MPS I (McKusick 607014) is an autosomal recessive lysosomal storage disorder that is caused by deficient enzyme activity of α-l-iduronidase (IDUA), leading to lysosomal accumulation of glycosaminoglycans (GAGs) in multiple tissues throughout the body. MPS I is a chronic, progressive disease affecting the heart, eyes, bones, joints, respiratory system, facial appearance, viscera, and often the central nervous system. It has historically been classified clinically into three syndromes based on age of onset, rapidity of progression, and presence and degree of cognitive involvement [23]. Hurler syndrome describes patients with the most severe form of MPS I, with signs and symptoms typically appearing in infancy and a median age of death of 6.8 years when untreated [20]. Patients with Scheie syndrome present later in childhood and demonstrate slower symptom progression with preservation of cognition and survival into adulthood [30]. Hurler–Scheie describes an intermediate form with no or mild cognitive impairment and death usually occurring in adolescence or early adulthood when untreated. Patients with Hurler–Scheie and Scheie syndromes also have been referred to as having attenuated MPS I. Collectively, these forms represent different degrees of severity along a disease spectrum without strict clinical, biochemical, or molecular diagnostic criteria in place to differentiate them.

With an overall prevalence of 1:100,000 live births [19, 20, 27] and significant variability in presentation, diagnosis of MPS I in all its forms poses a true challenge [8, 32]. Initial diagnosis is primarily based on physician recognition of signs and symptoms. Deficient IDUA activity and excess urinary GAG excretion are seen in all patients, but do not accurately predict disease severity or form. Although some genotype–phenotype correlations have been established [11, 29], most known disease-causing mutations (over 100 to date) are individually unique (“private”) and uncharacterized. Treatment of MPS I has also proven challenging as disease-specific treatment options are limited, intensive, and not curative. Hematopoietic stem cell transplantation (HSCT) has been used to treat more than 500 patients with MPS I since 1981 [1, 18] and is typically recommended for patients with Hurler syndrome under 2 years of age with normal cognition (DQ>70), as it can prolong survival, preserve neurocognition, and ameliorate some somatic features [21]. However, due to its significant morbidity and mortality, HSCT is reserved for the most severe form of MPS I [5, 6, 28]. The allogenic stem cell infusion is given following conditioning with chemotherapeutic agents used to suppress the immune response; when successful, the transplant is a one-time procedure, though graft failure may necessitate subsequent transplants. Enzyme replacement therapy (ERT) with laronidase (recombinant human α-l-iduronidase; Aldurazyme®, BioMarin Pharmaceutical and Genzyme, a Sanofi Company) was approved in 2003 to treat the non-neurologic manifestations of MPS I and is the primary treatment option for patients with Hurler–Scheie and Scheie syndromes. Laronidase is also used to treat Hurler patients who are not candidates for HSCT because of age, health status, access to transplant, or parental choice. Laronidase must be given as a weekly peripheral or central intravenous infusion and is a lifelong therapy.

The timing of treatment initiation, and therefore of diagnosis, is thought to be an important factor for the success of both HSCT and laronidase. Developmental outcomes are better when transplant occurs before 24 months of age [26]. Laronidase may also be more beneficial when started early, as suggested by a case report of a sib pair with Hurler–Scheie syndrome [15]. Other than laronidase and HSCT, additional management of MPS I is symptom-based and largely supportive, such as surgical interventions (e.g., adenotonsillectomy, hernia repair, ventriculoperitoneal shunt, cardiac valve replacement, carpal tunnel release, spinal decompression); physical, occupational, and speech therapies; respiratory support (e.g., continuous positive pressure ventilation with oxygen supplementation); hearing aids; and medications for pain and gastrointestinal disturbances.

Our data show that the median age at diagnosis has not decreased over time for any form of MPS I, despite available treatment options. Although Hurler patients tend to be diagnosed within a few months of symptom onset, Hurler–Scheie and Scheie patients still remain undiagnosed for years after symptom onset (Fig. 1). This gap not only represents years of reduced quality of life that would likely be ameliorated by treatment, but also a lost opportunity for preventing or delaying irreversible disease manifestations, as well as for genetic counseling about the risk of future siblings being affected. Sibling case studies and studies in the MPS I dog model suggest that starting enzyme replacement therapy with laronidase shortly after birth can significantly improve clinical outcome [13–15, 33]. Most patients who begin treatment at a very young age have an older sibling with a known diagnosis of MPS I. While studies of affected sib pairs will certainly provide more information about the potential impact of early laronidase treatment, prompt clinical diagnosis will be imperative for the majority of MPS I patients to benefit from this information. Demonstration of substantial improvement in clinical outcomes with earlier diagnosis and treatment of MPS I along with an enhanced ability to predict phenotype at birth through genotype–phenotype correlations and/or disease biomarkers will underscore the need for broad implementation of a newborn screening program for this rare, life-threatening disorder and will aid in decisions of which patients to treat with what therapies, and how early to treat them.

As would be expected, the time interval from diagnosis to initiation of disease-specific treatment decreased following the availability of laronidase in 2003, especially for Hurler–Scheie and Scheie patients, who until then had generally been offered only palliative, symptom-based treatments. Prior to 2003, ERT with laronidase was available only through clinical trials, the largest of which enrolled mostly older children, adolescents, and young adults with a mean duration of 13 years since symptom onset [9]. In addition, the proportion of untreated patients has decreased over time. Despite the decrease in time from diagnosis to treatment, there still exists a delay of 0.5 year and 1.4 years between median ages at diagnosis and treatment for Hurler–Scheie and Scheie patients, respectively, during the most recent time interval of 2006–2009. In comparison, for patients with the Hurler form, there was almost no delay between diagnosis and treatment. This may be due to parents and/or diagnosing physicians perceiving the attenuated phenotypes as milder, or less urgent, thereby further delaying time to treatment. In addition, it may represent time needed for laronidase approval by reimbursement authorities [7]. There may also be regional differences in the delay between diagnosis and treatment, given that laronidase was not approved outside the European Union and the USA until 2005.

Interestingly, when looking at Fig. 1, the age of symptom onset appears to have decreased somewhat in both the Hurler–Scheie and Scheie populations. Rather than a true change in the natural history of MPS I disease, this finding is more likely to be secondary to small patient numbers and the retrospective awareness that certain common early symptoms (such as hernia and chronic otitis media) are often related to MPS I. Also, while the actual age of diagnosis has not greatly improved, parents and physicians may have improved in the retrospective recognition of the common early manifestations of the disease, which led to younger ages of symptom onset in the attenuated patient populations.

Of note, patients with an unknown disease form tended to present with MPS I symptoms between the ages of patients classified as Hurler and Hurler–Scheie. Similarly, they were typically diagnosed and treated at ages in between those of Hurler and Hurler–Scheie patients as well. This suggests that patients in the Registry with an unknown disease form are more likely to be on the more severe end of the MPS I spectrum.

This analysis identified several shifts in clinical practice, such as the increasing use of laronidase among transplanted patients, particularly in the peri-transplant period, and the increasing use of cord blood as a stem cell source. The proportion of unrelated versus related donors for HSCT has remained relatively stable as unrelated bone marrow donors have been replaced by unrelated cord blood donors. Use of laronidase in the peri-transplant period has been reported to be safe and well tolerated without interfering with engraftment or increasing the risk of graft-versus-host disease [6, 12, 16, 17, 31, 34]. Laronidase treatment may be particularly beneficial in patients in poor clinical condition prior to HSCT, to help improve their eligibility for transplant and tolerance of the full-intensity transplant conditioning [12, 16, 17, 24, 31].

In addition, an increasing proportion of Hurler patients in the Registry is receiving laronidase alone (Fig. 2), reflecting the fact that HSCT is not available in many parts of the world, while the majority of transplanted patients are from North America and Europe. A recent MPS I Registry analysis comparing patients from Latin America to those from the rest of the world found that less than 1% of patients in Latin America had been transplanted, compared to 27% of patients from the rest of the world [22]. Our MPS I Registry patients came from over 30 countries in Europe and the Middle East, North America, Latin America, and Japan and Asia Pacific (Table ​(Table1).1). Regional differences in treatment availability would also impact the ages at treatment initiation as well as the proportion of untreated patients. For example, in Brazil, which has a universal-access public health care system, neither laronidase nor HSCT is covered by government or specialized pharmaceutical programs [7].

Narrowing the gap between symptom onset and MPS I diagnosis is of the utmost importance and largely relies on increased recognition of clinical red flags by community physicians and pediatric specialists managing the many MPS I-related symptoms, such as otolaryngologists, orthopedists, rheumatologists, and ophthalmologists. While there is significant variability of first presenting symptom both within and between phenotypes, certain symptoms have been consistently noted to appear earlier than others in the MPS I population. Coarse facial appearance, abdominal distension, and corneal clouding are among the most common presenting symptoms in children with Hurler syndrome [4, 10]. In the patients with attenuated forms, joint stiffness/contractures, recurrent ENT symptoms, corneal clouding, and umbilical hernias are the most prevalent initial symptoms [4, 30, 32]. In addition, certain constellations of symptoms should raise a physician’s suspicion of MPS I. In a 2009 study of surgical procedures in 544 MPS I Registry patients representing all clinical forms, 72% had had at least one surgical procedure, with a median of 3 to 4 surgeries per patient, and with nearly half of the patients reporting two or more surgeries by age 4 years [2]. Surgeries often appeared unrelated, such as combinations of ear tubes, hernia repair, and tendon releases in the same patient, and often preceded the patient’s MPS I diagnosis, particularly in the attenuated phenotypes. Many procedures were also performed at ages atypical for the general pediatric population, such as younger ages of tonsillectomy/adenoidectomy, and older ages of hernia repair in patients with MPS I.