Long-term neurodevelopmental outcomes of hematopoietic stem cell transplantation for late-infantile Krabbe disease.

Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in galactocerebrosidase. The only effective treatment is hematopoietic stem cell transplantation (HSCT). Approximately 85% of Krabbe disease cases are the infantile subtypes, among which ∼20% are late infantile. Prior studies have demonstrated that HSCT is effective for early-infantile patients (0-6 months of age) who undergo transplantation while asymptomatic, compared with those receiving transplants while symptomatic. However, no studies evaluated the efficacy of HSCT for late-infantile patients (6-36 months). In this prospective, longitudinal study, patients were evaluated at a single site according to a standardized protocol. Survival analysis was performed using the Kaplan-Meier method. Differences between groups were estimated using mixed regression models to account for within-person repeated measures. Nineteen late-infantile patients underwent HSCT (March 1997 to January 2020). Compared with untreated patients, transplant recipients had a longer survival probability and improved cognitive and language function. Gross and fine motor development were most affected, with variable results. Asymptomatic patients benefitted the most from transplantation, with normal to near-normal development in all domains and some gross motor delays. Among symptomatic patients, those with disease onset at >12 months of age had better cognitive outcomes than untreated patients. Those with disease onset at ≤12 months were comparable to untreated patients. We found that HSCT prolonged the lifespan and improved the functional abilities of late-infantile patients with Krabbe disease, particularly those who underwent transplantation before onset of symptoms. In addition, our findings support prior literature that reclassifies late-infantile Krabbe disease to be symptom onset at 12 to 36 months of age.

General anesthesia safety in progressive leukodystrophies: A retrospective study of patients with Krabbe disease and metachromatic leukodystrophy.

BACKGROUND: Krabbe disease and metachromatic leukodystrophy are leukodystrophies characterized by neurologic degeneration and early death. Patients often require general anesthesia for diagnostic and therapeutic interventions. METHODS: A retrospective review of medical records was conducted for patients with Krabbe disease and metachromatic leukodystrophy receiving general anesthesia at a large children's hospital between 2012 and 2017. Patient complications and American Society of Anesthesiologists Physical Status were recorded for all procedures. The Neurodevelopment in Rare Disorders classification system was created to categorize the severity of the patient's disease progression based on clinical markers. Descriptive and inferential statistics were used to compare: (a) complication rate of affected patients vs the general hospital population; (b) the accuracy of the novel Neurodevelopment in Rare Disorders classification system vs American Society of Anesthesiologists Physical Status regarding the assessment of complication risk; (c) complication rate in patients with hematopoietic stem cell transplantation vs those without transplantation; (d) complication rate in immunosuppressed patients vs nonimmunosuppressed patients; and (e) complication rate of the three most commonly performed procedures. RESULTS: A total of 96 patients underwent 287 procedures. Of these, 11 cases had complications, yielding a rate of 3.8%. This is significantly higher than the overall complication rate at our institution of 0.246%. Statistical analysis showed better correlation between the Neurodevelopment in Rare Disorders classification system and complication rate than American Society of Anesthesiologists Physical Status and complication rate. The system also showed better accuracy in differentiating low-risk and high-risk patients. No statistically significant difference in complication rate was found for patients with transplantation vs those without transplantation or for immunosuppressed vs nonimmunosuppressed patients. Of the three most common procedures, central catheter placement/removal exhibited the highest complication rate. CONCLUSIONS: Although the complication rate for patients with Krabbe disease and metachromatic leukodystrophy is higher than the general population, most complications were mild and self-limiting. These results suggest that, in experienced hands, general anesthesia is well tolerated in most children. Findings show that the Neurodevelopment in Rare Disorders classification system is a better indicator for assessing complication risk in patients with Krabbe and metachromatic leukodystrophy than American Society of Anesthesiologists Physical Status.

A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life.

BACKGROUND: Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in the lysosomal enzyme galactocerebrosidase. Patients with Krabbe disease present with a variable disease course depending on their age of onset. The purpose of this prospective cohort study was to characterize the natural progression of Krabbe disease in a large group of patients with disease onset between 6 and 36 months of life who were evaluated with a standardized protocol. METHODS: All patients with Krabbe disease who had onset between 6 and 36 months of age and were prospectively evaluated between 2000 to 2017 were included. Standardized neurodevelopmental, physical, and neurological examinations were performed. Other assessments included neuroradiologic and neurophysiologic tests, enzyme level, cerebrospinal fluid analysis, and GALC pathogenic variants when available. Descriptive statistics were used for analysis. Survival curve was estimated using the Kaplan-Meier method. RESULTS: Thirty-five patients (26 boys, 9 girls) with disease onset between 6 and 36 months of age were evaluated. Median age at symptom onset was 11.5 months, with a median delay of 3.5 months between onset of symptoms and diagnosis. Of the 32 symptomatic patients, 23 presented with initial signs or symptoms of disease between 6 and 12 months of life; nine presented after 12 months. The most common initial signs and symptoms were loss of acquired developmental milestones, irritability, abnormal gait, motor delay, and abnormal muscle tone. The most common magnetic resonance imaging abnormality was increased T2 signal in the periventricular white matter. Nerve conduction velocity results were abnormal for 21 of 24 patients. Patients with onset after 12 months had less peripheral nerve involvement and slower disease progression. Abnormal cerebrospinal fluid protein levels were obtained for 13 of 16 symptomatic children. Protein levels were normal in all asymptomatic children. CONCLUSIONS: Based on our findings, we propose reclassifying the group of patients with onset ≤12 months as infantile and the > 12 month group as late-infantile. Patients with onset > 12 months are more likely to benefit from hematopoietic stem cell transplantation. The proposed change in classifications will allow physicians to improve their ability to recognize and diagnose patients and more precisely assess potential treatment effects after transplantation.

Developmental outcomes of cord blood transplantation for Krabbe disease: A 15-year study.

OBJECTIVE: To describe long-term outcomes of children with early-infantile Krabbe disease who underwent hematopoietic stem cell transplantation (HSCT) in the first 7 weeks of life. METHODS: In this prospective longitudinal study, evaluations performed at baseline and follow-up included brain imaging, neurodiagnostic tests, and neurobehavioral evaluations. RESULTS: Of the 18 patients in this study (11 girls, 7 boys; mean follow-up 9.5 years, range 4-15), 5 died (3 of peritransplant complications, 1 of a surgical complication unrelated to Krabbe disease, 1 of disease progression). One of the surviving patients has normal cognitive function and 10 continue to develop cognitive skills at a slightly slower rate than normal. All surviving patients continue to gain receptive language skills, with 7 falling within the normal range. Ten patients receive speech therapy, and 2 of these patients require augmentative communication devices. Gross motor development varies widely, but 3 patients can walk independently, and 7 walk with assistive devices. Spasticity ranges from mild to severe, and 12 patients wear orthotics. Fine motor skills are generally preserved. Brain myelination and atrophy stabilized in 8 patients, improved in 4 patients, and worsened in 1 patient. Nerve conduction velocities initially improved but continue to be abnormal in most patients. CONCLUSIONS: The surviving patients function at a much higher level than untreated children or symptomatic children who underwent HSCT. These results show that early HSCT changes the natural history of this disease by improving both lifespan and functional abilities. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for children with early-infantile Krabbe disease, early HSCT improves lifespan and functional abilities.

Early disease progression of Hurler syndrome.

BACKGROUND: Newborn screening for mucopolysaccharidosis type I (MPS I) shows promise to improve outcomes by facilitating early diagnosis and treatment. However, diagnostic tests for MPS I are of limited value in predicting whether a child will develop severe central nervous system disease associated with Hurler syndrome, or minimal or no central nervous system involvement associated with the attenuated phenotypes (Hurler-Scheie and Scheie syndromes). Given that the optimal treatment differs between Hurler syndrome and the attenuated MPS I phenotypes, the absence of a reliable prognostic biomarker complicates clinical decision making for infants diagnosed through newborn screening. Information about the natural history of Hurler syndrome may aid in the management of affected infants, contribute to treatment decisions, and facilitate evaluation of treatment effectiveness and prognosis. Thus, the aim of this study was to characterize the progression and timing of symptom onset in infants with Hurler syndrome. RESULTS: Clinical data from 55 patients evaluated at a single center were retrospectively reviewed. Information about each child's medical history was obtained following a standardized protocol including a thorough parent interview and the review of previous medical records. All patients underwent systematic physical and neurodevelopmental evaluations by a multidisciplinary team. Nearly all patients (98%) showed signs of disease during the first 6 months of life. Common early disease manifestations included failed newborn hearing screen, respiratory symptoms, difficulty latching, and otitis media. Other symptoms such as kyphosis, corneal clouding, cardiac disease, joint restrictions, and enlarged head circumference typically appeared slightly later (median age, 8-10 months). During the first 12 months, gross motor development was the most severely affected area of functioning, and a significant number of patients also experienced language delays. Cognition was typically preserved during this period. CONCLUSIONS: In this large cohort of patients with Hurler syndrome, the vast majority showed signs and symptoms of disease during the first months of life. More research is needed to determine the extent to which early clinical manifestations of MPS I can predict phenotype and treatment outcomes.

Clinical management of Krabbe disease.

Krabbe disease (KD) is a rare neurodegenerative disorder caused by mutations in the gene encoding the galactocerebrosidase enzyme. The early- and late-infantile subtypes, which are the most common forms of the disease, are rapidly progressive and lead to early death, whereas the later-onset types are clinically heterogeneous. The only disease-modifying treatment currently available is hematopoietic stem cell transplantation, which is effective only when performed early in the course of the disease. Because most patients with KD are diagnosed too late for treatment, primary care physicians are faced with the challenge of caring for a child with severe neurologic impairment. This Review describes presenting symptoms, diagnosis, and disease manifestations of KD and provides basic guidelines for its management. Symptomatic treatment and supportive care that address the unique requirements of these patients can greatly improve the quality of life of patients and their families. © 2016 Wiley Periodicals, Inc.

Thickening of the cauda equina roots: a common finding in Krabbe disease.

OBJECTIVES: Evaluation of Krabbe disease burden and eligibility for hematopoietic stem cell transplantation are often based on neuroimaging findings using the modified Loes scoring system, which encompasses central but not peripheral nervous system changes. We show that quantitative evaluation of thickened cauda equina nerve roots may improve the evaluation of Krabbe disease and therapeutic guidance. METHODS: Lumbar spine MRI scans of patients obtained between March 2013 and September 2013 were retrospectively evaluated and compared to those of controls. Quantitative evaluation of cauda equina roots was performed on the axial plane obtained approximately 5 mm below the conus medullaris. The largest nerves in the right and left anterior quadrants of the spinal canal were acquired. RESULTS: Fifteen symptomatic patients with Krabbe disease (5-44 months old) and eleven age-matched controls were evaluated. The average areas (mm(2)) of anterior right and left nerves were 1.40 and 1.23, respectively, for patients and 0.61 and 0.60 for controls (differences: 0.79 and 0.63; p < 0.001). CONCLUSIONS: Cauda equina nerve root thickening is associated with Krabbe disease in both treated and untreated patients. Adding lumbar spine MRI to the current neurodiagnostic protocols, which fails to account for peripheral nerve abnormalities, will likely facilitate the diagnosis of Krabbe disease. KEY POINTS: • Neuroimaging is valuable for evaluating cauda equina nerve abnormality in Krabbe disease • MRI can be used to quantitatively evaluate cauda equina nerve thickening • Lumbar MRI could be useful for diagnosis and treatment monitoring of Krabbe disease.

Long-term functional outcomes of children with hurler syndrome treated with unrelated umbilical cord blood transplantation.

OBJECTIVES: Hurler syndrome is characterized by progressive multisystem deterioration leading to early death in childhood. This prospective study evaluated the long-term outcomes of patients with Hurler syndrome who underwent umbilical cord blood transplantation from unrelated donors. STUDY DESIGN: Only patients with Hurler syndrome who underwent umbilical cord blood transplantation between December 1995 and March 2006 (n = 25) and who were followed for at least 5 years (n = 19) were included in the analysis. The patients were longitudinally evaluated by a multidisciplinary team of specialists following a standardized protocol. RESULTS: Median age at transplantation was 15.9 months (range 2.1-35), and patients were followed up until a median age of 10.1 years (range 7.2-14.9). Overall survival was 80%. All successfully transplanted patients achieved full donor chimerism and normal enzyme levels, and all children continue to make gains in development. Gross motor function was the most affected area. Vision and hearing were compromised in a minority of the patients, with some requiring corneal transplant or hearing aids. Cardiopulmonary function improved. Some children required orthopedic surgery, but severe complications were prevented in most patients. Although longitudinal growth was lower than that of unaffected children, it was considerably higher than expected from the natural course of the disease. Head circumference normalized. Hydrocephalus was not observed at longer follow-up, and cerebral atrophy decreased over time. CONCLUSIONS: In this descriptive study of children with Hurler syndrome, unrelated umbilical cord blood transplantation was associated with improved somatic disease and neurodevelopment.

Early treatment is associated with improved cognition in Hurler syndrome.

OBJECTIVE: Hurler syndrome is the most clinically severe form of an autosomal recessive lysosomal disorder characterized by the deficiency of α-L-iduronidase. The resulting accumulation of glycosaminoglycans causes progressive multisystem deterioration, resulting in death in childhood. Umbilical cord blood transplantation from unrelated donors has been previously shown to improve neurological outcomes of children <2 years of age and prolong life. The purpose of this article is to determine whether age at transplantation can predict cognitive outcomes. METHODS: Between June 1997 and February 2013, 31 patients with Hurler syndrome underwent umbilical cord blood transplantation and were evaluated at baseline and every 6 to 12 months thereafter. All 31 patients underwent complete neurodevelopmental evaluation (median follow-up = 7.3 years, range = 2-21.7) and a median of 7.0 evaluations (range = 3-18). RESULTS: Younger age at transplantation was associated with improved cognitive function (p = 0.001), receptive and expressive language (p = 0.004 and p = 0.01), and adaptive behavior (p = 0.03). INTERPRETATION: Early age at transplantation is a strong predictor of cognitive, language, and adaptive behavior outcomes. Children younger than 9 months at the time of transplant showed normal cognitive development. Our results demonstrate that early diagnosis is necessary for optimal outcomes and support the need for newborn screening, because most patients are not identified at this young age.

Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an inherited demyelinating disease that causes progressive neurologic deterioration, leading to severe motor disability, developmental regression, seizures, blindness, deafness, and death. The disease presents as a late-infantile, juvenile, or adult form. Hematopoietic stem cell transplantation has been shown to slow disease progression. The purpose of this longitudinal study was to evaluate long-term treatment outcomes after unrelated donor umbilical cord blood (UCB) transplantation in pediatric patients according to disease burden and age at onset (ie, late-infantile versus juvenile). Engraftment, survival, treatment-related toxicity, graft-versus-host disease, neurophysiologic measures, and neurodevelopmental function were assessed. To evaluate whether signal intensity abnormalities on magnetic resonance imaging (ie, modified Loes scores) predict post-transplant cognitive and gross motor development, a general linear mixed model was fit to the data. Twenty-seven patients underwent transplantation after myeloablative chemotherapy; 24 patients engrafted after the initial transplantation. Seven patients died of infection, regimen-related toxicity, or disease progression. Twenty patients (6 with late-infantile onset and 14 with juvenile onset) were followed for a median of 5.1 years (range, 2.4 to 14.7). We found that patients with motor function symptoms at the time of transplant did not improve after transplantation. Brainstem auditory evoked responses, visual evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilized or improved in juvenile patients but continued to worsen in most patients with the late-infantile presentation. Pretransplant modified Loes scores were highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who were asymptomatic at the time of transplantation benefited most from the procedure. Children with juvenile onset and minimal symptoms showed stabilization or deterioration of motor skills but maintained cognitive skills. Overall, children with juvenile onset had better outcomes than those with late-infantile onset. As in other leukodystrophies, early intervention correlated with optimal outcomes. We conclude that UCB transplantation benefits children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD.

Early brain overgrowth in autism associated with an increase in cortical surface area before age 2 years.

CONTEXT: Brain enlargement has been observed in 2-year-old children with autism, but the underlying mechanisms are unknown. OBJECTIVE: To investigate early growth trajectories in brain volume and cortical thickness. DESIGN: Longitudinal magnetic resonance imaging study. SETTING: Academic medical centers. PARTICIPANTS: Fifty-nine children with autism spectrum disorder (ASD) and 38 control children. INTERVENTION: Children were examined at approximately 2 years of age. Magnetic resonance imaging was repeated approximately 24 months later (when aged 4-5 years; 38 children with ASD; 21 controls). MAIN OUTCOME MEASURES: Cerebral gray and white matter volumes and cortical thickness. RESULTS: We observed generalized cerebral cortical enlargement in individuals with ASD at both 2 and 4 to 5 years of age. Rate of cerebral cortical growth across multiple brain regions and tissue compartments in children with ASD was parallel to that seen in the controls, indicating that there was no increase in rate of cerebral cortical growth during this interval. No cerebellar differences were observed in children with ASD. After controlling for total brain volume, a disproportionate enlargement in temporal lobe white matter was observed in the ASD group. We found no significant differences in cortical thickness but observed an increase in an estimate of surface area in the ASD group compared with controls for all cortical regions measured (temporal, frontal, and parieto-occipital lobes). CONCLUSIONS: Our longitudinal magnetic resonance imaging study found generalized cerebral cortical enlargement in children with ASD, with a disproportionate enlargement in temporal lobe white matter. There was no significant difference from controls in the rate of brain growth for this age interval, indicating that brain enlargement in ASD results from an increased rate of brain growth before age 2 years. The presence of increased cortical volume, but not cortical thickness, suggests that early brain enlargement may be associated with increased cortical surface area. Cortical surface area overgrowth in ASD may underlie brain enlargement and implicates a distinct set of pathogenic mechanisms.

Methods for assessing neurodevelopment in lysosomal storage diseases and related disorders: a multidisciplinary perspective.

UNLABELLED: Lysosomal storage diseases and related disorders (LSRDs) are a heterogeneous group of rare diseases caused by genetic mutations that result in deficiencies of specific lysosomal enzymes. Some of these enzymes are necessary for normal development of the central and peripheral nervous systems. Because of the heterogeneity in clinical presentation and complexity of these disorders, evaluation of disease progression poses unique challenges. In recent years, recombinant enzyme replacement therapy and haematopoietic stem cell transplantation have been developed to treat some of these diseases. With the development of specific therapies and screening programmes, there is a need to systematically follow the natural course and effects of treatment in these disorders with standardized and validated tools. This review describes the limitations of currently available neurobehavioural tools in longitudinally tracking disease outcomes in patients with neurodegenerative LSRDs. A multidisciplinary team reviewed over 750 evaluations in 274 patients. These patients were found to have neurological, sensory and somatic problems that considerably influence the results of neurobehavioural testing. CONCLUSION: Treatment effects in patients with neurodegenerative LSRDs are best evaluated by repeated measures and longitudinal analysis of each domain of function.

Gross motor development of children with hurler syndrome after umbilical cord blood transplantation.

BACKGROUND AND PURPOSE: Little is known about the gross motor development of children with Hurler syndrome who have undergone umbilical cord blood transplantation (UCBT). The purpose of this study was to provide a description of gross motor development in children with Hurler syndrome after UCBT. SUBJECTS AND METHOD: Longitudinal changes in gross motor abilities were documented on the gross motor subtests of the Peabody Developmental Motor Scales, second edition (PDMS-2) for 21 children with Hurler syndrome. Each child was assessed between 1 and 6 times after UCBT. The participants had a mean age (+/-SD) of 32.2+/-16.0 months at the time of the first assessment. The mean time (+/-SD) between UCBT and the first assessment was 16.2+/-16.5 months. RESULTS: The participants had marked gross motor delays, with a mean gross motor quotient 2 standard deviations below the mean for children who were developing typically. The rate of development differed between the subtests of the PDMS-2. The participants gained abilities at the slowest rate on the stationary subtest and at the fastest rate on the locomotor subtest. DISCUSSION AND CONCLUSION: The participants had varying degrees of delay in different gross motor domains. While gaining new gross motor abilities over time, these children continued to have delays up to 48 months after UCBT. Physical therapists treating children with Hurler syndrome after UCBT should use assessment tools that will capture these differences and should individualize treatment plans accordingly. Additional research is needed to document the efficacy of physical therapy intervention with this population.

Temporal and spatial gait characteristics of children with Hurler syndrome after umbilical cord blood transplantation.

BACKGROUND AND PURPOSE: Recent medical advances are increasing the life expectancy of children with Hurler syndrome; however, little is known about the motor abilities of children who have received these medical interventions. The purpose of this study was to describe the temporal and spatial gait parameters of children with Hurler syndrome following umbilical cord blood transplantation (UCBT) in reference to gait parameters of children with typical development. SUBJECTS: The group with Hurler syndrome consisted of 18 children between 19.6 and 96.8 months of age who were examined 1 to 4 times between 2.9 and 72.2 months after UCBT. Four hundred thirty-eight children with typical development between the ages of 14.4 and 131.8 months served as a comparison group. METHODS: Temporal and spatial gait parameters were assessed using a GAITRite electronic walkway. Step length, gait speed, and cadence were normalized for body stature. RESULTS: Children with Hurler syndrome had slower gait speeds and shorter step lengths than children with typical development at 2 and 3 years of age. Time since transplantation was a predictor of gait speed and step length. DISCUSSION AND CONCLUSION: Children with Hurler syndrome after UCBT were delayed in maturation of temporal and spatial gait parameters.

Outcomes of unrelated umbilical cord blood transplantation for X-linked adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a defect in the metabolism of long chain fatty acids leading to demyelination, neurodegeneration, and death. The disease typically presents in young boys and adolescent boys. Allogeneic bone marrow transplantation has been used to halt progression of the disease. However, many patients lack suitable HLA- matched related donors and must rely on unmatched donors for a source of stem cells. The purpose of this study was to evaluate outcomes of unrelated donor umbilical cord blood transplantation after chemotherapy-based myeloablative conditioning and retrospectively determine if baseline studies correlate and help predict outcome. Between November 22, 1996, and November 3, 2005, 12 boys with X-linked ALD who lacked HL- matched related donors were referred to Duke University Medical Center for transplantation. These children were conditioned with myeloablative therapy including busulfan, cyclophosphamide, and antithymocyte globulin before receiving umbilical cord-blood transplants from unrelated donors. Baseline studies of neurophysiologic, neuroimaging, and neurodevelopmental status were performed and patients were subsequently evaluated for survival, engraftment, graft-versus-host disease, and neurodevelopmental outcomes. A substudy evaluated whether baseline neuroimaging and neurophysiologic studies correlated with cognitive and motor function and if these studies were predictive of posttransplantation outcomes. The umbilical cord blood grafts had normal levels of very long chain fatty acids. They delivered a median of 6.98 x 10(7) nucleated cells per kilogram of recipient body weight and were discordant for up to 4 of 6 HLA markers. Neutrophil engraftment occurred at a median of 22.9 days after transplantation. Three patients had grade II-IV acute graft-versus-host disease; 2 had extensive chronic graft-versus-host disease. Cumulative incidence of overall survival of the group at 6 months is 66.7% (95% confidence interval 39.9-93.3%). Median follow-up was 3.3 years (range 12 days to 6.3 years). As previously reported with bone marrow transplantation, symptomatic patients faired poorly with lower survival and rapid deterioration of neurologic function. This study included 3 patients transplanted at a very young age (2.6-3.5 years) before the onset of clinical symptoms who continue to develop at a normal rate for 3-5 years posttransplant. Although baseline Loes scores correlated with cognitive and motor outcome, neurophysiologic studies failed to show statistically significant differences. Transplantation of boys with X-linked ALD using partial HLA-matched umbilical cord blood yields similar results to those previously reported after bone marrow transplantation. Superior outcomes were seen in neurologically asymptomatic boys less than 3.5 years of age at the time of transplantation. Baseline Loes scores were a strong predictor of cognitive and motor outcome.

Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease.

BACKGROUND: Infantile Krabbe's disease produces progressive neurologic deterioration and death in early childhood. We hypothesized that transplantation of umbilical-cord blood from unrelated donors before the development of symptoms would favorably alter the natural history of the disease among newborns in whom the disease was diagnosed because of a family history. We compared the outcomes among these newborns with the outcomes among infants who underwent transplantation after the development of symptoms and with the outcomes in an untreated cohort of affected children. METHODS: Eleven asymptomatic newborns (age range, 12 to 44 days) and 14 symptomatic infants (age range, 142 to 352 days) with infantile Krabbe's disease underwent transplantation of umbilical-cord blood from unrelated donors after myeloablative chemotherapy. Engraftment, survival, and neurodevelopmental function were evaluated longitudinally for four months to six years. RESULTS: The rates of donor-cell engraftment and survival were 100 percent and 100 percent, respectively, among the asymptomatic newborns (median follow-up, 3.0 years) and 100 percent and 43 percent, respectively, among the symptomatic infants (median follow-up, 3.4 years). Surviving patients showed durable engraftment of donor-derived hematopoietic cells with restoration of normal blood galactocerebrosidase levels. Infants who underwent transplantation before the development of symptoms showed progressive central myelination and continued gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills, but a few had mild-to-moderate delays in expressive language and mild-to-severe delays in gross motor function. Children who underwent transplantation after the onset of symptoms had minimal neurologic improvement. CONCLUSIONS: Transplantation of umbilical-cord blood from unrelated donors in newborns with infantile Krabbe's disease favorably altered the natural history of the disease. Transplantation in babies after symptoms had developed did not result in substantive neurologic improvement.