Long-Term Cardiorespiratory, Endocrine, Ophthalmic, and Functional Outcomes in Adult Patients with Mucopolysaccharidosis Type I (Hurler Syndrome) Post Haematopoietic Stem Cell Transplantation: The Irish Experience

Abstract

Mucopolysaccharidosis type IH (MPS IH) is caused by homozygous IDUA gene pathogenic variants. This results in deficiency of the enzyme α-L-iduronidase (IDUA), which is necessary for the degradation of glycosaminoglycans (GAGs). This study outlines the long-term outcomes in adult Irish patients affected with MPS IH, who were followed up for mean 28 years post Haematopoietic Stem Cell Transplantation. Nineteen adult MPS IH patients underwent HSCT in childhood. The participant cohort represents 6 families. Among the 13 patients with Irish Traveller ethnicity, 6 patients were either siblings or first cousins. All these related patients were homozygous for p. Trp402Ter (W402X). Mean age at the first transplantation was 8 months (range 3-21). Five patients had undergone a second transplantation (n=5, 26%) in childhood, due to graft failure. None of the patients had a cardiac valve surgery at the time of the study. 14/19 patients had mild to moderate aortic or mitral valve insufficiency or stenosis. 3/19 patients used non-invasive ventilation at night. Two patients had tracheostomy in situ. Both sensorineural as well as conductive hearing defects. No corneal clouding post corneal transplantation (n=8) was observed. Six patients attended regular secondary school. Multidisciplinary follow-up is needed to address the disease specific complications in adulthood.

Keywords:
Mucopolysaccharidosis type I; MPS IH; Hurler syndrome; Haematopoietic stem cell transplantation; long-term outcomes

Introduction

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by bi-allelic IDUA gene pathogenic variants resulting in a deficiency of the enzyme α-L-iduronidase (IDUA), which is necessary for the degradation of the glycosaminoglycans (GAGs) dermatan and heparan sulphate [1].

The lysosomal accumulation of incompletely metabolised GAGs in nearly all organ systems results in clinical symptoms which can manifest as early as in infancy and follow a progressive course. Serious cardiac, airway, pulmonary, orthopaedic, ophthalmologic and auditory problems, hepatosplenomegaly and neurologic dysfunction (including an increased risk for hydrocephalus and spinal cord compression) are common features of MPS I [2].

Based on clinical severity and age of symptom onset, there is an attenuated form (Hurler-Scheie; MPS IH/S; intermediate, OMIM 607015 or Scheie syndrome, attenuated, OMIM 607016, MPS IS) and a severe phenotype (Hurler syndrome, MPS IH, severe, OMIM 607014) [3]. The latter often involves rapid and remarkable neurologic deterioration during early childhood including intellectual developmental decline and death in the first decade of life in untreated cases [4].

The Inheritance is autosomal recessive. At least 295 different pathogenic variants in the IDUA gene have been described in the Human Gene Mutation Database [5]. The disorder has an estimated incidence of 0.69 to 3.8 per 100,000 live births [6,7,8]. In the Irish population, the condition is more common among the Irish Traveller ethnic group [9]. Median age at diagnosis of 10 months [4], has now improved with the introduction of the newborn screening in some countries [10,11].

Hematopoietic stem cell transplantation (HSCT) has been a reported therapy for MPS IH since 1980 [12], with a favourable impact on the natural history of the disease and cases of survival well into adulthood [13]. HSCT corrects the enzyme deficiency in MPS IH by providing donor-derived enzyme-competent cells into vascular and extravascular compartments of the body. Donor-derived microglia like cells provide enzyme to the Central Nervous System (CNS), with resultant arrest in neurologic damage and disease progression. The remarkable ability of donor microglia to correct CNS disease in MPS I makes HSCT a more promising therapy than enzyme replacement therapy (ERT) in MPS IH, as the currently available recombinant enzyme formulation is unable to cross the blood-brain barrier (BBB) [14]. A potential merit of HSCT for treating MPS IH is that marrow-derived donor macrophages can provide a continuous source of secreted enzyme that are taken up by various cell types and gain access to sites throughout the body where GAGs are stored [15].

Studies of patients with long-term engraftment have shown that the visceral disease is significantly lessened, with reduction of GAGs in urine, cerebrospinal fluid (CSF), liver, lymph and skin. Episodes of sleep apnoea, heart failure and pneumonia are reduced, if not eliminated. Thus, it is generally accepted that some improvement from these pathologies occurs following HSCT [16]. Overall, transplantation has tremendously improved morbidity and mortality of patients with the severe MPS IH phenotypeb [17], with resultant arrest in neurologic deterioration, stable cognition, improved metabolic correction and extended survival beyond the first decade of life [16,18,19,12,20,21]

However, the clinical response to HSCT is variable across organs and some features-such as musculoskeletal manifestations-show little improvement [22]. Dysostosis multiplex, particularly in weight-bearing joints, remains an unresolved problem. In addition, long-term survivors of HSCT are at increased risk of cardiovascular disease [23], mainly cardiac valve disease [24].

HSCT carries considerable risks of 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% [25] and improved health related quality of life (QoL) [26].

This study aimed to examine the long-term outcomes of Irish MPS IH adults following HSCT.

Methods

Study Design

Retrospective evaluation of clinical outcomes and review of medical records were undertaken of patients, registered with the National Centre for Inherited Metabolic Disorders (NCIMD)- Adult Services, Mater Misericordiae University Hospital (MMUH) in Dublin. The data collection, anonymisation and analysis included all the patients who had transitioned from the paediatric site, NCIMD-Children’s Health Ireland, to the adult site, NCIMD-MMUH.

Participants

All patients affected with Hurler syndrome (MPS IH) and who were followed up by the Adult NCIMD in 2017 were included in the study. All patients underwent HSCT in childhood between 1987 and 2001 (Table 1), prior to availability of enzyme therapy. All the patients in our cohort underwent a chemotherapy regimen before 2004.

Table 1.
Demographics and aspects related to transplantation.

Patient characteristics		n	Median age (range)
Overall		19
Gender	Males	11
Ethnicity:	Caucasian, Irish:
	Travellers	13
	Non-Travellers	6
Genotype:	Homozygous:
	p.Trp402Ter (W402X)	17
	Compound heterozygous:
	p.Trp402Ter (W402X)/p.Ala75Thr (A75T)	1
	p.Trp402Ter (W402X)/ p.Gln70Ter (Q70X)	1
Donor characteristics
Related:		12
Relatives	Patients 5 and 15 were cousins; patient 1,2,3 were siblings; all 5 were cousins to patient 14.
Donors: Carrier status (Heterozygous)		5
Source:
Bone marrow		18
Cord blood		1
Transplantation characteristics
No of HSCT:
1		14	8mths (3-21)
2		5	18mths(18-31)
Conditioning regimen:	Bu/Cy	11	(transplanted elsewhere)
	Bu/Procarbazine	1
	Bu/Cy/CAMPATH	7
GVHD prophylaxis:	CSA/MTX	12
	CSA only	6
	CSA/prednisolone	1
IDUA activity after transplantation (10-50umol/g/h)		17	18 (8.6-40.7) N=19
<reference range		2
Chimerism after transplantation	100%	14
	99%	1
	<90%	2
	N/A	2
Urine GAGS	Within normal ranges	19	1-12 mg/mmol
Age (years) at last visit			28 (22-37)

• HSCT- haematopoietic stem cell transplantation;
• Bu- busulfan, Cy- cyclophosphamide, CAMPATH- alemtuzumab;
• GVHD-graft versus host disease;
• CSA- cyclosporine, MTX- methotrexate;
• IDUA-alpha-L-iduronidase.
• GAG- glycosaminoglycans

Engraftment

Engraftment was assessed by measuring leukocyte IDUA enzyme activity [27] or polymerase chain reaction analysis estimating the variable number of tandem repeat (VNTR) alleles. Assay for IDUA activity: measured on leucocytes isolated from peripheral blood at diagnosis and monitored on a regular basis post-transplant. DNA was extracted from peripheral blood and amplified for the following VNTR alleles.

Engraftment at 1 year following HSCT was confirmed by using corrected presence of at least 25% of normal IDUA enzyme activity and/or presence of at least 10% donor cell chimerism.

Prophylaxis and grading of graft-versus-host disease (GVHD)

Graft versus host disease (GVHD) prophylaxis regimen was reviewed.

Clinical and biochemical investigations

Biochemical investigations (including hormonal profile, lipid profile, urine glycosaminoglycans), pulmonary function tests, overnight sleep study outcome, and an echocardiogram, were part of the standard panel tests requested. Patients attended regular ophthalmology, audiology, cardiology, orthopaedic and metabolic/genetic clinics.

Statistical analysis

Descriptive statistics was used to describe the patient demographic data. Basic statistical tests were used to calculate mean, median (±SD).

Results

Participants characteristics

Patients’ characteristics are presented in Table 1: age at last clinic visit, age at HSCT, gender, donor, ethnicity, genotype. Donors were classified as unrelated (normal) and related (heterozygous or unaffected). Mean age at diagnosis was not available. Mean age at the first transplantation was 8 months (range 3-21 months).

The participant cohort of 19 patients represents 6 families. Patient number 15 and 5 are siblings and are cousins of patient number 1, 2 and 3 from the same sibship. All 5 individuals are cousins of patient number 14. All 13 patients with Irish Traveller ethnicity, were homozygous for p.Trp402Ter (W402X).

Monitoring the graft outcome

Data on graft outcomes after transplantation measured in childhood is demonstrated in Table 1.

Enzyme activity was within normal ranges in majority of cases (17/19). In two patients it was reported just below the lower cut off value of 10 umol/L. Table 1 presents the most recent result.

Measurement of urine glycosaminoglycans: measured using dimethyl methylene blue. Urine GAG results were all within normal ranges after the HSCT.

Chimerism was reported as 100% in 14/19 cases and 99% in one case. In two patients it was reported <90% and was corresponding with reduced IDUA activity.

Five patients underwent a second transplantation (n=5, 26%) in childhood, due to graft failure. which was performed between 18 and 31 months of life.

Clinical outcomes

Table 2 presents outcomes for cardiorespiratory, endocrine, audiological, ophthalmic, mobility, intellectual disability and education.

Among the 19 patients, in 12 cases a donor was related to the patient, which might have contributed to the diverse outcomes (Table 2).

Table 2.
Long-term outcomes in patients with Mucopolysaccharidosis type IH after Haematopoietic Stem Cell Transplantation in childhood.

OUTCOME	RELATED DONOR		UNRELATED DONOR
	Travellers	Non-Travellers	Travellers	Non-Travellers
Number of patients	n=10 (6M/4F)	N=2 (1M/1F)	n=3 (2M/1F)	N=4 (2M/2F)
ECHO: EF<55% MVR and/or AR Symptomatic ACE inhibitor use History of cardiac surgery	0 8 0 0 0	0 2 0 0 0	0 2 0 0 0	0 2 0 0 0
CPAP at night	2	0	1	0
Death in adulthood	0	0	0	0
ENT: Hearing impairment Hearing aid History of tracheostomy	9 bilateral and 1 unilateral 6 1	1 bilateral 0 1	1 bilateral and 1 unilateral 2 1	2 bilateral and 1 unilateral 1 0
Eye: Corneal clouding Corneal transplantation Glaucoma Others	10 8 1 Myopia (1), blepharitis (1), trabeculotomies (1), hypermetopia (2)	2 0 1 1	3 0 1 Hypermetropia (2/7), myopia (2/7)	4 0 1 Hypermetropia (1), myopia (2),
Mobility: Barthel Index of Activities of Daily Living Median (min-max) Mean Wheelchair use: Hip surgeries in adulthood: Spinal cord compression:	(n=6) 15 (10-20) 14.6 1 1 3	(n=2) 20, p<0.03 20 0 0 1	(n=0) 0 1 1 2 0	(n=3) 18.6 (17-20) 19 0 0 0
Neurocognitive assessment IQ	Mild/moderate disability 7 Moderate disability 2 Severe 0 Normal 0 N/A 1 45-60	Mild/moderate disability 1 Moderate disability 0 Severe 0 Normal 1 N/A	Mild/moderate 2 Severe 1 Normal 0 N/A	Mild/moderate 3 Severe 0 Normal 1 104 (in 1 case)
Education: Special education Regular (secondary school) No education Unknown	7 4 1 0		3 2 0 2
ENDOCRINOLOGY
Hypothyroidism: Lipid profile (mean, mmol/L): Total cholesterol Triglycerides LDL-cholesterol HDL-cholesterol BMI (kg/m2) Median (min-max) Mean	0 4.4 1.6 2.7 1.2 27 (17-36) 27	0 4.7 1.6 2.5 1.5 23.5 (21-26) 23.5, p=0.19	1 borderline primary hypothyroidism 4.9 1.4 3.1 1.2 29 (28-31) 29.3	0 5.2 1.2 3.2 1.11 25 (24-27) 25.25, p<0.005
	Females		Females
Primary amenorrhea or POI (FSH>30 IU/l)	4 (one started irregular bleeding at the age of 16 years, after HRT) FSH 52.9-70.9 U/L, oestradiol <92 pmol/L	1	1	1
Regular menses Age at menarche	1 11	1 13	1 12	1 13
	Males		Males
Primary hypergonadotrophic hypogonadism	1 low testosterone, BMI >35 kg/m2)	0	1	0
History of undescended testicles (required surgery)	1	0	1	0

• POI- premature ovarian insufficiency

Cardiac

None of the patients had a cardiac valve surgery at the time of the study. 14/19 patients has mild to moderate aortic or mitral valve insufficiency or stenosis. 3/19 patients used non-invasive ventilation at night. Two patients had tracheostomy in situ at the time of the study.

Respiratory

In our cohort, only 3 patients with Irish Traveller ethnicity required CPAP at night. Some patients continue to take prophylactic antibiotics during the winter season in addition to prophylactic penicillin due to increased risk of infection by encapsulated organisms.

Endocrine

Hypertension or lipid abnormalities were not apparent, which was consistent with previous observations in a different cohort of adult MPS IH post HSCT [28]. For all 19 patients no pregnancies were documented. Two patients required a referral to the endocrine team for hormonal stimulation (oestrogen therapy). There was a significant difference in body mass index (BMI) between 4 subgroups (29 vs 25 kg/m2, p<005; Table 2).

In our cohort, we found out that all females from the group with Irish Traveller ethnicity and 2/3 from the non-Traveller group had primary hypogonadism, which was not observed in other studies [29]. Endocrine abnormalities also included: thyroid function abnormalities, central obesity and serum lipid profile abnormalities (Table 2), which is in keeping with the literature [28]. Females require close follow up with a joint endocrine/ metabolic clinic for close monitoring of their ovarian reserve and Tanner stage development [30].

Audiological

Both sensorineural as well as conductive hearing defects were observed in up to 79% of the patients (Table 2), with progression over time leading to increasing reliance on hearing aids. We found that 10/13 from the group with Irish traveller ethnicity and 3/6 of the non-Traveller patient group had hearing impairment.

Ophthalmological

In the cohort of patients, recurrence of corneal clouding post corneal transplantation (n=8) was not observed. Visual acuity varied among the 8 patients who underwent corneal transplant (Table 2). At the time of the study, none of the patients had a repeat corneal transplantation. In 4/19 patients an elevated intraocular pressure was reported.

Intellectual disability

The intellectual ability among the patients was diverse, although not always formally evaluated in adulthood. 6/19 patients attended regular secondary school, with a need for learning support throughout their education in most cases; 10/19 attended special education settings and for 3/19 educational data was not available. The secondary educational outcomes were comparable for those patients who received their transplant from a related and unrelated donor (4/12 (30%) vs. 2/7 (28.5%).

IQ assessments, where available, varied from 45-60 in patients from the group with Irish traveller ethnicity who had a related (and heterozygous) donor to 104 in a patient from non-Traveller cohort who had a non-related (non carrier) donor (Table 2).

Mobility

The Barthel score (0-20), with a lower score indicating disability, was used to assess mobility and walking aids reliance in our cohort. The score confirmed the finding from the literature that the QoL of our patients was limited because of pain and limited mobility. Within the related donor group, the Barthel score was higher among non-Travellers (P<0.03; Table 2)

Discussion

This publication outlines the long-term outcomes in adult Irish patients affected with MPS IH (Hurler syndrome) who underwent HSCT in childhood. The study included the single site evaluation of a group of adults with MPS IH who have undergone HSCT and have been followed up for up to 30 years after the procedure.

Irish Travellers

Irish Travellers are an endogamous, nomadic, ethnic minority population in Ireland, with a smaller population found in Europe, and the USA [8]. Due to founder effects and consanguinity, the incidence of certain recessive disorders caused by homozygous variants, including MPS IH, are increased in the Irish Traveller population [8].

Most patients in this study were homozygotes for the common variant, p.Trp402Ter (W402X) [31] with compound heterozygosity in a subset of patients (10.4%). The incidence of MPS IH in Ireland is estimated as 1 in 26,000 and as high as 1 in 371 amongst babies born to Irish Traveller couples [9].

Early Diagnosis

Due the high incidence of the disease in Ireland, its early diagnosis and referral to the appropriate centre for treatment have led to a robust diagnostic pathway in Ireland.

MPS IH is currently not included in the Irish national newborn bloodspot programme. International experience with screening for MPS IH is growing and may be relevant in the Irish context, especially given the relatively high incidence, in the future. Newborn screening aims to diagnose individuals with MPS I, especially MPS IH, at an age when CNS and somatic involvement may be minimal [32]. At present in Ireland the diagnostic yield of testing for MPS IH among the people with Irish traveller ethnicity is very high and awareness of the disorder in this cohort amongst paediatricians is good. This along with family history of MPS IH are the main reasons for the early diagnosis of MPS IH in the Traveller group. Diagnosis is typically made at a later age and stage in babies who are not from the Traveller community.

HSCT Protocol

In this study we evaluated the long-term therapeutic efficacy of HSCT in a cohort of adults with MPS IH. Successful HSCT has resulted in an improvement in the clinical course of Irish patients with MPS IH. However, residual disease burden was noted in all cases. As life expectancy is significantly increased after HSCT, with survival up to at least a mean of 28 years at the last clinic review in this study, several manifestations became apparent after long-term follow-up. The cohort of Irish patients have not had a prior exposure to ERT.

The documented observations in our study cohort were similar to clinical outcomes described in the literature [13,14,16,33,34] growth, ophthalmological and mobility complications progressed over a mean follow up of 28 years, with striking differences in clinical manifestations among the studied Irish patient group.

Variability in outcomes were related to the different ages at transplantation (youngest 3 months, oldest 21 months). The type of donor (63% were related donors) and the regimen applied (chemotherapy) and re-transplantation (n=5, 26%) were other predictors of the prognosis in these group of patients. Several cases (n= 5) involved a carrier donor, which is not ideal as residual enzyme activity would be anticipated to be lower, when compared with a non-carrier donor.

Transplant Morbidity

Our study demonstrates long-term follow-up with a detailed description of clinical outcomes, which are related to the disease progression rather than the HSCT procedure itself. As previously reported [13,16], the adverse effect of total body irradiation (TBI/TLI) appears to diminish more than 10 years after HSCT.

Among patients from the Irish Traveller community, both intra-familial and inter-familial phenotypic variability have been observed [8]. Variable expressivity of the same pathogenic variant is one possible explanation. Although multiple recessive disorders are often observed in this population, none of our patients with Hurler syndrome was found to be affected with another condition.

All the patients in our cohort received a transplant and chemotherapy regimen pre 2004. Since then the use of targeted busulfan dosing was introduced and it is expected that the long-term post HSCT outcomes may be better [34]. The study did not have any control group transplanted after 2004 to enable comments on the long-term disease-specific clinical complications.

The neuropsychological needs of adults with MPS IH are unmet [35] and it should be emphasized during the transfer of care from paediatric to adult metabolic/genetic services [36].

The non-related donor is less likely to be a carrier for a pathogenic variant, and provided that it is HLA matched, they are optimal donors [37]. In 2016, Boelens et al. reported the best way to achieve an “event-free” survival after an HSCT; the best donor sources are identically matched HLA non-carrier siblings or identical antigen matched cord blood, and the next best are 5/6 HLA-matched cord blood or 10/10 HLA-matched unrelated donors [38].

Long-term follow-up is key to learn more about hormonal (dys)function among post-transplant patients and managed accordingly. Lack of protocols and recommended guidelines is one of the recognised unmet needs [39]. Robust protocols are essential tools to identify hormonal abnormalities, replace the insufficient hormones (oestradiol/ testosterone) and to instigate the onset of puberty.

Quality of Life

Accumulated evidence supports that morbidity, QoL, and survival in these patients can be improved by allogeneic HSCT [26]. Additionally, successful HSCT improves growth and psychomotor development [40,41,42,43,44,45].

HSCT for MPS IH has been shown to improve QoL with restoration of CNS involvement. However, skeletal manifestations affect the QoL. [20] and the therapeutic effect of MPS IH on bone pathology is minimal, presumably because of poor enzyme penetration into chondrocytes and the failure to correct or replace osteocytes. Skeletal manifestations (dysostosis multiplex) observed in MPS IH [26,45,44], include abnormally shaped vertebrae and ribs, enlarged skull, spatulate ribs, hypoplastic epiphyses, thickened diaphyses, bullet-shaped metacarpals, hip dysplasia, genu valgum, and spinal cord compression [33,46]. This was apparent in our cohort of adults with MPS IH.

Significant and progressive orthopaedic anomalies often persist however, despite successful HSCT which may require additional interventions such as major orthopaedic surgery for genu valgum, acetabular hip dysplasia, kyphoscoliosis, carpal tunnel syndrome, and trigger digits [47,48,49,41,43,44]. Based on the Irish experience [50], although patients with MPS IH undergo high-risk corrective surgical procedures, they are of limited benefit and arthropathy, joint pain and stiffness is very common in the adult population. Kennedy et al (2013) have shown that active surgical intervention did not prevent the development of radiologic deterioration and clinically significant hip arthritis [50].

Conclusions

Our study provides retrospective data on long-term outcome after HSCT in a large Irish cohort of MPS IH. Currently, HSCT remains the standard of care to both prolong survival, prevent further neurological decline and slow the progression of the visceral features of the disease. Future clinical studies and long-term follow up is warranted to improve the understanding of the correlation, or lack thereof, between the biochemical correction and clinical outcomes in these patients. Multidisciplinary follow-up is needed to address the disease specific complications in adulthood and therefore the Adult NCIMD-MMUH have recently established a multispecialty, multidisciplinary Lysosomal Storage Disease Clinic and are currently developing a patient registry which will capture, among other data, clinical outcomes.

Acknowledgments

The authors would like to thank Dr Anne O’Meara, an oncologist from the national HSCT centre in Children Hospital in Crumlin, Dublin for initiating the transplantation programme for MPS IH in Ireland; the Willink Biochemical Genetics scientists Alan Cooper, Heather Church and Karen Tylee for the analysis of biochemical markers, and all the MPS patients in Ireland, and orthopaedic surgeons especially Mr Jacques Noel, Ms Paula Kelly and Mr Esmond Fogarty; Dental surgeon Mr Paddy Fleming; Ms Mairead O’Brien and Ms Elaine Smith, transplant CNS and clinic coordinators who all provided holistic care for this group of patients until and sometimes into adulthood

References

• 1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, eds The online metabolic and molecular bases of inherited disease Volume chapter 136. New York, NY: McGraw-Hill; 2007
• 2. Giugliani R, Federhen A, Rojas MV, et al. Mucopolysaccharidosis I, II, and VI: Brief review and guidelines for treatment. Genet Mol Biol 2010;33(4):589-604. doi:10.1590/S1415-47572010005000093.
  » https://doi.org/10.1590/S1415-47572010005000093
• 3. Muenzer J, Fisher A. Advances in the treatment of mucopolysaccharidosis type I. N Engl J Med 2004;350(19):1932-1934. doi:10.1056/NEJMp048084.
  » https://doi.org/10.1056/NEJMp048084
• 4. Pastores GM, Arn P, Beck M, et al. The MPS I registry: Design, methodology, and early findings of a global disease registry for monitoring patients with Mucopolysaccharidosis Type I. Mol Genet Metab 2007;91(1):37-47. doi:10.1016/j.ymgme.2007.01.011.
  » https://doi.org/10.1016/j.ymgme.2007.01.011
• 5. The Human Genome Mutation Database (HGMD). IDUA mutations. https://www.hgmd.cf.ac.uk/ac/gene.php?gene=IDUA Published 2023.
  » https://www.hgmd.cf.ac.uk/ac/gene.php?gene=IDUA
• 6. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28(6):1011-1017. doi:10.1007/s10545-005-0112-z.
  » https://doi.org/10.1007/s10545-005-0112-z
• 7. Beck M, Arn P, Giugliani R, et al. The natural history of MPS I: Global perspectives from the MPS I Registry. Genet Med 2014;16(10):759-765. doi:10.1038/gim.2014.25.
  » https://doi.org/10.1038/gim.2014.25
• 8. Lynch SA, Crushell E, Lambert DM, et al. Catalogue of inherited disorders found among the Irish Traveller population. J Med Genet 2018;55(4):233-239. doi:10.1136/jmedgenet-2017-104974.
  » https://doi.org/10.1136/jmedgenet-2017-104974
• 9. Murphy AM, Lambert D, Treacy EP, O'Meara A, Lynch SA. Incidence and prevalence of mucopolysaccharidosis type 1 in the Irish republic. Arch Dis Child 2009;94(1):52-54. doi:10.1136/adc.2007.135772.
  » https://doi.org/10.1136/adc.2007.135772
• 10. Fillman T, Matteson J, Tang H, et al. First three years' experience of mucopolysaccharidosis Type-I newborn screening in California. J Pediatr 2023;263:113644. doi:10.1016/j.jpeds.2023.113644.
  » https://doi.org/10.1016/j.jpeds.2023.113644
• 11. Lin SP, Lin HY, Wang TJ, et al. A pilot newborn screening program for Mucopolysaccharidosis type I in Taiwan. Orphanet J Rare Dis 2013;8:147. doi:10.1186/1750-1172-8-147.
  » https://doi.org/10.1186/1750-1172-8-147
• 12. Hobbs JR, Hugh-Jones K, Barrett AJ, et al. Reversal of clinical features of Hurler's disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet 1981;2(8249):709-712. doi:10.1016/s0140-6736(81)91046-1.
  » https://doi.org/10.1016/s0140-6736(81)91046-1
• 13. Rodgers NJ, Kaizer AM, Miller WP, Rudser KD, Orchard PJ, Braunlin EA. Mortality after hematopoietic stem cell transplantation for severe mucopolysaccharidosis type I: The 30-year University of Minnesota experience. J Inherit Metab Dis 2017;40(2):271-280. doi:10.1007/s10545-016-0006-2.
  » https://doi.org/10.1007/s10545-016-0006-2
• 14. Lum SH, Stepien KM, Ghosh A, et al. Long term survival and cardiopulmonary outcome in children with Hurler syndrome after haematopoietic stem cell transplantation. J Inherit Metab Dis 2017;40(3):455-460. doi:10.1007/s10545-017-0034-6.
  » https://doi.org/10.1007/s10545-017-0034-6
• 15. Taylor M, Khan S, Stapleton M, et al. Hematopoietic stem cell transplantation for mucopolysaccharidoses: Past, present, and future. Biol Blood Marrow Transplant 2019;25(7):e226-e246. doi:10.1016/j.bbmt.2019.02.012.
  » https://doi.org/10.1016/j.bbmt.2019.02.012
• 16. Aldenhoven M, Wynn RF, Orchard PJ, et al. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: An international multicenter study. Blood 2015;125(13):2164-2172. doi:10.1182/blood-2014-11-608075.
  » https://doi.org/10.1182/blood-2014-11-608075
• 17. Moore D, Connock MJ, Wraith E, Lavery C. The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK. Orphanet J Rare Dis 2008;3:24. doi:10.1186/1750-1172-3-24.
  » https://doi.org/10.1186/1750-1172-3-24
• 18. Neufeld E, Muenzer J. The mucopolysaccharidoses. In: Schriver CR, Beaudet AL , Sly WS, Walle W, eds. The metabolic and molecular bases of inherited disease 8th ed. New York, NY: McGraw-Hill ; 2001:3421-3452.
• 19. Muenzer J, Wraith JE, Clarke LA; International Consensus Panel on Management and Treatment of Mucopolysaccharidosis I. Mucopolysaccharidosis I: Management and treatment guidelines. Pediatrics 2009;123(1):19-29. doi:10.1542/peds.2008-0416.
  » https://doi.org/10.1542/peds.2008-0416
• 20. Aldenhoven M, Boelens JJ, de Koning TJ. The clinical outcome of Hurler syndrome after stem cell transplantation. Biol Blood Marrow Transplant . 2008;14(5):485-498. doi:10.1016/j.bbmt.2008.01.009.
  » https://doi.org/10.1016/j.bbmt.2008.01.009
• 21. Wynn RF, Wraith JE, Mercer J, et al. Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J Pediatr 2009;154(4):609-611. doi:10.1016/j.jpeds.2008.11.005.
  » https://doi.org/10.1016/j.jpeds.2008.11.005
• 22. Schmidt M, Breyer S, Löbel U, et al. Musculoskeletal manifestations in mucopolysaccharidosis type I (Hurler syndrome) following hematopoietic stem cell transplantation. Orphanet J Rare Dis 2016;11(1):93. doi:10.1186/s13023-016-0470-7.
  » https://doi.org/10.1186/s13023-016-0470-7
• 23. Inamoto Y, Lee SJ. Late effects of blood and marrow transplantation. Haematologica 2017;102(4):614-625. doi:10.3324/haematol.2016.150250.
  » https://doi.org/10.3324/haematol.2016.150250
• 24. Cross B, Stepien KM, Gadepalli C, et al. Pre-operative considerations in adult mucopolysaccharidosis patients planned for cardiac intervention. Front Cardiovasc Med 2022;9:851016. doi:10.3389/fcvm.2022.851016.
  » https://doi.org/10.3389/fcvm.2022.851016
• 25. Boelens JJ, Prasad VK, Tolar J, Wynn RF, Peters C. Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders. Pediatr Clin North Am 2010;57(1):123-145. doi:10.1016/j.pcl.2009.11.004.
  » https://doi.org/10.1016/j.pcl.2009.11.004
• 26. Prasad VK, Kurtzberg J. Cord blood and bone marrow transplantation in inherited metabolic diseases: scientific basis, current status and future directions. Br J Haematol 2010;148(3):356-372. doi:10.1111/j.1365-2141.2009.07974.x.
  » https://doi.org/10.1111/j.1365-2141.2009.07974.x
• 27. Kresse H, von Figura K, Klein U, Glössl J, Paschke E, Pohlmann R. Enzymic diagnosis of the genetic mucopolysaccharide storage disorders. Methods Enzymol 1982;83:559-572. doi:10.1016/0076-6879(82)83052-8.
  » https://doi.org/10.1016/0076-6879(82)83052-8
• 28. Stepien KM, Stewart FJ, Hendriksz CJ. The factors affecting lipid profile in adult patients with Mucopolysaccharidosis. Mol Genet Metab Rep 2017;12:35-40. doi:10.1016/j.ymgmr.2017.05.006.
  » https://doi.org/10.1016/j.ymgmr.2017.05.006
• 29. Polgreen LE, Tolar J, Plog M, et al. Growth and endocrine function in patients with Hurler syndrome after hematopoietic stem cell transplantation. Bone Marrow Transplant 2008;41(12):1005-1011. doi:10.1038/bmt.2008.20.
  » https://doi.org/10.1038/bmt.2008.20
• 30. Stepien KM. Hormonal dysfunction in adult patients affected with inherited metabolic disorders. J Mother Child 2020;24(2):21-31. doi:10.34763/jmotherandchild.20202402si.2018.000005.
  » https://doi.org/10.34763/jmotherandchild.20202402si.2018.000005
• 31. Ghosh A, Mercer J, Mackinnon S, et al. IDUA mutational profile and genotype-phenotype relationships in UK patients with Mucopolysaccharidosis Type I. Hum Mutat 2017;38(11):1555-1568. doi:10.1002/humu.23301.
  » https://doi.org/10.1002/humu.23301
• 32. Parini R, Broomfield A, Cleary MA, et al. International working group identifies need for newborn screening for mucopolysaccharidosis type I but states that existing hurdles must be overcome. Acta Paediatr 2018;107(12):2059-2065. doi:10.1111/apa.14587.
  » https://doi.org/10.1111/apa.14587
• 33. Tanaka A, Okuyama T, Suzuki Y, et al. Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: A nationwide survey in Japan. Mol Genet Metab 2012;107(3):513-520. doi:10.1016/j.ymgme.2012.09.004.
  » https://doi.org/10.1016/j.ymgme.2012.09.004
• 34. Boelens JJ, Wynn RF, O'Meara A, et al. Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: A risk factor analysis for graft failure. Bone Marrow Transplant 2007;40(3):225-233. doi:10.1038/sj.bmt.1705718.
  » https://doi.org/10.1038/sj.bmt.1705718
• 35. Chen C, Methley A, Naicker R, Rust S, Stepien KM. Neuropsychology assessment and outcomes in adult mucopolysaccharidosis - A systematic review as the first step to service development in a large tertiary Lysosomal Storage Disorders centre. Mol Genet Metab 2023;138(2):106980. doi:10.1016/j.ymgme.2022.106980.
  » https://doi.org/10.1016/j.ymgme.2022.106980
• 36. Lampe C, McNelly B, Gevorkian AK, et al. Transition of patients with mucopolysaccharidosis from paediatric to adult care. Mol Genet Metab Rep 2019;21:100508. doi:10.1016/j.ymgmr.2019.100508.
  » https://doi.org/10.1016/j.ymgmr.2019.100508
• 37. Rodgers NJ, Kaizer AM, Miller WP, Rudser KD, Orchard PJ, Braunlin EA. Mortality after hematopoietic stem cell transplantation for severe mucopolysaccharidosis type I: The 30-year University of Minnesota experience. J Inherit Metab Dis 2017;40(2):271-280. doi:10.1007/s10545-016-0006-2.
  » https://doi.org/10.1007/s10545-016-0006-2
• 38. Boelens JJ, van Hasselt PM. Neurodevelopmental outcome after hematopoietic cell transplantation in inborn errors of metabolism: Current considerations and future perspectives. Neuropediatrics 2016;47(5):285-292. doi:10.1055/s-0036-1584602.
  » https://doi.org/10.1055/s-0036-1584602
• 39. Stepien KM, Braunlin EA. Unmet cardiac clinical needs in adult mucopolysaccharidoses. Front Cardiovasc Med 2022;9:907175. doi:10.3389/fcvm.2022.907175.
  » https://doi.org/10.3389/fcvm.2022.907175
• 40. Summers CG, Purple RL, Krivit W, et al. Ocular changes in the mucopolysaccharidoses after bone marrow transplantation. A preliminary report. Ophthalmology 1989;96(7):977-985. doi:10.1016/s0161-6420(89)32795-3.
  » https://doi.org/10.1016/s0161-6420(89)32795-3
• 41. Krivit W, Lockman LA, Watkins PA, Hirsch J, Shapiro EG. The future for treatment by bone marrow transplantation for adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome. J Inherit Metab Dis 1995;18(4):398-412. doi:10.1007/BF00710052.
  » https://doi.org/10.1007/BF00710052
• 42. Shapiro EG, Lockman LA, Balthazor M, Krivit W. Neuropsychological outcomes of several storage diseases with and without bone marrow transplantation. J Inherit Metab Dis 1995;18(4):413-429. doi:10.1007/BF00710053.
  » https://doi.org/10.1007/BF00710053
• 43. Souillet G, Guffon N, Maire I, et al. Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant 2003;31(12):1105-1117. doi:10.1038/sj.bmt.1704105.
  » https://doi.org/10.1038/sj.bmt.1704105
• 44. Staba SL, Escolar ML, Poe M, et al. Cord-blood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med 2004;350(19):1960-1969. doi:10.1056/NEJMoa032613.
  » https://doi.org/10.1056/NEJMoa032613
• 45. Peters C, Shapiro EG, Anderson J, et al. Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The storage disease collaborative study group. Blood . 1998;91(7):2601-2608.
• 46. Yasuda E, Mackenzie W, Ruhnke K, et al. Molecular genetics and metabolism report long-term follow-up of post hematopoietic stem cell transplantation for Hurler syndrome: Clinical, biochemical, and pathological improvements. Mol Genet Metab Rep 2015;2:65-76. doi:10.1016/j.ymgmr.2014.12.006.
  » https://doi.org/10.1016/j.ymgmr.2014.12.006
• 47. Masterson EL, Murphy PG, O'Meara A, Moore DP, Dowling FE, Fogarty EE. Hip dysplasia in Hurler's syndrome: Orthopaedic management after bone marrow transplantation. J Pediatr Orthop 1996;16(6):731-733. doi:10.1097/00004694-199611000-00006.
  » https://doi.org/10.1097/00004694-199611000-00006
• 48. Odunusi E, Peters C, Krivit W, Ogilvie J. Genu valgum deformity in Hurler syndrome after hematopoietic stem cell transplantation: Correction by surgical intervention. J Pediatr Orthop 1999;19(2):270-274. doi:10.1097/00004694-199903000-00026.
  » https://doi.org/10.1097/00004694-199903000-00026
• 49. Van Heest AE, House J, Krivit W, Walker K. Surgical treatment of carpal tunnel syndrome and trigger digits in children with mucopolysaccharide storage disorders. J Hand Surg Am 1998;23(2):236-243. doi:10.1016/S0363-5023(98)80120-2.
  » https://doi.org/10.1016/S0363-5023(98)80120-2
• 50. Kennedy J, Noel J, O'Meara A, et al. A long-term retrospective evaluation of functional and radiographic outcomes of pediatric hip surgery in Hurler Syndrome. J Pediatr Orthop 2016;36(1):25-28. doi:10.1097/BPO.0000000000000385.
  » https://doi.org/10.1097/BPO.0000000000000385

• Ethics Approval and Consent to Participate

  The study was registered as a service evaluation study/audit at the Mater Missericordiae University Hospital

Publication Dates

• Publication in this collection
  26 July 2024
• Date of issue
  2024

History

• Received
  07 Dec 2023
• Accepted
  19 June 2024