Published online August 21, 2006
PEDIATRICS
Vol. 118
No. 3
September 2006, pp.
e879-e889
(doi:10.1542/peds.2006-0747)
A Staging System for Infantile Krabbe Disease to Predict Outcome After Unrelated Umbilical Cord Blood Transplantation
Maria L. Escolar, MDa,
Michele D. Poe, PhDb,
Holly R. Martin, MDa and
Joanne Kurtzberg, MDc
a Program for Neurodevelopmental Function in Rare Disorders, Clinical Center for the Study of Development and Learning
b Frank Porter Graham Child Development Institute, University of North Carolina at Chapel Hill, North Carolina
c Division of Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, North Carolina
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ABSTRACT
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OBJECTIVE. Infantile Krabbe disease, a rare neurodegenerative disorder that leads to rapid demyelination, dysmyelination, and death in the first 2 years of life, is responsive to treatment with umbilical cord blood transplantation provided that the patient is treated in the first weeks of life. At present, family history is the only way to identify patients that are asymptomatic with most patients being diagnosed after onset of symptoms. We hypothesized that a staging system based on clinical indicators and neurophysiological and neuroimaging measures can predict posttreatment variation in patients diagnosed with infantile Krabbe disease.
METHODS. A retrospective review of pretransplant clinical indicators and neurodevelopmental, brain imaging and neurophysiological measures was performed in 42 patients being considered for treatment with umbilical cord blood transplantation. Based on these evaluations, an expert system approach was used to develop a staging system for infantile Krabbe disease. Another set of analyses in the subset of patients who were transplanted (n = 29) evaluated the association between pretransplant stage of disease and posttransplant neurodevelopmental outcomes.
RESULTS. A staging algorithm for infants with infantile Krabbe disease was developed and tested for predicting neurodevelopmental outcome after umbilical cord blood transplantation. Standard neurophysiological and neuroimaging tests were not useful in the staging algorithm. Clinical indicators were found to best classify stage of disease. Pretransplant stage was found to be predictive of neurodevelopmental outcome.
CONCLUSIONS. We conclude that the clinical staging system based solely on signs and symptoms of disease can be used to predict outcomes after umbilical cord blood transplantation. This staging system can be used prospectively to guide physicians unfamiliar with the disorder in evaluating, monitoring, and counseling families about treatment outcomes. The staging will be useful for both patients diagnosed with infantile Krabbe disease because of clinical symptoms and those identified through neonatal screening programs.
Key Words: neurodevelopmental • classification • lysosomal storage disease • outcome analysis • neurologic disease
Abbreviations: UCBT—umbilical cord blood transplantation • CSF—cerebrospinal fluid • NCV—nerve conduction velocity • BAERS—brainstem auditory evoked responses • VEP—visual evoked potential • EEG—electroencephalogram
Infantile Krabbe disease, or globoid cell leukodystrophy, is an autosomal recessive neurodegenerative disorder that, left untreated, leads to demyelization and death in early childhood. The disorder is because of a lack of the lysosomal enzyme galactocerebrosidase, which aids in the breakdown and removal of galactolipids found in myelin. The accumulation of galactolipids results in inflammation, dysmyelination, and demyelination of the central and peripheral nervous systems. More than 75 genetic mutations have been found that decrease the production of galactocerebrosidase.1 The phenotypic expressions of these mutations vary widely with disease presentation in an infantile, juvenile, and adult form. The infantile presentation is the most frequent with an incidence of 1 in 70000 to 100000.2
Two broad classifications of infantile Krabbe disease have been defined relating to time at which first symptoms appear. In the early-infantile form, symptoms appear before 6 months of age and include irritability, dysphagia, progressive spasticity, mental deterioration, blindness, deafness, seizures, and death usually before 2 years of age. In the late-infantile form, symptoms appear between 6 months and 4 years of age.2 Although these classifications help categorize the disease onset, they do not reflect the degree of disease progression at the time of diagnosis and transplantation, the key factor in determining outcome. Previous studies demonstrate that minimally symptomatic juvenile and adult patients stabilize and improve after treatment.3 A recent study using umbilical cord blood transplantation (UCBT) to treat infantile Krabbe disease demonstrated that the level of disease progression at the time of transplantation is highly predictive of developmental outcomes.4 However, in this study, outcomes were examined as related to 2 broad categories (symptomatic and asymptomatic), where asymptomatic was defined as any child detected by prenatal or neonatal testing and transplanted before 2 months of age. Symptomatic children were those whose disease was diagnosed later in the first year of life after significant symptoms appeared. Among the symptomatic children there was no variation in developmental outcomes, but in those children transplanted in the first weeks of life, there was great variation in gross motor outcomes with some children fully ambulatory and others unable to walk. We questioned whether this variation was related to subtle neurologic differences, which could be captured by a clinical staging system, and whether radiologic and neurophysiological measures routinely performed during the pretransplant evaluation would help predict posttreatment variation in both early- and late-infantile patients.
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METHODS
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Medical charts of 42 children with infantile Krabbe Disease were reviewed. These children were referred by the Division of Pediatric Blood and Marrow Transplantation at Duke University Medical Center for baseline evaluation before possible treatment with UCBT. All of the infants were evaluated by the same neurodevelopmental pediatrician (M.L.E.) between December 1998 and March 2006. The evaluations were done at the Program for Neurodevelopmental Function in Rare Disorders, Center for the Study of Development and Learning, University of North Carolina at Chapel Hill or Duke University. The study was approved by the internal review board at both the University of North Carolina and Duke University Medical Center. Written informed consent was obtained from the parents of the children who served as subjects of the investigation and who underwent transplantation therapy.
A retrospective review was conducted and included results of routinely performed neurophysiological, neuroimaging, cerebrospinal fluid (CSF) protein, and standardized, validated neurobehavioral and motor tools.5–12 Initial CSF protein, enzyme level, brain MRI, nerve conduction velocities (NCVs), brainstem auditory evoked responses (BAERS), visual evoked potential (VEPs), and electroencephalograms (EEGs) were performed within a week of the baseline neurodevelopmental examination.
Neurodevelopmental Assessments
Results of neurobehavioral testing were compared with norms of typically developing children. Age equivalents were used to allow for comparison across tests and to allow evaluation of the development of new skills. Gross motor, cognitive, receptive and expressive language, adaptive behavior, and fine motor skills were assessed.
Neurophysiologic Studies
EEGs, NCVs, VEPs, and BAERS were interpreted according to the guidelines established by the American Electroencephalographic Society.13 EEGs were considered abnormal if focal or generalized slowing, spikes, or sharp waves were present. The flash VEP was considered normal if the P100 wave was present and abnormal if it was absent. The brainstem auditory evoked responses were considered abnormal if either the wave I to V interpeak latency was prolonged or if any of the obligate wave forms (I, III, or V) were absent. Nerve conduction studies were considered abnormal if they showed prolongation of the distal latency, low amplitude, absent evoked response, or prolonged F-wave latency.
MRI
A board-certified neuroradiologist who was blinded to the clinical status of patients reviewed all of the MRI scans of the brain. Myelination was determined to be normal or abnormal by examining the hyperintense signal intensity on T1-weighted images and hypointense signal intensity on T2-weighted images in age-appropriate regions on axial images. These included the posterior limb of the internal capsule, genu and splenium of the corpus callosum, corona radiata, centrum semiovale, and subcortical white matter.
A retrospective analysis of the data collected at initial evaluation was used to create the staging system. Patients were classified as early infantile if they became symptomatic before 6 months of age and late infantile if they were symptomatic after 6 months but before 4 years. The patients transplanted as newborns because of family history were classified according to the age at which their family member developed the onset of symptoms. First, a series of rules that replicated the decision of the expert informant was developed using a decision tree.14,15 Second, information was gathered about each child in 13 domains: 6 developmental outcomes, enzyme levels, CSF protein, brain MRI, NCV, BAER, VEP, and EEG.
As part of the posttransplant protocol, patients were scheduled for follow-up tests that included neuroimaging, neurophysiological, and neurobehavioral tests. These were performed every 3 months for the first year, every 6 months for the second year, and once a year thereafter. The results of these tests were reported previously.4 The neurobehavioral data were used to evaluate outcomes as correlated with stage of disease.
Statistical Analysis
Among those patients who were transplanted, a follow-up analysis examined the relationship between stage of disease at time of transplant and longitudinal outcomes. Survival was assessed using a Cox regression model with stage and onset as predictors. The correlation between stage of disease and enzyme level at the patient's last visit was tested controlling for onset. Six developmental outcomes were evaluated: cognitive, fine motor, gross motor, adaptive, receptive, and expressive language. Because there was only 1 child in stage 4 who was transplanted and had limited follow-up data, this child was not included in these analyses. Mixed-regression models were used to estimate a mean developmental trajectory for each outcome. The dependent variable for each developmental domain was an age-equivalent score and the independent predictors included age (months), stage (1, 2, or 3), onset (early infantile or late infantile), and all interactions among age, stage, and onset. This framework tested for differences in developmental trajectories across both stage and onset. Linear correlations were calculated between stage of disease and baseline neurophysiologic and neuroimaging measures to test for trends in baseline symptoms across stages.
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RESULTS
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Staging Classification and Algorithm
A 4-level staging classification was developed as a frame before determining a more detailed staging algorithm (Table 1). Sixteen clinical indicators were selected by the expert clinician as good indicators of disease progression (Table 2). Because the staging system was developed to be used by clinicians who are not familiar with infantile Krabbe disease, a pediatrician who had not examined an infant with Krabbe disease and was blinded to the clinical status of the patient reviewed the charts (H.M.). Medical observations made by the expert clinician at the initial evaluation were reviewed, and the presence or absence of the 16 clinical indicators was recorded.
The results of CSF protein, brain MRI, NCV, BAERS, VEP, and EEG were coded as normal or abnormal. The coded information was placed into a database and examined for patterns that were common among patients in the same clinical stage. General rules were developed that duplicated the classification. The expert reviewed any discrepancies, and the rules were adjusted. This process continued until all of the children were correctly classified (Table 3). The algorithm for staging infantile Krabbe disease was developed and summarized (Table 4).
Combinations of the neurophysiological measures, neuroimaging, and clinical signs and symptoms were evaluated to assess whether this would aid in determining stage of disease. Although more abnormalities in the neurophysiological and neuroimaging measures were observed with advancing stage of disease (Table 5), the lack of established normative values, standardization, subjective interpretation, and inability to score these measures more precisely resulted in limited usefulness of these tests in determining stage of disease.
Patients Characteristics
Of the 42 patients with infantile Krabbe disease assessed for possible treatment with hematopoietic stem cell transplantation, 37 patients had adequate data. Thirty-five patients were white, 2 were Hispanic, 1 was black, and 1 was unknown. Of the 37 patients, 18 were girls and 19 were boys. Twenty nine were treated, 26 with UCBT (16 boys and 10 girls) and 3 with matched related donor bone marrow transplant (1 boy and 2 girls) from a sibling. Age at initial evaluation ranged from 1 week to 40 months of age. Twenty-six patients had early-infantile presentation and 11 patients had late-infantile presentation (Table 6).
Clinical Measures
Clinical signs and symptoms were accurate indicators of disease progression (Table 5). As a group, children in stage 1 showed very few neurologic signs, such as intermittent thumb clasp, slow feeding, and hypotonia of the shoulder girdle and gastroesophageal reflux. Children in stage 2 showed evidence of the previous symptoms and more evident abnormalities, such as fixed thumb clasp, mild-to-moderate changes in muscle tone, and more severe feeding difficulties. Children in stage 3 showed evidence of spastic extremities, severe trunk hypotonia or hypertonia, seizures, abnormal reflexes, exaggerated startle response, visual tracking difficulties, or abnormalities in pupillary response. In stage 4, infants progressed to being blind, deaf, and developed severe weakness with limited responsiveness and loss of most primitive reflexes.
CSF Protein
CSF protein levels did not show a specific pattern across the stages of disease. Although stage 4 subjects did have the highest CSF protein levels (mean: 260), subjects in stage 1 had the second highest (mean: 239; r = –0.04; P = .84; Fig 1). Of the 12 patients in stage 1, CSF protein was available for 10 patients. Of these 10 patients, 9 were newborn samples, and 6 with early-infantile presentation had elevated CSF protein. Of the remaining 3 patients, 1 with early-infantile presentation and 2 with late-infantile presentation had normal levels of CSF protein. One late-infantile patient in stage 2 had normal CSF protein. This patient had an unusual presentation with better motor skills than cognitive development. His symptoms may have reflected a comorbid condition.
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FIGURE 1 Pretransplant CSF protein measurements in the 27 subjects used to create the staging system. There was no association between clinical staging and pretransplant CSF protein levels. Early- and late-infantile onset are represented by diamonds and circles, respectively. Normal cerebrospinal fluid levels range from 70 to 120 mg/dL for newborns and from 5 to 40 mg/dL for infants.
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Enzyme Levels
Undetectable enzyme confirmed the diagnosis in all of the patients, therefore, this measure was not useful for staging.
MRI
The MRI showed abnormalities early in the disease progression with 75% of patients in stage 1 and 100% patients in stages 2, 3, and 4 showing abnormalities on their pretransplant MRI (r = 0.38; P = .020). These included abnormal hyperintense signal on T2-weighted images in the posterior limb of the internal capsule; within the white matter adjacent to the lateral ventricles; and in the centrum semiovale, corona radiata, and white matter and dentate nuclei of the cerebellum.
BAER
BAER failed to correlate with staging but became progressively more abnormal (r = 0.47; P = .007). Among those patients in stage 1, 63% were abnormal, in stage 2, 75% were abnormal, and in stages 3 and 4, 100% had abnormal baseline results.
EEG
EEGs became progressively more abnormal with increasing stage of disease (r = 0.49; P = .003). Thirty-three percent of children in stage 1 and 25% of children in stage 2 had abnormal EEGs at the initial pretransplant visit. The percentage of abnormal increased to 73% for children in stage 3 and 100% of children in stage 4.
VEP
VEP also showed no correlation with stage of disease (r = 0.12; P = .52). Children in the 4 stages had both normal and abnormal VEPs, with abnormalities present in 43% of patients in stage 1, 25% in stage 2, 46% in stage 3, and 60% in stage 4.
NCV
NCV was found to be abnormal early in the disease process and was not correlated with stage of disease (r = 0.28; P = .12), with 75% abnormalities in stage 1 subjects, 75% in stage 2 subjects, 93% in stage 3 subjects, and 100% in stage 4 subjects.
Clinical Outcomes of Untreated Patients
Eight patients in stage 4 at the time of evaluation did not undergo transplantation. All of these patients deteriorated, lost complete motor function, developed vision impairment and seizures, became spastic, and died. Hearing was not formally assessed.
Correlation of Outcomes With Stage of Disease at the Time of Transplantation
Mortality After Transplantation
Twenty-nine patients underwent transplantation therapy, 26 with unrelated donor cord blood and 3 with matched related sibling bone marrow. All of the children were prepared for transplant with high-dose chemotherapy, busulfan, cyclophosphamide, and antithymocyte globulin. The survival rate was 100% for both the stage 1 and 2 subjects. However, stage 3 subjects had a lower survival rate of 61.5% (P = .032). The mean survival time after transplant for the 5 subjects who died after receiving transplant was 21.4 months (range: 7.5–50 months). Only 1 child in stage 4 was transplanted and died a few weeks after transplant.
Enzyme Levels
Enzyme levels after transplant were not associated with disease stage (r = –0.26; P = .19; Fig 2).
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FIGURE 2 Staging of disease was not predictive of posttransplant enzyme levels. Interestingly, some children in stages 3 and 4 never achieved normal levels (1–7 nmol/hour/mL).
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Clinical Outcomes
Vision and Hearing
Although the majority of patients in stages 1 and 2 had normal vision, some required corrective glasses. All of the patients in stages 3 and 4 had moderate-to-severe vision impairment. Patients in all of the stages had normal peripheral hearing but abnormal BAERS at last follow-up. Despite these abnormalities, all of the patients in stages 1 and 2 who were >6 months of age and able to respond to behavioral audiometry showed normal peripheral hearing in at least the better ear.
Growth
Eighty percent of patients in stages 1 and 2 had failure to thrive, and 33% required gastrostomy tube placement to supplement oral feeds. All of the patients in stages 3 and 4 required gastrostomy tubes because of dehydration or choking while eating and drinking. These resulted in better weight gain.
Developmental Outcomes
For the correlation between stage of disease at the time of transplant and the subsequent longitudinal development in 6 domains (cognitive, receptive and expressive language, fine motor, gross motor, and adaptive behavior), data were available in 22 of the 29 patients. The remaining patients died or did not return for follow-up (Fig 3 A–F). Patients in stage 1 had mean slopes >0.5 for all of the domains except for gross motor development. Patients in stage 2 had cognitive and fine motor mean slopes that were close to a mean slope of 0.5. Patients in stage 3 showed no gains or a loss of skills across all of the domains. Patients in stages 1 and 2 showed no statistically significant difference in cognitive, adaptive, and gross motor development; however, both showed significantly better development than children in stage 3. For receptive language and fine motor development, the slopes for all 3 of the stages were significantly different. For expressive language, stages 2 and 3 were not found to differ significantly, but both showed smaller gains in development compared with stage 1 children (Table 7).
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FIGURE 3 A–F, Each patient's development is represented by a unique line. The gray area represents the approximate normal 95% range in the general population, and the dark gray diagonal line in the middle represents typical population development. Each color represents a different stage of disease at the time of transplant: Stage 1: red, stage 2: blue, stage 3: black. Children <3 years were assessed with the Bayley Scales of Infant Development, the Mullen Scales of Early Learning, and the Clinical Adaptive Test/Clinical Linguistic Auditory Milestone Scale. Children from 3 to 5 years were assessed with the Mullen Scales of Early Learning. Children >5 years were assessed with the Differential Ability Scales. Gross motor development was assessed using the Peabody Developmental Motor Scale, and adaptive behavior was assessed with the Scales of Independent Behavior Revised. A, cognitive development early-infantile onset; B, cognitive development late-infantile onset; C, adaptive development early-infantile onset; D, adaptive development late-infantile onset; E, receptive language development early-infantile onset; F, receptive language development late-infantile onset; G, expressive language development early-infantile onset; H, expressive language development late-infantile onset; I, gross motor development early-infantile onset; J, gross motor development late-infantile onset; K, fine motor development early-infantile onset; L, fine motor development late-infantile onset.
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Stage 1
Eleven children were in stage 1 at the time of transplant. As a group, they continued to show adequate rate of development in all of the domains except for gross motor development. Nine of the children have shown cognitive development within the average range. Receptive language development was available for 9 of the 11 children, and, as of the last evaluation, all 9 were within the average range. The greatest variation was in gross motor development. Although these children seem to gain skills normally for a period of time after transplant, most show evidence of an eventual plateau in motor development.
Stage 2
The child with late-infantile onset (n = 1) has continued to show evidence of developmental gains in all of the domains but gross motor, where skills are starting to plateau. The children with early-infantile onset (n = 2) showed slower gains in most domains except gross motor skills. One child with early-infantile form in stage 2 had similar overall development to those in stage 1 except in the gross motor area where his outcome was worse than the infants in stage 1 but better than those in stage 3.
Stage 3
Posttransplant developmental data were available for 10 subjects. Children with early-infantile onset (n = 6) showed no developmental gains in any of the 6 domains over time. Children with late-infantile onset (n = 4) maintained some level of development in language, cognition, and adaptive functioning, but their gross motor skills deteriorated.
Stage 4
No posttransplant data were available for the patient in stage 4, because the patient was unable to complete any tasks and died shortly after transplant.
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DISCUSSION
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We have developed a staging system for infantile Krabbe disease based on detailed clinical evaluation that is predictive of neurodevelopmental outcome after allogeneic transplantation. In a retrospective analysis, patients in stages 1 and 2 had 100% survival, whereas patients in stages 3 and 4 had significantly higher mortality rate or severe disability. Therefore, only patients in stages 1 and 2 should be considered for transplantation. As described previously, patients in stage 1 continued to gain skills in all of the areas, a range of variation in gross motor outcome with plateau of skills after initial normal gains was observed.4 Additional research will be needed to identify pretransplant predictors of this variation, as well as the cause for continued gross motor dysfunction.
Although early-infantile patients in stage 2 had gains in nonmotor-related function, patients in stages 3 and 4 had no developmental gains. Late-infantile patients in stage 2 continued to gain skills in all of the areas but plateau in gross motor. Late-infantile patients in stage 3 showed very minimal gains in most developmental areas and had no gains in motor function.
Clinical interpretations of brain MRI, NCV, EEG, VEP, BAER studies, and CSF protein levels at initial evaluation failed to correlate with disease stage. Although abnormalities in these measures were found in some infants in stage 1, they were not correlated with overall neurodevelopmental outcome. However, clinical signs and symptoms alone were sufficient in staging the disease, and these stages were highly predictive of neurodevelopmental outcomes after transplantation.
Detailed analyses of neurophysiological and brain imaging studies were not conducted because of lack of adequate standardization of these tools in infants and unknown correlation between abnormal findings and developmental function. Although additional analysis of these tests may help monitor disease progression, they require additional scoring and interpretation that is not available to most clinicians when counseling families regarding treatment. Finally, whereas the presence of abnormalities in these studies at the time of diagnosis was not associated with staging or functional outcomes after transplantation, the lack of abnormalities in CSF protein, MRI, NCV, and BAER probably represent a later disease onset and better prognosis after transplantation. Future studies using detailed analysis of abnormal findings will be needed to evaluate the use of brain imaging, CSF protein, and neurophysiological measures in assessing treatment efficacy and predicting outcome.
The staging system is a predictive tool that can be used by clinicians unfamiliar with the disease process to counsel parents at the time of their child's diagnosis regarding developmental outcomes after transplantation therapy. With the future inclusion of Krabbe disease in newborn screening programs, infants will be identified early, and decisions regarding treatment will be time sensitive. For example, in these series, 2 infants identified at birth and evaluated within the first 2 weeks of life were already in stage 2 and went on to develop significant motor compromise after transplant. The use of this tool would have facilitated more accurate education and counseling of parents who needed to make an urgent decision about whether or not to proceed with transplantation therapy. In conclusion, the staging system will provide the clinician with an objective tool at the time of diagnosis to counsel families about treatment, monitor disease in untreated patients, and evaluate effects of future therapies.
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ACKNOWLEDGMENTS
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This work was supported by the Hunter's Hope Foundation (grant to Dr Escolar).
We thank the patients, their families, and their siblings. This report would not be possible without the dedication and hard work of the medical, nursing, and allied health care workers involved in the care of these patients. We thank the staff of the Pediatric Blood and Marrow Transplant Program at Duke University and the multidisciplinary team of developmental specialists at the Center for Development and Learning and the Neurodevelopmental Research Center at the University of North Carolina.
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FOOTNOTES
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Accepted Mar 4, 2006.
Address correspondence to Maria L. Escolar, MD, Campus Box 7255, University of North Carolina, Chapel Hill, NC 27599-7255. E-mail: maria.escolar{at}cdl.unc.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES
|
|---|
- Wenger DA, Rafi MA, Luzi P, et al. Krabbe disease: genetic aspects and progress toward therapy.
Mol Genet Metab. 2000;70
:1
–9[CrossRef][ISI][Medline]
- Wenger D, Suzuki K, Yoshiuyki S, et al. Galactosylceramide lipidosis: gloiboid cell leukodystrophy (Krabbe disease). In: Scriver CR, Sly WS, Childs B, Beaudet AL, Valle D, Kinzler KW, Vogelstein B, eds.
The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:3669–3694
- Krivit W, Shapiro EG, Peters C, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy.
N Engl J Med. 1998;338
:1119
–1126[Abstract/Free Full Text]
- Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease.
N Engl J Med. 2005;352
:2069
–2081[Abstract/Free Full Text]
- Mullen E.
The Mullen Scales of Early Learning. AGS ed. Circle Pines, MN: American Guidance Service; 1995
- Hoon AH, Jr, Pulsifer MB, Gopalan R, et al. Clinical Adaptive Test/Clinical Linguistic Auditory Milestone Scale in early cognitive assessment.
J Pediatr. 1993;123
:S1
–S8[CrossRef][ISI][Medline]
- Bayley N.
Bayley Scales of Infant Development. 2nd ed. San Antonio, TX: Psychological Corporation; 1993
- Elliott CD.
Differential Abilities Scales: Administration and Scoring Manual. Orlando, FL: Psychological Corporation; 1990
- Folio MR, Fewell RR.
Peabody Developmental Motor Scales. 2nd ed, Examiner's Manual. Austin, TX: PRO-ED; 2000
- Rossetti LM.
The Rossetti Infant-Toddler Language Scale: A Measure of Communication and Interaction. East Moline, IL: LinguiSystems Inc; 1990
- Zimmerman IL, Steiner VG, Pond RE.
Preschool Language Scale. 3rd ed. San Antonio, TX: Psychological Corporation; 1992
- Bruininks RH, Woodcock RW, Weatherman RF, Hill BK.
Scales of Independent Behavior Revised. Itasca, IL: Riverside Publishing; 1996
- American Electroencephalographic Society. Guideline 9: guidelines on evoked potentials.
J Clin Neurophysiol. 1994;11
:40
–73[Medline]
- Leondes CT, ed.
Expert Systems: The Technology of Knowledge Management for the 21st Century. San Diego, CA: Academic Press; 2001
- Kidd AL, ed.
Knowledge Acquisition for Expert Systems: A Practical Handbook. New York, NY: Plenum Press; 1987
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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ABSTRACT
METHODS
