Alport syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities.

People with Alport syndrome experience progressive loss of kidney function. Almost all affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys. Many people with Alport syndrome also develop high levels of protein in their urine (proteinuria). The kidneys gradually lose their ability to efficiently remove waste products from the body, resulting in end-stage kidney disease (ESKD).

In late childhood or early adolescence, many people with Alport syndrome develop sensorineural hearing loss, which is caused by abnormalities of the inner ear. Affected individuals may also have misshapen lenses in their eyes (anterior lenticonus) and abnormal coloration of the retina, which is the light-sensitive tissue at the back of the eye. These eye abnormalities seldom lead to vision loss.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the COL4A3, COL4A4, and COL4A5 genes cause Alport syndrome. These genes each provide instructions for making one component of a protein called collagen IV. Collagen IV plays an important role in the kidneys, specifically in structures called glomeruli. Glomeruli are clusters of specialized blood vessels that remove water and waste products from blood and create urine.

Variants in these genes result in the production of abnormal versions of collagen IV in glomeruli. Kidneys with abnormal collagen IV cannot properly filter the blood, which allows blood and protein to pass into the urine, causing hematuria and proteinuria. Gradual scarring of the kidneys occurs, eventually leading to kidney failure in many people with Alport syndrome.

Collagen IV is also an important component of inner ear structures, particularly the organ of Corti, that transform sound waves into nerve impulses for the brain. Altered versions of collagen IV in the inner ear impair its function, which can lead to hearing loss.

In the eye, collagen IV is important for maintaining the shape of the lens and the normal color of the retina. Abnormal versions of collagen IV in the eye can result in misshapen lenses and an abnormally colored retina.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Alport syndrome can have different inheritance patterns. About two out of three cases are caused by variants in the COL4A5 gene and are inherited in an X-linked pattern. The COL4A5 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), a variant in the only copy of the COL4A5 gene in each cell is sufficient to cause kidney failure and other severe symptoms of the disorder. In females (who have two copies of the X chromosome), a variant in one copy of the COL4A5 gene usually only results in hematuria, but some people experience more severe symptoms. Significant hearing loss, eye abnormalities, and progressive kidney disease are more common in males with the X-linked form of Alport syndrome than in affected females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In approximately 15 percent of cases, Alport syndrome is caused by variants in both copies of the COL4A3 or COL4A4 gene and is inherited in an autosomal recessive pattern. The parents of an individual with the autosomal recessive form of this condition each have one copy of the altered gene and are called carriers. Some carriers are unaffected, while others develop a less severe condition called thin basement membrane nephropathy, which is characterized by hematuria.

Alport syndrome is inherited in an autosomal dominant pattern in about 20 to 30 percent of cases. People with this form of Alport syndrome have one variant in either the COL4A3 or COL4A4 gene in each cell. It remains unclear why some individuals with one variant in the COL4A3 or COL4A4 gene have progressive kidney disease (autosomal dominant Alport syndrome) and others have only hematuria (thin basement membrane nephropathy).

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Alport syndrome occurs in approximately 1 in 50,000 newborns.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Glomerular basement membrane lamellation · Very frequent (99-80%)

Presence of abnormal additional layers of the basement membrane of the glomerulus.

Hematuria · Very frequent (99-80%)

The presence of blood in the urine. Hematuria may be gross hematuria (visible to the naked eye) or microscopic hematuria (detected by dipstick or microscopic examination of the urine).

Bilateral sensorineural hearing impairment · Frequent (79-30%)

A form of sensorineural hearing impairment that affects both ears.

Hypertension · Frequent (79-30%)

The presence of chronic increased pressure in the systemic arterial system.

Mesangial hypercellularity · Frequent (79-30%)

Increased numbers of mesangial cells per glomerulus, defined as more than 3 nuclei fully surrounded by matrix in one or more mesangial areas, not including perihilar region, on a standard 3-micron-thick tissue section, best evaluated on periodic acid-Schiff (PAS) stain.

Proteinuria · Frequent (79-30%)

Increased levels of protein in the urine.

Renal insufficiency · Frequent (79-30%)

A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.

Retinal flecks · Frequent (79-30%)

Presence of multiple yellowish-white lesions of various size and configuration on the retina not related to vascular lesions.

Other findings in the same source

From: Orphanet

Additional reported features include Stage 5 chronic kidney disease (Frequent (79-30%)); Thin glomerular basement membrane (Frequent (79-30%)); Reduced visual acuity (Frequent (79-30%)); Abnormal corneal endothelium morphology (Occasional (29-5%)); Anterior lenticonus (Occasional (29-5%)); Corneal erosion (Occasional (29-5%)); Edema (Occasional (29-5%)); Focal segmental glomerulosclerosis (Occasional (29-5%)); Microscopic hematuria (Occasional (29-5%)); Myopia (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Alport syndrome is Nephrology, with a nephrologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• How is kidney function being assessed over time?
• Are any current medicines or supplements relevant to kidney safety?
• Is there an individual recommendation about fluids, diet or blood pressure?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Alport syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.