Publications by authors named "Paul J Orchard"

120 Publications

Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I.

JIMD Rep 2021 Mar 8;58(1):89-99. Epub 2020 Dec 8.

Department of Pediatrics The Lundquist Institute at Harbor-UCLA Medical Center Torrance California USA.

Background: Orthopedic disease progresses in mucopolysaccharidosis type I (MPS I), even with approved therapies and remains a major factor in persistent suffering and disability. Novel therapies and accurate predictors of response are needed. The primary objective of this study was to identify surrogate biomarkers of future change in orthopedic disease.

Methods: As part of a 9-year observational study of MPS I, range-of-motion (ROM), height, pelvic radiographs were measured annually. Biomarkers in year 1 were compared to healthy controls. Linear regression tested for associations of change in biomarkers over the first year with change in long-term outcomes.

Results: MPS I participants (N = 19) were age 5 to 16 years and on average 6.9 ± 2.9 years post treatment initiation. Healthy controls (N = 51) were age 9 to 17 years. Plasma IL-1β, TNF-α, osteocalcin, pyridinolines, and deoxypyridinolines were higher in MPS than controls. Within MPS, progression of hip dysplasia was present in 46% to 77%. A 1 pg/mL increase in IL-6 was associated with -22°/year change in ROM (-28 to -15; < .001), a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -0.024 Z-score/year change in height Z-score (-0.043 to -0.005; = .016), and a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -2.0%/year change in hip dysplasia measured by Reimers migration index (-3.8 to -0.1; = .037).

Conclusions: Inflammatory cytokines are high in MPS I. IL-6 and PYD were associated with progression in joint contracture, short stature, and hip dysplasia over time. Once validated, these biomarkers may prove useful for predicting response to treatment of skeletal disease in MPS I.
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http://dx.doi.org/10.1002/jmd2.12190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932872PMC
March 2021

Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement.

Biomolecules 2021 Jan 29;11(2). Epub 2021 Jan 29.

Immusoft Corp, Minneapolis, MN 55413, USA.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.
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http://dx.doi.org/10.3390/biom11020189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911293PMC
January 2021

Consensus opinion on immune-mediated cytopenias after hematopoietic cell transplant for inherited metabolic disorders.

Bone Marrow Transplant 2021 Jan 13. Epub 2021 Jan 13.

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

Hematopoietic stem cell transplantation (HCT) has been increasingly used for patients with inherited metabolic disorders (IMD). Immune mediated cytopenias (IMCs) after HCT, manifesting as hemolytic anemia, thrombocytopenia, and/or neutropenia, are recognized as a significant complication in this patient population, yet our understanding of the incidence, risk factors, and pathophysiology is currently limited. Review of the published literature demonstrates a higher incidence in younger patients who undergo HCT for a nonmalignant disease indication. However, a few reports suggest that the incidence is even higher among those with IMD (incidence ranging from 10 to 56%). This review summarizes the literature, provides an approach to better understanding of the possible etiology of IMCs, and proposes a diagnostic and management plan for patients with IMD who develop single or multi-lineage cytopenias after HCT.
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http://dx.doi.org/10.1038/s41409-020-01179-5DOI Listing
January 2021

MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines.

J Inherit Metab Dis 2020 Dec 29. Epub 2020 Dec 29.

Division of Neurogenetics and The Moser Center for Leukodystrophies, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland, USA.

Background: Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy.

Methods: To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus.

Results: One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI.

Conclusion: Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.
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http://dx.doi.org/10.1002/jimd.12356DOI Listing
December 2020

White matter alteration and cerebellar atrophy are hallmarks of brain MRI in alpha-mannosidosis.

Mol Genet Metab 2021 03 3;132(3):189-197. Epub 2020 Dec 3.

Department of Radiology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic. Electronic address:

Objective: Despite profound neurological symptomatology there are only few MRI studies focused on the brain abnormalities in alpha-mannosidosis (AM). Our aim was to characterize brain MRI findings in a large cohort of AM patients along with clinical manifestations.

Methods: Twenty-two brain MRIs acquired in 13 untreated AM patients (8 M/5F; median age 17 years) were independently assessed by three experienced readers and compared to 16 controls.

Results: Focal and/or diffuse hyperintense signals in the cerebral white matter were present in most (85%) patients. Cerebellar atrophy was common (62%), present from the age of 5 years. Progression was observed in two out of 6 patients with follow-up scans. Cortical atrophy (62%) and corpus callosum thinning (23%) were already present in a 13-month-old child. The presence of low T signal intensity in basal ganglia and thalami was excluded by the normalized signal intensity profiling. The enlargement of perivascular spaces in white matter (38%), widening of perioptic CSF spaces (62%), and enlargement of cisterna magna (85%) were also observed. Diploic space thickening (100%), mucosal thickening (69%) and sinus hypoplasia (54%) were the most frequent non-CNS abnormalities.

Conclusion: White matter changes and cerebellar atrophy are proposed to be the characteristic brain MRI features of AM. The previously reported decreased T signal intensity in basal ganglia and thalami was not detected in this quantitative study. Rather, this relative MR appearance seems to be related to the diffuse high T signal in the adjacent white matter and not the gray matter iron deposition that has been hypothesized.
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http://dx.doi.org/10.1016/j.ymgme.2020.11.008DOI Listing
March 2021

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

Transplant Cell Ther 2021 Jan 20;27(1):91.e1-91.e4. Epub 2020 Sep 20.

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

We report the outcomes of cord blood transplantation (CBT) with a busulfan (Bu) pharmacokinetics-targeted myeloablative conditioning regimen in 97 children with Hurler syndrome (HS) performed between 2004 and 2016. The median age at CBT was 10.8 months (range, 0.23 to 63.2 months). The median duration of follow-up for surviving patients was 4.2 years (range, 1.0 to 12.8 years). Five-year overall survival (OS) and engrafted survival (ES) were 88% and 79%, respectively. OS was 95% in patients who received Bu/fludarabine (Flu)/antithymocyte globulin (ATG) conditioning, 90% in those who received Bu/cyclophosphamide (Cy)/ATG, and 74% in those who received Bu/Cy/alemtuzumab (P = .02). ES was 84% for recipients of Bu/Flu/ATG conditioning, 83% for recipients of Bu/Cy/ATG conditioning, and 65% for recipients of Bu/Cy/alemtuzumab conditioning (P = .34). Receipt of washed CB units (P = .03) and HLA matching ≤6/10 (P = .02) were associated with significantly lower ES. The 1-year cumulative incidence of graft failure was 11% (95% confidence interval, 6% to 21%). Five patients (5%) had grade III-IV acute GVHD, 5 patients had limited chronic GVHD, and 1 patient had extensive GVHD. The incidence of veno-occlusive disease was higher in patients conditioned with Bu/Cy compared with those conditioned with Bu/Flu (19% [n = 10] versus 5% [n = 2]: P = .03). Of the 11 patients with graft failure, 8 (73%) were aplastic, and 3 (27%) had autologous reconstitution. Of 11 patients with graft failure, 9 underwent a second CBT, and 8 (89%) survived. Full donor chimerism was observed in 89% patients after first CBT and in all patients after second CBT. Survival after CBT for HS has improved, but better strategies are still needed to improve graft outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.033DOI Listing
January 2021

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.

Cells 2020 08 5;9(8). Epub 2020 Aug 5.

Immusoft Corp, Minneapolis, MN 55413, USA.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues. If untreated, patients with the severe phenotype die within the first decade of life. Early diagnosis is crucial to prevent the development of fatal disease manifestations, prominently cardiac and respiratory disease, as well as cognitive impairment. However, the initial symptoms are nonspecific and impede early diagnosis. This review discusses common phenotypic manifestations in the order in which they develop. Similarities and differences in the three animal models for MPS I are highlighted. Earliest symptoms, which present during the first 6 months of life, include hernias, coarse facial features, recurrent rhinitis and/or upper airway obstructions in the absence of infection, and thoracolumbar kyphosis. During the next 6 months, loss of hearing, corneal clouding, and further musculoskeletal dysplasias develop. Finally, late manifestations including lower airway obstructions and cognitive decline emerge. Cardiac symptoms are common in MPS I and can develop in infancy. The underlying pathogenesis is in the intra- and extracellular accumulation of partially degraded GAGs and infiltration of cells with enlarged lysosomes causing tissue expansion and bone deformities. These interfere with the proper arrangement of collagen fibrils, disrupt nerve fibers, and cause devastating secondary pathophysiological cascades including inflammation, oxidative stress, and other disruptions to intracellular and extracellular homeostasis. A greater understanding of the natural history of MPS I will allow early diagnosis and timely management of the disease facilitating better treatment outcomes.
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http://dx.doi.org/10.3390/cells9081838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463646PMC
August 2020

N-acetylcysteine Provides Cytoprotection in Murine Oligodendrocytes through Heme Oxygenase-1 Activity.

Biomedicines 2020 Jul 23;8(8). Epub 2020 Jul 23.

Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455, USA.

Oligodendrocytic injury by oxidative stress can lead to demyelination, contributing to neurodegeneration. We investigated the mechanisms by which an antioxidant, N-acetylcysteine (NAC), reduces oxidative stress in murine oligodendrocytes. We used normal 158N and mutant 158JP cells with endogenously high reactive oxygen species (ROS) levels. Oxidative stress was induced in 158N cells using hydrogen peroxide (HO, 500 μM), and both cells were treated with NAC (50 µM to 500 µM). ROS production, total glutathione (GSH) and cell survival were measured 24 h after treatment. In normal cells, HO treatment resulted in a ~5.5-fold increase in ROS and ~50% cell death. These deleterious effects of oxidative stress were attenuated by NAC, resulting in improved cell survival. Similarly, NAC treatment resulted in decreased ROS levels in 158JP cells. Characterization of mechanisms underlying cytoprotection in both cell lines revealed an increase in GSH levels by NAC, which was partially blocked by an inhibitor of GSH synthesis. Interestingly, we observed heme oxygenase-1 (HO-1), a cytoprotective enzyme, play a critical role in cytoprotection. Inhibition of HO-1 activity abolished the cytoprotective effect of NAC with a corresponding decrease in total antioxidant capacity. Our results indicate that NAC promotes oligodendrocyte survival in oxidative stress-related conditions through multiple pathways.
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http://dx.doi.org/10.3390/biomedicines8080240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460204PMC
July 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

Volume of Gadolinium Enhancement and Successful Repair of the Blood-Brain Barrier in Cerebral Adrenoleukodystrophy.

Biol Blood Marrow Transplant 2020 10 26;26(10):1894-1899. Epub 2020 Jun 26.

Department of Diagnostic Radiology, University of Minnesota Medical Center, Minneapolis, Minnesota.

Up to 40% of boys with adrenoleukodystrophy develop a severe central nervous system demyelinating form (cALD) characterized by white matter changes and gadolinium enhancement on magnetic resonance imaging (MRI). Hematopoietic cell transplant (HCT) is the only proven means to attenuate cALD progression. The elimination of active neuroinflammation is indicated radiographically by the resolution of gadolinium (Gd) enhancement and correlates to speed of donor neutrophil recovery. We analyzed 66 boys with cALD undergoing HCT for biomarkers correlating with early (30 days post-HCT) Gd signal resolution. We found that log Gd volume (cm) on pre-HCT MRI strongly positively correlated to day 30 Gd resolution (P = .0003) with smaller volume correlating to higher proportion resolved, as was the baseline gadolinium intensity score (P = .04), plasma chitotriosidase activity (P = .04), and faster absolute neutrophil count recovery (P = .03). In multivariate analysis, log Gd volume remained superior in determining which patients would have Gd signal resolution by 30 days post-HCT (P = .016). A final analysis indicated that early Gd resolution also correlated with less neurologic progression from baseline to 1 year following HCT (P = .006). MRI Gd volume may serve as a contributing biomarker to better delineate outcomes and an important metric in comparing therapies in the treatment of cALD.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.019DOI Listing
October 2020

The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.

Cells 2020 06 5;9(6). Epub 2020 Jun 5.

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

The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
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http://dx.doi.org/10.3390/cells9061411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348849PMC
June 2020

Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy.

Biol Blood Marrow Transplant 2020 07 9;26(7):1247-1256. Epub 2020 Mar 9.

BMT & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin.

The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years the field has not only seen an improvement in transplantation technology, thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells, including chimeric antigen receptor T cells and engineered T-cell receptors, has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established a multiple stakeholder task force consisting of transplant experts, payer representatives, and a patient advocate to provide guidance on indications for HCT and IECT. This article presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence; (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but have been shown to be effective therapy; (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exists but large clinical trials and observational studies are not feasible; (4) Developmental, for diseases where preclinical and/or early-phase clinical studies show HCT/IECT to be a promising treatment option; and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.
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http://dx.doi.org/10.1016/j.bbmt.2020.03.002DOI Listing
July 2020

Outcomes of Children Who Present to the Emergency Department After Hematopoietic Cell Transplantation.

Pediatr Emerg Care 2020 Feb 24. Epub 2020 Feb 24.

Division of Emergency Medicine, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN.

Objectives: Our primary objective was to describe emergency department (ED) presentation, treatment, and outcomes for children after hematopoietic cell transplantation (HCT). Our secondary objective was to identify factors associated with serious infection in this population.

Methods: This is a retrospective review of HCT patients who presented to our university children's hospital ED from January 1, 2011, to June 30, 2013. Emergency department presentation, treatment, and outcomes were described. Descriptive statistics were used to compare children with definite serious infection with those without serious infection. Multiple binary logistic regression was performed for risk factors associated with definite serious infection.

Results: Fifty-four HCT patients (132 encounters) presented to our ED. Most were transplanted for a malignant (46%) or metabolic (36%) diagnosis and were recipients of bone marrow (51%) or umbilical cord blood (45%). Fever was the most common complaint (25%). Emergency department laboratory (64%) or imaging (58%) studies were frequently obtained. Admission was common (n = 70/132, 53%), with 79% (n = 55) of admissions to intensive care or bone marrow transplant units. Thirty-five encounters had definite serious infection, 5 had probable serious infection, and 92 had no serious infection. Fever (P < 0.001) and high-risk white blood cell (WBC) count of less than 5 or greater than 15 k/μL (P < 0.001) were associated with definite serious infection. Fever (odds ratio = 8.84, 95% confidence interval = 2.92-26.73) and high-risk WBC (odds ratio = 6.67, 95% confidence interval = 2.24-19.89) remained significantly associated with definite serious infection in our regression model.

Conclusions: Children presenting to the ED after HCT require extensive support and resources, with more than half requiring admission. Fever and high-risk WBC are associated with serious infection.
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http://dx.doi.org/10.1097/PEC.0000000000002060DOI Listing
February 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

A Phase 2 Trial of KIR-Mismatched Unrelated Donor Transplantation Using in Vivo T Cell Depletion with Antithymocyte Globulin in Acute Myelogenous Leukemia: Children's Oncology Group AAML05P1 Study.

Biol Blood Marrow Transplant 2020 04 21;26(4):712-717. Epub 2019 Dec 21.

Bone Marrow Transplant Department, St Jude Children's Research Hospital, Memphis, Tennessee.

Patients with acute myelogenous leukemia (AML) who undergo killer immunoglobulin-like receptor (KIR)-mismatched haploidentical hematopoietic stem cell transplantation (HSCT) have improved survival. Children's Oncology Group AAML05P1 is a prospective phase 2 trial of unrelated donor (URD) HSCT in which KIR typing of donors was available to the treating physician at donor selection, aiming to determine feasibility (defined as the ability to obtain donor samples from URDs and obtain KIR data before transplantation) of prospective selection of KIR-mismatched donors and effect on outcomes. Patients age ≤30 years with high-risk AML at presentation or relapsed AML were eligible; the study accrued 90 evaluable patients. After enrollment, as many as 5 potential URD samples were KIR-typed (including gene expression) in a central laboratory and results reported to the treating physician, who made the final donor selection. Cases were categorized as KIR-matched or KIR-mismatched using different published strategies. Overall survival (OS), disease-free survival (DFS), and relapse did not differ significantly by KIR mismatch status. Acute graft-versus-host disease (GVHD) was significantly lower in recipients of KIR-mismatched stem cells (35% versus 60%; P = .027). We examined DFS according to time to natural killer (NK) receptor recovery after HSCT. NK p44 recovery was significantly associated with KIR mismatch and with decreased DFS and increased relapse risk in multivariate Cox analysis (P = .006 and .009, respectively). We show that prospective selection of URD according to KIR type was feasible, acute GVHD was reduced, but survival did not differ using any model of KIR mismatch. However, the study enrolled mostly matched transplants, so ligand-ligand mismatch was rare, and thus the sample size was insufficient to determine potential benefit according to this model. Cord blood recipients demonstrated a trend toward improved DFS with KIR mismatch, but the study was not powered to detect a difference in this small subset of patients. Our data suggest that recovery of NK receptor expression might influence DFS after HSCT.
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http://dx.doi.org/10.1016/j.bbmt.2019.12.723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198330PMC
April 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

Choice of conditioning regimens for bone marrow transplantation in severe aplastic anemia.

Blood Adv 2019 10;3(20):3123-3131

Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

Allogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.
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http://dx.doi.org/10.1182/bloodadvances.2019000722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849938PMC
October 2019

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

TCIRG1 Transgenic Rescue of Osteoclast Function Using Induced Pluripotent Stem Cells Derived from Patients with Infantile Malignant Autosomal Recessive Osteopetrosis.

J Bone Joint Surg Am 2019 Nov;101(21):1939-1947

Stem Cell Institute (W.C., K.T., and J.T.) and Division of Blood and Marrow Transplantation (C.E., M.J.R., P.J.O., and J.T.), Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.

Background: Osteoclasts are hematopoietic stem cell-derived multinucleated cells necessary for bone remodeling and resorption. TCIRG1 encodes a protein that is an adenosine triphosphate (ATP)-dependent vacuolar proton pump required for this process. Recessive loss-of-function mutations in both copies of this gene lead to impairment of osteoclast function, with increased bone density, increased skeletal mass, and early mortality.

Methods: We isolated fibroblasts from a patient with the compound heterozygous TCIRG1 mutations c.1549G>A (p.517D>N) and c.2236C>T (p.746Q>X), and reprogrammed them into iPS (induced pluripotent stem) cells. The function of osteoclasts derived from these cells was then rescued by transgenic expression of TCIRG1 cDNA.

Results: In addition to the known effects of TCIRG1 loss of function, iPS cell-derived osteoclasts from this patient had reduced expression of the bone remodeling enzymes cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP), leading to reduced in vitro bone remodeling. Expression of both genes and pit formation were restored in iPS cell-derived osteoclasts following transgenic restoration of TCIRG1 expression.

Conclusions: Transgenic overexpression of TCIRG1 was sufficient to restore osteoclast function in iPS cell-derived osteoclasts from a patient with infantile malignant autosomal-recessive osteopetrosis.

Clinical Relevance: This work provides a proof of concept for an autologous approach to treating osteopetrosis, potentially avoiding the risks associated with hematopoietic stem cell transplantation in a young patient population.
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http://dx.doi.org/10.2106/JBJS.19.00558DOI Listing
November 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

Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance.

Orphanet J Rare Dis 2019 06 13;14(1):137. Epub 2019 Jun 13.

Center for Rare Diseases at Host Schmidt Kliniken, Wiesbaden, Germany and Department of Paediatrics University of Padova, Padova, Italy.

Introduction: Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA.

Methods: Twenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.

Results: A total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).

Conclusion: This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.
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http://dx.doi.org/10.1186/s13023-019-1074-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567385PMC
June 2019

Recommendations for the management of MPS VI: systematic evidence- and consensus-based guidance.

Orphanet J Rare Dis 2019 05 29;14(1):118. Epub 2019 May 29.

Center for Rare Diseases at Host Schmidt Kliniken, Wiesbaden, Germany and Department of Paediatrics, University of Padova, Padova, Italy.

Introduction: Mucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI.

Methods: 26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.

Results: A total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).

Conclusion: This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.
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http://dx.doi.org/10.1186/s13023-019-1080-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541999PMC
May 2019

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

A report on state-wide implementation of newborn screening for X-linked Adrenoleukodystrophy.

Am J Med Genet A 2019 07 10;179(7):1205-1213. Epub 2019 May 10.

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

Minnesota became the fourth state to begin newborn screening (NBS) for X-linked adrenoleukodystrophy (X-ALD) in 2017. As there is limited retrospective data available on NBS for X-ALD, we analyzed Minnesota's NBS results from the first year of screening. C26:0 lysophosphatidylcholine (C26:0-LPC) screening results of 67,836 infants and confirmatory testing (ABCD1 gene and serum VLCFA analysis) for screen positives were obtained. Fourteen infants (nine males, five females) screened positive for X-ALD and all were subsequently confirmed to have X-ALD, with zero false positives. The birth prevalence of X-ALD in screened infants was 1 in 4,845 and 1 in 3,878 males, more than five times previous reported incidences. Pedigrees of affected infants were analyzed, and 17 male (mean age of 17) and 24 female relatives were subsequently diagnosed with X-ALD. Phenotypes of these family members included self-reported mild neuropathy symptoms in two males and seven females, and childhood cerebral disease (ccALD) and adrenal insufficiency in one male. We observed fewer cases of ccALD and adrenal insufficiency than expected in male family members (5.9% of males for both) compared to previous observations. Together, these findings suggest that the spectrum of X-ALD may be broader than previously described and that milder cases may previously have been underrepresented. Other challenges included a high frequency of variants of uncertain significance in ABCD1 and an inability to predict phenotypic severity. We posit that thoughtful planning to address these novel challenges and coordination by dedicated specialists will be imperative for successful implementation of population-based screening for X-ALD.
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http://dx.doi.org/10.1002/ajmg.a.61171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619352PMC
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

Cerebral adrenoleukodystrophy is associated with loss of tolerance to profilin.

Eur J Immunol 2019 06 10;49(6):947-953. Epub 2019 Mar 10.

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

Childhood cerebral adrenoleukodystrophy (cALD) is a devastating manifestation of ALD accompanied by demyelination, inflammation, and blood brain barrier (BBB) disruption with shared characteristics of an auto-immune disease. We utilized plasma samples pre- and postdevelopment of cALD to determine the presence of specific auto-antibodies. Mass spectrometry of protein specifically bound with post-cALD plasma antibody identified Profilin1 (PFN1) as the target. In a screen of 94 boys with cALD 48 (51%) had anti-PFN1 antibodies, whereas only 2/29 boys with ALD but without cerebral disease, and 0/30 healthy controls showed anti-PFN1 immunoreactivity. Cerebral spinal fluid from those with cALD showed higher levels of PFN1 protein compared with non-cALD samples (324 ± 634 versus 42 ± 23 pg/mL, p = 0.04). Boys that were anti-PFN positive had a significant increase in the amount of gadolinium signal observed on MRI when compared to boys that were anti-PFN1 negative (p = 0.04) possibly indicating increased BBB disruption. Anti-PFN1 positivity was also associated with elevated levels of very long chain fatty acids (C26 of 1.12 ± 0.41 versus 0.97 ± 0.30 mg/dL, p = 0.03) and increased plasma BAFF (973 ± 277 versus 733 ± 269 pg/mL, p = 0.03). In conclusion, anti-PFN may be a novel biomarker associated with the development of cALD in boys with ALD.
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http://dx.doi.org/10.1002/eji.201848043DOI Listing
June 2019

Treatment of thoracolumbar kyphosis in patients with mucopolysaccharidosis type I: results of an international consensus procedure.

Orphanet J Rare Dis 2019 01 18;14(1):17. Epub 2019 Jan 18.

Amsterdam UMC, University of Amsterdam, Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx", Meibergdreef 9, Amsterdam, Netherlands.

Background: In all patients with mucopolysaccharidosis type I (MPS I), skeletal disease (dysostosis multiplex) is a prominent, debilitating, condition related complication that may impact strongly on activities of daily living. Unfortunately, it is not alleviated by treatment with hematopoietic cell transplantation (HCT) or enzyme replacement therapy (ERT). Although early kyphosis is one of the key features of dysostosis multiplex, there is no international consensus on the optimal management. Therefore, an international consensus procedure was organized with the aim to develop the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients.

Methods: A literature review was conducted to identify all available information about kyphosis and related surgery in MPS I patients. Subsequently, a modified Delphi procedure was used to develop consensus statements. The expert panel included 10 spinal orthopedic surgeons, 6 pediatricians and 3 physiotherapists, all experienced in MPS I. The procedure consisted of 2 written rounds, a face-to-face meeting and a final written round. The first 2 rounds contained case histories, general questions and draft statements. During the face-to-face meeting consensus statements were developed. In the final round, the panel had the opportunity to anonymously express their opinion about the proposed statements.

Results: Eighteen case series and case reports were retrieved from literature reporting on different surgical approaches and timing of thoracolumbar kyphosis surgery in MPS I. During the face-to-face meeting 16 statements were discussed and revised. Consensus was reached on all statements.

Conclusion: This international consensus procedure resulted in the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients, focusing on the goals and timing of surgery, as well as the optimal surgical approach, the utility of bracing and required additional assessments (e.g. radiographs). Most importantly, it was concluded that the decision for surgery depends not only on the kyphotic angle, but also on additional factors such as the progression of the deformity and its flexibility, the presence of symptoms, growth potential and comorbidities. The eventual goal of treatment is the maintenance or improvement of quality of life. Further international collaborative research related to long-term outcome of kyphosis surgery in MPS I is essential as prognostic information is lacking.
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http://dx.doi.org/10.1186/s13023-019-0997-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339313PMC
January 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

Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 03 4;25(3):538-548. Epub 2018 Oct 4.

Pediatric Blood and Marrow Transplantation Center, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P = .01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE status is a strong predictor of disease progression in untreated patients.‎ This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.036DOI Listing
March 2019