Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by a deficiency of the enzyme α-L-iduronidase (IDUA)  and has an estimated prevalence of 0.69 to 3.8 per 100,000 live births [2, 3]. Inheritance is autosomal recessive and more than 100 different mutations in the IDUA gene have been described . Reduced or absent IDUA activity results in accumulation of the glycosaminoglycans (GAGs) heparan and dermatan sulfate throughout the body which leads to widespread cellular, tissue, and organ dysfunction, and thus progressive disease.
Historically, MPS I is delineated into three disease phenotypes based on clinical presentation: MPS I-H (Hurler syndrome, severe phenotype), MPS I-H/S (Hurler-Scheie syndrome, intermediate phenotype) and MPS I-S (Scheie syndrome, attenuated phenotype). Patients with MPS I-H have an early-onset, rapidly progressive disease with CNS involvement, which, if left untreated, results in early death, usually within the first two decades of life. Patients with MPS I-S have a much slower disease progression without clinical involvement of the CNS and with a near normal life expectancy. Other common MPS I features include coarse facial features, hepatosplenomegaly, cardiac disease, joint stiffness, skeletal deformities and corneal clouding, all with highly variable severity [1, 5].
Currently, the phenotype is recognized as a continuous spectrum, ranging from severe, with progressive involvement of the central nervous system resulting in cognitive decline, to attenuated, without clinical involvement of the central nervous system. Delineation of the different MPS I phenotypes can be difficult and is based on the age of presentation, rate of progression and the genotype of the patient .
Intravenous enzyme replacement therapy (ERT) with laronidase (recombinant IDUA, Aldurazyme®) has proven to be safe and effective in MPS I patients across a wide range of ages and disease severity, significantly ameliorating somatic disease [7–12]. Laronidase is unable to cross the blood brain barrier in significant quantity, at least in the recommended dose (100 IU/kg/week) , and will therefore not prevent cognitive decline in patients with MPS I-H. A recent report showed that early and higher-dose intravenous ERT can reduce lysosomal storage of GAGs in the brain in dogs with MPS I . However, this has not been studied in humans.
Hematopoietic stem cell transplantation (HSCT) is the treatment of choice in the more severely affected patients with CNS involvement. It has been shown to preserve intellectual development when performed early in the course of disease [15, 16]. Currently, HSCT is considered to be indicated for MPS I-H patients under the age of 2 years and with no or only moderate cognitive impairment (Developmental Quotient (DQ) > 70) . HSCT carries considerable risks for procedure-related morbidity and mortality. However, in recent years, transplant related mortality has declined and the rate of engraftment has improved, resulting in survival rates with donor cell engraftment of over 90% . In addition, laronidase is increasingly used as an adjuvant treatment before HSCT to improve the pre-transplant clinical condition [6, 17].
With increasing insight in the efficacy and limitations of both disease-modifying treatments, it is important to update guidelines for treatment. Preferably, these guidelines are based on high-level empirical evidence. However, due to the extreme rarity of the disease, until now only one randomized controlled trial has been performed, which was on the efficacy of laronidase . Efficacy of HSCT in improving clinical outcome has only been assessed by retrospective analyses of cohorts, and no trials have been done comparing both treatment modalities.
In order to update management guidelines, combining all available published evidence with current expert knowledge, a European consensus procedure was organized with the participation of a group of pediatricians experienced in treatment of patients with MPS I, and comprising both metabolic specialists and bone marrow transplant specialists. The goal was to obtain consensus on crucial issues related to the two different therapeutic modalities in MPS I in order to provide clinical guidelines.