Mucopolysaccharides (Glycosaminoglycans) and the Mucopolysaccharidoses (MPS)

What Are Mucopolysaccharides?

• Dermatan sulfate
• Heparan sulfate
• Keratan sulfate
• Chondroitin sulfate (4- and 6-sulfate)
• Hyaluronan (not sulfated)

General Features of All MPS Disorders

• Storage of GAGs within lysosomes (lysosomal storage diseases)
• Progressive accumulation due to defective degradation
• Multisystem involvement: skeletal, cardiac, respiratory, neurologic, ocular, hepatosplenic
• All are autosomal recessive except MPS II (Hunter), which is X-linked recessive
• Diagnosis: urinary GAG excretion pattern + specific enzyme assay + gene analysis
• Characteristic "gargoyle" or coarse facial features in several types

Classification of the Mucopolysaccharidoses

Individual Syndromes - Clinical Detail

MPS I - Hurler Syndrome

• Onset: end of the first year of life
• Clinical triad: coarse "gargoyle" facies, corneal clouding, intellectual disability
• Skeletal: dwarfism, kyphosis, broad hands with stubby fingers, flexion contractures at knees and elbows
• Hearing loss (conductive), hepatosplenomegaly, valvular heart disease, recurrent respiratory infections, hernias
• Biochemistry: absence of α-L-iduronidase → accumulation of dermatan + heparan sulfate in tissues and urine
• Also increased ganglioside content in brain neurons
• Death: mid-adolescence from cardiac failure and respiratory infections
• Diagnosis: metachromatic granules in leukocytes; increased urinary GAGs; confirmed by enzyme assay (α-L-iduronidase) and IDUA gene analysis

MPS II - Hunter Syndrome

• X-linked recessive (only X-linked MPS)
• Onset: 2-5 years; males affected
• Hurler-like but milder: coarse facies, joint stiffness, deafness, organomegaly, developmental delay
• No corneal clouding (key distinguishing feature from Hurler)
• Two forms: severe (death in mid-teens) and mild (relatively normal intelligence, survival to middle age)
• Enzyme deficiency: iduronate sulfate sulfatase (IDS gene)
• Urine: excess dermatan + heparan sulfate

MPS III - Sanfilippo Syndrome

• Most common MPS
• Predominant neuropsychiatric presentation: behavioral problems, intellectual regression, hyperactivity, seizures
• Mild somatic features (unlike other MPS types)
• Four subtypes (A-D) from four different enzymes, all degrading heparan sulfate:
  • IIIA: N-sulphoglucosamine sulphohydrolase (SGSH gene)
  • IIIB: α-N-acetylglucosaminidase (NAGLU gene)
  • IIIC: Heparan-α-glucosaminide N-acetyltransferase (HGSNAT gene)
  • IIID: N-acetylglucosamine-6-sulfatase (GNS gene)
  • Types A and B account for 90% of cases
• Death: early adult life

MPS IV - Morquio Syndrome

• Onset: 2-3 years
• Skeletal dysplasia without intellectual impairment (intelligence normal)
• Short stature, thoracic deformity, kyphoscoliosis
• Risk: spinal cord compression from odontoid hypoplasia and cervical instability
• Slight corneal clouding; cardiac and respiratory complications
• Urine: keratan sulfate
• Enzyme: galactosamine-6-sulfatase (MPS-IVA, GALNS gene) or β-galactosidase (MPS-IVB, GLB1 gene)
• Prevalence: ~1 in 200,000-300,000

MPS VI - Maroteaux-Lamy Syndrome

• Hurler-like somatic features: coarse facies, short stature, kyphosis, joint restriction, corneal clouding, cardiac valve abnormalities
• Intelligence normal
• Enzyme deficiency: N-acetylgalactosamine-4-sulfatase / arylsulfatase B (ARSB)
• Urine: dermatan sulfate
• Spinal cord compression can occur
• Two forms: severe (survival to early adulthood) and mild

MPS VII - Sly Syndrome

• Enzyme deficiency: β-Glucuronidase (GUSB gene)
• Wide range of severity
• Severe form: fetal hydrops - can cause stillbirth or perinatal death
• Later-onset form: short stature, coarse facies, hepatosplenomegaly

Diagnosis

1. Urine GAG quantification and fractionation - screening test (increased dermatan, heparan, keratan, or chondroitin sulfate excretion patterns are type-specific)
2. Enzyme activity assay - in serum, leukocytes, or cultured fibroblasts - confirmatory
3. Molecular gene analysis - IDUA, IDS, NAGLU, GALNS, GUSB, etc.
4. Newborn screening (NBS): MPS I added to recommended NBS panels in several US states; Pompe disease similarly screened

Treatment

Enzyme Replacement Therapy (ERT)

• MPS I: Laronidase (recombinant α-L-iduronidase) - effective for visceral/cardiac/respiratory manifestations; does not cross blood-brain barrier (no direct CNS benefit)
• MPS II: Idursulfase - weekly IV; addresses visceral manifestations; no CNS penetration
• MPS IVA: Elosulfase alfa - approved; improves ambulatory mobility and decreases pain; no treatment for MPS IVB
• MPS VI: Galsulfase (arylsulfatase B) - FDA approved
• MPS VII: Vestronidase alfa-vjbk - approved

Hematopoietic Stem Cell Transplantation (HSCT)

• Standard treatment for MPS I presenting at <2 years of age with neurologic involvement
• Stabilizes CNS disease, reverses hepatosplenomegaly, improves cardiac/respiratory disease
• Does not improve corneal disease or progressive skeletal disease
• HSCT has not been successful in treating CNS disease in MPS II
• Not helpful in Hunter or Sanfilippo diseases
• Combination ERT + HSCT is being tried (ERT before transplant to reduce disease burden)

Supportive Management

• For MPS (airway): adenotonsillectomy, CPAP, or tracheotomy (tonsil/adenoid/tongue hypertrophy and tracheobronchial deposits cause obstructive sleep apnea and chronic pulmonary disease - a major cause of death)
• Regular lifelong cardiac and respiratory follow-up even after successful HSCT

Wound Healing Role

• "Hunter = Heparan + dermatan + Hemizygous (X-linked)" - the only X-linked MPS
• "Sanfilippo = Smart (normal IQ early) then degenerates + Sulfate of heparan only"
• "Morquio = Musculoskeletal (skeletal dysplasia) + Mind intact (normal intelligence)"
• "Maroteaux-Lamy = like Hurler but Lucid (normal intelligence)"

Glucose Transporters (GLUT/SGLT) in the Intestine

Overview

1. SGLT1 (apical/brush-border membrane) - for glucose and galactose
2. GLUT5 (apical/brush-border membrane) - for fructose
3. GLUT2 (basolateral membrane) - exit route for all three monosaccharides into portal blood

The Classic Diagram (Normal/Low Glucose Load)

Step-by-Step Mechanism

Step 1: Na⁺/K⁺-ATPase Creates the Driving Force (Basolateral Membrane)

• The Na⁺/K⁺-ATPase pump on the basolateral membrane (BLM) continuously pumps Na⁺ out of the enterocyte and K⁺ in, using ATP
• This keeps intracellular Na⁺ low and maintains an inside-negative membrane potential
• The resulting electrochemical Na⁺ gradient is the ultimate energy source for glucose absorption - this is secondary active transport

Step 2: SGLT1 - Apical/Brush-Border Membrane Entry (Glucose & Galactose)

Step 3: GLUT5 - Apical Membrane Entry (Fructose Only)

• Fructose enters the enterocyte purely by concentration gradient via GLUT5
• No Na⁺, no ATP required
• Rate of fructose absorption is ~half that of glucose/galactose as a result

Step 4: GLUT2 - Basolateral Membrane Exit (All Three Sugars)

• All three monosaccharides that enter the enterocyte exit across the BLM via GLUT2 into the paracellular space and then into portal blood
• The low affinity is physiologically important - it ensures sugars only exit when intracellular concentrations exceed portal blood concentrations (i.e., net export only when the cell is loaded)
• GLUT2 also functions in the pancreas (β-cells) as a glucose sensor to trigger insulin secretion proportional to blood glucose

The Dynamic Model: GLUT2 Trafficking Under High-Glucose Load

• SGLT1-mediated glucose entry acts as the signal that triggers trafficking of GLUT2 from the BLM to the BBM (apical membrane)
• GLUT2 then appears on both membranes simultaneously
• Because GLUT2 is a low-affinity, high-capacity transporter, its presence on the BBM under high-load conditions allows rapid, high-volume absorption that SGLT1 alone (high affinity but lower capacity) cannot achieve
• This GLUT2 recruitment to the BBM also facilitates fructose absorption - since SGLT1 cannot transport fructose, the apical GLUT2 provides an extra route for fructose entry beyond GLUT5
• Evidence from SGLT1 knockout mice confirms this: Sglt1-null mice cannot recruit Glut2 to the BBM, confirming SGLT1-mediated entry as the trigger

Summary Table: The Three Intestinal Sugar Transporters

Knockout Mouse Evidence

Some Fructose Becomes Glucose Inside the Enterocyte

1. Phosphorylated
2. Converted to glucose intracellularly
3. Transported as glucose into the portal circulation

Clinical Relevance