The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK

Mucopolysaccharidosis type I (MPS I) is a panethnic, chronic and progressive, autosomal recessive lysosomal storage disease in which degradation of the glycoaminoglycans (GAGs) dermatan and heparan sulphate is deficient. First described by Hurler in 1919, a milder phenotype was later identified by Scheie in 1962 [1]. Currently three clinical syndromes are often referred to which, from severe through intermediate to mild phenotypes, are termed Hurler, Hurler-Scheie and Scheie. It is clear however that this is an oversimplification and that the full phenotypic spectrum of disease forms a continuum.

The deficient enzyme in MPS I is α-L-iduronidase responsible for removing terminal iduronic acid residues during the sequential degradation of dermatan and heparan sulphates [1]. The disease is characterised by inappropriate storage of these GAGs with accompanying organ enlargement, the excretion of abnormal quantities of GAGs in urine, and disrupted GAG turnover that especially affects connective tissue [1]. The multi-system sequelae result in clinical manifestations that vary between individuals but may include mental retardation, skeletal abnormalities, enlarged liver and spleen, respiratory problems, heart disease and reduced life expectancy [1].

Traditionally treatments for MPS I have aimed at relieving symptoms. More radical treatments have been explored including bone marrow transplantation which has become the treatment of choice for carefully selected Hurler patients. Enzyme replacement therapy (alpha-L-iduronidase, Aldurazyme^®) is now available to treat the intermediate and milder phenotypes (Hurler-Scheie and Scheie) as well as recently more severely affected patients [2]. The development of enzyme enhancement therapy, substrate reduction strategies and also of gene therapy for lysosomal storage diseases and other metabolic disorders, and the various combinations of such strategies, are possible future developments.

In view of the extremely high cost of some new therapies that have been or are being developed under the exclusivity provided by orphan drug legislation it becomes important to estimate the health gains returned with use of these treatments so that a clear understanding can inform the deployment of limited health resources. Difficulties arise in taking appropriate account of the clinical and cost-effectiveness of such interventions because of the sparsity of good quality data as amply exemplified in recent Health Technology Assessment of enzyme replacement therapy for Gaucher's disease [3‐5]. Many data-collecting initiatives are prompted by marketing of new technologies with or without recommendation from regulatory authorities. However such data collection will usually only gain good quality (i.e. prospective) information for patients on-treatment and fails to provide evidence about 'natural progression' of disease in the absence of the new technology since patients that are off-treatment are not representative of the whole disease population and are likely to differ from those on-treatment. Therefore there is very little evidence from such sources with which a new technology can be assessed. This leads to difficulties for physicians and health-care commissioners in determining the clinical and ultimately the relative cost-effectiveness of a technology under conditions of competing budgetary requests.

In order to gauge the effectiveness of new and future treatments it is necessary to understand the natural progression of the disease especially with regard to patients' quality of life and life-expectancy. In general such data on the natural history of lysosomal storage diseases is sparse. Here we analyse patient survival in MPS I and disease prevalence of MPS I using a unique longitudinal data set initiated and maintained over a period of more than 20 years by the Society for Mucopolysaccharide Diseases (UK). This data will be of interest to clinicians, health care authorities, commissioning bodies, those engaged in diagnosis of rare diseases and to patient societies and patient families.

The Society for Mucopolysaccharide Diseases UK (SMD) made available anonomysed records of MPS I patients held in its registry. The Society has aimed to collect data on every UK MPS I sufferer. As most, if not all, patients are now seen at a small number of designated centres, most if not all UK patients are entered into the register. While the number of patients likely to be missing from the register is unknown, it is estimated by collators of the register and by clinicians treating MPS I patients to be zero or very few. Therefore, the dataset can be considered as virtually complete for all UK patients from 1981.

The dataset was analysed for patients entered in to the register between 1981 and May 2005. This registry holds information on birth dates and country of birth, diagnosed MPS I syndrome, receipt of bone marrow transplantation (BMT) and date of transplant, receipt of enzyme replacement therapy (ERT) and date of death. Date of diagnosis and genotype of a significant proportion of patients is also recorded but is incomplete; as would be expected [6] the recorded genotypes were highly variable and mostly private except for the W402X mutation which was fairly common.

At the time of analysis the registry held data on a total of 196 MPS I patients covering the 24 years 1981 to 2005. The patients were categorised according to syndrome as follows: 143 Hurler, 41 Hurler-Scheie, and 12 Scheie.

In this retrospective study, utilising a registry of patient data encompassing most, if not all, UK patients with MPS I, the prevalence of the disease was 1.07/100,000. The prevalence not only falls within all definitions of an orphan disease but meets the definition of an ultra-orphan disease (less then 2/100,000) as defined by the National Institute for Health and Clinical Excellence [17]. This is the largest reported prevalence study, involving nearly twice as many cases and a slightly bigger population pool of the next largest (see Table 1). The prevalence obtained was similar to that from other studies with a large population pool from which cases were ascertained. All studies have been undertaken in developed countries with predominantly Caucasian populations. The prevalence of the sub-syndromes of MPS I reported here are of the same order of magnitude as other studies that have been able to measure the prevalence or have reported it (see Table 1) [15]. The prevalence of Hurler syndrome is highest and Sheie the lowest. The effect of detection bias due to the more ready identification of severe compared to less severe syndromes within these findings is unclear.

As expected survival analysis indicated the relative severity of Hurler's syndrome, with median survival of 8.7 years, and the relative mildness of Sheie syndrome relative to Hurler-Sheie syndrome and all MPS I patients. Median survival could not be calculated for the Hurler-Sheie or Sheie syndromes at present due to the longer duration of follow up required.

Although 60% (25/41) of Hurler-Scheie and 33% (4/12) of Sheie patients had received treatment with enzyme replacement therapy the small sample sizes and the too recent emergence of treatment precluded the possibility of estimating an effect of the therapy on survival. With regard to bone marrow transplant in Hurler patients, censoring those patients who received a transplant reduced survival indicating the better prognosis of those selected to receive BMT and/or the benefit of BMT. The survival of Hurler patients post-BMT was very similar in this study to that recently reported for a pan-European multicentre study [16] which contained twice as many cases (n = 148 compared to 68), with survival rates at one year being 68% and remaining relatively stable for those followed for up to 10 years.

Surveillance of long term effectiveness and of adverse events relating to drug and other treatments is best reliant on large, population-based, disease-specific, well organised studies. For very rare conditions, disease specific registries would represent the best way of monitoring treatment effectiveness in terms of survival and other patient-centred outcome measures. Furthermore, they are very useful for measuring adverse events which are doubly difficult to monitor through hopefully low frequency of such events and the rarity of the disease. Whilst the treatment licensing bodies can request post-marketing studies, in addition to post-marketing reporting of adverse events, these usually only collect data on patients treated with the specific intervention and thus untreated patients or patients treated with other interventions (licensed or otherwise) are often not included [18]. Furthermore, the US Food and Drug Administration documentation demonstrates that post-marketing studies committed to by the pharmaceutical industry are infrequently implemented or completed [19]. The clinical registries of individual or multiple specialist centres set up for disease-specific conditions and unique charitable registries, such the one utilised in this report set up by the Society for Mucopolysaccharide Diseases UK [20], may offer the only reliable source of information on the natural history and the effect of therapies for specific rare conditions. With more therapies on the horizon, their likely marketing approval under orphan drug legislation and relative great expense, it is important that properly functioning registries be created or supported if they already exist, to record data on all patients whether treated with emerging technologies or not.

This study, with the most extended follow up to date in a large target population, sets the birth prevalence of MPS I at 1.07/100,000 live births and median survival at 11.6 years.