Health and Disease

Alport Syndrome In Women

Alport Syndrome is a genetically inherited kidney disease. It is caused by genetic mutations of the collagen IV family of proteins, which are a major part of basement membranes present in all tissues, including the kidney, inner ear, and eye. This analysis will identify clinical features of this disease, its diagnosis, and common types and symptoms.

What is Alport Syndrome?

Alport Syndrome is a genetically inherited kidney disease. It is caused by genetic mutations of the collagen IV family of proteins, which are a major part of basement membranes present in all tissues, including the kidney, inner ear, and eye. Genetic mutations of collagen IV (COL4A5 is situated on the X chromosome, while COL4A3 and COL4A4 are situated on chromosome 2) cause thinning and splitting of the glomerular basement membrane. X-linked Alport Syndrome (XLAS) is caused by mutations in the COL4A5 gene which encodes the collagen IV α5 chain . Autosomal recessive disease is caused by two mutations in trans (on different chromosomes) in the COL4A3 or COL4A4 genes, which are code for the collagen IV α3 and α4 chains, respectively. The collagen IV α3, α4, and α5 chains form a heterotrimer that is the predominant network of the basement membranes of the glomerular filter, the cochlea, cornea, lens capsule, and retina. The collagen IV heterotrimer consists of a long series of Gly-Xaa-Yaa repeats, where Gly is present at each third residue, and X and Y are often hydroxyproline and proline. This process leads to scarring throughout the kidney, and may later lead to kidney failure. It may also cause abnormalities in the ears and eyes, which can lead to vision and hearing loss.


Hematuria – Blood in urine

Abnormal urine color

Proteinuria – Large amounts of protein “spilling” into the urine

Foamy urine

Edema – Swelling in parts of the body, most noticeable around the eyes, hands and feet, and abdomen

Low Blood Albumin Levels

Flank pain

Decreased or loss of vision (more common in males)

Loss of hearing (more common in females)

High Cholesterol in some cases

High Blood Pressure in some cases

Tendency to form Blood Clots if spilling large amounts of protein

Kidney Failure (in only some cases) as the disease progresses


1)CLASSIC Alport Syndrome: X-linked syndrome with haematuria, sensorineural deafness, and conical deformation of the anterior lens surface(lenticonus)

2)X-LINKED FORMED ASSOCIATED with diffuse leiomyomatosis



Autosomal dominant and recessive forms both cause renal disease without deafness or lenticonus.


Many renal physicians think of Alport Syndrome as primarily affecting men. However, twice as many women are also affected by X-linked Alport Syndrome. The women who are affected are commonly undiagnosed. Half of their sons and daughters are also affected. Recessive inheritance is suspected when women develop early-onset renal failure or lenticonus. Their family may be consanguineous. Other generations, including parents and offspring, are not affected, and on average only one in four of their siblings inherit the disease. 

X-LINKED Alport Syndrome(XLAS):

In cases of X-linked inheritance, the genetic defect causing the disease is on the X chromosome. Since men, unlike women, have only one copy of the X chromosome, X-linked Alport Syndrome is more likely to affect men. Women with one faulty copy of the X chromosome can develop the disease, but it is usually less severe in women because their other X chromosome can compensate. Most go undiagnosed or underdiagnosed due to variations in symptom severity and course of disease progression. Between 15 and 30 % of women with XLAS develop kidney failure by the age of 60 and symptoms of hearing loss by their middle ages.


Women have two copies of the X chromosomes, but one of them is randomly turned off or inactivated during development in a process called LYONIZATION. Thus, in each cell, there is only one active X chromosome and one inactive X chromosome. Since lyonization is random in people and varies from cell to cell, the X chromosome that remains active may either be carrying the normal gene or the defective gene. Depending on the proportion of cells in which the normal X chromosome is active, the symptoms can vary from no symptoms at all to those that are quite severe.

Sometimes, X chromosome inactivation can be preferential (also called skewed X-Inactivation) and the normal X chromosome can be unfavored, resulting in most cells expressing the mutated gene. Such women can be as severely affected by XLAS as men.


X-linked Alport Syndrome is underdiagnosed or undiagnosed in women, which is observed in generational skipping. This occurs because female relatives of affected men are not systematically screened in adult nephrology practice.

A male with X-linked disease has inherited the disease from his mother in 85% of cases. On average, half of the male’s affected family include his sisters, brothers, and daughters, but none of his sons.

For females with X-linked disease, the situation is more complex since the disease can be inherited from her father or mother. If a woman inherits the disease from her father, then all of her sisters are also affected, but if she inherits the disease from her mother, then half of her sisters and half her brothers are also affected. In addition, half an affected woman’s sons and half her daughters are affected.

Clinical features of Alport Syndrome in women:

Clinical features in females depend on mutation type and “lyonization.” Lyonization produces a mosaic distribution of the mutant collagen IV α5 chain and disease in the female kidney and skin. This may result in a normal clinical phenotype (a severe or an intermediate), and the staining pattern for diagnostic testing may be confusing.

Hematuria: Nearly all females with X-linked Alport Syndrome have persistent hematuria from infancy. The presence of even short stretches of lamellation suggests Alport Syndrome.

Albuminuria: Albuminuria is not well-studied in women with Alport Syndrome. 

ESRD: 30% of all women with X-linked Alport Syndrome develop ESRD by the age of 60. Affected women should be strongly advised not to donate a kidney to an affected male relative, even when urine protein excretion is normal. This is because of their own risk of ESRD. It is important, though, to confirm genetically if the mother is actually affected because of the small chance (15%) of a de novo mutation in her son.

Autosomal recessive Alport Syndrome: It affects about one in 40,000 individuals, and is suspected in young women with renal failure and hearing loss, or lenticonus. The family may be consanguineous. Typically, the only other affected family member, if any, is a sibling. The affected woman’s parents, grandparents, and children may have hematuria and thin basement membrane nephropathy, but do not develop renal failure.


Women with Alport Syndrome should be identified at an early age once proteinuria appears.

Accurate diagnosis of Alport Syndrome in girls and women can be challenging because many affected females exhibit only microscopic haematuria and glomerular basement membrane attenuation. In such patients, family history and immunohistochemical analysis of type IV collagen expression in basement membranes of the skin or kidney may be helpful. Alport Syndrome should be suspected in women with haematuria and a positive family history of kidney failure. A negative family history for renal failure does not, however, exclude a diagnosis of Alport Syndrome. In some women with longstanding haematuria, a diagnosis of Alport Syndrome is established only after the diagnosis is made in a child. An individualized approach should be taken toward female members of Alport Syndrome whose haematuria is associated with atypical symptoms, such as dysuria or flank pain, or unexpectedly severe abnormalities of renal function, such as heavy proteinuria or azotemia at a young age.

Type IV IHC abnormalities that are distinguishing characteristics in females include-

I) Typical ARAS female-Renal basement membranes are entirely negative for the α3(IV) and α4(IV) chains, and glomerular basement membranes are completely negative for the α5(IV) chain, reflecting the failure to deposit α3α4α5(IV) trimers.

II) Bowman’s capsules, distal tubular basement membranes and EBM are positive for α5(IV) chains, because formation and deposition of α5α5α6(IV) trimers are preserved.


Renal transplantation is usually very successful in women with Alport Syndrome who progress to end-stage renal failure. Even though anti-GBM nephritis of the renal allograft occurs in about 3% of transplanted Alport males, the risk of this complication in females with XLAS should theoretically be close to zero. Women with ARAS, due to certain COL4A3 mutations, can develop anti-GBM nephritis of the allograft.

By Pratiksha Baliga (India), Youth Medical Journal

Reference sites:

“Alport Syndrome.” NephCure Kidney International,

Kashtan, Clifford E. “Alport Syndrome and the X Chromosome: Implications of a Diagnosis of Alport Syndrome in Females.” OUP Academic, Oxford University Press, 29 Mar. 2007,

Naqvi, Erum. “Alport Syndrome in Women.” Alport Syndrome News, Bionews Services, 25 Apr. 2018,

Savige, Judy, et al. “Alport Syndrome in Women and Girls.” Clinical Journal of the American Society of Nephrology : CJASN, American Society of Nephrology, 7 Sept. 2016,

By Pratiksha Baliga

Pratiksha Baliga is a medical student residing in Mumbai,India. She's interested in the fields of Neurology, Radiology, Medicine. She aspires to be a Neurologist.

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