A 28-year-old woman from Kerala presents with recurrent joint dislocations, hyperextensible skin, and easy bruising. On examination, she has marked skin hyperelasticity and hypermobility of all major joints. Her mother had similar features and died of aortic rupture at age 42. Genetic testing reveals a mutation in the COL5A1 gene. Which of the following best explains the biochemical defect in this patient?

Explanation

## Clinical Diagnosis: Ehlers-Danlos Syndrome (EDS), Classical Type ### Pathophysiology of COL5A1 Mutations **Key Point:** Type V collagen is a quantitatively minor but structurally critical component of connective tissue. It acts as a **nucleator** for fibril assembly and regulates the diameter and organization of collagen fibrils. Mutations in COL5A1 (which encodes the α1 chain of type V collagen) disrupt this nucleation function. **High-Yield:** In classical EDS (caused by COL5A1 or COL3A1 mutations), the defect is NOT in the post-translational modification machinery (hydroxylation, cross-linking) but in the **primary structure or quantity of collagen itself**. ### Why Type V Collagen Matters Type V collagen: - Comprises ~5–10% of skin collagen but is essential for fibril organization - Nucleates the assembly of type I collagen fibrils - Regulates fibril diameter and mechanical properties - Mutations → abnormal fibril morphology, reduced tensile strength, and tissue fragility ### Biochemical Consequence Defective type V collagen → **disorganized, thinner, mechanically weaker collagen fibrils** → hyperextensible skin, joint hypermobility, vascular fragility (aortic rupture risk). ### Differential Pathophysiology in Other Collagen Disorders | Disorder | Gene | Defect | Mechanism | |----------|------|--------|----------| | **EDS, Classical** | COL5A1, COL3A1 | Abnormal collagen structure | Impaired fibril nucleation/organization | | **EDS, Kyphoscoliotic** | PLOD1 | Lysyl hydroxylase deficiency | Defective cross-linking (↓ lysine hydroxylation) | | **EDS, Vascular** | COL3A1 | Type III collagen mutation | Fragile vessels, aortic rupture | | **Osteogenesis Imperfecta** | COL1A1, COL1A2 | Type I collagen mutations | Brittle bones, blue sclerae | | **Scurvy** | Vitamin C deficiency | Impaired prolyl/lysyl hydroxylation | Defective collagen cross-linking | **Clinical Pearl:** The presence of **aortic rupture risk** in this patient's family history strongly suggests either classical EDS (COL5A1) or vascular EDS (COL3A1). The COL5A1 mutation is confirmed here, making classical EDS the diagnosis. ## Why the Correct Answer is Correct COL5A1 encodes type V collagen, which is essential for fibril nucleation. Mutations cause abnormal collagen fibril assembly and organization, not a defect in post-translational modification or cross-linking enzymes.