MPS-2 Hunter Disease

1. DEFINITION AND GENETICS

Definition: A rare, progressive lysosomal storage disorder caused by the deficiency of iduronate-2-sulfatase (IDS).
Inheritance: X-Linked Recessive (The only MPS with X-linked inheritance; all others are Autosomal Recessive).
Epidemiology: Almost exclusively affects males. Rarely seen in females due to skewed X-inactivation.
Gene: IDS gene located on chromosome Xq28.
- High molecular heterogeneity: Point mutations, deletions, and rearrangements (major deletions often correlate with severe phenotype).

Enzyme Defect: Deficiency of Iduronate-2-sulfatase.
Storage Material: Inability to degrade glycosaminoglycans (GAGs) leads to intralysosomal accumulation of Dermatan Sulfate and Heparan Sulfate.
Consequence: Progressive cellular dysfunction, hypertrophy, and multisystem tissue damage (skeletal, visceral, CNS).

Clinical spectrum ranges from severe (neuropathic) to attenuated (somatic).

Onset: 2–4 years of age.
Life Expectancy: Death typically in the second decade (10–15 years) due to neurological deterioration or cardiorespiratory failure.
Neurologic:
- Significant developmental delay and intellectual disability.
- Behavioral problems: Hyperactivity, aggression, sleep disturbances.
- Communicating hydrocephalus.
Somatic: Similar to Hurler syndrome but generally slower progression.

Onset: Later childhood.
Life Expectancy: Normal or near-normal; can survive into adulthood (60s–80s).
Neurologic: Normal intelligence; minimal or no CNS involvement.
Somatic: Significant morbidity from airway obstruction, joint stiffness, and cardiac disease.

Ophthalmologic (CRITICAL DIFFERENTIATOR):
- Corneal Clouding is ABSENT (Clear corneas distinguish Hunter from Hurler).
- Retinal degeneration and papilledema may occur.
Dermatologic:
- "Pebbly" Skin: Distinctive grouped ivory-colored papules/nodules on the back, shoulders, and upper arms (pathognomonic but not present in all).
- Mongolian Spots: Extensive congenital dermal melanocytosis reported in mild/severe cases.
Craniofacial: Coarse facies, macrocephaly, macroglossia, broad nose.
Skeletal (Dysostosis Multiplex):
- Joint stiffness (claw hands).
- Short stature.
- Thickened ribs, ovoid vertebrae, hip dysplasia.
Respiratory: Upper airway obstruction, sleep apnea, noisy breathing, recurrent infections.
Cardiac: Valvular disease (mitral/aortic regurgitation), cardiomyopathy.
Gastrointestinal: Hepatosplenomegaly, chronic diarrhea, inguinal hernias.

Screening:
- Urine GAGs: Quantitative elevation of Dermatan Sulfate and Heparan Sulfate.
- Newborn Screening (NBS): Available in some regions (assaying enzyme activity in dried blood spots).
Confirmatory (Gold Standard):
- Enzyme Assay: Deficient iduronate-2-sulfatase activity in plasma, leukocytes, or fibroblasts.
- Note: Normal activity of other sulfatases (to rule out Multiple Sulfatase Deficiency).
Molecular Genetics: IDS gene sequencing (essential for carrier testing in females and genetic counseling).

Multidisciplinary approach is mandatory.

Drug: Idursulfase (Recombinant human iduronate-2-sulfatase).
Efficacy: Improves somatic features (liver/spleen volume), respiratory function (FVC), and walking distance (6MWT).
Limitation: Does not cross the blood-brain barrier; ineffective for cognitive decline in severe forms.

Role: Controversial in MPS II.
Unlike Hurler syndrome (MPS I), HSCT has shown variable and often limited efficacy in preventing neurocognitive decline in severe Hunter syndrome.
Generally not recommended as first-line standard of care, though umbilical cord blood transplant is explored in very early diagnosed severe cases.

Airway: CPAP/BiPAP for sleep apnea; tonsillectomy/adenoidectomy; tracheostomy if severe.
Neurologic: VP shunt for hydrocephalus.
Orthopedic: Management of contractures; carpal tunnel release.
Hernia repair.