The evolution of pulmonary function in childhood onset Mucopolysaccharidosis type I

https://doi.org/10.1016/j.ymgme.2020.07.004Get rights and content

Abstract

Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9–32) years post HSCT and 14.34 (range = 3.89–20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed.

Section snippets

Background

The rare autosomal recessive inherited disorder Mucopolysaccharidosis Type I (MPS I), results from deficit activity of the lysosomal enzyme α-l-iduronidase (MIM 252800). The resultant excess accumulation of sulphated dermatan and heparan species triggers multiple pathological cascades, ultimately generating damaging local inflammatory responses [1,2]. The severity of the enzymic impairment is the chief phenotypic determinant. Those with either severe or moderate impairment, traditionally

Methodology

A retrospective case note review was undertaken of all paediatric patients with MPS I treated in one of the three nationally commissioned paediatric tertiary specialist centres in England. The study involved anonymised data collected from case notes; ethics committee approval was not required. Good Clinical Practice standards were adhered to throughout.

Inclusion criteria were: diagnostic enzymology demonstrating a significant reduction in α-L-iduronidase activity; diagnosis prior to the age of

Results

Overall the notes of the 64 patients that had undergone HSCT and 24 patients that had enzyme replacement therapy that had been under regular review by the Paediatric centre were examined. In total 66 MPS I patients satisfying the inclusion criteria were identified. Of these 46 were transplanted (45 Hurler and 1 Hurler-Scheie) and 20 were treated with ERT (17 Hurler-Scheie patients and 3 Hurler patients diagnosed too late for transplant). Of the 18 HSCT patients excluded due to inability to

Discussion

This is the largest non-pharmaceutically supported case series of pulmonary function testing so far reported in paediatric MPS I patients. The duration of follow-up with a medium time of 12.4 years post HSCT and 14.4 years on ERT is also, to the authors' understanding, the longest thus far described. The serial spirometry performed demonstrates that all patients, regardless of therapeutic intervention, have a degree of restrictive lung disease. In the post HSCT group, 55% of patients had mild

Conclusion

This study indicates that despite current treatment modalities all Hurler and Hurler-Scheie patients develop a degree of restrictive lung disease. While this may not be as prominent clinical concern as in some of the other MPS diseases and indeed was improving in approximately a quarter of the patients reported here, it remains a potentially significant cause of morbidity. Further work is required to precisely delineate the degree of obstructive overlay that likely interacts with restrictive

Declaration of Competing Interest

Dr. A Broomfield declares travel assistance from Takeda Pharmaceutical, Sanofi and Biomarin Pharmaceutical and consulting fees from Sanofi, unrelated to this work.

Dr. A Ghosh declares travel assistance from Biomarin Pharmaceutical and honoraria from Alexion Pharmaceuticals, unrelated to this work.

Dr. KM Stepien has received travel grants from BioMarin, Genzyme, Alexion, Takeda Pharmaceutical and honoraria from Biomarin Pharmaceutical Chiesi, Sanofi, Orchard Therapeutics and Takeda unrelated to

Acknowledgements

Contribution: AB, PH, KMS, SAJ, SW originally conceived of the idea. JS, JM, OA, NPB, KT, RW helped data capture. NBW, SW and AAB analysed the data and all authors were involved in the review of the manuscript.

Funding: N/A.

Consent: No consent was required for this retrospective audit.

Guarantor: AAB.

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