MUCOPOLYSACCHARIDOSES

Mucopolysaccharidoses — lysosomal storage disorders with FDA-approved enzyme replacement therapies and emerging gene therapies, where treatment before irreversible skeletal and neurological damage determines the difference between independent function and severe disability.

Whole genome sequencing evaluates all MPS genes — IDUA, IDS, SGSH, NAGLU, GALNS, GUSB, and others — providing the molecular subtype diagnosis that determines enzyme replacement therapy eligibility and HSCT candidacy.

IDUA
IDS
SGSH
NAGLU
GALNS
ARSB
GUSB

About this condition

Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of enzymes that degrade glycosaminoglycans (GAGs) — complex sugar chains on cell surfaces and in connective tissue. Undegraded GAGs accumulate in lysosomes, disrupting cell and organ function. Seven MPS types are recognized: MPS I (Hurler/Scheie, IDUA), MPS II (Hunter, IDS — X-linked), MPS III (Sanfilippo A-D, SGSH/NAGLU/HGSNAT/GNS), MPS IV (Morquio A-B, GALNS/GLB1), MPS VI (Maroteaux-Lamy, ARSB), MPS VII (Sly, GUSB), and MPS IX (HYAL1). Combined incidence is approximately 1 in 25,000 births.

MPS disorders produce progressive multisystem disease: coarse facial features, skeletal dysplasia (dysostosis multiplex), joint stiffness, hepatosplenomegaly, cardiac valve disease, corneal clouding, hearing loss, and — in severe forms — progressive neurocognitive decline. The most severe neurological phenotype occurs in MPS I Hurler, MPS II (severe form), and MPS III (all subtypes). MPS IV and MPS VI have severe skeletal disease but preserved cognition. This distinction — cognitive involvement vs. cognitive preservation — is critical because it determines whether hematopoietic stem cell transplant (HSCT) or enzyme replacement therapy (ERT) is the primary treatment strategy.

Multiple FDA-approved therapies exist: ERT for MPS I (laronidase/Aldurazyme), MPS II (idursulfase/Elaprase), MPS IVA (elosulfase/Vimizim), MPS VI (galsulfase/Naglazyme), and MPS VII (vestronidase/Mepsevii). HSCT is the treatment of choice for severe MPS I (Hurler syndrome) when performed before age 2, as transplanted donor-derived enzyme-producing cells can cross the blood-brain barrier and partially protect the CNS — but only if sufficient myelination and brain development have not yet been damaged. Gene therapy trials are active for MPS I, MPS II, MPS IIIA, and MPS IIIB.

HSCT for MPS I Hurler must be performed before age 2 to protect the brain. Every month of diagnostic delay reduces the neurological benefit of transplantation. Newborn screening for MPS I is now expanding across the US.

Gene locus: IDUA (4p16.3), IDS (Xq28), SGSH (17q25.3), NAGLU (17q21.2), GALNS (16q24.3), ARSB (5q14.1), GUSB (7q11.21)

MPS I newborn screening is expanding, but other MPS types are not yet screened. Clinical diagnosis is delayed by the gradual onset of features. WGS identifies all MPS subtypes from a single test.

HSCT before age 2 preserves cognition in MPS I Hurler — but requires molecular diagnosis in infancy

Severe MPS I (Hurler syndrome) causes progressive neurocognitive decline beginning in toddlerhood. HSCT performed before age 2 — ideally before significant neurological involvement — provides donor-derived IDUA-producing cells that partially protect the CNS from further deterioration. After age 2, the neurological benefit of HSCT diminishes as irreversible brain damage accumulates. Newborn screening for MPS I is expanding, but many infants are still diagnosed clinically — often after developmental regression prompts specialist evaluation at 12-18 months, leaving a narrow treatment window.

MPS III (Sanfilippo syndrome) has no FDA-approved therapy — gene therapy trials are the best hope, and enrollment requires molecular diagnosis

MPS III (Sanfilippo syndrome) causes progressive neurocognitive decline in childhood with death typically in the second or third decade. Unlike MPS I, II, IV, VI, and VII, there is no FDA-approved ERT for MPS III (the enzymes do not cross the blood-brain barrier effectively). Intrathecal ERT and AAV-based gene therapy are in clinical trials for MPS IIIA (SGSH) and MPS IIIB (NAGLU). Enrollment requires confirmed molecular diagnosis. WGS identifies the specific MPS III subtype (A, B, C, or D) — each caused by a different gene — directing families to the correct gene-specific clinical trial.

Mucopolysaccharidoses — lysosomal storage disorders with FDA-approved enzyme replacement therapies and emerging gene therapies, where treatment before irreversible skeletal and neurological damage determines the difference between independent function and severe disability.

Mucopolysaccharidoses

MPS I newborn screening is expanding, but other MPS types are not yet screened. Clinical diagnosis is delayed by the gradual onset of features. WGS identifies all MPS subtypes from a single test.

HSCT before age 2 preserves cognition in MPS I Hurler — but requires molecular diagnosis in infancy

MPS III (Sanfilippo syndrome) has no FDA-approved therapy — gene therapy trials are the best hope, and enrollment requires molecular diagnosis

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