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BI6.1-3 | Extracellular Matrix — SDL Guide (Part 2)

Collagen Disorders — Genetic and Acquired

Osteogenesis Imperfecta (OI) — Brittle Bone Disease:
- Mutations in COL1A1 or COL1A2 genes (Type I collagen)
- Even a single Gly→X substitution in the Gly-X-Y repeat disrupts triple helix assembly → unstable collagen
- Features: recurrent fractures with minimal trauma, blue sclerae (thin scleral collagen lets choroid show through), hearing loss (ossicular chain damage), dentinogenesis imperfecta
- Severe forms: intrauterine fractures, death in neonatal period. Mild forms: "the child with lots of fractures" seen at district hospitals — must distinguish from non-accidental injury

Ehlers-Danlos Syndrome (EDS):
- Heterogeneous group of connective tissue disorders — 13 types
- Most common: defects in Type V collagen → Classic EDS (hyperextensible skin, joint hypermobility, easy bruising)
- Vascular EDS (Type IV): Type III collagen defect → risk of arterial/bowel/uterine rupture — life-threatening
- Joints in EDS feel "loose" because the ECM holding the joint capsule together is mechanically weak

Alport Syndrome:
- X-linked defect in Type IV collagen (COL4A5 gene) → defective glomerular basement membrane
- Features: haematuria from childhood, progressive nephritis, sensorineural deafness, ocular abnormalities

Figure: Collagen Disorders — Genetic and Acquired

Glycosaminoglycans (GAGs) — Hydrated Scaffolds

Glycosaminoglycans (GAGs) are long, unbranched polysaccharide chains built from repeating disaccharide units, usually containing:
- A hexosamine (glucosamine or galactosamine), often sulphated
- A uronic acid (glucuronic acid or iduronic acid)

The dense negative charges (from sulphate and carboxylate groups) attract water and cations → GAGs form highly hydrated gels that resist compressive forces.

Major GAGs:

GAG	Key Feature	Location	Clinical Note
Hyaluronic acid	Unsulphated, very large	Joints, vitreous, umbilical cord	Viscosupplementation in OA
Chondroitin sulphate	Most abundant sulphated GAG	Cartilage, bone, skin	Decreases in osteoarthritis
Heparan sulphate	Anticoagulant-related	Basement membranes, cell surfaces	Binds growth factors
Heparin	Most sulphated	Mast cells, lung	Anticoagulant drug
Dermatan sulphate	Contains iduronic acid	Skin, blood vessels	MPS type I/II disorders
Keratan sulphate	Contains galactose instead of uronic acid	Cornea, cartilage	MPS IVA (Morquio)

Hyaluronic acid is unique: it has no sulphation, is not covalently linked to protein (free chain), and is the longest GAG chain (up to 25,000 disaccharides). It forms the backbone to which proteoglycans attach.

Figure: Glycosaminoglycans (GAGs) — Hydrated Scaffolds

Proteoglycans and Mucopolysaccharidoses

Proteoglycans = core protein + many GAG chains covalently attached. They are the shock absorbers of the ECM.

Key proteoglycans:
- Aggrecan — the major cartilage proteoglycan; binds to hyaluronic acid via link proteins to form huge aggregates that resist compression in joints
- Perlecan — basement membrane proteoglycan; binds to type IV collagen and laminin
- Syndecan, Glypican — cell surface heparan sulphate proteoglycans; co-receptors for growth factors (FGF, VEGF)

Mucopolysaccharidoses (MPS) — lysosomal storage diseases caused by deficiency of specific lysosomal enzymes that degrade GAGs:
- MPS I (Hurler syndrome): α-L-iduronidase deficiency → accumulation of heparan + dermatan sulphate. Features: coarse facies, corneal clouding, hepatosplenomegaly, intellectual disability, cardiac valve disease. Autosomal recessive. Enzyme replacement therapy available.
- MPS II (Hunter syndrome): Iduronate-2-sulphatase deficiency (X-linked). Similar but milder; no corneal clouding.
- MPS IVA (Morquio): N-acetylgalactosamine-6-sulphatase deficiency → keratan sulphate accumulation. Skeletal dysplasia, atlantoaxial instability.

Diagnosis: urine GAG quantitation and typing, enzyme assay in leucocytes/fibroblasts, gene sequencing.

Figure: Proteoglycans and Mucopolysaccharidoses