Browsing by Author "Ream, Margie A"

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    ItemOpen Access
    Benefits of Newborn Screening and Hematopoietic Cell Transplant in Infantile Krabbe Disease.
    (Blood advances, 2022-01-18) Page, Kristin M; Ream, Margie A; Rangarajan, Hemalatha G; Galindo, Rafael; Mian, Ali Y; Ho, Mai-Lan; Provenzale, James; Gustafson, Kathryn E; Rubin, Jennifer; Shenoy, Shalini; Kurtzberg, Joanne
    Infantile Krabbe Disease (IKD) can be treated with hematopoietic cell transplantation (HCT) if done during the first weeks of life before symptoms develop. To facilitate this, newborn screening (NBS) has been instituted in eight U.S. states. An application to add KD to the Recommended NBS Panel (RUSP) is currently under review. In this report, the outcomes of newborns with IKD diagnosed through NBS and treated with HCT are presented. The unique challenges associated with NBS for this disease are discussed including opportunities for earlier diagnosis and streamlining treatment referrals. This is a retrospective review of infants with IKD detected by NBS and referred for HCT. The timing from diagnosis to HCT were examined and both HCT and neurodevelopmental outcomes are described. Six infants were diagnosed and referred for HCT. Neurologic testing before HCT revealed evidence of active IKD in all infants. All underwent HCT between 24-40 days of age, successfully engrafted, and are alive 30-58 months later (median, 47.5 months). All are gaining developmental milestones albeit at a slower pace than unaffected age-matched peers. Gross motor function is most notably affected. NBS for these patients enabled early access to HCT, the only currently available treatment for infants with IKD. All children are alive and have derived developmental and neurologic benefits from timely HCT. Long-term follow up is ongoing. Optimization of HCT and further development of emerging therapies, all of which must be delivered early in life, are expected to further improve outcomes of infants with IKD.
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    ItemOpen 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, Joanne

    Objective

    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.
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    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, Dietrich

    Purpose

    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.