport syndrome.

Family history

Family history positive for hematuria, deafness, and/or ESRD is frequently seen.
Family history of hematuria or renal failure may be negative because 10%-15% of males with XLAS have the disorder as the result of a de novo pathogenic variant and approximately 15% of affected individuals have ARAS.

Testing

Urinalysis

Males with XLAS; males and females with ARAS. Urinalysis typically shows hematuria (dozens to hundreds of erythrocytes per high-power microscope field). Overlap with normal results is minimal. Proteinuria develops in essentially 100% of affected individuals, although the timing is variable.

Female heterozygotes for XLAS. Approximately 95% of heterozygotes exhibit persistent or intermittent microhematuria. Proteinuria develops in approximately 75% of heterozygous females.

Both males and females with XLAS may have intermittent or constant gross hematuria.

Both males and females with ADAS. Urinalysis frequently shows microhematuria although some individuals are asymptomatic. A substantial proportion of affected individuals eventually develop proteinuria.

Establishing the Diagnosis

The diagnosis of Alport syndrome is established in a proband with a pathogenic variant(s) in COL4A3, COL4A4, or COL4A5 identified on molecular genetic testing. See Table 1.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Alport syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical features in whom the diagnosis of Alport syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of Alport syndrome, the recommended molecular genetic testing approach is the use of a multigene panel.

A multigene panel that includes COL4A3, COL4A4, COL4A5, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Note: Some laboratories may offer targeted analysis for pathogenic variants, which may vary by laboratory. The pathogenic variants particularly common in the United States include the following:

c.4692G>A (p.Cys1564Ser)
c.4946T>G (p.Leu1649Arg)
c.5030G>A (p.Arg1677Gln)

Option 2

When the diagnosis of Alport syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: Pathogenic variants in COL4A3 and COL4A4 can be heterozygous (autosomal dominant) or biallelic (autosomal recessive). Pathogenic variants in COL4A5 are hemizygous or heterozygous (X-linked).

Table 1.

Molecular Genetic Testing Used in Alport syndrome (AS)

Gene ^1, 2	Proportion of AS Attributed to Pathogenic Variants in This Gene ³		Proportion of Pathogenic Variants ⁴ Detectable by This Method
Gene ^1, 2			Sequence analysis ⁵	Gene-targeted deletion/duplication analysis ⁶
COL4A3	12%-15%	Inheritance	~98% ⁷	~2% ⁸
COL4A3	12%-15%	AR: ~45% AD: ~55%	~98% ⁷	~2% ⁸
COL4A4	5%-8%	AR: ~45% AD: 55%	~98% ⁷	~2% ⁹
COL4A5	80%-85%	XL: 100%	85%-90% ^10, 11	10%-15% ¹²

1.: Genes are listed in alphabetic order.
2.: See Table A. Genes and Databases for chromosome locus and protein.
3.: Fallerini et al [2014], Morinière et al [2014], Bullich et al [2018]
4.: See Molecular Genetics for information on allelic variants detected in this gene.
5.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
6.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
7.: Storey et al [2013], Fallerini et al [2014], Morinière et al [2014]
8.: Morinière et al [2014], Oka et al [2014], Mencarelli et al [2015], Bullich et al [2018], Daga et al [2018]
9.: Gross et al [2003], Morinière et al [2014], Oka et al [2014], Bullich et al [2018]
10.: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
11.: Plant et al [1999], Bekheirnia et al [2010], Hanson et al [2011], Fallerini et al [2014], Morinière et al [2014]
12.: Renieri et al [1995], Plant et al [1999], Jais et al [2003], Arrondel et al [2004], King et al [2006], Bekheirnia et al [2010], Hanson et al [2011], Morinière et al [2014], Nozu et al [2017]

Digenic inheritance. Mencarelli et al [2015] have described digenic inheritance of Alport syndrome in several families. The causative allelic variants may be in cis or in trans, and result in variable clinical features and transmission patterns.

Clinical Characteristics

Clinical Description

In Alport syndrome a spectrum of phenotypes ranging from progressive renal disease with extrarenal abnormalities to isolated hematuria with a nonprogressive or very slowly progressive course is observed.

Alport syndrome has renal and, frequently, cochlear and ocular manifestations. Approximately two thirds of Alport syndrome is X-linked (XLAS); approximately 15% is autosomal recessive (ARAS), and approximately 20% is autosomal dominant (ADAS). In the X-linked form of Alport syndrome, disease manifestations are typically more severe in affected males. However, affected females with either XLAS or ARAS may have severe involvement as well. ADAS is typically a slowly progressive disorder; renal insufficiency and sensorineural hearing loss (SNHL) may not develop until relatively late in life.

Renal Manifestations

The hallmark of Alport syndrome is microscopic hematuria (microhematuria). Males with XLAS have persistent microhematuria from early in life. Episodic gross hematuria can occur, especially during childhood. More than 90% of females with XLAS have microhematuria, although it may be intermittent. Individuals with ARAS have persistent microhematuria, with no gender difference. Individuals with a heterozygous COL4A3 or COL4A4 pathogenic variant associated with ARAS have an estimated 50% incidence of persistent or intermittent microhematuria.

All males with XLAS develop proteinuria and, eventually, progressive renal insufficiency, which leads to end-stage renal disease (ESRD). Overall, an estimated 60% reach ESRD by age 30 years, and 90% by age 40 years [Jais et al 2000]. The rate of progression to ESRD is influenced by the nature of the COL4A5 pathogenic variant (see Genotype-Phenotype Correlations).

Approximately 12% of females with XLAS develop ESRD before age 40 years, increasing to 30% by age 60 years and 40% by age 80 years [Jais et al 2003].

Most individuals with ARAS develop significant proteinuria in late childhood or early adolescence and ESRD before age 30 years. Progression to ESRD occurs at a slower pace in individuals with ADAS (frequently delayed until later adulthood) than in those with XLAS or ARAS.

Renal Biopsy

Immunohistochemical analysis

Males with XLAS typically show complete absence of immunostaining for the collagen α3(IV) chain, α4(IV) chain, and α5(IV) chain on renal biopsy.
Approximately 20% of males with XLAS show normal staining of renal basement membranes for the collagen α3(IV) chain, α4(IV) chain, and α5(IV) chain.
Females heterozygous for XLAS typically exhibit patchy loss of staining for the collagen α3, α4, and α5(IV) chains in GBMs and tubular basement membranes [Kashtan et al 1996]. Some heterozygous females exhibit normal staining for the collagen α3, α4, and α5(IV) chains in renal basement membranes.
Individuals with ARAS show abnormalities of renal type IV collagen expression that differ from those of individuals with X-linked disease. Individuals with ARAS typically exhibit complete absence of staining for the collagen α3(IV) chain and α4(IV) chain. However, whereas their GBMs show no staining for the collagen α5(IV) chain, staining of Bowman's capsules and tubular basement membranes for the collagen α5(IV) chain is positive [Gubler et al 1995]. Some individuals with ARAS exhibit normal renal basement membrane staining for the collagen α3(IV) chain, α4(IV) chain, and α5(IV) chain.
Individuals with ADAS exhibit normal GBM staining for the collagen α3(IV) chain, α4(IV) chain, and α5(IV) chain.

Electron microscopy

Normal. The normal glomerular capillary wall has a trilaminar appearance consisting of a homogeneous electron-dense layer (lamina densa) sandwiched between two electron-lucent layers (the laminae rara interna and externa).
The outer (subepithelial) aspect of the glomerular capillary wall, where it abuts the foot processes of the glomerular visceral epithelial cells, is smooth and regular.
A variety of techniques have been used to measure GBM width. The cutoff value in adults ranges from 250 nm to 330 nm, depending on technique. The cutoff value in children ranges from 200 nm to 250 nm, depending on technique (250 nm is within 2 SD of the mean at age 11 years).
Alport syndrome. When diffusely present, the following three alterations are pathognomonic of Alport syndrome:
- The lamina densa appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving.
- The lacunae between these strands are frequently occupied by round, electron-dense bodies (possibly entrapped cytoplasm).
- The glomerular capillary wall is diffusely thickened and its epithelial aspect is scalloped.
However, the earliest change in Alport syndrome is diffuse thinning of the GBM. Children with XLAS and ARAS frequently exhibit only GBM thinning on renal biopsy. Women with XLAS and individuals with ADAS also may exhibit only GBM thinning. Marked variability in GBM width within a glomerulus in an individual with persistent microhematuria should raise suspicion of Alport syndrome.

Skin Biopsy

When renal biopsy is contraindicated (and genetic testing is not possible), a skin biopsy could be performed in place of the renal biopsy with the following findings:

Males with XLAS. In about 80% of males, incubation of a skin biopsy specimen with a monoclonal antibody directed against the collagen α5(IV) chain shows complete absence of staining of epidermal basement membranes. Approximately 20% of males show normal staining.
Females heterozygous for XLAS. Approximately 60%-70% of heterozygous females exhibit discontinuous staining of the collagen α5(IV) chain [van der Loop et al 1999]. This is attributed to X-chromosome inactivation, by which it would be expected that one half of the basilar keratinocytes would express a normal collagen α5(IV) chain.
Individuals with ARAS. All individuals have normal skin reactivity for the collagen α5(IV) chain.
Individuals with ADAS. All individuals have normal skin reactivity for the collagen α5(IV) chain.

Cochlear Manifestations

Hearing loss in Alport syndrome is never congenital. Diminished hearing is frequently detectable by late childhood or early adolescence in boys with XLAS. In its early stages, the hearing deficit is detectable only by audiometry, with bilateral reduction in sensitivity to tones in the 2,000- to 8,000-Hz range. In affected males, the hearing loss is progressive and eventually extends to other frequencies, including those of conversational speech. Hearing loss is frequently identifiable by formal assessment of hearing in late childhood, but in some families is not detectable until relatively late in life.

SNHL develops in 80%-90% of males with XLAS by age 40 years [Jais et al 2000]. The course of the hearing loss depends on the pathogenic variant (see Genotype-Phenotype Correlations). Hearing impairment in members of families with Alport syndrome is always accompanied by evidence of renal involvement; no convincing evidence that deaf males lacking renal disease can transmit Alport syndrome to their offspring has been reported. In females with XLAS, hearing loss is less frequent and tends to occur later in life.

There do not appear to be gender differences in the incidence or course of hearing loss in ARAS. Individuals with ARAS typically exhibit juvenile onset of hearing loss. Hearing loss may be a very late development in individuals with ADAS.

A histologic study of cochleas in individuals with Alport syndrome suggests that defective adhesion of the organ of Corti to the basilar membrane may underlie the hearing deficit [Merchant et al 2004].

Ocular Manifestations

Ocular lesions are common in Alport syndrome, occurring in 30%-40% of individuals with XLAS. The spectrum of ocular lesions appears to be similar in XLAS and ARAS. Ocular lesions appear to be relatively uncommon in ADAS.

Anterior lenticonus, in which the central portion of the lens protrudes into the anterior chamber, is virtually pathognomonic in Alport syndrome. When present, anterior lenticonus is bilateral in approximately 75% of individuals. It is absent at birth, usually appearing during the second to third decade of life. Progressive distortion of the lens may occur, accompanied by increasing myopia. Lens opacities may be seen in conjunction with lenticonus, occasionally resulting from rupture of the anterior lens capsule.
All reported individuals with anterior lenticonus who have been adequately examined have exhibited evidence of chronic nephritis and sensorineural hearing loss. It is far more common in affected males but can occur in females. The frequency of lenticonus in males with XLAS was 13% in one large series; its occurrence is related to the pathogenic variant (see Genotype-Phenotype Correlations).
Maculopathy consisting of whitish or yellowish flecks or granulations in the perimacular region was found in approximately 14% of males with XLAS in a large series. While the maculopathy is usually not associated with any visual abnormalities, some individuals have developed macular holes associated with severe thinning of the retina.
Corneal endothelial vesicles (posterior polymorphous dystrophy) and recurrent corneal erosion may also be seen in individuals with Alport syndrome.
Bilateral posterior subcapsular cataracts also occur frequently in individuals with Alport syndrome with diffuse leiomyomatosis (see Other).

Other

Aneurysms of the thoracic and abdominal aorta have been described in a small number of males with Alport syndrome [Lyons et al 2007, Kashtan et al 2010]. These aneurysms are notable for the relatively early age of diagnosis (age <40 years) and have required surgical intervention.

Diffuse leiomyomatosis. The association of Alport syndrome with diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in several dozen families [Antignac & Heidet 1996, Mothes et al 2002]. This results from large deletions that span the adjacent 5' ends of COL4A5 and COL4A6 [Zhou et al 1993] (see Genotype-Phenotype Correlations). Symptoms usually appear in late childhood and include dysphagia, postprandial vomiting, retrosternal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor. Affected females in these kindreds typically exhibit genital leiomyomas as well, causing clitoral hypertrophy with variable involvement of the labia majora and uterus.

Genotype-Phenotype Correlations – XLAS

Risk for end-stage renal disease (in untreated individuals)

Large rearrangements and pathogenic nonsense and frameshift variants confer a 90% probability of end-stage renal disease (ESRD) before age 30 years, with 50% reaching ESRD by age 20 years [Jais et al 2000].
In affected individuals with splice site variants, the probability of ESRD before age 30 years is 70%, with 50% reaching ESRD by age 25 years.
Missense variants are associated with only a 50% probability of ESRD before age 30 years and a renal half-life (the time it takes for 50% of the group to reach end stage; i.e., the need for dialysis or transplantation) of 32 years.
In one study, COL4A5 missense variants that alter glycine and non-glycine residues in the 3' portion of COL4A5 were associated with earlier development of ESRD, compared with missense variants that alter glycine residues in the 5' portion of the gene [Gross et al 2002]. In another study, pathogenic variants at the 5' end of COL4A5 were associated with earlier ESRD, hearing loss, and ocular changes [Bekheirnia et al 2010].

Risk for deafness

In individuals with large rearrangements of COL4A5 or nonsense, frameshift, or splice site variants, the risk for deafness is 50% at age ten years.
In individuals with missense variants, the risk for deafness does not reach 50% until age 20 years.

Risk for anterior lenticonus. Anterior lenticonus occurs in approximately 15% of males with XLAS. Anterior lenticonus is almost entirely restricted to families with Alport syndrome with hearing loss and progression to ESRD before age 30 years. This observation is explained by the finding that lenticonus is significantly more common in individuals with a COL4A5 deletion or a small pathogenic variant resulting in a premature stop codon than in those with pathogenic missense or splice site variants [Jais et al 2000].

Risk for diffuse leiomyomatosis

All families in which XLAS cosegregates with diffuse leiomyomatosis exhibit large deletions that span the adjacent 5' ends of COL4A5 and COL4A6. These deletions involve varying lengths of COL4A5, but the COL4A6 breakpoint is always located in the second intron of the gene [Antignac & Heidet 1996].
Leiomyomatosis does not occur in individuals with deletions of COL4A5 and COL4A6 that extend beyond intron 2 of COL4A6.
Pathogenic variants of COL4A6 alone do not appear to cause Alport syndrome, a finding consistent with the absence of the α6(IV) chain from normal GBM.

Penetrance

Penetrance may be decreased in ADAS; at present, data are insufficient to draw a definitive conclusion.

Nomenclature

The term "benign familial hematuria," previously applied to Alport syndrome, is a misnomer that should no longer be used.

Prevalence

The prevalence of Alport syndrome has been estimated at 1:50,000 live births [Levy & Feingold 2000]. Data from several series suggest that approximately one fifth of children evaluated by pediatric nephrologists for isolated microhematuria receive a diagnosis of Alport syndrome. According to the United States Renal Data System (USRDS), approximately 0.2% of adults and 3% of children in the United States with ESRD carry a diagnosis of Alport syndrome.

Differential Diagnosis

Conditions with Hematuria

Alport syndrome most often presents in childhood, and thus must be differentiated from other causes of persistent (>6 months in duration) microhematuria in children.

The first step in the evaluation of hematuria in children is to attempt to establish the source of the hematuria (renal/glomerular, renal/post-glomerular, post-renal).
- This often involves evaluation of urinary erythrocyte morphology by phase contrast microscopy, urinary calcium measurement, and/or renal ultrasound examination.
- Family history is an important component of the initial evaluation of the child with hematuria. When possible, obtaining urinalyses on first-degree relatives can also be informative.
Once microhematuria is provisionally localized to the glomeruli, possible etiologies include a number of chronic glomerulopathies.
In the child with no known family history of hematuria, the most likely diagnoses are IgA nephropathy, Alport syndrome, and C3 glomerulopathy).

Combined Nephritis and Deafness

MYH9-related disorders. MYH9-related disorders (MYH9RD) are characterized by large platelets and thrombocytopenia, both of which are present from birth. MYH9RD is variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, elevation of liver enzymes, and renal disease manifesting initially as glomerular nephropathy. Before identification of pathogenic variants in MYH9, individuals with MYH9RD were diagnosed as having Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, or Sebastian syndrome based on the combination of different clinical findings at the time of diagnosis. Some individuals with MYH9RD exhibit ultrastructural changes of the glomerular capillary wall reminiscent of those seen in individuals with Alport syndrome. MYH9RD is inherited in an autosomal dominant manner.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Alport syndrome, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 2.

Recommended Evaluations Following Initial Diagnosis in Individuals with Alport Syndrome

System/ Concern	Evaluation	Comment
Renal	Baseline testing of urine protein excretion	Overt proteinuria (urine protein-creatinine ratio >0.2 or, in a child, 24-hr urine protein >4 mg/m²/hr) is an important indicator of renal disease progression in individuals w/Alport syndrome.
Hearing	Baseline audiogram	High-frequency sensorineural deafness typically becomes detectable by audiogram in late childhood.
Vision	Baseline ophthalmologic evaluation	Evaluate for maculopathy & anterior lenticonus, which are typically asymptomatic.
Other	Consultation w/clinical geneticist &/or genetic counselor

Treatment of Manifestations

Clinical practice recommendations for the treatment of individuals with Alport syndrome have been published [Kashtan et al 2013]. These recommendations encourage early detection of microalbuminuria and proteinuria through regular surveillance and early intervention aimed at suppressing proteinuria using angiotensin antagonists (click here for full text).

Table 3.

Treatment of Manifestations in Individuals with Alport Syndrome

Manifestation/ Concern	Treatment	Considerations/Other
Renal disease	Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker	Early treatment delays onset of ESRD. ¹
	Standard management for hypertension
	Renal transplantation for ESRD	Special considerations apply to selection of potential living related kidney donors for individuals w/XLAS (see Note on selection of kidney donors).
Hearing deficit	Hearing aids as needed
Vision issues	Cataract removal
Diffuse leiomyomatosis	Symptomatic leiomyomas may require surgical intervention.

1.: Gross et al [2012]

Note on selection of kidney donors. The following discussion considers potential donors on the basis of gender and the presence or absence of hematuria:

Male relative without hematuria. The optimal living related donor is a male who has a normal urinalysis and is therefore unaffected.
Male relative with hematuria. A related male with hematuria probably has Alport syndrome and cannot be a kidney donor.
Female relative without hematuria. Female relatives who have normal urinalyses are probably unaffected, although approximately 5% of females heterozygous for a COL4A5 pathogenic variant are asymptomatic. It is rare for asymptomatic females whose children are also asymptomatic to be heterozygous. Asymptomatic females can probably donate a kidney safely but should be informed of their risk of having affected male children to whom they will not be able to donate a kidney. Genetic status can be confirmed or excluded by molecular genetic testing if the pathogenic variant in the family is known.
Female relative with hematuria (i.e., heterozygous female). Females heterozygous for a COL4A5 pathogenic variant should only be considered as potential kidney donors if no asymptomatic living donors are available.
- The presence of proteinuria or sensorineural deafness is an absolute contraindication to kidney donation as these are risk factors for progression to ESRD.
- Heterozygous females younger than age 40 years should not be used as donors, even in the absence of proteinuria or deafness.
- Heterozygous females age 40 years or older who have normal renal function, blood pressure, and hearing and no proteinuria can be considered as donors because the risk of late progression to ESRD appears to be low in such individuals. However, the donor should be informed of the risk (albeit low) of late progression to ESRD.

Surveillance

Clinical practice recommendations for the treatment and health surveillance of individuals with Alport syndrome have been published [Kashtan et al 2013].

Table 4.

Recommended Surveillance for Individuals with Alport Syndrome

System/ Concern	Evaluation	Frequency
Renal