ABSTRACT
In neuronopathic Hunter syndrome, neurobehavioral symptoms are known to be serious but have been incompletely described. While families face significant stress stemming from this complex and far-reaching array of symptoms, neither caregiver burden nor the neurobehavioral symptoms have been measured comprehensively. We delineated these neurobehavioral characteristics and their impact on the caregiver using multiple approaches. Methods: As part of the initial phase of developing a Hunter-specific behavioral assessment tool, we used multiple methods to obtain data on patient behaviors and caregiver burden, with the intention of drafting item sets for the tool. We utilized 1) caregiver descriptions from focus groups and individual interviews, 2) observations from video-recorded play of affected children, 3) descriptions from historic chart review, 4) consultation with patient advocacy groups and international experts, 5) reports from a caregiver advisory board, and 6) literature review. Results: Neurobehavioral symptoms were diverse and categorized as focus/attention, impulsivity/heightened activity, sensation seeking, emotional/behavioral function, social interaction, and sleep. A significant reported challenge was susceptibility to misinterpretation of some behaviors as defiant or aggressive, particularly if physical. Caregiver burden involved social isolation, exhaustion, stress, and financial and vocational strain. These new descriptions will aid in developing quantitative measures of change in neurobehavioral symptoms and family burden. These descriptions will be the foundation of a neurobehavioral rating scale, which is very much needed to aid in patient management and assess interventions for individuals with neuronopathic Hunter syndrome.
ABSTRACT
The long-term cognitive and functional outcomes of children with mucopolysaccharidosis type I (MPS-IH) post-hematopoietic cell transplant (HCT) are not well documented, and the role of genetic and treatment factors in these outcomes has yet to be defined. In this multi-site, international study, we (1) characterize the cognitive and functional status of 47 individuals (ages 2-25, mean of 10.6 years) with MPS-IH who are 1-24 years post HCT (mean = 9 years) and (2) examine contributions of genotype, transplant characteristics, and sociodemographic factors to cognitive ability, adaptive behavior, and quality of life. The overall cognitive ability of our sample was mildly impaired, more than two standard deviations below general population norms. Parent reported adaptive behaviors (i.e., communication, daily living, and motor skills) were similarly impaired with a relative strength in socialization. Quality of life, as reported by parents, fell more than two standard deviations below population norms for physical functioning; however, psychosocial quality of life (emotional well-being) approximated population norms. In linear regression analysis, adjusted for demographic and treatment factors, mutation severity was associated with lower cognitive ability (p = 0.005) and adaptive functioning (p = 0.004), but not parent ratings of children's quality of life. Older age at HCT was associated with poorer physical quality of life (p = 0.002); lower socioeconomic status (p = 0.028) and unrelated bone marrow HCT (p = 0.010) were associated with poorer psychosocial quality of life. Implications for screening and early intervention for children at risk for poorer cognitive and functional outcomes are described.
ABSTRACT
An iterative method for computing the channel capacity of both discrete and continuous input, continuous output channels is proposed. The efficiency of new method is demonstrated in comparison with the classical Blahut - Arimoto algorithm for several known channels. Moreover, we also present a hybrid method combining advantages of both the Blahut - Arimoto algorithm and our iterative approach. The new method is especially efficient for the channels with a priory unknown discrete input alphabet.
ABSTRACT
The Research Challenges in CNS Manifestations of Inborn Errors of Metabolism workshop was designed to address challenges in translating potential therapies for these rare disorders, and to highlight novel therapeutic strategies and innovative approaches to CNS delivery, assessment of effects and directions for the future in the treatment of these diseases. Therapies for the brain in inborn errors represent some of the greatest challenges to translational research due to the special properties of the brain, and of inborn errors themselves. This review covers the proceedings of this workshop as submitted by participants. Scientific, ethical and regulatory issues are discussed, along with ways to measure outcomes and the conduct of clinical trials. Participants included regulatory and funding agencies, clinicians, scientists, industry and advocacy groups.
Subject(s)
Biomedical Research , Central Nervous System , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/therapy , Animals , Biomedical Research/ethics , Biomedical Research/trends , Central Nervous System/pathology , Clinical Trials as Topic/ethics , Humans , Metabolism, Inborn Errors/physiopathology , Rare Diseases/therapyABSTRACT
Wolman disease is the infantile form of autosomal recessive acid lipase deficiency, typically presenting in early infancy with diarrhea, massive hepatosplenomegaly, failure to thrive, and calcification of adrenal glands. Hematopoietic cell transplantation (HCT) is the only therapy reported to prevent hepatic failure and death, which without treatment occurs within the first year of life. We report a single institution's experience with HCT treatment of four Wolman patients, two of whom are long-term survivors (the longest survival reported to date, (4 and 11 years). Survivors showed resolution of diarrhea within weeks after engraftment, normalized hepatic function, improved hepatosplenomegaly, and in one patient normal adrenal function. The older patient has normal adaptive functions but mild to moderate neurocognitive deficiencies thought to be secondary to treatment and other medical problems. The younger patient has age-appropriate neurodevelopmental and adaptive abilities. We conclude that Wolman disease can be successfully treated with HCT, and that hepatic and cognitive function can be preserved with early diagnosis and timely referral to a transplant center.
Subject(s)
Hematopoietic Stem Cell Transplantation , Wolman Disease/therapy , Endocrine System/pathology , Female , Gastrointestinal Tract/pathology , Hematopoietic System/pathology , Humans , Infant , Infant, Newborn , Liver/pathology , Male , Survivors , Wolman Disease/metabolism , Wolman Disease/pathology , Wolman Disease/psychologyABSTRACT
Hurler syndrome (mucopolysaccharidosis type I, MPS IH) is characterized by a deficiency of alpha-L-iduronidase resulting in progressive multiorgan dysfunction. We sought to determine whether enzyme replacement therapy (ERT) with iduronidase in the peritransplant period affects outcome of hematopoietic stem cell transplantation (HSCT) for MPS IH. Seven children with MPS IH at a median age of 1.5 years at the time of myeloablative HSCT were eligible. All patients had null mutations in IDUA gene. Iduronidase (0.58 mg/kg per dose) was administered intravenously in 11-14 weekly doses before HSCT and 8 weekly doses after HSCT. The infusions were well tolerated. All patients developed antibodies to iduronidase but all engrafted with >90% donor hematopoiesis. A majority of patients had significant pulmonary complications before ERT and HSCT but all are alive and well with a median follow-up of more than 1 year after HSCT. This suggests that ERT prior to HSCT is unlikely to alter engraftment. In addition, morbidity was acceptable, despite a previous history of pulmonary difficulties that suggested that these patients were high risk for these complications. Therefore, we recommend treatment of MPS IH patients with combination of ERT and HSCT therapy to further investigate its potential to enhance outcomes with HSCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Iduronidase/administration & dosage , Mucopolysaccharidosis I/therapy , Combined Modality Therapy , Graft Survival , Humans , Iduronidase/blood , Infant , Infusion Pumps , Lung Diseases/etiology , Mucopolysaccharidosis I/complicationsABSTRACT
Hematopoietic stem cell transplantation as a treatment for childhood cerebral adrenoleukodystrophy (ALD) has historically only been successful in early disease. As ALD is associated with oxidative damage, we reasoned that adjunctive therapy with an antioxidant agent, N-acetyl-L-cysteine (NAC), may provide protection from rapid neurologic decline in boys with advanced cerebral disease. We report three boys with advanced ALD, whose neurologic status and brain radiographic findings were stabilized by treatment including NAC 8-11 months after hematopoietic stem cell transplantation. These results contrast with previous survival data in cerebral ALD patients who had a similar degree of brain involvement, all of whom died within 1 year of stem cell infusion despite a full donor engraftment. Thus, NAC merits investigation as a therapeutic strategy for patients with advanced ALD as an intervention that could change this lethal disease to a condition amendable to treatment with hematopoietic stem cell transplantation.
Subject(s)
Acetylcysteine/therapeutic use , Adrenoleukodystrophy/complications , Adrenoleukodystrophy/drug therapy , Antioxidants/therapeutic use , Hematopoietic Stem Cell Transplantation , Brain Diseases/etiology , Child , Combined Modality Therapy , Humans , Kaplan-Meier Estimate , Magnetic Resonance Imaging , Male , Pilot Projects , Severity of Illness Index , Treatment OutcomeABSTRACT
BACKGROUND: Early detection of white matter lesions in childhood-onset cerebral adrenoleukodystrophy (ALD) is important as hematopoietic cell transplantation (HCT), currently the only effective treatment, is beneficial only if performed early in the disease course. OBJECTIVE: To establish reliable biochemical markers of cerebral disease progression in patients with ALD to aid in treatment planning. METHODS: The authors used proton magnetic resonance spectroscopy (MRS) in combination with LCModel analysis to quantify brain metabolites in small volumes (3 to 16 mL) in the occipital and frontal white matter and the splenium of the corpus callosum of 17 unsedated patients and 26 healthy volunteers (adult n = 21, age-matched n = 5) at 4 tesla. RESULTS: Absolute concentrations of 12 metabolites were reliably determined, seven of which were established as markers of lesion development. Among these, creatine and choline containing compounds were the weakest markers while N-acetylaspartate, glutamine, and lipids + lactate were the strongest. The large extent of changes in the markers enabled detection of early neurochemical changes in lesion formation prior to detection of abnormalities by conventional MRI. Concentrations of a number of metabolites were also significantly different between normal appearing white matter of patients and controls indicating biochemical alterations in the absence of cerebral disease. Neurochemical improvements following HCT were measured in six patients. CONCLUSIONS: The progression of adrenoleukodystrophy, as well as effectiveness of its treatment, can be assessed with high precision using high field 1H magnetic resonance spectroscopy in individual patients without the need for sedation.
Subject(s)
Adrenoleukodystrophy/therapy , Brain Chemistry , Magnetic Resonance Spectroscopy , Adolescent , Adrenoleukodystrophy/classification , Adrenoleukodystrophy/diagnosis , Adrenoleukodystrophy/metabolism , Aspartic Acid/analogs & derivatives , Aspartic Acid/analysis , Child , Child, Preschool , Creatine/analysis , Disease Progression , Follow-Up Studies , Glutamine/analysis , Hematopoietic Stem Cell Transplantation/mortality , Humans , Inositol/analysis , Lactates/analysis , Lipids/analysis , Magnetic Resonance Spectroscopy/methods , Male , Neuropsychological Tests , PrognosisABSTRACT
Hurler syndrome (HS) is an autosomal recessive, inherited metabolic storage disorder due to deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. Untreated patients develop progressive mental retardation and multisystem morbidity with a median life expectancy of 5 years. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and even improvement of intellect, with long-term survival. However, children with HS have an increased incidence of graft failure, usually with concomitant autologous marrow reconstitution. Between 1983 and 2000, 71 Hurler children underwent HCT at the University of Minnesota. Of these 71, 19 (27%) experienced graft failure. We report HCT outcomes in all 11 Hurler patients receiving a second HCT at the University of Minnesota. Median age at second HCT was 25 months (range, 16 to 45 months); median time from first HCT was 8 months (range, 4 to 18.5 months). The conditioning regimen consisted of cyclophosphamide/TBI/ATG (n = 8) or busulfan/cyclophosphamide/ATG (n = 3). The source of bone marrow was an unrelated donor in six, matched sibling in four, and mismatched related in one. Five of the 11 grafts were T cell depleted prior to infusion. Overall, 10 of 11 patients showed donor-derived engraftment, of whom three developed grade 3 to 4 acute GVHD. Five of 11 patients are surviving a median of 25 months (range, 2 months to 12 years) with an overall actuarial survival of 50% (95% CI, 27% to 93%) at 4 years. All five show sustained donor engraftment with normalization of IDU activity levels. Three of five evaluable patients demonstrated stabilization of neuropsychological function after second HCT. Currently, allogeneic donor-derived hematopoiesis provides the only chance for long-term survival and improved quality of life in Hurler patients. While graft failure in Hurler patients requires further investigation, a timely second HCT can be well-tolerated and beneficial.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Mucopolysaccharidosis I/surgery , Adolescent , Adult , Female , Graft vs Host Disease/pathology , Humans , Iduronidase/deficiency , Iduronidase/genetics , Iduronidase/metabolism , Leukocytes/enzymology , Living Donors , Male , Middle Aged , Mucopolysaccharidosis I/enzymology , Mucopolysaccharidosis I/psychology , Neuropsychological Tests , Survival Analysis , Transplantation, Homologous/methods , Treatment OutcomeABSTRACT
Current electronic portal imaging devices (EPID) are limited in their ability to provide direct and quick verification and monitoring of patients during both setup and treatment of breathing synchronized radiotherapy (BSRT, including breathing gated, voluntary and forced breath-hold radiotherapy treatment.) These limitations are largely due to their slow image capture rate and poor image quality. An amorphous silicon array flat panel electronic portal imaging device (si-EPID) is emerging to meet the challenge. The purpose of this study is threefold: (1) to characterize the performance of a prototype si-EPID; (2) to compare image quality against that of digitized films; and (3) to evaluate the device in terms of verification of patient setup and monitoring during BSRT. In this study a Varian prototype si-EPID detector array and Clinic accelerator at the University of California Davis Cancer Center were used for imaging. Three quality assurance phantoms: a Lutz PVC phantom, a modified "Las Vegas" phantom, and a RMI model 1151 phantom, were used to characterize the imaging system. A Rando head phantom was used for anthropomorphic imaging tests. Images were obtained with the si-EPID and a Fuji RX film in a Kodak X-Omatic cassette. To investigate the clinical application, two sets of si-EPID images were collected from a lung cancer patient during a 22 s breath-hold and normal breathing. The quality of images obtained with the fast mode was found to be comparable to that obtained with the digitized films. The images with the standard mode were found to be better than the digitized film images. With this prototype si-EPID, it is possible to collect the images at the beginning, middle, and end of each breath-hold for those patients who can hold their breath for longer than 15 s. The si-EPID images can provide a quick verification of the initial patient setup and subsequent treatment position throughout the daily fractionation.
Subject(s)
Lung/diagnostic imaging , Radiotherapy/methods , Respiration , Artifacts , Calibration , Humans , Image Enhancement/methods , Lung Neoplasms/radiotherapy , Models, Theoretical , Monitoring, Physiologic , Movement , Pancreatic Neoplasms/radiotherapy , Phantoms, Imaging , Posture , Radiography , Radiotherapy/instrumentation , Time FactorsABSTRACT
Over 400 patients with lysosomal and peroxisomal storage diseases have received hematopoietic stem cell transplantation from normal donors. Without treatment, all of these diseases have an inexorable fate leading to central nervous system deterioration and early death. On the other hand, all of the engrafted hosts have had a remarkable positive clinical improvement in response to normalization of previously deficient enzymatic activity. Survival data for those engrafted indicates continued life-span as long as two decades beyond transplantation. The particular diseases treated in this way are included in this article. The specific indications and methods for transplantation are also included in this article.
Subject(s)
Bone Marrow Transplantation , Central Nervous System Diseases/therapy , Metabolism, Inborn Errors/therapy , Bone Marrow Transplantation/methods , Bone Marrow Transplantation/standards , Central Nervous System Diseases/etiology , Humans , Metabolism, Inborn Errors/complications , Treatment OutcomeABSTRACT
Untreated patients with Hurler syndrome (MPSIH) experience progressive neurologic deterioration and early death. Allogeneic bone marrow transplantation (BMT) ameliorates or halts this course. The Storage Disease Collaborative Study Group was formed to evaluate the effectiveness and toxicity of BMT. Effectiveness was defined as engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte alpha-L-iduronidase enzyme activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55% for HIR patients. The probability of extensive chronic GVHD was 0% for GIS and 24% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children transplanted before 24 months had a mean baseline MDI of 78, while those transplanted after 24 months had a mean baseline MDI of 63 (P = . 0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients transplanted after 24 months of age, only three showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with a baseline MDI greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte alpha-L-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte alpha-L-iduronidase enzyme activity. Children who developed acute GVHD of grade II or worse had significantly poorer cognitive outcomes (P < .009). No difference in the post-BMT MDI was observed between patients whose preparative therapies did (n = 10; radiation dose, 300 to 1,400 cGy) or did not (n = 16) include radiation. We conclude that MPSIH patients, particularly those less than 24 months of age with a baseline MDI greater than 70, can achieve a favorable long-term outcome with continuing cognitive development and prolonged survival after successful BMT from a related donor with homozygous normal enzyme activity.
Subject(s)
Bone Marrow Transplantation , Graft Survival , Mucopolysaccharidosis I/therapy , Child, Preschool , Female , HLA Antigens/immunology , Histocompatibility Testing , Humans , Infant , Male , Mucopolysaccharidosis I/immunology , Mucopolysaccharidosis I/mortality , Survival Analysis , Transplantation, HomologousABSTRACT
BACKGROUND: Globoid-cell leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS: Five children with globoid-cell leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS: Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS: Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.
Subject(s)
Central Nervous System Diseases/therapy , Hematopoietic Stem Cell Transplantation , Leukodystrophy, Globoid Cell/therapy , Central Nervous System Diseases/etiology , Central Nervous System Diseases/prevention & control , Cerebrospinal Fluid Proteins/analysis , Child , Child, Preschool , Female , Galactosylceramidase/metabolism , Humans , Infant , Leukocytes/enzymology , Leukodystrophy, Globoid Cell/complications , Male , Transplantation, HomologousABSTRACT
Soliton propagation in a cascaded dispersion-managed optical amplifier system with zero net dispersion is examined. We present a qualitative physical explanation for the recently discovered fact that a soliton with finite energy can propagate down a fiber line with zero or normal average dispersion. We describe a specific practical system for the main properties of such a soliton, namely, the dependence of the soliton power on the pulse width at chirp-free points and the soliton average energy and width at chirp-free points as functions of the dispersion-allocation (strength of the map) parameter.
Subject(s)
Developmental Disabilities/etiology , Developmental Disabilities/prevention & control , Hematopoietic Stem Cell Transplantation/methods , Mucopolysaccharidosis I/complications , Mucopolysaccharidosis I/therapy , Age Factors , Child, Preschool , Disease Progression , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Infant , Treatment OutcomeABSTRACT
PURPOSE: To determine early signs of disease in patients with childhood-onset cerebral adrenoleukodystrophy (COCALD) with the use of proton MR spectroscopy. METHODS: Eleven children with posterior COCALD involvement and three children with anterior COCALD involvement were studied with single-voxel proton MR spectroscopy and neuropsychological testing. Findings were compared with those in five healthy control subjects. RESULTS: Areas of abnormal T2 signal intensity in children with COCALD showed abnormal metabolite ratios relative to those of control subjects as follows: decreased N-acetylaspartate (NAA)/Creatine (Cr) and NAA/Choline (Ch) and increased Ch/Cr. Metabolite ratios from normal-appearing brain regions in the same patients also were abnormal, with reduced NAA/Cr and NAA/Ch and increased Ch/Cr values. The mean metabolite ratios in normal-appearing regions were between those in the abnormal regions and those found in the control subjects. Statistical comparison of these ratios with neuropsychological test scores, which are specific for anterior and posterior brain functions, showed a significant correlation with the abnormal metabolite ratios. Our results indicate that the normal-appearing brain regions in these patients are metabolically abnormal. CONCLUSION: Proton MR spectroscopy could be a useful noninvasive tool to evaluate extent of disease in patients with COCALD.
Subject(s)
Adrenoleukodystrophy/diagnosis , Brain Diseases, Metabolic/diagnosis , Energy Metabolism/physiology , Magnetic Resonance Spectroscopy , Neuropsychological Tests , Adolescent , Adrenoleukodystrophy/physiopathology , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Brain/physiopathology , Brain Diseases, Metabolic/physiopathology , Brain Mapping , Child , Child, Preschool , Choline/metabolism , Cohort Studies , Creatine/metabolism , Female , Humans , MaleABSTRACT
Optical 10-Gbit / s return-to-zero pulse transmission in cascaded communication systems using dispersion compensation of the standard monomode fiber with large amplifier spacing is examined. It is shown that pulse distortions that are due to Kerr nonlinearity are significantly diminished by symmetrical ordering of the compensation sections when the total number of precompensation and postcompensation sections is equal. Repositioning of these sections is not critical.
ABSTRACT
We present a theory of chirped breathing pulse propagation in optical transmission systems with strong dispersion management. Fast changes of pulse width and chirp over one period are given by a simple model that is verified by direct numerical simulations. An average pulse evolution in the leading order is described by the nonlinear Schrödinger equation, with additional parabolic potential that can be a trapping (when a grating is used) or a nontrapping (without a grating) type.
ABSTRACT
Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 10(8) cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 10(8) cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.