Mucopolysaccharidosis Type IH Research Articles

Modeling skeletal dysplasia in Hurler syndrome using patient-derived bone marrow osteoprogenitor cells.

Dysostosis multiplex is a major cause of morbidity in Hurler syndrome (mucopolysaccharidosis type IH [MPS IH], OMIM #607014) because currently available therapies have limited success in its prevention and reversion. Unfortunately, the elucidation of skeletal pathogenesis in MPS IH is limited by difficulties in obtaining bone specimens from pediatric patients and poor reproducibility in animal models. Thus, the application of experimental systems that can be used to dissect cellular and molecular mechanisms underlying the skeletal phenotype of MPS IH patients and to identify effective therapies is highly needed. Here, we adopted in vitro/in vivo systems based on patient-derived bone marrow stromal cells to generate cartilaginous pellets and bone rudiments. Interestingly, we observed that heparan sulphate accumulation compromised the remodeling of MPS IH cartilage into other skeletal tissues and other critical aspects of the endochondral ossification process. We also noticed that MPS IH hypertrophic cartilage was characterized by dysregulation of signaling pathways controlling cartilage hypertrophy and fate, extracellular matrix organization, and glycosaminoglycan metabolism. Our study demonstrates that the cartilaginous pellet-based system is a valuable tool to study MPS IH dysostosis and to develop new therapeutic approaches for this hard-to-treat aspect of the disease. Finally, our approach may be applied for modeling other genetic skeletal disorders.

Aspects of Surgical Treatment of Spinal Pathology in the Patient with Gurler Syndrome

The clinical case of surgical treatment of combined spinal pathology in the child with Gurler syndrome is described in the article. Indications, major risk factors and aspects of surgical treatment of spinal pathology at this nosology are described in detail; all the approaches are analyzed according to the literature. Background. We would like to draw the attention of our colleagues to this problem with this clinical case. We want to emphasize the peculiarities of orthopedic manifestations in patients with mucopolysaccharidosis type IH (MPS IH). The most crucial is timely detection and surgical treatment. Clinical case description. This article describes the aspects of surgical treatment of spinal pathology in the patient with MPS IH: progressive kyphotic deformation, stenosis and craniovertebral junction instability, significant neurological deficit, internal organs functional disorders. Conclusion. Patients with MPS are characterized by multilevel orthopedic pathology which requires continuous follow-up throughout the life by single multidisciplinary team of specialists.

Impact of extended post-HSCT enzyme replacement therapy (ERT) on linear growth in mucopolysaccharidosis type IH (MPS IH)

Maroteaux–Lamy syndrome (mucopolysaccharidosis type VI, MPS VI) is a rare progressive metabolic disorder characterized by coarse facial features, hepatosplenomegaly, restrictive pulmonary function, cardiac abnormalities and stiff joints. The disease is caused by a deficiency of the lysosomal enzyme N-acetyl galactosamine 4-sulfatase which leads to glycosaminoglycan (GAG) storage in various tissues. It presents as a clinical spectrum with varying disease progressions and severities. While the phases I/II/III studies proved the effectiveness of enzyme-replacement therapy (ERT) with recombinant human arylsulfatase B, long-term data are still scarce.Over treatment periods ranging from 1.3 to 5.4 years, this prospective open-label follow-up study in 11 Dutch mucopolysaccharidosis type VI patients (age 2–18 years) showed that ERT had significant positive effects on cardiac-wall diameters (IVSd and LVMI), left and right shoulder flexions (p < 0.001), liver size and spleen size (p < 0.001), urinary GAG excretion (p < 0.001), and the scales of quality of life (motor functioning and body functioning). ERT did not affect cardiac valve regurgitation or hearing function; HRQoL decreased slightly in two domains (‘anxiety’ and ‘negative emotions’), and patients with the rapid and slow progressive forms of the disease differed with regard to baseline GAG excretion and GAG decrease during treatment.In conclusion, ERT had an effect on several clinical parameters. This effect was established in an open cohort of young mucopolysaccharidosis type VI patients.

Mgta-456 Cell Therapy in Inherited Metabolic Disease (IMD) Yields Rapid and Durable Long-Term Improvement of Disease-Specific Outcomes in a Phase 2 Trial

<h3>Background</h3> Hematopoietic stem cell transplant (HSCT) in IMDs prevents progression of fatal neurodegeneration. Cord blood as a preferred donor source is disadvantaged by delayed engraftment and graft failure due to low CD34+ cell numbers. Higher cell doses are correlated with improved outcomes and cross-correction of disease. MGTA-456 is a novel cell therapy which provides a high dose of CD34+ cells and is being investigated in an ongoing Phase 2 clinical study to assess the safety and long-term outcomes in IMD patients. <h3>Methods</h3> A Phase 2 trial (NCT03406962) is enrolling 12 patients <16 yo with a diagnosis of cerebral onset adrenoleukodystrophy (cALD), mucopolysaccharidosis type IH (MPS I), metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy (GLD). Patients receive a myeloablative conditioning regimen. Patients are followed for 1 year after transplant and eligible patients may enroll in a long-term follow-up study (NCT04008849). <h3>Results</h3> 2 patients with cALD and 3 with MPS I, have been treated per protocol and with follow-up up to 1 year. In patients with cALD, resolution of gadolinium enhancement on MRI occurred by one month and was sustained throughout the follow-up period (Fig 1). Loes scores, a measure of disease severity, and Neurologic Function Scores remained stable over this time period consistent with a halt in disease progression. Neurocognitive function remains stable to date with no deterioration in Wechsler IQ Scale and Vineland Adaptive Behavior Scales. MPS I patients showed normalization of blood a-L-iduronidase and excretion of MPS I-specific urinary glycosoaminoglycans declined from baseline over the period of observation (Fig 2). Neurologic development and function scores as measured by Bayley Infant Development and Vineland Scales are being collected. Patients received a median CD34⁺ dose of 110 × 10⁶ cells/kg and TNC dose of 26 × 10⁷ cells/kg with a median duration of neutropenia of 1 day (range 0-9) compared to a median of 8 days for historical controls. Myeloid chimerism was ≥98% donor in evaluable patients by day +14 and immune reconstitution of CD4 and CD8 T cell subsets were comparable or better than historical controls. Two steroid-responsive episodes of skin-only aGVHD were observed and no cGVHD developed. Data on additional patients receiving cryopreserved MGTA-456 will be reported. <h3>Conclusions</h3> Treatment with MGTA-456 in patients with IMDs shows early, robust engraftment and immune reconstitution, features that are highly associated with improved clinical outcomes. Disease-specific outcomes up to one-year post-transplant in MPS I and cALD patients show crucial, durable stabilization in biochemical, MRI and clinical/neurodevelopmental assessments. In summary, the high CD34+ cell doses delivered by MGTA-456 shows compelling potential to rapidly and durably improve outcomes in IMD patients.

Generation of human induced pluripotent stem cell line UNIGEi001-A from a 2-years old patient with Mucopolysaccharidosis type IH disease.

Mucopolysaccharidosis type I-Hurler (MPS1-H) is the most severe form of inherited metabolic diseases caused by mutations in the IDUA gene. The resulting deficiency of alpha L-iduronidase enzyme leads to a progressive accumulation of glycosaminoglycans in lysosomes which damages multiple organs and highly reduces life expectancy of affected children. Skin fibroblasts of a 2-year-old MPS1-H male, carrying two mutations in each IDUA alleles (H358_T364del; W402X), were reprogrammed into induced pluripotent stem cells (iPSCs) using the CytoTune-iPS Sendai Reprogramming method applying Yamanaka-factors (OCT4, SOX2, KLF4, c-MYC). iPSCs expressed pluripotency transcription factors while iPSC-derived embryoid bodies reveal markers of the three germ layers.

Robust Engraftment with Mgta-456, a CD34+ Expanded Cell Therapy Product in Patients with Inherited Metabolic Disorders (IMD): Preliminary Phase 2 Trial Results

Background Mucopolysaccharidosis type IH (MPS1/Hurler Syndrome), cerebral adrenoleukodystrophy (cALD), metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD) are fatal IMDs affecting the central nervous system treatable through allogeneic hematopoietic stem cell transplantation (HSCT). In the absence of a non-carrier HLA matched related donor, cord blood (CB) is the preferred source of cells in IMDs due to rapid availability and flexibility in matching. However, prolonged neutropenia and high graft failure rates present a challenge, particularly with reduced intensity conditioning regimens. MGTA-456 is produced from a single CB unit using an aryl hydrocarbon receptor antagonist in a 15-day expansion culture of CD34+ cells. In previous phase 1/2 studies, hematologic malignancy patients treated with myeloablative conditioning and MGTA-456, with median 324-fold CD34+ expansion, showed 100% engraftment with a 9 day reduction in time to neutrophil recovery. As higher CD34+ doses have been correlated with improved engraftment in IMD transplant patients, we hypothesize MGTA-456 may reduce duration of neutropenia and risk of graft failure and more rapidly correct the metabolic deficiency in IMD patients. Patients and Methods A Phase 2, open-label trial (NCT03406962) initiated in Feb 2018 is enrolling up to 12 patients Results Five patients have been treated per protocol to date (Figure 1). MGTA-456 contained a median 561-fold expansion of CD34+ cells after culture with a median infused CD34+ cell dose of 110 × 106 cells/kg and median total nucleated cell dose of 26.4 × 107 (Figure 2). The median duration of neutropenia was 1 day (range 0-9), in contrast to a median of 8 days for a historical cohort (Figure 3). Myeloid chimerism was ≥98% donor by day +14 in evaluable patients. Two patients developed autoimmune cytopenia, a known complication in IMD patients after HSCT, unrelated to MGTA-456. Time to discharge after transplant was a median of 19.5 days at time of reporting. Preliminary data from MPS1 patients demonstrated normalization of blood alpha-L-iduronidase enzyme activity and decreased urinary glycosoaminoglycan levels after transplant. Conclusions Treatment of IMD patients with MGTA-456 showed early and robust engraftment in all patients with marked reduction in days of neutropenia compared to a historical cohort. These preliminary data, in combination with the previous hematologic malignancy patients treated, suggest MGTA-456 substantially enhances engraftment and rate of neutrophil recovery.

Preliminary Phase 2 Results Demonstrate Engraftment with Minimal Neutropenia with MGTA-456, a CD34+ Expanded Cord Blood (CB) Product in Patients Transplanted for Inherited Metabolic Disorders (IMD)

▪Background: IMDs including mucopolysaccharidosis type IH (MPS1/Hurler Syndrome), metachromatic leukodystrophy (MLD), globoid cell leukodystrophy (GLD) and cerebral adrenoleukodystrophy (cALD) are progressive, fatal diseases affecting the central nervous system which are treatable through allogeneic hematopoietic stem cell transplantation (HSCT). CB, in the absence of a matched donor, is the preferred source of stem cells as it is rapidly available and allows greater flexibility in allele matching. As a result of low cell doses, CB transplants in IMD are associated with prolonged periods of neutropenia and reported graft failure rates in up to ~20% (Lum et al 2017 Bone Marrow Transplant 52:846-53; Mallhi et al 2017 BBMT 23:119-25). MGTA-456 is a first-in-class cell therapy produced from a single CB unit using an aryl hydrocarbon receptor antagonist in a 15-day expansion culture of CD34+ cells. In previous phase 1/2 studies, 24 adult and 3 pediatric patients with hematologic malignancies treated with myeloablative conditioning (MAC) and MGTA-456 demonstrated a median 324-fold expansion of CD34+ cells, all patients engrafted, and the time to neutrophil recovery was significantly reduced by a median of 9 days compared to historical controls (Wagner et al 2016 Cell Stem Cell 18:144-55; Wagner et al 2017 Blood 130 supp:662 abstr). Furthermore, higher CD34+ dose has been correlated with improved engraftment and outcomes in IMD transplant patients (Prasad et al 2008 Blood 112:2979-89). Based on these promising data, we postulate the increased CD34+ dose provided by MGTA-456 would reduce the length of neutropenia and risk of graft failure in IMD patients.Patients and Methods: A Phase 2, open-label trial (NCT03406962) initiated in Feb 2018 is enrolling up to ~12 patients <16 yo with a diagnosis of MPS1, cALD, MLD, and GLD lacking a non-carrier matched related donor. Eligible CB units were matched at ≥ 6 of 8 HLA loci (A, B, C and DRB1) using allele-based typing. The reduced toxicity MAC regimen consists of anti-thymocyte globulin (days -9 to -6) followed by fludarabine (40 mg/m2 days -5 to -2) and busulfan (total exposure 21,000 to 22,000 μM/min/L-1 days -5 to -2). Immunoprophylaxis consists of cyclosporin and methylprednisolone.Results: Four patients have been treated thus far (Table 1). The MGTA-456 process provided a marked expansion of CD34+ cells (median 482-fold, Figure 1) with a median infused CD34+ cell dose of 84 x 106 cells/kg and median total nucleated cell (TNC) dose from the expanded fraction of 19.6 x 107 (Table 1). TNC dosing was capped at 27.0 x 107 cells/kg per protocol. The only infusion-related reaction noted was grade 3 nausea in 1 patient. Two patients had no days of neutropenia and 2 patients had 1 and 4 days respectively (mean 1.25 days) in contrast to a mean of 7.8 days for a historical cohort of 27 IMD patients undergoing CB transplantation at the same institution with identical conditioning (Figure 2). Myeloid chimerism (CD33+/66+) achieved ≥98% donor by day +14 in all patients. For the 3 patients with data at time of reporting, days to discharge after transplant were 17, 12 and 18. No patients experienced acute or chronic GVHD. One patient developed autoimmune cytopenia (not related to MGTA-456) which is a known complication reported in 20-56% of IMD patients undergoing HSCT that resulted in death at day +143 (Page et al 2008 BBMT 14:1108-17; Khalil et al 2014 Sci World J 581657). Long-term disease specific outcome measures including enzymatic activity are being collected and will be reported over time.Conclusions: Preliminary results of transplantation in IMD patients with MGTA-456, containing highly expanded CD34+ cell doses, demonstrated early and robust engraftment in all patients with marked reduction in days of neutropenia (to 0-4 days or mean 1.25 days) in comparison to a historical cohort. MGTA-456 was well tolerated with one infusion-related event of grade 3 nausea. These data, in combination with the previous 27 hematologic malignancy patients treated, suggest that MGTA-456 substantially enhances the engraftment potential of CB. Based on these promising data, MGTA-456 has potential to improve transplant-related outcomes in patients undergoing HSCT and increasing the availability of well-matched CB units that may have been previously excluded due to inadequate CD34+ dose. [Display omitted] DisclosuresOrchard:Magenta Therapeutics: Research Funding. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Condon:Magenta Therapeutics: Employment, Equity Ownership. Monaghan:Magenta Therapeutics: Employment, Equity Ownership. Vernet:Magenta Therapeutics: Employment. Sheirr:Magenta Therapeutics: Employment, Equity Ownership. Braun:Magenta Therapeutics: Research Funding. Shanley:Magenta Therapeutics: Research Funding. Lund:Magenta Therapeutics: Research Funding. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership. Wagner:Novartis: Research Funding; Magenta Therapeutics: Consultancy, Research Funding.

Metabolic Syndrome and Cardiovascular Risk Factors after Hematopoietic Cell Transplantation in Severe Mucopolysaccharidosis Type I (Hurler Syndrome)

Hematopoietic cell transplantation is a life-saving procedure, but one associated with increasing long-term cardiovascular risk requiring frequent long-term follow-up. This therapy has significantly lengthened survival in mucopolysaccharidosis type IH (Hurler syndrome), a disease with known coronary artery involvement. Metabolic syndrome—a constellation of central obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose—is associated with increased cardiovascular risk, and occurs when any 3 or more of these 5 components is present within a single individual. The incidence of metabolic syndrome and its components is poorly defined after transplantation for Hurler syndrome. Chart review of all long-term survivors of hematopoietic cell transplantation for Hurler syndrome ≥9 years of age for factors comprising the metabolic syndrome: obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose. Sixty-three patients were evaluated, 20 of whom had components of the metabolic syndrome available for review. There was no significant difference in age at transplantation, sex, number of transplants, pretransplant radiation, or percent engraftment between those with and without these data. Median follow-up after transplantation for the 20 patients with data was 14.3 years. Only 1 (5%) patient of this group fulfilled the criteria for metabolic syndrome. Fifty-three percent of the patients had 1 or more components of metabolic syndrome: the most common was high blood pressure occurring in 40%. Metabolic syndrome is uncommon in this cohort of long-term survivors of hematopoietic cell transplantation for Hurler syndrome but almost half of the patients had 1 or more components of the syndrome, with high blood pressure being the most common. Further studies are needed to develop guidelines in this diagnosis as well as other nonmalignant diseases of children.

Dilated cardiomyopathy at presentation of mucopolysaccharidosis type IH (Hurler syndrome): Clinical characteristics and management outcome

Lipin-1 deficiency is a major cause of rhabdomyolysis that are precipitated by febrile illness. The prognosis is poor, with one-third of patients dying from cardiac arrest during a crisis episode. Apart from acute rhabdomyolysis, most patients are healthy, showing normal clinical and cardiac ultrasound parameters.We report cardiac and exercise examinations of 8 children carrying two LPIN1 mutations. The examinations were performed outside of a myolysis episode, but one patient presented with fever during one examination.All but one patient displayed normal resting cardiac function, as determined by echocardiography. One patient exhibited slight left ventricular dysfunction at rest and a lack of increased stroke volume during cycle ramp exercise. During exercise, peripheral muscle adaptation was impaired in 2 patients compared to healthy controls: they presented an abnormal increase in cardiac output relative to oxygen uptake: dQ/dVO2 = 8.2 and 9.5 (> 2DS of controls population). One patient underwent 2 exercise tests; during one test, the patient was febrile, leading to acute rhabdomyolysis in the following hours. He exhibited changes in recovery muscle reoxygenation parameters and an increased dQ/dVO2 during exercise compared with that under normothermia (7.9 vs 6), which did not lead to acute rhabdomyolysis. The four patients assessed by cardiac 1H-magnetic resonance spectroscopy exhibited signs of intracardiac steatosis.We observed abnormal haemodynamic profiles during exercise in 3/8 patients with lipin-1 deficiency, suggesting impaired muscle oxidative phosphorylation during exercise. Fever appeared to be an aggravating factor. One patient exhibited moderate cardiac dysfunction, which was possibly related to intracardiac stored lipid toxicity.

Social Functioning and Behaviour in Mucopolysaccharidosis IH [Hurlers Syndrome

Mucopolysaccharidosis type IH (MPS-IH) [Hurlers Syndrome] is a developmental genetic disorder characterised by severe physical symptoms and cognitive decline. This study aimed to investigate the behavioural phenotype of MPS-IH treated by haematopoietic cell transplantation, focusing on social functioning and sleep. Parental stress was also measured. Participants were 22 children with MPS-IH (mean age 9years 1 month), of whom 10 were male (45%). Parents completed the Social Responsiveness Scale (SRS), Child Behaviour Checklist (CBCL), Children's Sleep Habit Questionnaire and Parent Stress Index, Short Form (PSI-SF). Twenty-three per cent of children with MPS-IH scored in the severe range of the SRS, suggesting significant difficulties in social functioning. Children with MPS-IH were more than 30 times more likely to receive scores in the severe range than typically developing children. Thirty-six per cent scored in the mild-to-moderate range, suggesting milder, but marked, difficulties in social interaction. Although children with MPS-IH did not show significantly higher rates of internalising, externalising or total behaviour problems than the normative sample, they received scores that were significantly higher on social, thought and attention problems and rule-breaking behaviour, and all the competence areas of the CBCL. Parents of children with MPS-IH did not score significantly higher on parental stress than parents in a normative sample. Parents of children with MPS-IH rate their children as having problems with social functioning and various areas of competence more frequently than previously thought, with implications for clinical support.

The impact of bone marrow transplant treatment for mucopolysaccharidosis type IH on family functioning: Social, emotional and financial factors

The impact of bone marrow transplant treatment for mucopolysaccharidosis type IH on family functioning: Social, emotional and financial factors

Unrelated CD3/CD19-Depleted Peripheral Stem Cell Transplantation for Hurler Syndrome

For patients with mucopolysaccharidosis type IH (MPS1-H; Hurler syndrome), early allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice. One boy and one girl aged 20.5 and 22 months, respectively, with MPS1-H received a conditioning regimen consisting of thiotepa, fludarabine, treosulfan, and ATG. Grafts were peripheral blood stem cells from unrelated donors (10/12 and 11/11 matched), that were manipulated by CD3/CD19 depletion and contained 20.3 and 28.2 × 106 CD34+ cells/kg body weight, respectively. Both patients achieved stable hematopoietic engraftment and stable donor chimerism. Neither acute or chronic graft-versus-host disease (GVHD) nor other severe transplant-related complications occurred. At a follow-up of 48 and 37 months, both patients are alive and well with normal levels of α-L-iduronidase and have made major neurodevelopmental progress. Treosulfan-based conditioning offers the advantage of reduced toxicity; the use of unrelated CD3/CD19-depleted peripheral stem cell grafts allows transfusion of high CD34+ cell numbers together with a “tailored” number of CD3+ cells as well as engraftment facilitating cells in order to achieve rapid hematopoietic engraftment while reducing the risk of graft rejection and GVHD. This regimen might be an additional option when unrelated donor HSCT is considered for a patient with MPS1-H.

Mucopolysaccharidosis Type IIIA presents as a variant of Klüver–Bucy syndrome

Mucopolysaccharidosis Type IIIA (MPS IIIA) is a neurodegenerative disease with behavioral symptoms unique among the mucopolysaccharidoses. Children with MPS IIIA reportedly mouth things, explore novel environments almost continuously, disregard danger, and empathize/socialize and comply less with parents. These characteristics resemble Klüver–Bucy syndrome (K-Bs). To test the K-Bs hypothesis, 30 children with MPS IIIA were compared to 8 “posttransplant” mucopolysaccharidosis Type IH patients in an experimental “risk room.” The room contained attractive and mildly frightening objects, exposure to a 92-dB startle noise triggered by contact with an attractive toy, mother's return after a brief absence, and compliance with her cleanup directive. Children with MPS IIIA: (a) left mother sooner, (b) wandered more, (c) were more likely to approach frightening objects, (d) were less likely to respond to loud noise with whole body startle, (e) were less likely to avoid the toy associated with the startle noise, (f) interacted less with mother upon her return, and (g) complied less with her cleanup command. K-Bs is associated with loss of amygdala function. Brain magnetic resonance imaging (MRI) of a subset of the children with MPS IIIA showed volume loss that was greater in the amygdala than in the hippocampus; only amygdala loss correlated with reduced fearfulness. MPS IIIA may be the first identified pediatric disease presenting systematically as a K-Bs variant. If validated by further studies, the K-Bs hypothesis of MPS IIIA would provide important clinical and theoretical information for the guidance of families as well as markers for natural disease progression and treatment effects.

Multi-Institutional Assessments of Transplantation for Metabolic Disorders

INTRODUCTION more expediently, potentially increasing availability The rational for allogeneic transplantation as therapy for inherited metabolic disease was provided by the fundamentally important work done by Neufeld’s group over 40 years ago, confirming that normal cells could “cross-correct” cells with storage diseases such as Hurler syndrome. Initial reports in the early 1980s confirmed that these patients could be transplanted, resulting in improvement in visceral disease in patients with mucopolysaccharide accumulation. Later investigations suggested that transplantation arrested neurologic deterioration in some disorders, such as Hurler syndrome (mucopolysaccharidosis type IH [MPS IH]), but is less effective in achieving stabilization of cognitive function in MPS II (Hunter) and MPS III (Sanfilippo). It is thought that the engraftment of donor-derived microglia results in the delivery of enzyme in the central nervous system, but the reasons transplantation is more successful for MPS IH than MPS II or MPS III remain elusive. Transplantation was also tested as therapy for lysosomal leukodystrophies, including Krabbe (globoid cell leukodystrophy, or GLD) and metachromatic leukodystrophy (MLD). ALthough isolated reports of success in disease stabilization for GLD and MLD exist, due to heterogeneity of disease phenotypes and degree of disease advancement at the time of transplantation, analysis of these outcomes are difficult, and there are no large multicenter reports of outcomes. Reports of success in the use of transplantation for adrenoleukodystrophy (ALD) were first published in the 1990s. Because ALD is a peroxisomal disorder, the biology by which transplantation exerts its beneficial effects is distinct from that of GLD and MLD. Other rare inherited metabolic diseases, including osteopetrosis, mannosidosis, MaroteauxLamy syndrome (MPS VI), and Wolman disease, for instance, have also been reported to respond to transplantation. New developments have affected approaches to transplantation for these disorders. The availability of enzyme replacement therapy (ERT) has provided the opportunity to explore combination therapy in disorders such as Hurler syndrome, whereas in other diseases, such as MaroteauxLamy syndrome, ERT has essentially replaced transplantation as standard therapy. In addition, cord blood (CB) transplantation has allowed patients to move to transplant

Enzyme Replacement is Associated with Better Cognitive Outcomes after Transplant in Hurler Syndrome

To investigate whether intravenous enzyme replacement therapy (ERT) benefits cognitive function in patients with mucopolysaccharidosis type IH (Hurler syndrome) undergoing hematopoietic cell transplantation (HCT). Data were obtained for 9 children treated with HCT + ERT (ERT group) and 10 children treated with HCT only (no-ERT group) from neuropsychologic evaluations before HCT and at 1-year and 2-year post-HCT follow-up. At 2 years after HCT, children in the ERT group lost 9.19 fewer IQ points per year compared with children in the no-ERT group (P = .031). Furthermore, the ERT group improved in nonverbal problem solving and processing, whereas the no-ERT group declined, resulting in a difference of 9.44 points per year between the 2 groups (P < .001). ERT in association with HCT enhances cognitive outcomes, providing new evidence that ERT is a valuable addition to the standard transplantation protocol. Although the mechanism responsible for this improved outcome is unknown, both direct benefits and indirect effects must be considered.

An exploratory study of brain function and structure in mucopolysaccharidosis type I: Long term observations following hematopoietic cell transplantation (HCT)

AimAlthough hematopoietic cell transplantation (HCT) arrests the cognitive decline in mucopolysaccharidosis type IH (Hurler syndrome, MPS IH), these children continue to have neuropsychological deficits as they age. Both compromised attention and effects on white matter have been observed in cancer patients who have had chemotherapy. Therefore, we explored the effects of disease and treatment on brain function in children with MPS I who have had HCT with those with attenuated MPS I treated with enzyme replacement therapy (ERT). MethodsSubjects: 7 MPS IH participants at least 5years post-HCT were compared with 7 attenuated participants who were treated with ERT. Measures: IQ, attention, spatial ability, and memory were assessed. Medical history and an unsedated MRI scan using diffusion tensor imaging (DTI) were acquired. ResultsDespite clinically equivalent IQ and memory, children with MPS IH had poorer attention span than those with attenuated MPS I as well as decreased fractional anisotropy (FA) of the corpus callosum. A relationship between attention scores and FA was found in the MPS IH group but not the attenuated group. FA was also related to the frequency of medical events. InterpretationIn children with MPS IH, both the treatment and the disease affect attention functions associated with poor white matter integrity.

Management of mucopolysaccharidosis type IH (Hurler's syndrome) presenting in infancy with severe dilated cardiomyopathy: a single institution's experience

Mucopolysaccharidosis type IH (MPSIH) is a lysosomal storage disorder whose untreated course involves progressive multisystem deterioration and death within the first decade of life. Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment modality that improves functional outcome and long-term survival. Optimal outcome requires transplantation early in life and with myeloablative conditioning. Severe cardiomyopathy can be present at diagnosis and may seemingly preclude this approach. We performed a retrospective review of those cases transplanted in Manchester since 2000 that initially presented with established cardiomyopathy, with a view to identifying general management principles. Of 44 MPSIH children transplanted in this period, 6 had displayed moderate or severe cardiomyopathy at presentation; symptomatic cardiac failure was the predominant presenting feature in five of these. Echocardiographic and clinical improvement in cardiac function was observed with extended enzyme replacement therapy (ERT) in all cases, with recovery of fractional shortening to ≥25% achieved in all patients before coming to transplant (after median 19weeks ERT). All were transplanted successfully, with good functional and cardiologic outcomes. However, cyclophosphamide conditioning was implicated in acute post-transplant cardiac decompensation in several cases. Our experiences highlight three important messages: (1) A diagnosis of MPSIH should be considered in any infant presenting with unexplained severe cardiac failure; (2) ERT pre-transplant can improve cardiac function sufficiently to permit safe HSCT using myeloablative conditioning; and (3) High dose cyclophosphamide should be avoided in conditioning these patients.

Total Hip Arthroplasty in Mucopolysaccharidosis Type IH

Children affected by mucopolysaccharidosis (MPS) type IH (Hurler Syndrome), an autosomal recessive metabolic disorder, are known to experience a range of musculoskeletal manifestations including spinal abnormalities, hand abnormalities, generalised joint stiffness, genu valgum, and hip dysplasia and avascular necrosis. Enzyme therapy, in the form of bone marrow transplantation, significantly increases life expectancy but does not prevent the development of the associated musculoskeletal disorders. We present the case of a 23-year-old woman with a diagnosis of Hurler syndrome with a satisfactory result following uncemented total hip arthroplasty.

Prenatal diagnosis of the Hurler syndrome by microsatellite markers analysis

Summary Hurler's syndrome or mucopolysaccharidosis type IH (MPS IH) is the most severe form of mucopolysaccharidosis type I (MPS I). It is caused by the deficiency of the alpha- l -iduronidase (IDUA) activity. The accumulation of undegraded MPS affects various organs and tissues. Prenatal diagnosis MPS IH is possible on both cultured amniotic fluid cells and chorionic villus biopsies and it is preferably achieved by the assay of IDUA in uncultured chorionic villus as this allows early (12th week), rapid (2–3 days) and reliable results. Aim of the study We summarise the results of antenatal diagnosis in a woman of 36-year-old which has previously tow children affected by Hurler disease. Patients and methods Molecular analysis confirmed the diagnosis for the MPS I studied families. Sequencing of the DNA and multiplex fluorescent PCR were employed for mutation analysis, contamination detection and diagnosis of Hurler syndrome. Results Sequencing of genomic DNA extracted from trophoblaste and the two parents showed the heterozygous status of p.F602X. Microsatellite markers study confirmed the sequencing results and showed the absence of contamination of the foetal DNA by maternal DNA. Conclusion The molecular prenatal diagnosis is now easy and helps some Tunisian family to detect and identify the inherited fetal alleles.

89. Progression of organ manifestations upon enzyme replacement therapy in a patient with mucopolysaccharidosis type IH prior to hematopoietic stem cell transplantation

89. Progression of organ manifestations upon enzyme replacement therapy in a patient with mucopolysaccharidosis type IH prior to hematopoietic stem cell transplantation