Glycosaminoglycans and Mucopolysaccharidoses

Comprehensive practice flashcards covering structure, properties, types, clinical features, MPS classifications, and treatment of Glycosaminoglycans and I-cell disease.

Glycosaminoglycans (GAGs)

Long, unbranched heteropolysaccharides made up of repeating disaccharide units.

Disaccharide unit of GAG

The structural repeating unit of a glycosaminoglycan, consisting of an amino sugar and an acidic sugar.

Amino sugars in GAGs

Glucosamine and galactosamine, which serve as the amino sugar components of repeating disaccharide units.

Acidic sugars in GAGs

Glucuronic acid and iduronic acid, which serve as the acidic sugar components of repeating disaccharide units.

Epimers in GAG acidic sugars

Glucuronic acid and iduronic acid, which are stereoisomers differing at a single stereocenter.

Negative charge of GAGs

Charge conferred by acetyl groups ($\text{CH}_3\text{COO}^-$), sulfate groups ($\text{SO}_4^{2-}$) attached to amino groups, and acidic sugar carboxyl groups ($\text{COO}^-$).

Acetyl group in GAGs

$\text{CH}_3\text{COO}^-$ attached to the amino group, contributing to the overall negative charge of GAGs.

Sulfate group in GAGs

$\text{SO}_4^{2-}$ attached to the amino group, contributing to the negative charge of GAGs.

Repulsion of like charges in GAGs

Electrostatic repulsion between negative charges that imparts a slippery nature to mucus secretions and facilitates joint mobility.

Slippery nature of mucus secretion

Physical property of mucus resulting from the mutual repulsion of like negative charges on GAGs.

Joint mobility in GAGs

Movement facilitated in cartilage, bones, and synovial fluid due to high GAG content and like-charge repulsion.

Compressibility and lubrication of GAGs

Functional properties resulting from the ability of GAGs to attract water, providing resilience to joints.

Action of GAG within water

Mechanism of shrinking upon releasing $\text{H}_2\text{O}$ during compression, and swelling upon absorption of $\text{H}_2\text{O}$ during relaxation.

Hyaluronic acid disaccharide unit

$N\text{-acetyl glucosamine} + \text{Glucuronic acid}$.

Hyaluronic acid locations

Skin, synovial fluid, loose connective tissue, bone, and cartilage.

Hyaluronic acid covalent attachment

Distinguishing feature of hyaluronic acid, as it is not covalently attached to proteins.

Hyaluronic acid sulfate content

Unique property of hyaluronic acid containing no sulfate group.

Hyaluronic acid cell migration function

Facilitates cell migration during wound repair, tumor metastasis, and embryogenesis.

Hyaluronic acid in cartilage

Provides compressibility to cartilage tissue.

Keratan sulfate (KS) disaccharide unit

$N\text{-acetyl glucosamine} + \text{Galactose (non-uronic acid)}$.

Keratan sulfate types (KS I and KS II)

KS I is located in the cornea and maintains corneal transparency; KS II is located in loose connective tissue.

Keratan sulfate uronic acid content

Characteristic feature of keratan sulfate containing no uronic acid.

Most heterogeneous GAG

Keratan sulfate (KS).

Chondroitin sulfate disaccharide unit

$N\text{-acetyl galactosamine} + \text{Glucuronic acid}$.

Chondroitin sulfate locations

Bone, cartilage, and central nervous system (CNS).

Most abundant GAG

Chondroitin sulfate.

Chondroitin sulfate distribution

Most widely distributed GAG, providing compressibility to cartilage.

Dermatan sulfate disaccharide unit

$N\text{-acetyl galactosamine} + \text{Iduronic acid}$.

Dermatan sulfate locations

Skin and eye, serving as a structural component of the sclera.

Atherogenic GAG

Dermatan sulfate, which is synthesized from smooth muscle and attracts LDL, leading to atherosclerosis.

Structure of sclera GAG

Dermatan sulfate, which serves as a structural component of the sclera.

Heparan sulfate disaccharide unit

$\text{Glucosamine} + \text{Glucuronic acid}$.

Heparan sulfate locations

Skin and glomerular basement membrane (GBM).

Heparan sulfate plasma membrane role

Functions as a receptor in the plasma membrane and is present in synaptic vesicles.

Heparan sulfate LPL anchoring

Anchors lipoprotein lipase (LPL) on the endothelial surface.

Charge selectiveness of GBM

Function provided by heparan sulfate in the glomerular basement membrane that repels the entry of albumin into filtrate.

Heparin disaccharide unit

$\text{Glucosamine} + \text{Iduronic acid}$.

Heparin locations

Mast cells, lungs, and skin.

Only intracellular GAG

Heparin.

Heparin anticoagulant mechanism

Functions as an anticoagulant by binding to anti-thrombin III.

Heparin effect on LPL

Dislodges lipoprotein lipase (LPL) from its endothelial anchoring site.

Proteoglycan structure ratio

$95\%$ glycosaminoglycan (GAG) and $5\%$ protein.

Proteoglycan

Structure formed when glycosaminoglycans are usually attached to proteins.

Bottle brush shape of proteoglycan monomer

Structural appearance of a proteoglycan monomer in both side view and top view.

Small stalk of proteoglycan monomer

Linkage structure attaching GAG to core protein, composed of gal-gal-xyl ($\text{galactose-galactose-xylose}$).

Core protein

Central protein backbone to which GAG chains like chondroitin sulfate and keratan sulfate attach in a proteoglycan monomer.

Proteoglycan aggregate

Complex present in the extracellular matrix consisting of proteoglycan monomers attached to hyaluronic acid via link proteins.

Link protein

Protein that attaches proteoglycan monomers to the central hyaluronic acid backbone in proteoglycan aggregates.

Mucopolysaccharides

Another name (AKA) for glycosaminoglycans (GAGs).

GAG synthesis location

Rough endoplasmic reticulum (RER) and Golgi apparatus.

GAG degradation location

Lysosomes, via hydrolase enzymes.

Mucopolysaccharidosis (MPS)

A lysosomal storage disorder caused by defective hydrolase degradation leading to accumulation of GAGs in lysosomes.

MPS inheritance pattern

Autosomal recessive inheritance for all MPS types, except Hunter disease.

Hunter disease inheritance

X-linked recessive inheritance.

Gargoylic facies

Vertical facies appearance in MPS characterized by frontal bossing, depressed nasal bridging, gingival hypertrophy, and a large tongue.

Facial features of gargoylic facies

Frontal bossing, depressed nasal bridging, gingival hypertrophy, and a large tongue.

Upper respiratory tract infection sign in MPS

Copious nasal discharge resulting from gingival hypertrophy and large tongue.

Corneal clouding in MPS

Ocular clinical manifestation present in some MPS types but not present in all MPS.

Intellectual disability in MPS

Neurological clinical manifestation present in some MPS types but not present in all MPS.

Visceromegaly in MPS

Gastrointestinal clinical manifestation seen in MPS involving enlargement of visceral organs.

Umbilical hernia in MPS

Gastrointestinal physical feature present in MPS.

Claw hand

Hand abnormality feature seen in MPS.

Dysostoses multiplex

Radiological finding in MPS characterized by skeletal dysplasia and degeneration in vertebrae and metacarpals.

Beaking of vertebra

Radiological feature of MPS presenting as anterior vertebral body beaking and degeneration.

Bullet shaped middle phalanx

Radiological feature in MPS observed on hand X-rays.

Reilly body inclusions

Histological feature of MPS characterized by inclusion bodies inside leukocytes.

Hurler's disease (MPS IH) gene

IDA gene.

Hurler's disease enzyme defect

$\alpha\text{-L-iduronidase}$ deficiency.

Hunter's disease (MPS II) gene

IDS gene.

Hunter's disease enzyme defect

$\alpha\text{-L-iduronate sulfatase}$ deficiency.

Sanfilippo disease (MPS III) frequency

Most common (m/c) type of mucopolysaccharidosis.

Sanfilippo disease enzyme defect

Defect in an enzyme that degrades heparan sulfate.

Universal features present in all MPS

Coarse facial features, short stature, and dysostoses multiplex.

Natowicz syndrome (MPS IX)

Mucopolysaccharidosis caused by a defect in hyaluronidase.

Stem cell therapy in MPS

Treatment modality used specifically for Hurler's disease (MPS IH).

Aldurazyme and Elaprase

Enzyme replacement therapies for MPS: Aldurazyme for MPS I and Elaprase for MPS II.

Flavinoids in MPS treatment

Substrate reduction therapy used for MPS III (Sanfilippo disease).

Inclusion cell (I-cell) disease

Lysosomal protein targeting disorder caused by deficiency of N-acetylglucosamine phosphotransferase.

N-acetylglucosamine phosphotransferase

Enzyme deficient in I-cell disease that normally transfers phosphate groups to mannose to synthesize mannose 6-phosphate.

Pathophysiology of I-cell disease

Defective mannose 6-phosphate synthesis prevents transport of lysosomal enzymes into lysosomes, causing them to leak into plasma, resulting in inclusion body formation and mucopolysaccharide accumulation.