Alport syndrome Q87.8

The disease was named after the South African doctor Arthur Cecil Alport (1880-1959). Alport first described three generations of a family suffering from congenital progressive nephritis and hearing loss in 1927.

AS is a heterogeneous disease caused by variants in genes that code for collagen type IV. Six genes (COL4A1-COL4A6), corresponding to the six homologous collagen chains (α1-α6) for collagen type IV, are known. The mutations lead to a progressive disease of the glomerular basement membrane. This is combined with sensorineural hearing loss and eye changes (Weber S et al. (216).

Prevalence of X-linked Alport syndrome: 1.5000 -1:10.000. AS is the most common hereditary cause of terminal renal failure.

It is predominantly a male disorder. In men in the USA, AS is the cause in about 2.5% of cases of terminal renal failure, in India in 1.1%, in Europe in 0.64% of cases.

The course of the disease in the female sex is variable. Rarely are women severely affected (the normal allele on the other X chromosome has a partially compensatory effect). Girls and women with a heterozygous variant in COL4A5 show a wide range of clinical symptoms, both intra- and interfamily, ranging from microhaematuria to full AS. Up to 30 % of women develop renal insufficiency by the age of 60. In addition, there is a risk of approximately 30 % each for high frequency hearing loss and/or retinopathy. The cause of the phenotypic variability in girls and women is suspected to be  a. unfavourable X inactivation and the presence of genetic modifiers (Rheault MN (2012).

To date, more than 300 different mutations are known in AS (Weber S et al. 2016). In up to 95% of patients, causative variants can be detected in the previously known genes COL4A3, COL4A4 and COL4A5, mostly glycine, nonsense, splice site and frameshift variants as well as major deletions or duplications.

In up to 85% of cases X-linked inheritance with mutation of the COL4/A5 gene located on chromosome Xq22.3, which encodes the alpha35 chain of type IV collagen. In this mode of inheritance, about 40% of all variants are missense alterations, 10% are splice variants, 7% are nonsense alterations, and another 30% result in frameshift.

In 10-15% of cases autosomal recessive process with mutations of COL4/A3 and COL/A4 genes, In 10% there is an autosomal recessive inheritance, the mutation is located on chromosome 2, gene locus q35-36. The genes COL4A3 or COL4A4, which encode the alpha chains of type IV collagen, may be affected.

About 10% of cases of AS are due to new mutations.

Very rarely, Alport syndrome is based on an autosomal dominant inheritance.

The urine finding is pathological already after birth. Proteinuria and microhaematuria are present as an expression of incipient chronic glomerulonephritis. Intermittent macrohaematuria may also occur.

In young adults, bilateral sensorineural hearing loss occurs in 50% of cases, especially in the frequency range 2000-8000 Hz. In about 10% of cases, changes in the eye occur, mostly due to a conical bulge of the eye lens (lenticonus). Other eye diseases include:

• Keratoconus
• Cataract
• Changes of the ocular fundus like: retinal spots in the macula and in the middle of the periphery.

With increasing age a chronic progressive renal insufficiency develops, which usually requires renal replacement therapy at the beginning of the second decade of life.

Until recently, the course of the disease was considered fateful, although molecular genetic diagnosis is possible in infancy even before the onset of the disease.

IgA nephropathy

thin basement membrane syndrome

A causal therapy is currently not available. Preventive therapy with ACE inhibitors can delay the course of kidney disease by several years. It can be assumed that - in addition to the damage to the kidneys caused by Alport syndrome itself - it is above all the high blood pressure caused by renal insufficiency that damages kidney function. Therefore, an early start of blood pressure treatment with low target values (120/80 mmHg) is particularly important. It has been shown that ACE inhibitors delay dialysis by 18 years on average and clearly improve life expectancy (Gross O et al. 2014).

Dialysis becomes necessary in cases of progressive renal failure. Kidney transplantation is the final option.

Because of the X-linked chromosomal inheritance, mainly men are affected. The course of the disease is very variable, but often terminal renal insufficiency requiring dialysis already occurs in young adulthood.

Instead of "Alport Syndrome", the expert consensus guidelines advocate the term "Thin Basement Membrane Nephropathy" (TBMN) as the dominant inherited term, taking into account its limitations. Patients with TBMN are also considered carriers of AR-ATS, and variants in COL4A3, COL4A4 and COL4A5 are also detected in > 30% of patients with adult focal segmental glomerulosclerosis (FSGS ).

1. Gross O et al (2012) Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney International 81: 494-501
2. Gross O et al (2014) Alport syndrome from bench to bedside: the potential of current treatment beyond RAAS blockade and the horizon of future therapies. Nephrol Dial Transplant 29(Suppl 4):124-130
3. Mencarelli MA et al (2015) Evidence of digenic inheritance in Alport syndrome. J Med Genet. 52:163–174.
4. Temme J et al (2012) Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-linked and autosomal recessive Alport mutations. Kidney International 81: 779-783
5. Rheault MN (2012) Women and Alport syndrome. Pediatric Nephrol 27:41-46
6. Savige J et al (2018) Expert consensus guidelines for the genetic diagnosis of Alport syndrome. Pediatric Nephrol 34:1175 https://doi.org/10.1007/s00467-018-3985-4
7. Weber S et al (2016) Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy. Pediatric Nephrol 31:941-955