Alport syndrome can be inherited in one of the three ways: X-linked inheritance, which is the most common accounting for 85 percent of cases; autosomal recessive inheritance, seen in 10 to 15 percent of cases; and autosomal dominant inheritance, which is very rare and accounts for less than 5 percent of all cases.
In less common autosomal recessive and autosomal dominant modes of inheritance, the genetic defect is situated on an autosome, or non-sex chromosome. Since both men and women have a pair of each autosome, the risk of inheriting autosomal recessive or autosomal dominant Alport syndrome is the same between men and women.
X-linked Alport syndrome (XLAS)
In cases of X-linked inheritance, the genetic defect causing the disease is on the X chromosome, a sex chromosome. Since men have only one copy of the X chromosome, unlike women who have two, 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 percent of women with XLAS develop kidney failure by the age of 60 and symptoms of hearing loss by middle age.
Inheritance of XLAS in women
A woman with XLAS may inherit the disease either from her mother or from her father. If it is the father who has passed on the disease, it means that all her sisters will also have inherited the faulty gene. But if a woman inherited the disease from her mother, then her brothers and sisters have 50 percent chance of also inheriting the disease.
X chromosome inactivation in women
Since men have only one copy of the X chromosome, inheriting a faulty copy of the disease-causing gene will result in severe symptoms, because there is no healthy gene copy on another X chromosome.
Women have two copies of the X chromosomes, but one of them is randomly turned off or inactivated during development, 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 and disease-causing gene. Depending on the proportion of cells in which the normal X chromosome is active, the symptoms of the disease can vary greatly — 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.
Management of XLAS in women
Women with XLAS should undergo regular clinical evaluations for early signs of the disease in a similar manner to affected men. Due to the risk of kidney failure and of passing the faulty gene to their children, women suspected of having Alport syndrome or with a family history of the disease should be genetically tested even if their kidney function is normal.
A woman diagnosed with XLAS should be tested for the presence of albumin in her urine (also known as albuminuria), and high blood pressure (hypertension) at least once a year. Experts recommend that affected women with albuminuria be treated with drugs that block the body’s renin-angiotensin-aldosterone system (RAAS) — a complex communication between hormones that regulates kidney function and blood pressure — to delay kidney failure. Treatment should be accompanied by adequate birth control because of the risk of birth defects (teratogenic defect) associated with these medications.
Autosomal Alport syndrome in women
Autosomal recessive and autosomal dominant Alport syndrome (ARAS/ADAS) are less common, but symptoms of these two disease forms affect women and men with equal severity.
ARAS results when both copies of a gene are defective and women with ARAS usually develop early-onset kidney failure or lenticonus (cone-shaped eye lens). Experts recommend treatment with RAAS blockers begin at diagnosis. Women should also be offered genetic counseling, information about reproductive possibilities, and be closely examined during pregnancy to monitor their blood pressure.
ADAS, the rarest form of Alport syndrome, can cause symptoms similar to XLAS, like progressive kidney disease and hearing loss. But kidney failure usually begins to be evident later in life (after age 40). Each child of an affected ADAS parent has a 50 percent chance of inheriting this disease, and genetic counseling is advised.
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