Handbook of Genetic Counseling/Alport Syndrome

Alport Syndrome Genetic Etiology Three genes have been associated with Alport syndrome: COL4A3 COL4A4 COL4A5 About 80% of Alport syndrome is caused by mutations in COL4A5 and is X-linked inheritance About 15% of Alport syndrome is caused by mutations in COL4A3 and COL4A4 is autosomal recessive inheritance About 5% of Alport syndrome is caused by mutations in COL4A3 and COL4A4 is inherited in an autosomal dominant manner. Incidence and carrier frequency Approximately 1 in 50,000 Americans carry the Alport syndrome gene, not all of them get Alport syndrome Twice as many females carry the gene, but a higher percentage of males with the gene have symptoms of the syndrome. There are no racial or geographic concentrations of Alport syndrome Health issues for carriers: About 50% of carriers will have persistent or intermittent microhematuria (small amount of blood in the urine Risk to various family members Parents of a male proband: The father will not have the disease or be a carrier In a family with more than one affected male, the mother is an obligate carrier In a family with one affected male, the probability the mother is a carrier is 85-90%, chance for a de novo mutation is 10-15% The mother of a male with X-linked Alport syndrome should have a urinanalysis. The presence of microhematuria (blood in the urine too small to be seen by the naked eye) means she is likely a carrier. Siblings of a proband: at conception: If mother is affected: 50% risk of inheriting the mutation males will be affected if they inherit the mutations females will be carriers, may or may not be affected Offspring of a male proband: Will transmit the mutation to all of their daughters and none of their sons Clinical features The 3 main findings are renal, cochlear, and ocular involvement. Renal involvement: There is progressive deterioration of the glomerular basement membranes (GBMs), which are microscopic parts of the kidney. This deterioration may lead to chronic renal failure causing excess waste products in the blood (uremia). This kidney malfunction causes the loss of red blood cells and blood plasma proteins in the urine (hematuria, proteinuria). Bleeding into the glomerulus, a bunch of capillaries in the kidney, causes material (including various elements of the blood) to be excreted into the urine. Renal bone disease may occur as a result of renal failure. This can cause: abnormalities of bone abnormalities of calcium, phosphorus, and vitamin D metabolism abnormalities of parathyroid hormone secretion which regulates calcium and phosphate levels in the blood. Uremia (the presence of urea in the blood) can happen when the kidneys fail to remove waste products from the blood. Symptoms include: upset stomach, which may vary from loss of appetite to severe pain nausea vomiting of food and blood weakness fatigue excessive need for sleep dry often itchy skin peculiar-smelling breath similar to urine pale skin shortness of breath hypertension fluid retention swelling (edema) End-stage renal disease (ESRD) is the final stage in chronic renal failure when there is virtually no more functioning nephrons present. Patients with ESRD must depend upon hemodialysis machines to cleanse their blood of waste products. All males with X-linked Alport syndrome develop proteinuria and eventually progressive renal insufficiency, which leads to end-stage renal disease (ESRD). About 60% reach ESRD by age 30 years 90% by age 40 years Cochlear involvement Diminished hearing is usually detectable by late childhood or early adolescence in boys with XLAS. The hearing loss is progressive and about 80-90% of males with X-linked Alport syndrome have sensorineural deafness by age 40 years Ocular involvement Abnormalities of the eye may include: The surface of the eye's lens may be cone-shaped (lenticonus) or spherical (spherophakia) The lens of the eye may be opaque or cloudy (cataracts). White dots may appear on the retina (retinal macular flecks or fundus albipunctatis). Children with Alport syndrome may be nearsighted (myopic) Testing The diagnosis of Alport syndrome is made with the following criteria: history and physical examination, which may include audiologic and ophthalmic evaluation detailed family history and possibly urinalyses on first- and second-degree relatives immunohistochemical analysis of basement membrane type IV collagen expression, using skin and/or renal biopsy specimens examination of renal biopsy specimens by electron microscopy. With these guidelines a suspected diagnosis of Alport syndrome can be confirmed in the great majority of cases, and in most cases the genetic type of Alport syndrome can also be determined. Molecular genetic testing of the type IV collagen gene (COL4A5) implicated in X-linked Alport syndrome and the type IV collagen gene (COL4A3 and COL4A4) implicated in autosomal recessive Alport syndrome is available on a clinical basis detection of mutation >60% Prenatal testing is available for X-linked Alport syndrome Surveillance, management, and treatment options Chronic renal failure is aggressively treated: Renal function and certain components in the blood are regularly monitored. Fluid intake and diet, particularly salt and protein, may be restricted and regular medications prescribed. Control of blood pressure, prompt and aggressive treatment of urinary tract and ear infections is important. Hemodialysis may be used to treat chronic renal failure and ESRD. Dialysis involves removing blood from the patient's artery, cleansing it of unwanted substances that would normally be excreted in the urine, and returning the cleansed blood to a vein. Kidney transplantation is an alternative treatment. Because of the slight or inapparent disease in some female family members, great care must be taken in selecting living related kidney donors. Hearing loss may stabilize after successful kidney transplantation. Transplantation of the eye's cornea or removal of the eye's lens may be helpful in patients with visual problems. Differential diagnoses Benign familial hematuria/thin basement membrane disease Fechtner/Epstein syndrome Psychosocial issues For child: feelings of "being different" Concern and worry over the medical problems and frequent doctor visits Financial considerations, what will treatment cost? Who is their support network? Effects on relationships (parent/child) Concern about telling other family members Future reproductive decisions Possible disruption of marital relationships or family dynamics Support groups Hereditary Nephritis Foundation 1390 W 6690 S, #202 H Murray UT 84123 Phone #: 8012625901 e-mail: N/A Home page: National Kidney Foundation 30 East 33rd Street Suite 1100 New York, NY 10016 Phone: 800-622-9010; 212-889-2210 Fax: 212-689-9261 Email: info@kidney.org Sources Gene Reviews National Organization of Rare Diseases Notes The information in this outline was last updated in 2004.