Overview

Definition: Alport syndrome is a rare inherited disorder characterized by progressive hearing loss, kidney disease, and eye abnormalities, caused by mutations in genes encoding type IV collagen chains (COL4A3, COL4A4, COL4A5).
Epidemiology:
-It affects approximately 1 in 5,000 to 1 in 50,000 live births
-The X-linked form (COL4A5 mutations) is the most common, accounting for about 80% of cases
-autosomal recessive (COL4A3/COL4A4 mutations) and autosomal dominant forms are less frequent.
Clinical Significance: Early recognition and meticulous long-term follow-up are crucial to prevent irreversible kidney damage, manage hearing loss effectively, and provide genetic counseling to affected families, impacting long-term patient outcomes and quality of life.

Clinical Presentation

Symptoms:
-Sensorineural hearing loss, typically high-frequency
-Hematuria, often microscopic initially, progressing to proteinuria and kidney failure
-Recurrent urinary tract infections
-Ocular abnormalities like lenticonus, retinopathy.
Signs:
-Normal initial blood pressure
-Edema may appear in advanced stages
-Funduscopic examination may reveal anterior lenticonus
-Audiometry shows bilateral sensorineural hearing loss
-Urinalysis reveals hematuria and proteinuria.
Diagnostic Criteria:
-Diagnosis is suspected in individuals with a family history of Alport syndrome or isolated hematuria/proteinuria with sensorineural hearing loss and/or ocular abnormalities
-Definitive diagnosis requires genetic testing or renal biopsy showing characteristic ultrastructural abnormalities of the glomerular basement membrane.

Diagnostic Approach

History Taking:
-Detailed family history including kidney disease, hearing loss, and eye problems across generations
-Age of onset of symptoms
-Progression of renal symptoms
-Previous audiometry and ophthalmology reports
-History of recurrent infections or unexplained hematuria.
Physical Examination:
-Complete physical examination focusing on blood pressure, signs of edema
-Ocular examination for lenticonus
-Detailed neurological assessment for hearing deficits
-Skin examination for leiomyomatosis in some rare cases (in connection with Laugier-Hunziker syndrome).
Investigations:
-Urinalysis: persistent hematuria (red blood cell casts may be present), proteinuria
-Serum creatinine and estimated glomerular filtration rate (eGFR) to assess renal function
-Complete blood count to assess for anemia
-Audiometry: bilateral sensorineural hearing loss, often high-frequency
-Ocular examination: slit-lamp examination for anterior lenticonus
-Renal biopsy (if genetic testing is inconclusive or for definitive diagnosis): electron microscopy shows thinning and splitting of the glomerular basement membrane
-Genetic testing: sequencing of COL4A3, COL4A4, and COL4A5 genes to identify causative mutations.
Differential Diagnosis:
-Other causes of hereditary nephropathies (e.g., thin basement membrane nephropathy, focal segmental glomerulosclerosis)
-IgA nephropathy
-Systemic lupus erythematosus
-Hereditary nephritis without hearing loss or ocular findings.

Management

Initial Management:
-Early diagnosis and initiation of renal protective measures
-Regular monitoring of renal function, blood pressure, and proteinuria
-Referral to audiology and ophthalmology for baseline assessment and ongoing management.
Medical Management:
-Renin-angiotensin-aldosterone system (RAAS) inhibitors (ACE inhibitors or ARBs) are the cornerstone of renal management to reduce proteinuria and slow disease progression
-Target blood pressure typically <130/80 mmHg
-Strict glycemic control in diabetic patients
-Management of anemia and electrolyte imbalances
-Consider immunosuppressants only in select cases of rapidly progressive glomerulonephritis.
Supportive Care:
-Regular audiology follow-up and provision of hearing aids or cochlear implants as needed
-Genetic counseling for patients and families regarding inheritance patterns and reproductive options
-Lifestyle modifications including salt restriction and avoiding nephrotoxic agents
-Nutritional support and management of comorbidities.
Renal Transplantation:
-Kidney transplantation is the definitive treatment for end-stage renal disease (ESRD)
-Living related donors should be carefully screened to avoid donor-specific antibodies or pre-existing kidney disease
-Gene therapy is an investigational approach.

Hearing And Ocular Follow Up

Audiological Monitoring:
-Baseline audiometry in all diagnosed children and regular follow-up every 6-12 months, or more frequently if hearing loss is detected
-Audiological rehabilitation with hearing aids, assistive listening devices, or cochlear implants when indicated
-Counseling on speech and language development support.
Ophthalmological Monitoring:
-Annual eye examinations starting in childhood to detect anterior lenticonus, retinal flecks, and other ocular manifestations
-Prompt referral to ophthalmologist for evaluation and management of refractive errors, cataracts, or glaucoma
-Regular monitoring for visual acuity and visual field defects.
Timing Of Manifestations:
-Hearing loss typically begins in late childhood or adolescence, often starting with high-frequency deficits
-Ocular abnormalities like lenticonus may be present from birth or develop in early childhood
-These manifestations can precede significant renal dysfunction.

Renal Follow Up

Monitoring Frequency:
-Regular monitoring of urinalysis (hematuria, proteinuria) and renal function (serum creatinine, eGFR) at least every 6-12 months, or more frequently based on disease severity and progression
-Blood pressure monitoring at each visit.
Proteinuria Management:
-Aggressive management of proteinuria with RAAS inhibitors is critical
-Quantify proteinuria (e.g., spot urine protein-to-creatinine ratio) regularly
-Aim for significant reduction in proteinuria to slow CKD progression.
Progression To Esrd:
-Patients require close monitoring for progression to end-stage renal disease (ESRD)
-Factors like severity of proteinuria, degree of hematuria, genetic mutation type, and age at diagnosis influence the rate of progression
-Dialysis and transplantation are options for ESRD management.
Genetic Counseling:
-Essential for affected families to understand the inheritance patterns, recurrence risks, and implications for future generations
-Carrier screening and prenatal diagnosis may be offered.

Key Points

Exam Focus:
-Alport syndrome is a type IV collagenopathy
-Key triad: hearing loss, renal disease, ocular abnormalities
-X-linked is most common
-RAAS inhibitors are crucial for renal protection
-Early audiological and ophthalmological assessment is vital.
Clinical Pearls:
-Suspect Alport syndrome in any child with unexplained hematuria or persistent proteinuria
-Always perform audiometry and fundoscopy in such cases
-Long-term multidisciplinary follow-up is key to optimal outcomes.
Common Mistakes:
-Delaying diagnosis by attributing hematuria solely to benign causes
-Underestimating the progressive nature of hearing loss and kidney disease
-Inadequate monitoring of renal function and proteinuria
-Failure to offer genetic counseling to families.