Alport syndrome
Alport syndrome is a genetic disorder primarily characterized by kidney disease, hearing impairment, and eye abnormalities due to defects in type IV collagen proteins. It predominantly affects males, with a higher incidence linked to family history, occurring in about 1 in 50,000 live births. The syndrome manifests through symptoms such as hematuria (blood in urine) and, in later stages, proteinuria as kidney function declines. Hearing loss typically emerges during late childhood or early adolescence, while eye issues may include lens deformities and corneal changes. There are three primary genetic forms of Alport syndrome: the X-linked variant accounts for approximately 80% of cases, with the remaining cases being autosomal recessive or dominant. Diagnosis often involves urine tests, kidney biopsies, and genetic testing. Although there is currently no specific treatment, management focuses on controlling blood pressure and preparing for potential kidney transplant in cases of end-stage kidney disease. Early intervention and genetic counseling can aid in better outcomes and quality of life for affected individuals and their families.
Alport syndrome
ALSO KNOWN AS: AS; hereditary deafness and progressive kidney disease
DEFINITION Alport syndrome is a genetic condition affecting one of several subunits of type IV collagen proteins. These proteins form a major part of the basement membrane in the kidney (glomeruli), inner ear (cochlea), and eye.
Risk Factors
This disease is most common in males and has more severe consequences in men than in women. The biggest risk for developing Alport syndrome is a family history of the disease. The incidence is 1 in 50,000 live births, according to the Genetics Home Reference.
Etiology and Genetics
Basement membranes are found in many parts of the body. In Alport syndrome, the effect is most noticeable in the glomeruli that filter blood in the kidney. There is a defect in the production of the alpha chains of type IV collagen that promotes increased splitting and destruction of the glomerular basement membrane. This process produces scarring in the kidney and eventual kidney failure. A normal basement membrane in the cochlea of the ear and the eye are also important for normal function. In this disease, progressive sensorineural hearing loss is usually present by late childhood or early adolescence.
Alport syndrome is associated with three different genetic presentations that control the production of type IV collagen proteins. Approximately 80 percent of cases are the X-linked form of the disease, which increases the incidence in males. The mutation is in the gene COL4A5 and results in damage to the alpha-5 chain of type IV collagen.
In the other 20 percent of cases, the defect is on chromosome 2 and is either transmitted in a recessive form or a dominant form, with males and females equally affected. The autosomal recessive form is caused by mutations in COL4A3 or COL4A4 genes that encode the alpha-3 or alpha-4 subunits of type IV collagen. The autosomal dominant form (about 5 percent) is caused by mutations in these same genes but is transmitted in a dominant fashion. In both autosomal forms, kidney disease develops later in adolescence or adulthood. There is some indication that the autosomal dominant form of this disease may not be a true manifestation of Alport syndrome but another condition associated with kidney failure, deafness, and other blood abnormalities.
Symptoms
The primary symptoms in Alport syndrome are associated with kidney disease. Blood in the urine (hematuria) is usually discovered during the first years of life in the X-linked form. Protein in the urine (proteinuria) is usually absent in childhood but eventually develops in the X-linked and autosomal recessive form by the teenage years or early adulthood. In the autosomal dominant form, kidney disease develops later in adulthood. If individuals do not have hematuria during the first decade of life, then they are unlikely to have Alport syndrome.
Hearing loss is not usually present at birth and does not become apparent until late childhood or early adolescence, generally before the onset of kidney failure. There is a wide range of expression with this syndrome. Some families do not have hearing loss. Eye findings include lenticonus, which are abnormal spherical or cone-like protrusion on the lens of the eye, yellowish or whitish flecks in the macula of the inner eye, corneal changes, and recurrent corneal erosion.
Screening and Diagnosis
Alport syndrome is one of the diseases suspected when a child or young adult has recurrent microscopic or gross blood in the urine. Unique changes in the walls of the blood vessels of the glomeruli can be detected on a kidney biopsy. In the X-linked form, a skin biopsy will show abnormalities in the alpha-5 chain of type IV collagen that is normally present in the skin. Genetic testing is helpful when the diagnosis is not clear.
Treatment and Therapy
Early diagnosis can help postpone the complications of kidney disease by promoting good health care and prevention of other causes of kidney damage. Strict control of blood pressure is important. Patients who develop end-stage kidney disease usually require dialysis and/or kidney transplantation. The success rate of kidney transplantation is good, and patients often have excellent allograft survival rates.
While no specific treatment yet existed as of 2024, researchers had completed laboratory work to test a new treatment that had progressed to a clinical trial. These researchers were also conducting a clinical trial for a group of patients with a certain type of genetic defect that caused Alport syndrome and learning how the disease affects pregnant women.
Prevention and Outcomes
Alport syndrome is a rare disease, and morbidity and mortality are most often related to progressive kidney disease. The prognosis varies depending on the type of inheritance, the sex of the patient, and the type of mutations in type IV collagen genes. According to the National Kidney Foundation, about 90 percent of male patients with Alport syndrome develop end-stage kidney disease by forty years of age. The rate for females is significantly lower.
Prenatal testing is available for the X-linked and autosomal recessive forms of the syndrome. Testing for the autosomal dominant form may be available from specialized testing laboratories.
Bibliography
"Alport Syndrome." Genetics Home Reference. US National Library of Medicine, Dec. 2013. Web. 14 July 2014.
Kashtan, Clifford E. "Alport Syndrome: Achieving Early Diagnosis and Treatment." American Journal of Kidney Diseases, vol. 77, no. 2, pp. 272-79, doi.org/10.1053/j.ajkd.2020.03.026. Accessed 5 Sept. 2024.
Kashtan, Clifford E. "Alport Syndrome and Thin Basement Membrane Nephropathy." GeneReviews. U of Washington, Seattle, 28 Feb. 2013. Web. 14 July 2014.
Kliegman, Robert M., Bonita F. Stanton, Joseph St. Geme, Nina F. Schor, and Richard E. Behrman. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Saunders, 2011. Print.
Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard. Thompson and Thompson Genetics in Medicine. 7th ed. New York: Saunders, 2007. Print.
Reilly, Robert, and Mark Perazella. Nephrology in 30 Days. New York: McGraw, 2014. Print.
"Uniting to Meet the Challenge of Alport Syndrome." Kidney Research UK, 31 May 2024, www.kidneyresearchuk.org/2024/05/31/uniting-to-meet-the-challenge-of-alport-syndrome/. Accessed 5 Sept. 2024.
Watson, Simon, et al. Alport Syndrome, StatPearls, 2023, National Library of Medicine, www.ncbi.nlm.nih.gov/books/NBK470419/. Accessed 5 Sept. 2024.