Alport Syndrome in Women and Girls

Abstract

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Inheritance is X-linked (85%) or autosomal recessive (15%). Many renal physicians think of Alport syndrome as primarily affecting men. However, twice as many women are affected by the X-linked diseases. Affected women are commonly undiagnosed, but 15%-30% develop renal failure by 60 years and often hearing loss by middle age. Half of their sons and daughters are also affected. Autosomal recessive Alport syndrome is less common, but is often mistaken for X-linked disease. Recessive inheritance is suspected where women develop early-onset renal failure or lenticonus. Their family may be consanguineous. The prognosis for other family members is very different from X-linked disease. Other generations, including parents and offspring, are not affected, and on average only one in four of their siblings inherit the disease. All women with Alport syndrome should have their diagnosis confirmed with genetic testing, even if their renal function is normal, because of their own risk of renal failure and the risk to their offspring. Their mutations indicate the mode of inheritance and the likelihood of disease transmission to their children, and the mutation type suggests the renal prognosis for both X-linked and recessive disease. Women with X-linked Alport syndrome should be tested at least annually for albuminuria and hypertension. The "Expert guidelines for the diagnosis and management of Alport syndrome" recommend treating those with albuminuria with renin-angiotensin-aldosterone system (RAAS) blockade (and adequate birth control because of the teratogenic risks of angiotensin converting enzyme inhibitors), believing that this will delay renal failure. Current recommendations are that women with autosomal recessive Alport syndrome should be treated with RAAS blockade from the time of diagnosis. In addition, women should be offered genetic counseling, informed of their reproductive options, and monitored closely during pregnancy for the development of hypertension.

Keywords: ACE inhibitors; Alport syndrome; Chronic; Deafness; Female; Genetic Testing; Hearing Loss; Hereditary; Humans; Kidney Failure; Mutation; Nephritis; albuminuria; genetic renal disease.

Figure 1.

More women are affected than men in X-linked Alport syndrome. Families of offspring of a male (A) and a female (B) with X-linked Alport syndrome demonstrating more affected females than males in their combined offspring (three times as many, 3:1 in one generation; and overall twice as many, 4:2 in the two generations). Males are shown as squares and females as circles. Affected individuals are in black.

Figure 2.

The risk of siblings being affected depends on the mode of inheritance and the gender of the affected parent (in X-linked disease). Examples of families of females (arrows) who have inherited X-linked Alport syndrome from their father (A) or mother (B), indicating other family members who are likely to be affected. All the daughters of the affected father are affected, and half the sons and daughters of the affected mother. (C) Indicates the family of a woman with autosomal recessive disease. With autosomal recessive disease, males and females (with two COL4A3 or COL4A4 mutations) are affected equally often and equally severely, and disease occurs in only one generation. Other family members with only one mutation (half-shaded symbols) have thin basement membrane nephropathy and are much less likely to develop renal failure than females with X-linked Alport syndrome.

Figure 3.

Glomerular basement membrane (GBM) appearance and patterns of hearing loss in women with Alport syndrome. (A) Electron micrograph of kidney biopsy from a 40-year-old woman demonstrating a variably thinned glomerular capillary basement membrane, <200 nm in places, but without multilamellation, splitting, or GBM microparticles. The appearance was indistinguishable from thin membrane nephropathy and was misdiagnosed until recent genetic testing confirmed X-linked Alport syndrome; (B) audiometry 30 years later (age 70) from the same woman with X-linked Alport syndrome due to a R373× mutation in COL4A5 demonstrating a high tone sensorineural hearing loss in the left ear (above 6000 Hz); and (C) audiometry from a 50-year-old with X-linked Alport syndrome demonstrating a midtone sensorineural loss in the right ear.

Figure 4.

Characteristic ocular features in women with Alport syndrome. (A) Corneal opacity (arrow) in a 60-year-old woman with X-linked Alport syndrome and an in-frame COL4A5 deletion, hearing loss, and normal renal function; and (B) higher powered view of the same abnormality. Her son had a renal transplant and had a similar corneal lesion. (C) Peripheral fleck retinopathy in a 75-year-old woman, with mild renal impairment and hearing loss; and (D) higher power view demonstrating a dappled appearance due to the coalescent fleck retinopathy (arrow). (E) Central fleck retinopathy in a 30-year-old female with a R373× in COL4A5, and normal renal function (arrow). This figure demonstrates how difficult it can be to distinguish the fleck retinopathy from the retinal sheen of youth; and (F) a higher power view of the central fleck retinopathy (arrow). Vision was not affected. (G) Optical coherence tomography demonstrating a sagittal section through the retina and subtle thinning of the temporal versus nasal quadrants, and (H) optical coherence tomography measurements demonstrating different thicknesses in the temporal versus nasal quadrants which was consistent with moderate temporal retinal thinning (7.4%) (24).