Alport syndrome (AS) is a hereditary basement membrane disease caused by mutations in the genes encoding the α3, α4, and α5 chains of type IV collagen (COL4A3, COL4A4, COL4A5). It was first reported by A. Cecil Alport in 1927.
This syndrome begins in childhood with chronic hematuria and is characterized by a triad of progressive kidney disease, sensorineural hearing loss, and eye abnormalities. The estimated prevalence is 1 in 50,000 births, with a mutation frequency estimated at 1/5,000 to 1/10,000 6). It accounts for about 3% of chronic kidney disease in children and about 0.2% of end-stage renal failure in adults 1). It is the second most common hereditary kidney disease after autosomal dominant polycystic kidney disease 3).
Inheritance patterns are classified into three types.
| Inheritance pattern | Frequency | Causative gene |
|---|---|---|
| X-linked (XLAS) | Approximately 85% | COL4A5 |
| Autosomal recessive (ARAS) | Approximately 15% | COL4A3/COL4A4 |
| Autosomal dominant (ADAS) | Less than 5% | COL4A3/COL4A4 |
Next-generation sequencing reports suggest that autosomal dominant type may be more frequent (20–30%) than previously estimated1).
In X-linked type, males (hemizygotes) tend to be more severe, with about 90% progressing to end-stage renal failure by age 40. In contrast, X-linked females (heterozygotes) have a variable course, with only about 12% progressing to end-stage renal failure. Autosomal recessive and autosomal dominant types show equal incidence and severity in both sexes.
The ocular symptoms of this syndrome progress slowly.
Systemic symptoms include the following.
Ocular findings occur in eye tissues that contain abnormal type IV collagen (lens capsule, internal limiting membrane, Bruch’s membrane, Bowman’s membrane, Descemet’s membrane). In X-linked males, approximately 40% of children can be diagnosed based on ocular findings alone 3).
Lens Findings
Anterior lenticonus: The anterior surface protrudes conically due to thinning of the lens capsule. This is a pathognomonic finding in Alport syndrome. It is usually axial, measuring 2–7 mm. It presents with an oil droplet sign.
Cataract: Forms as lenticonus progresses.
Spontaneous anterior capsule rupture: Rarely, the weakened anterior capsule ruptures spontaneously, leaking lens material into the anterior chamber3). More common in young males.
Retinal Findings
Dot-and-fleck retinopathy: Superficial white to yellow granular changes. May be accompanied by a lozenge sign. Does not affect visual acuity.
Temporal macular thinning: Confirmed on OCT. Does not affect visual acuity.
Macular hole: May develop lamellar or full-thickness macular holes. Poor response to surgery.
Other ocular findings include the following.
腎臓の臨床所見として、微量アルブミン尿・蛋白尿の増悪、腎生検における糸球体基底膜（GBM）の菲薄化・肥厚・層状化（バスケットウィーブパターン）が特徴的である1)。
点状・斑点状網膜症と耳側黄斑菲薄化は視力に影響しない。ただし黄斑円孔は中心視力の低下を来し、手術への反応も不良である。網膜症の存在は早期腎不全への進行を示す予後因子となる。
アルポート症候群の原因はCOL4A3・COL4A4・COL4A5遺伝子の変異である。これらの遺伝子はIV型コラーゲンのα3・α4・α5鎖をコードする。
COL4A5遺伝子はX染色体（Xq22）に位置し、51エクソンから構成される6)。変異の種類はミスセンス変異（約38%）が最多で、欠失変異（約15.9%）、スプライシング変異（約14.9%）が続く6)。中国人X連鎖型AS患者の文献レビューでは、欠失変異を有する男性はミスセンス変異に比べ末期腎不全に進行する割合が高い（36.0% vs 15.4%、P=0.041）6)。
The COL4A3 gene is located on chromosome 2 (2q36-37) and consists of 52 exons 4). In patients with splicing mutations in COL4A3, the average age of onset of end-stage renal failure is reported to be 28 years 4). In consanguineous families, autosomal recessive homozygous mutations have been observed, and minigene experiments have confirmed exon skipping and partial deletion of the collagen domain of the α3(IV) chain in some cases 4).
The only risk factor is having an affected parent. Genetic counseling and family screening are important.
Yes, it differs. In X-linked type, large deletions, nonsense, and frameshift mutations are the most severe, with a 90% risk of end-stage renal failure before age 30. Splicing mutations have about a 70% risk, and missense mutations about 50% 6). Autosomal recessive homozygous and compound heterozygous mutations also tend to be severe 4).
Alport syndrome is likely if any of the following are present:
The diagnosis is confirmed by any of the following:
| Disease | Difference from Alport syndrome |
|---|---|
| Thin basement membrane nephropathy | Almost no extrarenal findings |
| IgA nephropathy | Positive IgA deposition on immunofluorescence |
| Pierson syndrome | LAMB2 mutation. More severe. |
Alport syndrome is sometimes misdiagnosed as IgA nephropathy 1). A 50-year-old woman was treated for IgA nephropathy for 4 years, but was diagnosed with Alport syndrome after reevaluation of electron microscopy findings and family history 1). Detailed family history taking and electron microscopy are essential for differential diagnosis.
There is currently no curative treatment for Alport syndrome. Renal protection with renin-angiotensin system inhibitors is the mainstay of therapy.
Lens extraction combined with intraocular lens implantation for anterior lenticonus and cataracts is expected to achieve good visual recovery. In reported cases, postoperative corrected visual acuity of 20/25 or better has been obtained 3). However, if a macular hole coexists, recovery of central vision is difficult.
Type IV collagen consists of six α chains (α1 to α6). Each α chain comprises three domains: an amino-terminal 7S domain, a collagen domain with approximately 1,400 Gly-X-Y repeats, and a carboxy-terminal NC1 domain 6).
The α3(IV), α4(IV), and α5(IV) chains assemble within the endoplasmic reticulum to form an α345(IV) heterotrimer 4). This trimer is secreted into the basement membranes of the GBM, lens capsule, cornea (Bowman’s membrane and Descemet’s membrane), inner ear (stria vascularis), and retina (inner limiting membrane and Bruch’s membrane).
When a pathogenic mutation occurs in any of the genes, the abnormal α chain inhibits trimer formation. In COL4A3 knockout mice, the α4 and α5 chains are absent in the glomerulus 4). In one family, a splicing mutation in COL4A3 (c.687+1G>T) causes skipping of exon 12, resulting in a deletion of 14 amino acids and partial loss of the Gly-X-Y repeats in the collagen domain 4). Immunofluorescence staining showed reduced expression and partial loss of all α3, α4, and α5 chains in the GBM of the proband 4).
In the basement membrane where the α345(IV) network is lost, the α1α1α2(IV) network remains compensatorily. This network has poor structural stability and is vulnerable to biomechanical strain.
Chen et al. (2025) reported a consanguineous family with a splicing mutation in COL4A3 (c.687+1G>T). Among 22 family members, one (the proband) had a homozygous mutation and nine had heterozygous mutations. The phenotypes of heterozygous carriers ranged from asymptomatic to microscopic hematuria, showing variability even within the same family 4).
Preimplantation genetic testing (PGT-M) has been reported as a means to prevent intergenerational transmission of Alport syndrome.
Hu et al. (2021) performed PGT-M combining targeted next-generation sequencing and SNP haplotyping in an XLAS family. Among three embryos obtained from a mother with a COL4A5 INDEL mutation (c.349_359del / c.360_361insTGC), one was judged normal, and a healthy boy was born after transplantation 7).
Gene therapy for AS is in the preclinical stage. Development of novel treatments such as chaperone therapy and stem cell therapy is underway.
Mismetti et al. (2022) reported metastatic pulmonary calcification in a 48-year-old woman on dialysis for chronic renal failure due to Alport syndrome. Bone scintigraphy showed diffuse accumulation in both lungs, which remained stable over 29 years of follow-up. This is the first report showing that pulmonary calcification associated with chronic renal failure can also occur in patients with Alport syndrome 8).
Liu et al. (2026) reported a 4-year-old boy with autosomal dominant polycystic kidney disease and Alport syndrome. A pathogenic variant in COL4A5 and a VUS in PKD1 were identified. This is a rare combination with only 4 cases reported in the literature, and the coexistence of both diseases may worsen renal prognosis 5).
