Mucopolysaccharidosis (MPS)

1. Definition

Definition: A group of hereditary, progressive lysosomal storage disorders caused by pathogenic variants in genes encoding lysosomal enzymes required for the degradation of glycosaminoglycans (GAGs).
Pathophysiology:
- Deficiency of specific lysosomal enzymes leads to the failure of stepwise degradation of GAGs (heparan sulfate, dermatan sulfate, keratan sulfate, chondroitin sulfate).
- Undegraded GAG fragments accumulate within lysosomes, causing lysosomal distension and cellular dysfunction.
- Accumulation leads to progressive damage to connective tissue, cartilage, bone, and visceral organs.
- Neurotoxicity: Impaired degradation of heparan sulfate is strongly associated with intellectual disability and CNS degeneration.
- Mesenchymal toxicity: Accumulation of dermatan, chondroitin, and keratan sulfate primarily causes skeletal and mesenchymal abnormalities.

Prevalence: Birth prevalence varies from 1.2 (USA) to 16.9 (Saudi Arabia) per 100,000 births.
Most Common Types: MPS III is often the most common, followed by MPS I and MPS II.
Inheritance:
- Autosomal Recessive (AR): All MPS types (I, III, IV, VI, VII, IX).
- X-Linked Recessive (XLR): MPS II (Hunter Syndrome).

Type	Eponym	Enzyme Defect	GAG Stored	Key Features
MPS I	Hurler (I-H) Scheie (I-S)	$α$ -L-Iduronidase	Heparan & Dermatan Sulfate	Severe somatic & CNS (Hurler); Normal IQ, corneal clouding (Scheie).
MPS II	Hunter	Iduronate-2-sulfatase	Heparan & Dermatan Sulfate	X-linked; No corneal clouding; Pebble skin lesions; CNS in severe form.
MPS III	Sanfilippo (A-D)	A: Heparan-N-sulfatase B: $α$ -N-acetylglucosaminidase C: Acetyl-CoA transferase D: N-acetylglucosamine-6-sulfatase	Heparan Sulfate	Predominant CNS/behavioral symptoms; Mild somatic features.
MPS IV	Morquio (A, B)	A: Galactose-6-sulfatase B: $β$ -Galactosidase	Keratan Sulfate	Skeletal dysplasia (short trunk); Odontoid hypoplasia; Normal IQ; Corneal clouding.
MPS VI	Maroteaux-Lamy	Arylsulfatase B	Dermatan Sulfate	Severe somatic features (Hurler-like); Normal IQ; Corneal clouding.
MPS VII	Sly	$β$ -Glucuronidase	Heparan, Dermatan, Chondroitin	Hydrops fetalis (severe) to mild forms.
MPS IX	-	Hyaluronidase	Hyaluronan	Periarticular masses; No Hurler phenotype.

Facies: Coarse features, frontal bossing, depressed nasal bridge, macroglossia, gingival hypertrophy.
Skeletal: Short stature, dysostosis multiplex, joint stiffness/contractures, claw hands.
Visceral: Hepatosplenomegaly, inguinal/umbilical hernias.
Ocular: Corneal clouding (ground-glass appearance), retinal degeneration, glaucoma.
ENT: Recurrent otitis media, hearing loss (conductive/sensorineural), noisy breathing, obstructive sleep apnea.
Cardiac: Valvular disease (mitral/aortic regurgitation or stenosis), cardiomyopathy, coronary artery narrowing.
CNS: Developmental delay, regression, communicating hydrocephalus.

MPS I (Hurler) [Severe]:
- Onset 6–24 months; death by 10 years.
- Severe intellectual disability, corneal clouding, pronounced dysostosis.
- Scheie (Mild): Onset >5 years; normal IQ, corneal clouding, aortic valve disease, joint stiffness.
MPS II (Hunter):
- Distinguishing Feature: Clear corneas (no clouding).
- Skin: Grouped skin papules (pebble-like) over scapula/thighs.
- Extensive Mongolian spots may be an early marker.
- Behavioral issues and neurodegeneration in severe form; normal IQ in mild form.
MPS III (Sanfilippo):
- “CNS severe, Somatic mild”: Severe behavioral problems (aggression, hyperactivity), sleep disturbance, progressive dementia.
- Somatic features are mild; diagnosis often delayed.
MPS IV (Morquio):
- “Skeletal severe, CNS normal”: Short-trunk dwarfism, pectus carinatum, genu valgum.
- Critical: Odontoid hypoplasia leading to atlantoaxial instability and cervical myelopathy (lifesaving fusion needed).
- Ligamentous laxity (unlike other MPS which have stiffness).
MPS VI (Maroteaux-Lamy):
- Phenotype resembles Hurler (severe somatic) but with preserved intelligence.
- Risk of cervical cord compression from dural thickening.

Skull: Macrocephaly, thickened calvarium, J-shaped sella turcica.
Spine: Ovoid/immature vertebral bodies, anterior beaking (often L1/L2), gibbus deformity/kyphosis.
Chest: Oar-shaped ribs (wide anteriorly, narrow posteriorly), short thick clavicles.
Pelvis: Flared iliac wings, shallow acetabula.
Long Bones: Shortened, thickened diaphyses, irregular metaphyses.
Hands: Bullet-shaped metacarpals, proximal pointing of metacarpals, V-shaped deformity.

Screening:
- Urine GAG Analysis: Quantitative (total GAGs) and Qualitative (electrophoresis for specific pattern).
  - Note: Morquio (Keratan sulfate) may be missed on standard urine screens.
Confirmatory:
- Enzyme Assay: Gold standard. Measured in leukocytes, plasma, or fibroblasts.
- Molecular Genetics: Gene panel or sequencing (essential for carrier testing in Hunter/X-linked).
Prenatal Diagnosis:
- Enzyme assay or DNA analysis on Chorionic Villus Sampling (CVS) or amniocytes.

Definitive Therapy:
- Hematopoietic Stem Cell Transplantation (HSCT):
  - Standard of care for MPS I-H (Hurler) if performed early (<24 months).
  - Prevents cognitive decline, improves hepatosplenomegaly, facial features, and cardiac findings.
  - Also used in MPS II, VI, and VII.
  - Does not correct skeletal dysplasia effectively.
- Enzyme Replacement Therapy (ERT):
  - Recombinant enzymes available for MPS I, II, IV, VI, VII.
  - Improves somatic features (visceromegaly, endurance, apnea) but does not cross blood-brain barrier (no effect on CNS).
Supportive Care:
- Neurosurgical: Shunt for hydrocephalus; cervical decompression/fusion for atlantoaxial instability (esp. Morquio, MPS VI).
- ENT: Tonsillectomy/adenoidectomy for airway obstruction; hearing aids.
- Cardiac: Valve replacement for severe regurgitation.
- Ophthalmology: Corneal transplant (if severe clouding).
- Orthopedic: Surgical correction of hip dysplasia, genu valgum, carpal tunnel release.

Severe forms (Hurler, severe Hunter): Death in 1st or 2nd decade (respiratory/cardiac failure).
Attenuated forms (Scheie, mild Hunter): Normal life expectancy possible.
Morquio: Risk of sudden death from cervical cord compression; respiratory compromise due to chest wall deformity.