Genetic Mutations and Alport Syndrome

Alport syndrome is a genetic disease primarily affecting the kidneys, ears, and eyes, resulting from an inherited mutation. There is no cure for Alport syndrome, but life-long medical care can help individuals manage the condition. Treatment focuses on relieving symptoms, correcting complications, and slowing the disease’s impact on the body.

What Causes Alport Syndrome?

Alport syndrome is caused by the mutation of a gene instrumental in the production of a type IV collagen protein, which plays a role in maintaining the structure and function of cells and tissues throughout the body. The mutation results in faulty protein production instructions, leading to abnormal type IV collagen.

Genetic Inheritance Patterns

Alport syndrome is an inherited disease, meaning it develops as a result of the mutated gene passing from parent to child, in either an X-linked or autosomal inheritance pattern. The development and progression of the disease is the same regardless of the inheritance pattern. Around 80% of Alport syndrome cases are X-linked.

X-Linked Recessive Inheritance

Alport syndrome may occur as a result of X-linked recessive inheritance of a single mutated COL4A5 gene. In this inheritance pattern, the mutated gene occurs in the X chromosome. It is uncommon for females, who have two X chromosomes, to have a mutated copy of the COL4A5 gene in both. The unaffected X chromosome typically prevents the development of the more acute symptoms of the Alport syndrome. Males who have inherited the mutated gene have just one X chromosome, however, and experience symptoms more acutely.

Autosomal Inheritance

Alport syndrome might also result from the autosomal inheritance of mutated genes. In this pattern, the mutation affects the COL4A3 or COL4A5 gene, and inheritance may be recessive or dominant. The person receives a copy of the mutated gene from each parent, carriers who sometimes — but not always — exhibit minor symptoms of the condition, primarily blood in the urine. In autosomal dominant inheritance, a person inherits just one copy of the mutated gene. These inheritance patterns are rare and affect males and females equally.

Symptoms and Signs of Alport Syndrome

Signs of Alport syndrome typically begin in childhood, starting with blood or protein in the urine. As the disease progresses, headaches, fatigue, weight loss, and swelling of the legs and feet are common. Many people with the condition also develop high blood pressure. These secondary symptoms usually stem from the most significant primary symptoms: kidney damage and failure, hearing loss, and vision defects.

Kidney Failure in Alport Syndrome

Alport syndrome affects the function of the kidneys and leads ultimately to kidney failure. Type IV collagen operates in waste and water removal and urine production. Genetic abnormalities affecting the production of this protein lead to inadequate filtering and scarring. This results in progressive loss of function in the kidneys.

Hearing and Vision Loss

Type IV collagen plays a role in the function of the inner ear, specifically in the organ of Corti, the structure responsible for transforming sound waves into nerve impulses. Those with Alport syndrome experience hearing loss as a result of nerve abnormalities in the inner ear and are typically deaf by the age of 40. The affected collagen also produces abnormalities in the eye, including lens deformity and discoloring of the retina. Alport syndrome does not typically result in blindness, but vision loss and corrective surgery are often necessary.

Diagnosis

A family history of Alport syndrome may lead to early genetic testing for the disease. The presentation of characteristic symptoms, including blood in the urine and early hearing loss, might also prompt further diagnostic tests. Doctors may request a urinalysis or eye exam, but a kidney biopsy usually confirms the diagnosis by identifying cellular abnormalities in the organs or the absence of type IV collagen.

Treatment

There is no cure for Alport syndrome; treatments address symptoms and manage progression. People with the condition often eventually require surgery to correct eye abnormalities and hearing aids. ACE inhibitors can help maintain kidney function, and the doctor will often prescribe dietary and fluid intake restrictions. Progressive kidney function loss leads to kidney failure when the organs can no longer adequately filter blood. This complication is treated with hemodialysis, and, ultimately, a kidney transplant.

Current Research on Alport Syndrome

Research on Alport syndrome is working to identify more effective treatment options and potential cures. Researchers in the field are developing a new drugs, antibodies, and surgical therapies intended to inhibit hearing loss and slow the progression of kidney failure. Some studies are investigating the possibility of curing Alport syndrome through DNA editing. This innovative, ground-breaking procedure involves implanting a single corrected gene into a person’s kidneys, essentially vaccinating the organs of the mutated genes.