Alport Syndrome is a rare inherited disorder caused by mutations in genes responsible for type IV collagen, a major component of basement membranes. It is characterized by hematuria, progressive kidney failure, hearing loss, and eye abnormalities. There are three main types - X-linked Alport Syndrome (85% of cases), autosomal recessive Alport Syndrome (10-15% of cases), and rare autosomal dominant cases. Patients typically develop end-stage renal disease by middle age. Extra-renal manifestations include sensorineural hearing loss and ocular abnormalities like anterior lenticonus and dot-and-fleck retinopathy. There is currently no cure for Alport Syndrome and treatment focuses on managing symptoms and complications.

2. Alport Syndrome Dr. Abrar Ali Katpar Resident Nephrology/Medicine King Khalid Hospital Hail, KSA

3. INTRODUCTION

6. Pathophysiology

10. Location and Mutations of the Genes Coding for Alpha (IV) Chains of Type IV Collagen in AS. * Autosomal recessive AS (mutations spanning 5' regions of COL4A5 and COL4A6 genes) † X-linked AS ‡ Autosomal recessive AS Leiomyomatosis ‡ x COL4A6 Alpha-6 (IV) XLAS † x COL4A5 Alpha-5 (IV) ARAS 2 COL4A4 Alpha-4 (IV) ARAS * 2 COL4A3 Alpha-3 (IV) Unknown 13 COL4A2 Alpha-2 (IV) Unknown 13 COL4A1 Alpha-1 (IV) Mutation Chromosomal Location Genes Alpha (IV) Chain

12. Tissue Distribution of Alpha (IV) Chains * Tubular basement membrane Distal TBM, epidermal basement membrane Alpha-6 (IV) GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea Alpha-5 (IV) GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea Alpha-4 (IV) GBM, distal TBM * , Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea Alpha-3 (IV) Ubiquitous Alpha-2 (IV) Ubiquitous Alpha-1 (IV) Tissue Distribution Alpha (IV) Chain

30. CLINICAL

45. Physical Examination

70. Electron micrograph of kidney biopsy from a patient with Alport syndrome (AS). Note the splitting and lamellation of the glomerular basement membrane

71. Alport syndrome

76. TREATMENT

81. MEDICATION

84. Category D in second and third trimester of pregnancy; caution in renal impairment (serum creatinine >3.5), valvular stenosis, or severe congestive heart failure; monitor serum potassium Precautions D - Unsafe in pregnancy Pregnancy NSAIDs may reduce hypotensive effects of enalapril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases enalapril levels; probenecid may increase enalapril levels; the hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics Interactions Documented hypersensitivity; angioedema Contraindications Not established Pediatric Dose 5 mg/d PO initial; not to exceed 40 mg/d Adult Dose Enalapril (Vasotec) -- Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion. Drug Name

85. Category D in second and third trimester of pregnancy; caution in renal impairment (serum creatinine >3.5), valvular stenosis, or severe congestive heart failure; monitor serum potassium Precautions D - Unsafe in pregnancy Pregnancy NSAIDs may reduce hypotensive effects of fosinopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases fosinopril levels; probenecid may increase fosinopril levels; the hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics Interactions Documented hypersensitivity; collagen vascular disease; angioedema Contraindications Not established Pediatric Dose 10 mg/d PO initial; not to exceed 80 mg/d Adult Dose Fosinopril (Monopril) -- Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion. Drug Name

86. Category D in second and third trimester of pregnancy; caution in renal impairment (serum creatinine >3.5), valvular stenosis, or severe congestive heart failure; monitor serum potassium Precautions D - Unsafe in pregnancy Pregnancy NSAIDs may reduce hypotensive effects of lisinopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases lisinopril levels; probenecid may increase lisinopril levels; the hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics Interactions Documented hypersensitivity; angioedema Contraindications Not established Pediatric Dose 10 mg/d PO initial; not to exceed 80 mg/d Adult Dose Lisinopril (Zestril, Prinivil) -- Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion. Drug Name

87. Category D in second and third trimester of pregnancy; caution in renal impairment (serum creatinine >3.5), valvular stenosis, or severe congestive heart failure; monitor serum potassium Precautions D - Unsafe in pregnancy Pregnancy NSAIDs may reduce hypotensive effects of enalapril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases enalapril levels; probenecid may increase enalapril levels; the hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics Interactions Documented hypersensitivity; angioedema Contraindications Not established Pediatric Dose 10 mg/d PO initial; not to exceed 80 mg/d Adult Dose Quinapril (Accupril) -- Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion. Drug Name

89. Category D in second and third trimester of pregnancy; caution in renal impairment (serum creatinine >3.5), valvular stenosis, or severe congestive heart failure; monitor serum potassium Precautions C - Safety for use during pregnancy has not been established. Pregnancy Ketoconazole, sulfaphenazole, and phenobarbital may decrease effects; cimetidine may increase effects of losartan Interactions Documented hypersensitivity Contraindications Not established Pediatric Dose 50 mg/d PO initial; not to exceed 100 mg/d Adult Dose Losartan (Cozaar) -- Nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors and do not affect the response to bradykinin and are less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors. Drug Name

90. Category D in second and third trimester of pregnancy; caution in renal impairment (serum creatinine >3.5), valvular stenosis, or severe congestive heart failure; watch for serum potassium Precautions C - Safety for use during pregnancy has not been established. Pregnancy Ketoconazole, sulfaphenazole, and phenobarbital may decrease effects; cimetidine may increase effects of candesartan Interactions Documented hypersensitivity Contraindications Not established Pediatric Dose 16 mg/d PO initial; not to exceed 32 mg/d Adult Dose Candesartan (Atacand) -- Nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors and do not affect the response to bradykinin and are less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors. Drug Name

93. Complications