Publications by authors named "Weston P Miller"

31 Publications

Outcome After Cord Blood Transplantation Using Busulfan Pharmacokinetics-Targeted Myeloablative Conditioning for Hurler Syndrome.

Biol Blood Marrow Transplant 2020 Sep 20. Epub 2020 Sep 20.

Department of Paediatric Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, UK. Electronic address:

Background: Successful hematopoietic cell transplantation (HCT) provides life-long disease-modifying therapy for children with Hurler syndrome (HS). Umbilical cord blood (CB) is an important alternative stem cell source for HS children requiring HCT but lacking a suitable human leucocyte antigen (HLA)-matched, non-carrier sibling donor. This is the largest unrelated cord blood transplantation (CBT) series for HS collected from three large, experienced metabolic transplant centers.

Objective: The aims of this study were to examine outcomes and performed a predictive analysis after a CBT for HS using intravenous busulfan pharmacokinetic (Bu-pk) directed myeloablative conditioning (MAC).

Study Design: This collaborative retrospective included 97 children with HS who received their first CBT between 2004 and 2016 at Royal Manchester Children's Hospital, University Medical Center Utrecht and University of Minnesota Children's Hospital. Outcomes of interest were overall survival (OS), engrafted survival (ES), graft failure, graft-versus-host disease (GvHD), latest donor chimerism and IDUA enzyme level. Engrafted survival (ES) was defined as the probability of being alive with ≥20% whole blood donor-cell engraftment after the first CBT. Cox proportional hazards regression modelling was used to perform univariate analysis of predictors on OS and ES. Cumulative incidence of GvHD was calculated using a competing risk analysis, considering death and graft failure as competing events. All factors associated with a p-value <0.10 by univariate analysis were included into multivariate analysis. All p-values quoted are two-sided, with a level of significance of 0.05. Statistical analyses were performed using STATA 14.2.

Results: Patient and transplantation characteristics were summarised in table 1. The median age at transplant was 10.8 months (range 0.23 - 63.2 months). The median follow-up for surviving patients was 4.2 years (range, 1.0 to 12.8 years). 5-year overall survival (OS) and engrafted survival (ES) were 88% and 79%. OS was 95% after BuFluATG, 90% after BuCyATG and 74% after BuCyAlemtuzumab (p=0.02) (Figure 1a). Age, conventional HLA matching, allele level HLA matching, washed CB, cell doses were not associated with OS. ES was 84% for BuFluATG, 83% for BuCyATG and 65% for BuCyAlemtuzumab (p=0.34). Washed CB unit (p=0.03, figure 1b) and HLA ≤ 6/10 (p=0.02) were associated with significantly lower ES. The one-year cumulative incidence of graft-failure was 11% (95% CI, 6-21%). Five (5%) had grade III-IV acute GvHD. Five had limited chronic GvHD and one had extensive GvHD. The incidence of veno-occlusive disease was higher in patients conditioned with BuCy (n=10, 19%) compared to BuFlu (n=2, 5%) (p=0.03). Of the 11 patients with graft failure, 8 (73%) were aplastic and 3 (27%) autologous reconstitution. Of 11 patients with graft failure, 9 received a second transplant, and 8 (89%) survived. 89% after first CBT and all after second transplant had full donor chimerism. All had IDUA enzyme levels of above the lower limit of normal range.

Conclusions: Survival after CBT for HS has improved but better strategies are needed to improve graft outcome. Mismatched ≤6/10 and washing of the cord blood graft are associated with inferior engrafted survival. Cord blood graft is associated with low risk of acute and chronic graft-versus-host disease.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.033DOI Listing
September 2020

Neurocognitive benchmarks following transplant for emerging cerebral adrenoleukodystrophy.

Neurology 2020 08 2;95(5):e591-e600. Epub 2020 Jul 2.

From the Departments of Pediatrics (E.I.P., R.S.Z., W.P.M., A.O.G., T.C.L., P.J.O., J.B.E.), Radiology (D.R.N.), Bioinformatics and Biostatistics Core (R.S.), and Neurology (D.L.K.-J.), University of Minnesota, Minneapolis; and Sangamo Therapeutics (W.P.M.), Richmond, CA.

Objective: To quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease.

Methods: Retrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0-16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients.

Results: Patients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score >2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased.

Conclusion: To realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.
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http://dx.doi.org/10.1212/WNL.0000000000009929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455349PMC
August 2020

Failure of intrathecal allogeneic mesenchymal stem cells to halt progressive demyelination in two boys with cerebral adrenoleukodystrophy.

Stem Cells Transl Med 2020 May 5;9(5):554-558. Epub 2020 Feb 5.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota.

Cerebral adrenoleukodystrophy is an inflammatory demyelinating condition that is the result of a mutation in the X-linked ABCD1 gene, a peroxisomal very long chain fatty acid transporter. Although mutations in this gene result in adrenal insufficiency in the majority of affected individuals, 40% of those affected develop the demyelinating cerebral form, cerebral adrenoleukodystrophy (CALD). CALD is characterized by imaging findings of demyelination and contrast enhancement on magnetic resonance imaging (MRI). Although allogeneic hematopoietic cell transplantation can arrest progression of CALD early in its course, there is no accepted therapy for patients with advanced CALD. Mesenchymal stem cells (MSCs) have been used in a variety of clinical trials to capitalize on their anti-inflammatory properties as well as promote tissue repair. We delivered MSCs via intrathecal (IT) route to two boys with rapidly advancing CALD. The first boy received three doses 1 week apart, whereas the second boy received a single dose of IT MSCs. We note delivery of IT MSCs was feasible and without complication. Follow-up MRI scans after IT MSC delivery showed progressive demyelination in the first patient and no change in demyelination or contrast enhancement in the second patient. Although the infusion of IT MSCs was safe, it did not halt CALD progression in this setting, and future studies should focus on patient selection and dose optimization.
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http://dx.doi.org/10.1002/sctm.19-0304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180290PMC
May 2020

Reduced-Toxicity (BuFlu) Conditioning Is Better Tolerated but Has a Higher Second Transplantation Rate Compared to Myeloablative Conditioning (BuCy) in Children with Inherited Metabolic Disorders.

Biol Blood Marrow Transplant 2020 03 18;26(3):486-492. Epub 2019 Nov 18.

Pediatric Blood and Marrow Transplant Program, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota.

Hematopoietic stem cell transplantation (HCT) is a primary treatment for various inherited metabolic disorders (IMDs). Achieving stable and sustained engraftment while minimizing transplantation-related morbidity and mortality is critical to optimizing outcomes for IMDs. Traditional regimens have used myeloablative approaches, primarily busulfan and cyclophosphamide (BuCy), which is associated with significant regimen-related toxicity. Alternatively, reduced-toxicity regimens, such as busulfan and fludarabine (BuFlu), have been proposed to offer similar efficacy with reduced toxicities. We compared transplantation-related outcomes with BuCy-based and BuFlu-based conditioning in patients with IMDs. We retrospectively analyzed the University of Minnesota's transplantation database for patients with IMDs who underwent HCT using a BuCy (with alemtuzumab) or BuFlu (with antithymocyte globulin) preparative regimen between March 2008 and September 2017. Overall survival (OS), event-free survival (EFS), and incidence of neutrophil and platelet recovery were determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis, and respiratory failure were compared. Graft failure includes primary and secondary aplastic graft failure with and without autologous recovery. The incidence of viral infections post-transplantation in the 2 regimens was also determined. A total of 99 patients underwent HCT for IMDs during the study period. Sixty-four patients received BuCy conditioning, and the other 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were the most common IMDs, and umbilical cord blood was the most common graft source (74%). One-year OS was similar in the 2 groups (81.2% in BuCy versus 85.5% in BuFlu; P = .8), with an EFS of 75% versus 63%, respectively. The 2 groups also had similar incidences of grade III-IV acute GVHD (9% versus 6%; P = .5) and chronic GVHD (9% versus 7%; P = .67). Neutrophil and platelet recovery were similar in the 2 groups, with a significantly shorter duration of hospital stay noted in the BuFlu cohort (median, 21 days versus 34 days; P = .002). The cumulative incidence of graft failure was significantly higher in the BuFlu group (29% versus 14%; P = .08), as was the rate of second HCT (27% versus 3%; P = .001). The incidences of adenoviral infection (14% versus 0%; P = .02) and hemorrhagic cystitis (23% versus 3%; P = .01) were higher in the BuCy group. T cell engraftment occurred significantly sooner with BuCy conditioning until 1-year post-transplantation, but donor myeloid engraftment was similar in the 2 groups. Our data indicate that reduced-toxicity conditioning is associated with lower rates of infection and other transplantation-related complications but is concerning for a higher rate of graft failure in patients with IMDs. Alternate immunosuppressive agents and novel techniques should be considered to minimize toxicities and reduce complications.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.014DOI Listing
March 2020

Post-transplant laronidase augmentation for children with Hurler syndrome: biochemical outcomes.

Sci Rep 2019 Oct 1;9(1):14105. Epub 2019 Oct 1.

University of Minnesota, Division of Pediatric Blood and Marrow Transplant, Minneapolis, 55455, USA.

Allogeneic hematopoietic cell transplantation (HCT) benefits children with Hurler syndrome (MPS-IH). However, survivors remain burdened by substantial MPS-IH related residual disease. We studied the feasibility, safety and biochemical impact of augmentative recombinant intravenous enzyme replacement therapy (IV-ERT) post transplantation. Ten children with MPS-IH and ≥2 years from successful HCT underwent IV-ERT for 2 years' duration. Patients were monitored for anti-drug antibody (ADA) development, including inhibitory capacity and changes in urinary excretion of glycosaminoglycans (uGAG). Three patients demonstrated low-level ADA at baseline, though all children tolerated IV-ERT well. Eight patients developed ADA over the 2-year study, with 3 (38%) meeting criteria for an inhibitory ADA response. The aggregate cohort experienced a reduction in uGAG from baseline to study end, which was enhanced in children with low or no ADA response. Conversely, children with inhibitory ADA showed increase in uGAG over time. IV-ERT in previously transplanted children with MPS-IH appears safe and can reduce uGAG, although this is reversed by the presence of inhibitory ADA. These data show a biochemical change after initiation of post-HCT IV-ERT, but the occurrence of ADA and inhibitory antibodies are a concern and should be monitored in future efficacy trials. This trial was registered at www.clinicaltrials.gov , NCT01173016, 07/30/2010.
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http://dx.doi.org/10.1038/s41598-019-50595-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773848PMC
October 2019

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

Pediatr Res 2020 01 21;87(1):104-111. Epub 2019 Aug 21.

University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.

Background: Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.

Methods: This 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.

Results: The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.

Conclusions: Laronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made.
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http://dx.doi.org/10.1038/s41390-019-0541-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960090PMC
January 2020

Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy.

Sci Rep 2019 05 27;9(1):7858. Epub 2019 May 27.

University of Minnesota, Division of Pediatric Blood and Marrow Transplantation, 55455, Minneapolis, USA.

Cerebral adrenoleukodystrophy (cALD) is an inflammatory neurodegenerative disease associated with mutation of the ABCD1 gene. Proteomic analysis of cerebral spinal fluid (CSF) from young males with active cALD revealed markers of inflammation including APOE4. APOE4 genotype has been associated with an inferior prognosis following acute and chronic neurologic injury. We assessed APOE4 inheritance among 83 consecutive young males with cALD prior to hematopoietic cell transplant and its association with markers of cerebral disease. The allele frequency of APOE4 was not significantly different from that of the general population at 17%. Young males with cALD that were APOE4 carriers had similar CSF protein and chitotriosidase activity to that of non-carriers. In contrast, APOE4 carriers had an increased burden of cerebral disease involvement as determined by MRI severity score (10.5 vs 7.0 points, p = 0.01), higher gadolinium intensity score (2.0 vs 1.3 points, p = 0.007), inferior neurologic function (neurologic function score 2.4 vs 1.0, p = 0.001), and elevated CSF MMP2 levels compared to that of non-carriers (13168 vs 9472 pg/mL, p = 0.01). These are the first data showing that APOE4 is associated with increased severity of cerebral disease in cALD and suggest it may be a modifier of disease.
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http://dx.doi.org/10.1038/s41598-019-44140-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536544PMC
May 2019

Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood-onset beta-mannosidosis.

Mol Genet Genomic Med 2019 07 21;7(7):e00712. Epub 2019 May 21.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota.

Background: Deficiency in the enzyme β-mannosidase was described over three decades ago. Although rare in occurrence, the presentation of childhood-onset β-mannosidase deficiency consists of hypotonia in the newborn period followed by global development delay, behavior problems, and intellectual disability. No effective pharmacologic treatments have been available.

Methods: We report 2-year outcomes following the first umbilical cord blood transplant in a 4-year-old boy with early childhood-onset disease.

Results: We show restoration of leukocyte β-mannosidase activity which remained normal at 2 years posttransplant, and a simultaneous increase in plasma β-mannosidase activity and dramatic decrease in urine-free oligosaccharides were also observed. MRI of the brain remained stable. Neurocognitive evaluation revealed test point gains, although the magnitude of improvement was less than expected for age, causing lower IQ scores that represent a wider developmental gap between the patient and unaffected peers.

Conclusion: Our findings suggest that hematopoietic cell transplant can correct the biochemical defect in β-mannosidosis, although preservation of the neurocognitive trajectory may be a challenge.
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http://dx.doi.org/10.1002/mgg3.712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625138PMC
July 2019

Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes.

Genet Med 2019 11 25;21(11):2552-2560. Epub 2019 Apr 25.

Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.

Purpose: Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change.

Methods: In addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association.

Results: Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant.

Conclusion: Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome.
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http://dx.doi.org/10.1038/s41436-019-0522-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831510PMC
November 2019

Successful donor engraftment and repair of the blood-brain barrier in cerebral adrenoleukodystrophy.

Blood 2019 03 11;133(12):1378-1381. Epub 2019 Jan 11.

Division of Pediatric Blood and Marrow Transplant, Department of Pediatrics, University of Minnesota, Minneapolis, MN.

Adrenoleukodystrophy (ALD) is caused by mutations within the X-linked gene, resulting in the inability to transport acylated very long chain fatty acids (VLCFAs) into the peroxisome for degradation. VLCFAs subsequently accumulate in tissues, including the central nervous system. Up to 40% of boys develop a severe progressive demyelinating form of ALD, cerebral ALD, resulting in regions of demyelination observed on brain magnetic resonance imaging that are associated with a "garland ring" of gadolinium contrast enhancement. Gadolinium enhancement indicates blood-brain barrier (BBB) disruption and an active inflammatory disease process. Only hematopoietic cell transplant (HCT) has been shown to halt neurologic progression, although the mechanism of disease arrest is unknown. We evaluated imaging- and transplant-related biomarkers in 66 males who underwent HCT. In 77% of patients, gadolinium contrast resolved by 60 days post-HCT. We determined that time to neutrophil recovery and extent of donor chimerism correlated significantly with time to contrast resolution post-HCT. Graft failure was associated with a significantly slower rate of contrast resolution ( < .0001). Time to neutrophil recovery remained significant in multivariate analysis with other biomarkers ( = .03). Our data suggest that robust donor myeloid recovery is necessary for timely repair of the BBB.
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http://dx.doi.org/10.1182/blood-2018-11-887240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440119PMC
March 2019

Post-transplant adaptive function in childhood cerebral adrenoleukodystrophy.

Ann Clin Transl Neurol 2018 03 22;5(3):252-261. Epub 2018 Jan 22.

University of Minnesota Minneapolis Minnesota.

Objective: Hematopoietic stem cell transplantation (HSCT) is the only treatment known to slow or halt inflammatory demyelination among boys with the cerebral form of X-linked adrenoleukodystrophy (cALD), a devastating childhood condition affecting the central nervous system. HSCT can lead to a range of adverse outcomes including fatality. Previous studies have examined the potential predictors of post-HSCT survival and neurologic functioning. However, little is known about patients' daily-life adaptive functional outcomes (i.e., ability to communicate, maintain social relationships, and independently execute tasks of daily living). The purpose of this retrospective cohort study was to identify which patient characteristics and treatment-related variables predict long-term adaptive function among the survivors of HSCT for cALD.

Methods: We obtained caregiver ratings of adaptive functioning of 65 transplant survivors at an average of 4.6 years (range: 1.0-24.1 years) post-HSCT. Using linear regression with penalized maximum likelihood estimation, we modeled the relative contribution of pre-transplant neurocognitive test performance, MRI severity, transplant regimen, and length of time since transplant on patient adaptive functioning outcomes.

Results: Higher radiographic disease severity and poorer performance on baseline neurocognitive tests requiring fine motor skills and visual perception were associated with inferior adaptive functioning after HSCT. Use of radiation during the transplant preparative regimen also predicted poorer adaptive outcomes.

Interpretation: In addition to radiological disease severity, baseline neurocognitive test performance is associated with post-transplant adaptive functional outcomes. Neurocognitive measures may play an important role in prognostic counseling and post-transplant treatment planning for patients considering HSCT for cALD.
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http://dx.doi.org/10.1002/acn3.526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846389PMC
March 2018

Publisher Correction: Fast, sensitive method for trisaccharide biomarker detection in mucopolysaccharidosis type 1.

Sci Rep 2018 Mar 19;8(1):4994. Epub 2018 Mar 19.

Drug Discovery, R&D, Sanofi, Waltham, MA, 02451, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-23332-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859120PMC
March 2018

Fast, sensitive method for trisaccharide biomarker detection in mucopolysaccharidosis type 1.

Sci Rep 2018 02 27;8(1):3681. Epub 2018 Feb 27.

Drug Discovery, R&D, Sanofi, Waltham, MA, 02451, USA.

Certain recessively inherited diseases result from an enzyme deficiency within lysosomes. In mucopolysaccharidoses (MPS), a defect in glycosaminoglycan (GAG) degradation leads to GAG accumulation followed by progressive organ and multiple system dysfunctions. Current methods of GAG analysis used to diagnose and monitor the diseases lack sensitivity and throughput. Here we report a LC-MS method with accurate metabolite mass analysis for identifying and quantifying biomarkers for MPS type I without the need for extensive sample preparation. The method revealed 225 LC-MS features that were >1000-fold enriched in urine, plasma and tissue extracts from untreated MPS I mice compared to MPS I mice treated with iduronidase to correct the disorder. Levels of several trisaccharides were elevated >10000-fold. To validate the clinical relevance of our method, we confirmed the presence of these biomarkers in urine, plasma and cerebrospinal fluid from MPS I patients and assessed changes in their levels after treatment.
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http://dx.doi.org/10.1038/s41598-018-22078-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829143PMC
February 2018

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.

N Engl J Med 2017 10 4;377(17):1630-1638. Epub 2017 Oct 4.

From Massachusetts General Hospital and Harvard Medical School (F.E., P.L.M.), Dana-Farber and Boston Children's Cancer and Blood Disorders Center (C. Duncan, M.A., C. Dansereau, D.A.W.), and Boston Children's Hospital, Harvard Medical School, and Harvard Stem-Cell Institute (D.A.W.), Boston, and Bluebird Bio, Cambridge (A.M.P., E.S., T.O., D.D.) - all in Massachusetts; University of Minnesota Children's Hospital, Minneapolis (P.J.O., T.C.L., W.P.M., G.V.R.); University of California, Los Angeles, Los Angeles (S.D.O., R.S., A.J.S.); University College London Great Ormond Street Hospital Institute of Child Health and Great Ormond Street Hospital NHS Trust, London (A.J.T., H.B.G., P.G.); Pediatric Neurology Department, Hôpital Bicêtre-Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France (C.S., P.A.); Fundacion Investigar, Buenos Aires (H.A.); and Women's and Children's Hospital, North Adelaide, SA, Australia (D.B., N.J.C.S.).

Background: In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.

Methods: We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.

Results: A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.

Conclusions: Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).
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http://dx.doi.org/10.1056/NEJMoa1700554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708849PMC
October 2017

Quality of life among boys with adrenoleukodystrophy following hematopoietic stem cell transplant.

Child Neuropsychol 2018 10 21;24(7):986-998. Epub 2017 Sep 21.

c University of Minnesota Medical School , Department of Pediatrics, Division of Blood & Marrow Transplantation , Minneapolis , MN , USA.

Hematopoietic stem cell transplant (HSCT) is the only accepted treatment capable of halting the progression of X-linked cerebral adrenoleukodystrophy (CALD). While survival and neurological outcomes have been described, there is little information regarding the quality of life (QoL) of transplanted patients with CALD. This analysis is a cross-sectional study of QoL in 16 males diagnosed with CALD who underwent HSCT at a single institution. Each child or parent proxy completed subscales from the Neuro-QoL and the PROMIS Pediatric Profile Instrument representing physical, mental, and social health domains. Descriptive statistics summarized the demographic characteristics and QoL subscale T-scores, Spearman Rho correlations identified the relationships among the variables, and Mann-Whitney tests examined group differences between those with pre-HSCT Loes scores <10 and those with pre-HSCT Loes scores ≥10. The median age of respondents at the time of transplant was 8 years at HSCT (5-14) with a median of 5 years since HSCT (0.5-11). Scores from the selected QoL subscales were similar to healthy peers, though those with pre-HSCT Loes scores ≥10 had lower mobility, upper extremity function, peer interaction, and higher scores for anxiety. Although HSCT has the capability of halting progression of CALD, those with pre-HSCT Loes scores ≥10 after HSCT are at-risk for poor QoL. Longitudinal monitoring is necessary to further appreciate the factors affecting QoL among boys with CALD after HSCT, and how this may be improved.
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http://dx.doi.org/10.1080/09297049.2017.1380176DOI Listing
October 2018

Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group.

J Clin Endocrinol Metab 2017 09;102(9):3111-3123

Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.

Background: Osteopetrosis encompasses a group of rare metabolic bone diseases characterized by impaired osteoclast activity or development, resulting in high bone mineral density. Existing guidelines focus on treatment of the severe infantile forms with hematopoietic cell transplantation (HCT) but do not address the management of patients with less severe forms for whom HCT is not the standard of care. Therefore, our objective was to develop expert consensus guidelines for the management of these patients.

Methods: A modified Delphi method was used to build consensus among participants of the Osteopetrosis Working Group, with responses to an anonymous online survey used to identify areas of agreement and conflict and develop a follow-up survey. The strength of recommendations and quality of evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation system.

Results: Consensus was found in the areas of diagnosis, monitoring, and treatment. We recommend relying on characteristic radiographic findings to make the diagnosis and found that genetic testing adds important information by identifying mutations associated with unique disease complications. We recommend ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement, anemia, leukopenia, and dental disease. We suggest that calcitriol should not be used in high doses and instead recommend symptom-based supportive therapy for disease complications because noninfantile osteopetrosis has no effective treatment.

Conclusions: Scarcity of published studies on osteopetrosis reduce the ability to develop evidence-based guidelines for the management of these patients. Expert opinion-based guidelines for this rare condition are nevertheless important to enable improved care.
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http://dx.doi.org/10.1210/jc.2017-01127DOI Listing
September 2017

The Frequency of Carpal Tunnel Syndrome in Hurler Syndrome After Peritransplant Enzyme Replacement Therapy: A Retrospective Comparison.

J Hand Surg Am 2017 Jul 4;42(7):573.e1-573.e8. Epub 2017 May 4.

Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, MN. Electronic address:

Purpose: Children with Hurler syndrome (HS) develop carpal tunnel syndrome (CTS) owing to glycosaminoglycan deposition secondary to enzyme deficiency. Advancement in the treatment of the underlying enzyme deficiency now commonly includes peritransplant intravenous enzyme replacement therapy (ERT). The primary objective of this study was to determine if the use of limited ERT in addition to hematopoietic stem cell transplantation (HCT) for the treatment of children with HS reduces the incidence of surgical intervention for CTS compared with a cohort of historical controls treated with HCT alone. The secondary objectives were to evaluate the impact of demographic and transplant-related characteristics on the incidence of CTS. Lastly, the results of surgical treatment of CTS in HS are reported.

Methods: Medical records for a historical group of 43 HS patients who underwent HCT alone (group 1) were compared with 31 HS patients who underwent HCT + ERT (group 2). Both groups were compared for genotype, age at transplant, sex, transplant graft source, median/ulnar nerve conduction study parameters as well as the incidence and treatment of CTS. Pre- and postoperative nerve conduction studies were compared for children treated surgically for CTS.

Results: The cumulative incidence of CTS at 5 years for HS children treated with HCT + ERT was 51% compared with 47% for HS children treated with HCT alone. The incidence of CTS did not depend upon graft source, age at transplant, or sex. Median nerve conduction velocity for both sensory and motor potentials demonstrated significant improvement after carpal tunnel release.

Conclusions: Although the administration of ERT prior to and for several months after HCT has become routine in our institution, our findings do not suggest this combined therapy is sufficient to decrease the development of CTS. Surgical intervention for median nerve compression remains the treatment of choice for CTS in HS children.

Type Of Study/level Of Evidence: Therapeutic IV.
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http://dx.doi.org/10.1016/j.jhsa.2017.03.036DOI Listing
July 2017

Neurocognitive Trajectory of Boys Who Received a Hematopoietic Stem Cell Transplant at an Early Stage of Childhood Cerebral Adrenoleukodystrophy.

JAMA Neurol 2017 06;74(6):710-717

Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis.

Importance: Untreated childhood cerebral adrenoleukodystrophy (cALD) is a fatal disease associated with progressive cerebral demyelination and rapid, devastating neurologic decline. The standard of care to enhance long-term survival and stabilize cerebral disease is a hematopoietic stem cell transplant (HSCT). Neurologic outcomes are better when HSCT occurs at an earlier stage of cALD, yet there is limited understanding of the neurocognitive trajectory of patients who undergo HSCT.

Objectives: To characterize neurocognitive outcomes of boys with cALD and early-stage cerebral disease who were treated with an allogeneic HSCT and to identify disease- and treatment-related factors associated with long-term functioning.

Design, Setting, And Participants: Baseline and follow-up neurocognitive test performance was analyzed for all boys with cALD who received an HSCT at the University of Minnesota between January 1, 1991, and October 20, 2014, and who had a pretransplant magnetic resonance imaging (MRI) severity score of less than 10 (scale range, 0-34; higher scores indicate greater severity).

Main Outcomes And Measures: Longitudinal neurocognitive test performance in 4 domains (verbal comprehension, perceptual [visual] reasoning, working memory, and processing speed) were the primary outcome measures. Secondary analysis at the most recent evaluation also included measures of sustained attention, verbal memory, visual-motor integration, and fine motor function.

Results: Among the 62 boys in this study (mean [SD] age at transplant, 8.37 [2.80] years; range, 4-16 years), there was a significant association of pretransplant MRI severity and baseline verbal comprehension (r = -0.340; P = .008), perceptual reasoning (r = -0.419; P = .001), and processing speed (r = -0.285; P = .03) scores. Higher pretransplant MRI severity scores were also associated with a steeper decline in neurocognitive functioning during the 5-year follow-up period. Twenty-two of 33 patients (67%) with available long-term follow-up neurocognitive testing had severe impairment in at least 1 neurocognitive domain at the most recent evaluation.

Conclusions And Relevance: Boys with cALD who have greater than minimal cerebral disease detected on MRI scans at the time of an HSCT are at risk for severe, persistent neurocognitive deficits. These findings motivate further exploration of methods of detecting cerebral disease prior to development of lesions observable on MRI scans, an endeavor that may be facilitated by newborn screening for adrenoleukodystrophy. These findings may serve a benchmark role in evaluating the efficacy of novel interventions for cALD.
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http://dx.doi.org/10.1001/jamaneurol.2017.0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540007PMC
June 2017

Mortality after hematopoietic stem cell transplantation for severe mucopolysaccharidosis type I: the 30-year University of Minnesota experience.

J Inherit Metab Dis 2017 03 4;40(2):271-280. Epub 2017 Jan 4.

Department of Pediatrics, Division of Pediatric Cardiology, Masonic Children's Hospital, University of Minnesota Medical School, Minneapolis, MN, 55454, USA.

Background And Aim: Mucopolysaccharidosis IH (MPS IH, Hurler syndrome) naturally leads to death within the first decade of life, primarily from cardiac and pulmonary causes. To determine how hematopoietic stem cell transplantation (HSCT) has altered mortality, we analyzed our institution's 30-year experience of patients with MPS IH undergoing HSCT.

Methods: Using chart review and the National Death Index, we determined survival status of 134 patients (males = 69) with MPS IH transplanted between 9/16/1983 and 7/25/2013 on 12/31/2013. Analysis included descriptive statistics, Kaplan-Meier curves, and regression analysis by Cox proportional hazards model.

Results: Overall survival (95% CI) at one- and 25-years was 70% (62-78%) and 37% (19-55%), respectively. From 2004 onward, overall survival at one- and 8-years was 84% (73-96%) and 81% (69-94%), respectively, compared to 65% (55-74%) and 57% (47-67%) prior to 2004 (Log-rank p = 0.032). Regardless of era, male survival was significantly better than female (HR 0.40, [95% CI: 0.21-0.74], p = 0.004). The cumulative incidence of death (95% CI) at 25 years was 63% (45-81%); incidence of pulmonary-related death was the highest at 27% (10-41%) compared to 8% (0.3-16%) for cardiac, 12% (6-17%) for infectious disease, and 16% (3-27%) from other complications.

Conclusions: HSCT has increased survival in MPS IH beyond the third decade of life and decreased the incidence of cardiac mortality, but deaths after the third year post-HSCT occur in excess of expected US mortality. It is important to determine if improved transplant strategies since 2004 result in better long-term survival in the current patient population.
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http://dx.doi.org/10.1007/s10545-016-0006-2DOI Listing
March 2017

Allele-Level HLA Matching Impacts Key Outcomes Following Umbilical Cord Blood Transplantation for Inherited Metabolic Disorders.

Biol Blood Marrow Transplant 2017 01 29;23(1):119-125. Epub 2016 Oct 29.

Division of Pediatric Blood and Marrow Transplant, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Allogeneic hematopoietic stem cell transplantation has demonstrated efficacy for numerous inherited metabolic disorders (IMDs). Umbilical cord blood transplant (UCBT) is increasingly used as a graft source in IMDs, but little is known of the impact of cord blood unit (CBU)/recipient HLA allelic disparity on key outcomes following UCBT for IMD. We reviewed outcomes of 106 consecutive first, single UCBTs for IMD at the University of Minnesota with regard to CBU/recipient HLA allelic matching (HLA-A, -B, -C, and -DRB1). The median age at UCBT was 1 year, and 87 patients (82%) received myeloablative conditioning. Primary diagnoses were Hurler syndrome (41%), cerebral adrenoleukodystrophy (35%), metachromatic leukodystrophy/globoid cell leukodystrophy (9%), and other (16%). The 5-year overall survival (OS) for the entire cohort was 70% (95% confidence interval, 59% to 79%). Rates of severe acute and chronic graft-versus-host disease were low (6% for each). CBU/recipient HLA conventional matching was based on antigen-level matching at HLA-A and -B, and on allele-level matching at HLA-DRB1. Of 46 conventional matched UCBTs, 20 (43%) were mismatched at 1 or more alleles. Of 49 conventional 5/6 UCBTs, 30 (61%) were mismatched at ≥2 alleles and 19 (39%) were mismatched at ≥3 alleles. Within the 6/6 conventional match stratum, comparisons of key outcomes between allele-matched and allele-mismatched UCBT were as follows: 5-year OS, 88% versus 42% (P < .01); 1-year engrafted survival (ES) with ≥90% donor chimerism, 73% versus 60% (P = .33); graft failure, 8% versus 30% (P = .05); and transplantation-related mortality (TRM), 8% versus 30% (P = .04). For patients undergoing conventional 5/6 HLA-matched UCBT, better allelic matching was associated with similar outcomes: 5-year OS, 77% versus 74% (P = .72); 1-year ES, 73% versus 47% (P = .06); graft failure, 17% versus 42% (P = .05); and TRM, 10% versus 16% (P = .54). On multivariable analyses, fewer allele-level mismatches within each conventional match stratum continued to predict more favorable outcomes following UCBT. These data provide evidence that allele-level HLA matching considerations within a conventional HLA match stratum may better predict outcomes of interest after UCBT for IMD. Larger studies are warranted to confirm these findings and explore other allele-level HLA match dynamics.
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http://dx.doi.org/10.1016/j.bbmt.2016.10.019DOI Listing
January 2017

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H.

Sci Rep 2016 12 2;6:38305. Epub 2016 Dec 2.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN, USA.

Mucopolysaccharidosis (MPS) type-IH is a lysosomal storage disease that results from mutations in the IDUA gene causing the accumulation of glycosaminoglycans (GAGs). Historically, children with the severe phenotype, MPS-IH (Hurler syndrome) develop progressive neurodegeneration with death in the first decade due to cardio-pulmonary complications. New data suggest that inflammation may play a role in MPS pathophysiology. To date there is almost no information on the pathophysiologic changes within the cerebral spinal fluid (CSF) of these patients. We evaluated the CSF of 25 consecutive patients with MPS-IH. While CSF glucose and total protein were within the normal range, we found a significantly mean elevated CSF opening pressure at 24 cm HO (range 14-37 cm HO). We observed a 3-fold elevation in CSF heparan sulfate and a 3-8 fold increase in MPS-IH specific non-reducing ends, I0S0 and I0S6. Cytokine analyses in CSF of children with MPS-IH showed significantly elevated inflammatory markers including: MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF in comparison to unaffected children. This is the largest report of CSF characteristics in children with MPS-IH. Identification of key biomarkers may provide further insight into the inflammatory-mediated mechanisms related to MPS diseases and perhaps lead to improved targeted therapies.
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http://dx.doi.org/10.1038/srep38305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133554PMC
December 2016

Impact of Graft-Recipient ABO Compatibility on Outcomes after Umbilical Cord Blood Transplant for Nonmalignant Disease.

Biol Blood Marrow Transplant 2016 11 2;22(11):2019-2024. Epub 2016 Aug 2.

Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota.

Existing literature shows mixed conclusions regarding the impact of ABO incompatibility on outcomes after hematopoietic stem cell transplantation. Because the future for umbilical cord blood (UCB) expansion technologies is bright, we assessed whether this typically overlooked graft characteristic impacted various outcomes after UCB transplantation (UCBT) for nonmalignant disorders (NMDs). A prospectively maintained institutional blood and marrow transplant program database was queried for all patients undergoing first UCBT for NMDs. UCB and recipient ABO compatibility was considered as matched, major mismatched, minor mismatched, or bidirectional mismatched. The impact of ABO incompatibility was assessed on overall survival, graft failure, acute and chronic graft-versus-host disease (GVHD), time to neutrophil and platelet recovery, day 0 to day 100 RBC transfusion burden, and donor hematopoietic chimerism. Through December 2014, 270 patients have undergone first UCBT for various NMDs. In both univariable and multivariable analyses, ABO compatibility status did not appear to impact any outcomes assessed, although a trend toward increased grades III to IV acute GVHD was seen in recipients of major mismatched units. When considering UCBT for treatment of NMDs, ABO compatibility between the donor unit and intended recipient does not appear to be an important consideration in the UCB unit choice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067229PMC
http://dx.doi.org/10.1016/j.bbmt.2016.07.019DOI Listing
November 2016

Cerebral Spinal Fluid levels of Cytokines are elevated in Patients with Metachromatic Leukodystrophy.

Sci Rep 2016 Apr 15;6:24579. Epub 2016 Apr 15.

Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, 55455, US.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulfatase A causing an accumulation of cerebroside sulfate, a lipid normally abundant in myelin. Sulfatide accumulation is associated with progressive demyelination and a clinical presentation in severe disease forms that is dominated by motor manifestations. Cerebral inflammation may contribute to the pathophysiology of MLD. To date, cytokine levels in the cerebral spinal fluid of MLD patients have not previously been reported. The objective of this study was to evaluate the concentration of inflammatory cytokines in the CSF of patients with MLD and to compare these levels to unaffected controls. Of 22 cytokines evaluated, we documented significant elevations of MCP-1, IL-1Ra, IL-8, MIP-1b and VEGF in the MLD patients compared to unaffected controls. The elevated cytokines identified in this study may play a significant role in the pathophysiology of MLD. Better understanding of the inflammatory and neurodegenerative process of MLD may lead to improved targeted therapies.
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http://dx.doi.org/10.1038/srep24579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832325PMC
April 2016

Progression of Hip Dysplasia in Mucopolysaccharidosis Type I Hurler After Successful Hematopoietic Stem Cell Transplantation.

J Bone Joint Surg Am 2016 Mar;98(5):386-95

Department of Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx," Academic Medical Center, Amsterdam, the Netherlands

Background: Dysostosis multiplex contributes substantially to morbidity in patients with Hurler syndrome (mucopolysaccharidosis type I Hurler phenotype [MPS I-H]), even after successful hematopoietic stem cell transplantation (HSCT). One of the hallmarks of dysostosis multiplex in MPS I-H is hip dysplasia, which often requires surgical intervention. We sought to describe in detail the course of hip dysplasia in this group of patients, as assessed by radiographic analysis, and to identify potential outcome predictors.

Methods: Longitudinal data were obtained from digitally scored pelvic radiographs of patients with MPS I-H using OrthoGon software for parameters including, but not limited to, the acetabular index, migration percentage, Smith ratio, and neck-shaft angle. Scoring was performed independently by two blinded observers. Additional information on genotype, enzyme replacement therapy pre-HSCT, donor chimerism, and enzyme activity post-HSCT were obtained. General trends and potential correlations were calculated with mixed-model statistics.

Results: Fifty-two patients (192 radiographs) were included in this analysis. Intraobserver and interobserver variation analysis showed an intraclass correlation coefficient ranging from 0.78 to 1.00. Among the twenty-one patients with follow-up beyond the age of five years, the acetabular index was in the range of severe hip dysplasia in up to 86% of the patients. Severe coxa valga was seen in 91% of the patients. Lateral and superior femoral displacement were highly prevalent, with the migration percentage outside the reference range in up to 96% of the patients. Finally, anterior pelvic tilt increased with age (p = 0.001). No correlations were identified between clinical parameters and radiographic findings.

Conclusions: Our study shows that progressive acetabular dysplasia as well as coxa valga and hip displacement are highly prevalent and progressive over time in patients with MPS I-H, despite successful HSCT. These data may provide essential natural history determinations for the assessment of efficacy of new therapeutic strategies aimed at improving skeletal outcomes in patients with MPS I-H.
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http://dx.doi.org/10.2106/JBJS.O.00601DOI Listing
March 2016

Management of Red Teeth in an International Patient with X-Linked Adrenoleukodystrophy.

Pediatr Dent 2015 Nov-Dec;37(7):550-3

Division of Pediatric Dentistry, Department of Developmental and Surgical Sciences, School of Dentistry, University of Minnesota, Minneapolis, Minn., USA.

Childhood cerebral X-linked adrenoleukodystrophy is a progressive, central nervous system, and endocrine disorder that typically leads to total neurologic disability and, eventually, death without appropriate, timely medical therapy. Hematopoietic stem cell transplantation has been found effective in slowing cerebral deterioration and improving long-term survival. The purpose of this case report was to describe the multidisciplinary management of red, discolored, pulpally treated primary molars identified in a nine-year-old Russian boy with childhood cerebral X-linked adrenoleukodystrophy preparing for myeloablative conditioning chemotherapy followed by hematopoietic stem cell transplantation.
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September 2017

Outcomes after hematopoietic stem cell transplantation for children with I-cell disease.

Biol Blood Marrow Transplant 2014 Nov 10;20(11):1847-51. Epub 2014 Jul 10.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota.

Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients.
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http://dx.doi.org/10.1016/j.bbmt.2014.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194244PMC
November 2014

Comparison of hypersensitivity reactions to PEG-asparaginase in children after intravenous and intramuscular administration.

J Pediatr Hematol Oncol 2013 Oct;35(7):e283-6

*Childrens Mercy Hospital, Kansas City, MO †Division of Blood and Marrow Transplantion, University of Minnesota, Minneapolis, MN ‡Sigma-Tau Pharmaceuticals, Washingtonian Boulevard, Gaithersburg, MD.

Introduction: Polyethylene-glycolated (PEG)-asparaginase (PEG-ASP) is a crucial component of pediatric acute lymphoblastic leukemia therapy. Although hypersensitivity reactions to PEG-ASP occur less frequently than with other formulations, they are not uncommon and have an adverse impact on patient outcomes. Intravenous (IV) administration of PEG-ASP reduces patient pain and anxiety and is being used with increasing frequency in children.

Materials And Methods: A retrospective review was performed to compare the incidence of hypersensitivity reactions to PEG-ASP in children when administered either by intramuscular (IM) or IV routes between January 2006 and May 2008.

Results: Of 68 patients studied, 7 experienced a hypersensitivity reaction (10.3%). Two of 16 patients (12.5%) who received only IV PEG-ASP and 3 of 27 patients (11.1%) exposed to only IM PEG-ASP experienced a hypersensitivity reaction. Severe reactions (grade 3 or 4) occurred only once after 119 total doses (0.8%) of IV PEG-ASP and once after 215 total doses (0.5%) of IM PEG-ASP (P=1.0). Thrombosis or pancreatitis were rare and were not increased after IV PEG-ASP administration.

Discussion: IV PEG-ASP is well tolerated and does not result in a significant increase in the incidence of hypersensitivity reactions in children.
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http://dx.doi.org/10.1097/MPH.0b013e31828e5471DOI Listing
October 2013

Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction.

PLoS One 2012 21;7(11):e50430. Epub 2012 Nov 21.

Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, United States of America.

Background: X-linked adrenoleukodystrophy results from mutations in the ABCD1 gene disrupting the metabolism of very-long-chain fatty acids. The most serious form of ALD, cerebral adrenoleukodystrophy (cALD), causes neuroinflammation and demyelination. Neuroimaging in cALD shows inflammatory changes and indicates blood-brain-barrier (BBB) disruption. We hypothesize that disruption may occur through the degradation of the extracellular matrix defining the BBB by matrix metalloproteinases (MMPs). MMPs have not been evaluated in the setting of cALD.

Methodology/principal Findings: We used a multiplex assay to correlate the concentration of MMPs in cerebrospinal fluid and plasma to the severity of brain inflammation as determined by the ALD MRI (Loes) score and the neurologic function score. There were significant elevations of MMP2, MMP9, MMP10, TIMP1, and total protein in the CSF of boys with cALD compared to controls. Levels of MMP10, TIMP1, and total protein in CSF showed significant correlation [p<0.05 for each with pre-transplant MRI Loes Loes scores (R(2) = 0.34, 0.20, 0.55 respectively). Levels of TIMP1 and total protein in CSF significantly correlated with pre-transplant neurologic functional scores (R(2) = 0.22 and 0.48 respectively), and levels of MMP10 and total protein in CSF significantly correlated with one-year post-transplant functional scores (R(2) = 0.38 and 0.69). There was a significant elevation of MMP9 levels in plasma compared to control, but did not correlate with the MRI or neurologic function scores.

Conclusions/significance: MMPs were found to be elevated in the CSF of boys with cALD and may mechanistically contribute to the breakdown of the blood-brain-barrier. MMP concentrations directly correlate to radiographic and clinical neurologic severity. Interestingly, increased total protein levels showed superior correlation to MRI score and neurologic function score before and at one year after transplant.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050430PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503955PMC
May 2013

Elevated cerebral spinal fluid cytokine levels in boys with cerebral adrenoleukodystrophy correlates with MRI severity.

PLoS One 2012 16;7(2):e32218. Epub 2012 Feb 16.

Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota, United States of America.

Background: X-linked adrenoleukodystrophy (ALD) is a metabolic, peroxisomal disease that results from a mutation in the ABCD1 gene. The most severe course of ALD progression is the cerebral inflammatory and demyelinating form of the disease, cALD. To date there is very little information on the cytokine mediators in the cerebral spinal fluid (CSF) of these boys.

Methodology/principal Findings: Measurement of 23 different cytokines was performed on CSF and serum of boys with cerebral ALD and patients without ALD. Significant elevations in CSF IL-8 (29.3±2.2 vs 12.8±1.1 pg/ml, p = 0.0001), IL-1ra (166±30 vs 8.6±6.5 pg/ml, p = 0.005), MCP-1 (610±47 vs 328±34 pg/ml, p = 0.002), and MIP-1b (14.2±1.3 vs 2.0±1.4 pg/ml, p<0.0001) were found in boys with cALD versus the control group. The only serum cytokine showing an elevation in the ALD group was SDF-1 (2124±155 vs 1175±125 pg/ml, p = 0.0001). The CSF cytokines of IL-8 and MCP-1b correlated with the Loes MRI severity score (p = 0.04 and p = 0.008 respectively), as well as the serum SDF-1 level (p = 0.002). Finally, CSF total protein was also significantly elevated in boys with cALD and correlated with both IL-8, MCP-1b (p = 0.0001 for both), as well as Loes MRI severity score (p = 0.0007).

Conclusions/significance: IL-8, IL-1ra, MCP-1, MIP-1b and CSF total protein were significantly elevated in patients with cALD; IL-8, MCP-1b, and CSF total protein levels correlated with disease severity determined by MRI. This is the largest report of CSF cytokine levels in cALD to date, and identification of these key cytokines will provide further insight into disease progression and perhaps lead to improved targeted therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032218PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281135PMC
August 2012

Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report.

Blood 2011 Aug 17;118(7):1971-8. Epub 2011 May 17.

Department of Pediatrics, Blood and Marrow Transplant Program, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

Cerebral adrenoleukodystrophy (cALD) remains a devastating neurodegenerative disease; only allogeneic hematopoietic cell transplantation (HCT) has been shown to provide long-term disease stabilization and survival. Sixty boys undergoing HCT for cALD from 2000 to 2009 were analyzed. The median age at HCT was 8.7 years; conditioning regimens and allograft sources varied. At HCT, 50% demonstrated a Loes radiographic severity score ≥ 10, and 62% showed clinical evidence of neurologic dysfunction. A total of 78% (n = 47) are alive at a median 3.7 years after HCT. The estimate of 5-year survival for boys with Loes score < 10 at HCT was 89%, whereas that for boys with Loes score ≥ 10 was 60% (P = .03). The 5-year survival estimate for boys absent of clinical cerebral disease at HCT was 91%, whereas that for boys with neurologic dysfunction was 66% (P = .08). The cumulative incidence of transplantation-related mortality at day 100 was 8%. Post-transplantation progression of neurologic dysfunction depended significantly on the pre-HCT Loes score and clinical neurologic status. We describe the largest single-institution analysis of survival and neurologic function outcomes after HCT in cALD. These trials were registered at www.clinicaltrials.gov as #NCT00176904, #NCT00668564, and #NCT00383448.
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http://dx.doi.org/10.1182/blood-2011-01-329235DOI Listing
August 2011