Browsing by Author "Gelb, Michael H"

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    ItemOpen Access
    Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease.
    (Orphanet journal of rare diseases, 2018-02) Kwon, Jennifer M; Matern, Dietrich; Kurtzberg, Joanne; Wrabetz, Lawrence; Gelb, Michael H; Wenger, David A; Ficicioglu, Can; Waldman, Amy T; Burton, Barbara K; Hopkins, Patrick V; Orsini, Joseph J
    BACKGROUND:Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly refer infants for human stem cell transplantation within the first few weeks of life. After 11 years of active screening in New York and the introduction of Krabbe disease newborn screening in other states, new information has been gained which can inform the design of newborn screening programs to improve infantile Krabbe disease outcomes. FINDINGS:Recent information relevant to Krabbe disease screening, diagnosis, and treatment were assessed by a diverse group of public health, medical, and advocacy professionals. Outcomes after newborn screening may improve if treatment for infantile disease is initiated before 30 days of life. Newer laboratory screening and diagnostic tools can improve the speed and specificity of diagnosis and help facilitate this early referral. Given the rarity of Krabbe disease, most recommendations were based on case series or expert opinion. CONCLUSION:This report updates recommendations for Krabbe disease newborn screening to improve the timeliness of diagnosis and treatment of infantile Krabbe disease. In the United States, several states have begun or are considering Krabbe disease newborn screening. These recommendations can guide public health laboratories on methodologies for screening and inform clinicians about the need to promptly diagnose and treat infantile Krabbe disease. The timing of the initial referral after newborn screening, the speed of diagnostic confirmation of infantile disease, and the transplantation center's experience and ability to rapidly respond to a suspected patient with newly diagnosed infantile Krabbe disease are critical for optimal outcomes.
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    Leukocyte and Dried Blood Spot Arylsulfatase A Assay by Tandem Mass Spectrometry.
    (Analytical chemistry, 2020-05) Hong, Xinying; Kumar, Arun Babu; Daiker, Jessica; Yi, Fan; Sadilek, Martin; De Mattia, Fabiola; Fumagalli, Francesca; Calbi, Valeria; Damiano, Roberta; Della Bona, Maria; la Marca, Giancarlo; Vanderver, Adeline L; Waldman, Amy T; Adang, Laura; Sherbini, Omar; Woidill, Sarah; Suhr, Teryn; Kurtzberg, Joanne; Beltran-Quintero, Maria L; Escolar, Maria; Aiuti, Alessandro; Finglas, Alan; Olsen, Amber; Gelb, Michael H
    Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays were developed to measure arylsulfatase A (ARSA) activity in leukocytes and dried blood spots (DBS) using deuterated natural sulfatide substrate. These new assays were highly specific and sensitive. Patients with metachromatic leukodystrophy (MLD) and multiple sulfatase deficiency (MSD) displayed a clear deficit in the enzymatic activity and could be completely distinguished from normal controls. The leukocyte assay reported here will be important for diagnosing MLD and MSD patients and for monitoring the efficacy of therapeutic treatments. ARSA activity was measured in DBS for the first time without an antibody. This new ARSA DBS assay can serve as a second-tier test following the sulfatide measurement in DBS for newborn screening of MLD. This leads to an elimination of most of the false positives identified by the sulfatide assay.
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    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 H

    Background

    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.
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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.