Browsing by Author "Escolar, Maria L"
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Item Open Access Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.(Genetics in medicine : official journal of the American College of Medical Genetics, 2016-12) Wasserstein, Melissa P; Andriola, Mary; Arnold, Georgianne; Aron, Alan; Duffner, Patricia; Erbe, Richard W; Escolar, Maria L; Estrella, Lissette; Galvin-Parton, Patricia; Iglesias, Alejandro; Kay, Denise M; Kronn, David F; Kurtzberg, Joanne; Kwon, Jennifer M; Langan, Thomas J; Levy, Paul A; Naidich, Thomas P; Orsini, Joseph J; Pellegrino, Joan E; Provenzale, James M; Wenger, David A; Caggana, MicheleBackground
Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006.Methods
Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT.Results
Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease.Conclusions
These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.Item Open Access Consensus recommendations for the classification and long-term follow up of infants who screen positive for Krabbe Disease.(Molecular genetics and metabolism, 2021-09) Thompson-Stone, Robert; Ream, Margie A; Gelb, Michael; Matern, Dietrich; Orsini, Joseph J; Levy, Paul A; Rubin, Jennifer P; Wenger, David A; Burton, Barbara K; Escolar, Maria L; Kurtzberg, JoanneObjective
To provide updated evidence and consensus-based recommendations for the classification of individuals who screen positive for Krabbe Disease (KD) and recommendations for long-term follow-up for those who are at risk for late onset Krabbe Disease (LOKD).Methods
KD experts (KD NBS Council) met between July 2017 and June 2020 to develop consensus-based classification and follow-up recommendations. The resulting newly proposed recommendations were assessed in a historical cohort of 47 newborns from New York State who were originally classified at moderate or high risk for LOKD.Results
Infants identified by newborn screening with possible KD should enter one of three clinical follow-up pathways (Early infantile KD, at-risk for LOKD, or unaffected), based on galactocerebrosidase (GALC) activity, psychosine concentration, and GALC genotype. Patients considered at-risk for LOKD based on low GALC activity and an intermediate psychosine concentration are further split into a high-risk or low-risk follow-up pathway based on genotype. Review of the historical New York State cohort found that the updated follow-up recommendations would reduce follow up testing by 88%.Conclusion
The KD NBS Council has presented updated consensus recommendations for efficient and effective classification and follow-up of NBS positive patients with a focus on long-term follow-up of those at-risk for LOKD.Item Open Access Lymphocyte Galactocerebrosidase Activity by LC-MS/MS for Post-Newborn Screening Evaluation of Krabbe Disease.(Clinical chemistry, 2017-08) Liao, Hsuan-Chieh; Spacil, Zdenek; Ghomashchi, Farideh; Escolar, Maria L; Kurtzberg, Joanne; Orsini, Joseph J; Turecek, Frantisek; Scott, C Ronald; Gelb, Michael HBackground
Deficiency of the lysosomal enzyme galactosylcerebrosidase (GALC) causes Krabbe disease. Newborn screening for Krabbe disease is ongoing, but improved methods for follow-up analysis of screen-positive babies are needed to better advise families and to optimize treatment. We report a new assay for the enzymatic activity of GALC in lymphocytes.Methods
T lymphocytes were isolated from venous blood by magnetic bead technology. The assay used a close structural analog of the natural substrate and LC-MS/MS to quantify the amount of product with the aid of a chemically identical internal standard.Results
The analytical range of the assay (ratio of assay response for the QC high standard to that from all non-enzymatic-dependent processes) was 20-fold greater than that for the conventional radiometric GALC assay. The LC-MS/MS could distinguish cells that were null in GALC from those that contained traces of active enzyme (down to 0.3% of normal). There was a good correlation between the level of residual GALC activity in lymphocytes and the severity of Krabbe disease.Conclusions
The new assay can measure small amounts of residual GALC activity in leukocytes with high accuracy compared to previous assays and can contribute, along with genotyping, biomarker analysis, and neurological imaging, a better plan for post-newborn screening follow-up for Krabbe disease.Item Open Access Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2013-04) Martin, Holly R; Poe, Michele D; Provenzale, James M; Kurtzberg, Joanne; Mendizabal, Adam; Escolar, Maria LMetachromatic 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.Item Open Access Newborn screening for Krabbe disease in New York State: the first eight years' experience.(Genetics in medicine : official journal of the American College of Medical Genetics, 2016-03) Orsini, Joseph J; Kay, Denise M; Saavedra-Matiz, Carlos A; Wenger, David A; Duffner, Patricia K; Erbe, Richard W; Biski, Chad; Martin, Monica; Krein, Lea M; Nichols, Matthew; Kurtzberg, Joanne; Escolar, Maria L; Adams, Darius J; Arnold, Georgianne L; Iglesias, Alejandro; Galvin-Parton, Patricia; Kronn, David F; Kwon, Jennifer M; Levy, Paul A; Pellegrino, Joan E; Shur, Natasha; Wasserstein, Melissa P; Caggana, Michele; New York State Krabbe Disease ConsortiumPurpose
Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006.Methods
Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination.Results
Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease.Conclusions
The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms.Item Open Access The critical role of psychosine in screening, diagnosis, and monitoring of Krabbe disease.(Genetics in medicine : official journal of the American College of Medical Genetics, 2020-06) Guenzel, Adam J; Turgeon, Coleman T; Nickander, Kim K; White, Amy L; Peck, Dawn S; Pino, Gisele B; Studinski, April L; Prasad, Vinod K; Kurtzberg, Joanne; Escolar, Maria L; Lasio, Maria Laura Duque; Pellegrino, Joan E; Sakonju, Ai; Hickey, Rachel E; Shallow, Natalie M; Ream, Margie A; Orsini, Joseph J; Gelb, Michael H; Raymond, Kimiyo; Gavrilov, Dimitar K; Oglesbee, Devin; Rinaldo, Piero; Tortorelli, Silvia; Matern, DietrichPurpose
Newborn screening (NBS) for Krabbe disease (KD) is performed by measurement of galactocerebrosidase (GALC) activity as the primary test. This revealed that GALC activity has poor specificity for KD. Psychosine (PSY) was proposed as a disease marker useful to reduce the false positive rate for NBS and for disease monitoring. We report a highly sensitive PSY assay that allows identification of KD patients with minimal PSY elevations.Methods
PSY was extracted from dried blood spots or erythrocytes with methanol containing d5-PSY as internal standard, and measured by liquid chromatography-tandem mass spectrometry.Results
Analysis of PSY in samples from controls (N = 209), GALC pseudodeficiency carriers (N = 55), GALC pathogenic variant carriers (N = 27), patients with infantile KD (N = 26), and patients with late-onset KD (N = 11) allowed for the development of an effective laboratory screening and diagnostic algorithm. Additional longitudinal measurements were used to track therapeutic efficacy of hematopoietic stem cell transplantion (HSCT).Conclusion
This study supports PSY quantitation as a critical component of NBS for KD. It helps to differentiate infantile from later onset KD variants, as well as from GALC variant and pseudodeficiency carriers. Additionally, this study provides further data that PSY measurement can be useful to monitor KD progression before and after treatment.