Hurler syndrome, the bone marrow transplant pioneer

In 1980, William Krivit and colleagues at the University of Minnesota performed the first allogeneic bone marrow transplant for a child with Hurler syndrome, the severe form of mucopolysaccharidosis type I. The premise was that donor-derived monocytes and microglia would deliver functional alpha-L-iduronidase, the missing enzyme, into tissues that the affected child's own cells could not service. The transplant worked. The child survived an interval longer than the natural history predicted. Hurler became the first inherited metabolic disease for which allogeneic HSCT was a standard treatment, and the experience built at Minnesota and a small number of other centers shaped the field of metabolic transplantation that now extends to Krabbe, MLD, X-ALD, and several other lysosomal and peroxisomal disorders.

What Hurler is

Mucopolysaccharidosis type I is an autosomal recessive lysosomal storage disorder caused by deficiency of alpha-L-iduronidase, IDUA, encoded by IDUA on chromosome 4p16. IDUA degrades the glycosaminoglycans dermatan sulfate and heparan sulfate inside the lysosome. When IDUA activity is reduced or absent, these glycosaminoglycans accumulate in lysosomes throughout the body. The clinical phenotype follows the tissues that depend most heavily on glycosaminoglycan turnover.

Three clinical forms are recognized along a continuum of residual enzyme activity. Hurler syndrome, the severe form, presents in infancy with progressive coarsening of facial features, hepatosplenomegaly, corneal clouding, recurrent respiratory infections, cardiac valve thickening, hydrocephalus, dysostosis multiplex (a characteristic skeletal dysplasia), and progressive cognitive decline. Without treatment, most affected children die in the first decade. Hurler-Scheie is an intermediate form with milder cognitive involvement and longer survival. Scheie syndrome is the attenuated form with somatic features but preserved intelligence and adult survival.

Reported live-birth incidence of MPS I in unselected populations runs roughly 1 in 100,000. The proportion of severe (Hurler) versus attenuated forms varies by population.

Detection

Newborn screening for MPS I uses IDUA enzyme activity on the dried blood spot, with second-tier glycosaminoglycan measurement and IDUA sequencing for confirmation. MPS I was added to the federal Recommended Uniform Screening Panel in 2016. Most US states screen.

A central screening problem is the same problem that affects Krabbe and several other lysosomal disorders: the assay reliably identifies a population enriched for affected infants, but distinguishing severe (Hurler) from attenuated (Hurler-Scheie or Scheie) forms at birth requires careful interpretation of enzyme activity, glycosaminoglycan profile, and IDUA variant data. The phenotype prediction matters because the treatment recommendation differs.

What management looks like

Standard of care depends on the form. For severe Hurler syndrome, allogeneic hematopoietic stem cell transplantation, performed before the age of 2 to 2.5 years and ideally before significant cognitive decline, is the standard treatment in centers experienced in metabolic transplantation. Engraftment of donor-derived cells provides a continuous source of IDUA across tissues including the central nervous system, where enzyme replacement therapy delivered intravenously cannot adequately reach. Outcomes after early HSCT include preservation of cognition, slowed progression of somatic disease, and substantially extended survival. Cardiac valvular disease, skeletal dysplasia, and corneal clouding can persist or progress despite transplant, and additional surgical interventions for spinal cord compression, hip dysplasia, and other orthopedic complications are common.

For attenuated MPS I and for severe MPS I diagnosed too late for HSCT to be effective, intravenous enzyme replacement therapy with laronidase (Aldurazyme), approved by the FDA in 2003, addresses peripheral disease. Laronidase does not cross the blood-brain barrier in meaningful quantities and therefore does not address central nervous system involvement. Lifelong weekly infusions are required.

Gene therapy programs for MPS I are in clinical development. Both ex vivo lentiviral approaches (analogous to Skysona for X-ALD and Lenmeldy for MLD) and in vivo AAV-delivered IDUA gene therapy are being pursued. As of 2024, no gene therapy is FDA-approved for MPS I.

Adjunctive surgeries for MPS I across all forms include spinal decompression for cervical cord compression, carpal tunnel release, hip osteotomies, cardiac valve repair or replacement, and corneal transplantation. The orthopedic and ophthalmologic burden remains substantial even after successful HSCT.

What this looks like for a family

A baby is born and the heel-prick is sent. On day 5, the state lab reports a low IDUA activity. On day 7, glycosaminoglycan analysis and IDUA sequencing confirm severe MPS I (Hurler) based on the variant combination and the glycosaminoglycan pattern. The family meets the metabolic geneticist, the bone marrow transplant team, and the multidisciplinary clinic that will follow the child for life. Donor search begins through the National Marrow Donor Program. Transplant happens before the second birthday.

Years pass. The child has had cardiac valve surgery, spinal decompression, hip surgery, corneal transplantation. Cognitive function is preserved. Somatic disease is partial. The family lives within a network of subspecialty clinics that, taken together, manage what would otherwise have been a fatal childhood disease.

That is what Hurler care looks like in practice when the screen catches it early. The transplant is not a cure. The transplant is what makes everything else worth doing.