Alport syndrome and thin basement membrane nephropathy

Alport syndrome is due to altered formation of basement membranes in the glomerulus (glomerular basement membrane or GBM), cochlea, lens and cornea. The most severe forms are associated with hemizygous (X-linked) or autosomal recessive pathogenic variants, causing renal failure and sensorineural deafness in teenage or early adult life. Heterozygous X-linked or autosomal pathogenic variants sometimes cause significant renal disease.

Thin basement membrane nephropathy (TBMN) is a biopsy appearance, coupled with a mild clinical presentation, that is often associated with heterozygosity for Alport variants.

Renal

Features of classic X-linked or autosomal recessive Alport syndrome include:

• Microscopic haematuria from infancy, sometimes with episodes of microscopic haematuria in infancy or childhood. (See ‘Adult with microscopic haematuria‘.)
• Proteinuria, developing later, that can reach levels causing nephrotic syndrome.
• Progressive loss of glomerular filtration rate (GFR), causing end-stage kidney disease in early life: on average by the late 20s without treatment, but ranging from under 10 to middle age.
• Cystic kidneys. Population and clinical studies have associated variants in Alport-associated genes with cystic kidneys, but, while they are quite common, even in heterozygotes they are rarely a prominent feature.

Variation in the kidney phenotype is, in part, attributable to the causative variant. Those with heterozygous pathogenic variants usually have only microscopic haematuria without extra-renal features, but a minority develop significant renal disease in their lifetime.

Other

Hearing and eye manifestations are mainly seen in males with X-linked disease and individuals with autosomal recessive disease. Extra-renal features are unusual in heterozygotes, and can include:

• Sensorineural deafness beginning in childhood or early adult life, after speech development and helped by hearing aids.
• Retinal flecks and anomalies on optical coherence tomography (OCT) that do not usually affect vision.
• Changes in lens (lenticonus) and cornea.

Type IV collagen is the major protein of basement membranes. It has six alpha chains, encoded by genes COL4A1 to COL4A6. The products of COL4A3, COL4A4 and COL4A5 (α3, α4, and α5 chains of type IV collagen) form a tissue-specific α345 triple helical protomer that assembles into a lattice-like network. In the glomerulus, cochlea, and some other tissues, the α345 network replaces the α112 network (encoded by COL4A1 and COL4A2) that is ubiquitous in other basement membranes. A rare deletion that affects the adjacent 5’ (five prime) ends of the COL4A5 and COL4A6 genes causes Alport syndrome with diffuse leiomyomatosis.

Genes and phenotypes

The table below provides more information about the types of conditions linked to alterations in the COL4 genes.

Terminology for conditions associated with heterozygosity for COL4A3 or COL4A4 variants

• TBMN, diagnosed by electron microscopy of a renal biopsy, is not synonymous with heterozygosity for COL4A3 or COL4A4 variants, but assumed prognosis and management are similar whether or not a genetic cause has been identified.
• The term ‘benign familial haematuria’, once used to describe TBMN, became obsolete when it was recognised that it is not always benign.
• In recent literature, the term ‘autosomal dominant Alport syndrome’ has been applied to COL4A3/4 heterozygotes, despite the low clinical impact of heterozygosity for most individuals and the frequency of pathogenic variants in the general population.
• The term ‘Alport spectrum’ is used to describe the range of pathogenic variants that can be found in COL4A3, A4, or A5.

• Alport syndrome should be suspected when persistent haematuria is present with at least one of the following findings:
  • bilateral high-frequency sensorineural hearing loss;
  • anterior lenticonus and/or perimacular flecks;
  • a family history of haematuria, chronic kidney disease, ESKD and deafness; and/or
  • characteristic renal biopsy findings of thin GBM, GBM thickening and lamellation.
• The diagnosis of Alport syndrome is based on clinical history and a family history of renal failure and/or deafness, with electron microscopy of the GBM as a confirmatory test.
• Genomic testing is the gold standard test for diagnosis. A positive genomic test result may avoid the need for a diagnostic renal biopsy if typical features of the disease are present.
• Alport Syndrome may be an unexpected finding in patients with kidney disease of unknown cause, or even in the presence of another diagnosis.
• Heterozygous pathogenic variants in COL4A3 or COL4A4 are found in about 1% of the UK population. They are therefore commonly identified during genomic testing, especially from large panels, whole exome or whole genome sequencing. Some associations may be chance findings (see ‘Incidental findings‘ for further information). See the table above for implications.
• Heterozygous variants in COL4A3, COL4A4 and COL4A5 are commonly reported when genomic testing is performed for proteinuria or nephrotic syndrome, ESKD, cystic kidney disease and focal segmental glomerulosclerosis (FSGS). They are over-represented in these and some other renal conditions, suggesting a contributory role in pathogenesis.
• If a causative variant is identified through a study such as the Generation Study, a referral to paediatric nephrology will be required.

Inheritance and genomic counselling

Alport Syndrome is inherited as an X-linked (COL4A5) or autosomal recessive (COL4A3 or COL4A4) condition. Fifteen percent of cases of X-linked Alport syndrome may be de novo, and mosaic inheritance has also been described.

Renal disease may occur in those with heterozygous pathogenic variants, particularly in COL4A5, as described in the table above. The average risk of significant kidney disease in those heterozygous for autosomal pathogenic variants (COL4A3, COL4A4) is low, but above background population risk.

Individuals with a chance of having a child with Alport syndrome, either X-linked or autosomal recessive, should be offered genomic counselling which will include a discussion about prenatal and preimplantation genetic testing.

There is good clinical evidence that early treatment slows the progression of renal disease in individuals with any form of Alport Syndrome. This is also true for those with heterozygous COL4 variants who develop proteinuria or reduced GFR, who are at increased risk of renal disease. Angiotensin converting enzyme (ACE) inhibitors are proven to slow disease progression. SGLT2 inhibitors and other interventions for proteinuric chronic kidney disease may help further. There are currently no disease-specific therapies available. ESKD should be managed as usual.

Impaired hearing is greatly helped by hearing aids. Regular testing is recommended in childhood to ensure full benefit from education.

This condition may be identified before any symptoms appear, for example through the Generation Study. Long-term follow-up to monitor for complications is required.

National Registry of Rare Kidney Diseases (RaDaR)

Those with Alport Syndrome, their heterozygous relatives, and others with TBMN, should be registered on the National Registry of Rare Kidney Diseases (RaDaR).  RaDaR facilitates translational and epidemiological research into rare diseases through a comprehensive clinical database. It is managed by the UK Renal Registry on behalf of the UK Kidney Association. Recruitment is open to all UK hospitals.

For clinicians

• Edinburgh Renal Unit: Alport Syndrome
• GeneReviews: Alport Syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory

References:

• Savige J. ‘Heterozygous Pathogenic COL4A3 and COL4A4 Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities’. Kidney International Reports 2022: volume 7, issue 9, pages 1933–1938. DOI: 10.1016/j.ekir.2022.06.001

For patients

• Alport UK
• Edinburgh Renal Unit: Alport Syndrome