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Newborn Screening and Follow-Up Diagnostic Testing for Krabbe Disease
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Newborn Screening and Follow-Up Diagnostic Testing for Krabbe Disease

A special issue of International Journal of Neonatal Screening (ISSN 2409-515X).

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 16547

Special Issue Editors

Dr. Joseph Orsini

E-Mail Website
Guest Editor
Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, NY 12201-2002, USA
Interests: newborn screening; lysosomal storage disorders; Krabbe disease; genetics
Dr. Michele Caggana

E-Mail Website
Guest Editor
Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, NY 12201-2002, USA
Interests: newborn screening; genetic testing; public health outcomes; new screening assay development/implementation

Special Issue Information

Dear Colleagues,

Newborn screening for Krabbe disease (KD) was initiated in New York State in 2006 using a tandem mass spectrometry-based enzyme assay. At the time screening was initiated, the reported incidence for disease was ~1:100,000. As of April 2109, New York has screened ~3 million newborns and has detected five early infantile KD cases and two infants with infantile KD. The low detection rate in New York was surprising, and now that multiple other states have initiated screening, it is of interest to learn how other state incidence rates compare to New York. For the first 8 years of screening in New York, the screen positive rate was 0.017%, a number that is very high relative to the true positive case rate. Effective March 2018, New York made major changes its algorithm, including the adoption of the Mayo Clinic Collaborative Laboratory Integrated Reports data analysis tool, which significantly reduced the screen positive rate to 0.006%. These screen positive rates will likely be further reduced when second-tier testing for psychosine is implemented. Psychosine is highly elevated in newborns with early infantile KD; thus, this analyte can be used to identify newborns in need of rapid evaluation and treatment, which is critical to improving outcomes in this population. Over this same period, New York also identified an additional 28 infants that are thought to be at risk for late onset KD. Some of these infants have genotypes consistent with late onset KD patients reported in the literature, and others do not. Most of these newborns have dried blood spot psychosine levels that are in an intermediate range when compared to screen-negative infants and those infants with early infantile KD.

This Special Issue on newborn screening for Krabbe disease in the International Journal of Neonatal Screening will focus on state-collected newborn screening data and short- and long-term follow-up of newborns identified with early or possible late onset forms of KD. It will also provide insight into the genetic and pathophysiological underpinnings of Krabbe disease.

The following topics could be interesting for the reader.

  1. State-wide newborn screening for Krabbe disease algorithms/testing/outcome reports.
  2. Genotype data for newborns identified with Krabbe disease and possible KD.
  3. Use of psychosine as a second-tier test.
  4. Long-term follow-up of newborns identified with possible late onset KD.
  5. Challenges for programs.

Dr. Joseph Orsini
Dr. Michele Caggana
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Neonatal Screening is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • newborn screening
  • Krabbe disease
  • psychosine
  • long-term follow-up

Published Papers (5 papers)

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Research

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8 pages, 224 KiB  
Article
Newborn Screening for Krabbe Disease—Illinois Experience: Role of Psychosine in Diagnosis of the Disease
by Khaja Basheeruddin, Rong Shao, Fran Balster, Pearlie Gardley and Laura Ashbaugh
Int. J. Neonatal Screen. 2021, 7(2), 24; https://doi.org/10.3390/ijns7020024 - 09 May 2021
Cited by 11 | Viewed by 3206
Abstract
Population-based newborn screening for Krabbe disease was initiated by measurement of galactocerebrosidase (GALC) activity in the state of Illinois in December 2017. Due to the poor specificity of GALC for the diagnosis of Krabbe disease, second-tier testing services were provided to reduce the [...] Read more.
Population-based newborn screening for Krabbe disease was initiated by measurement of galactocerebrosidase (GALC) activity in the state of Illinois in December 2017. Due to the poor specificity of GALC for the diagnosis of Krabbe disease, second-tier testing services were provided to reduce the false positive rates for disease monitoring. Using ultra-pressure liquid chromatography coupled to mass spectrometry assay, a total of 497,147 newborns were screened. In total, 288 infants’ specimens (0.06%) having reduced GALC activity were sent out for second-tier testing to a reference laboratory. All newborns’ reduced GALC specimens were tested for psychosine levels, the presence of a 30-kb deletion and GALC sequencing. The results showed that two infants had elevated psychosine levels (10 and 35 nM) and were referred immediately for evaluation and treatment for Infantile Krabbe disease, and six infants had intermediate PSY levels (≥2 to 5 nM) and are under observation as suspected candidates for late-onset Krabbe disease. In addition, 178 infants had pseudodeficiency alleles, all having psychosine levels < 2.0 nM. Our data show that a high percentage of reduced GALC activity (62%) was due to the presence of pseudodeficiency alleles in the GALC gene. In conclusion, incorporation of psychosine measurements can identify infants with infantile Krabbe disease and probable late-onset Krabbe infants. Furthermore, Krabbe disease screening can be achieved at public health laboratories, and infants with infantile Krabbe disease can be diagnosed in timely manner for better outcome. Full article
(This article belongs to the Special Issue Newborn Screening and Follow-Up Diagnostic Testing for Krabbe Disease)
7 pages, 640 KiB  
Article
Family Attitudes regarding Newborn Screening for Krabbe Disease: Results from a Survey of Leukodystrophy Registries
by Karlita Blackwell, Michael H. Gelb, Anna Grantham, Natasha Spencer, Christin Webb and Tara West
Int. J. Neonatal Screen. 2020, 6(3), 66; https://doi.org/10.3390/ijns6030066 - 20 Aug 2020
Cited by 4 | Viewed by 2833
Abstract
Newborn screening (NBS) for Krabbe disease (KD) is currently underway in eight states in the USA, and there is continued discussion of whether to implement KD NBS in additional states. Workgroup members sought to survey a large number of families affected by KD. [...] Read more.
Newborn screening (NBS) for Krabbe disease (KD) is currently underway in eight states in the USA, and there is continued discussion of whether to implement KD NBS in additional states. Workgroup members sought to survey a large number of families affected by KD. Families in KD and leukodystrophy family registries were contacted to seek their participation in The Krabbe Newborn Screening—Family Perspective Survey. The 170 respondents are comprised of the following: 138 family members with a KD individual diagnosed after development of symptoms, 20 notified about KD via NBS, and 12 with a KD individual diagnosed through family history of KD. The key results are that all NBS families with an early-infantile KD family member elected to pursue hematopoietic stem cell transplantation therapy. Of the 170 responders, 165 supported the implementation of KD NBS in all states in the USA. Full article
(This article belongs to the Special Issue Newborn Screening and Follow-Up Diagnostic Testing for Krabbe Disease)
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7 pages, 460 KiB  
Article
Achieving Congruence among Reference Laboratories for Absolute Abundance Measurement of Analytes for Rare Diseases: Psychosine for Diagnosis and Prognosis of Krabbe Disease
by Zackary Herbst, Coleman T. Turgeon, Chad Biski, Hamid Khaledi, Nancy B. Shoemaker, Patrick D. DeArmond, Sara Smith, Joseph Orsini, Dietrich Matern and Michael H. Gelb
Int. J. Neonatal Screen. 2020, 6(2), 29; https://doi.org/10.3390/ijns6020029 - 31 Mar 2020
Cited by 11 | Viewed by 3050
Abstract
Measurement of the absolute concentration of the biomarker psychosine in dried blood spots (DBS) is useful for diagnosis and prognosis of Krabbe disease and to support newborn screening of this leukodystrophy. As for assays for more common diseases, it is important to achieve [...] Read more.
Measurement of the absolute concentration of the biomarker psychosine in dried blood spots (DBS) is useful for diagnosis and prognosis of Krabbe disease and to support newborn screening of this leukodystrophy. As for assays for more common diseases, it is important to achieve congruence when multiple clinical laboratories provide testing. Four clinical laboratories, one research laboratory, and a commercial vendor collaborated with the goal to achieve congruence in quantitative psychosine measurement in DBS. A set of DBS calibrators was prepared by a single vendor and used in each reference laboratory to make a standard curve of measured psychosine in DBS versus the stated calibrator psychosine level. Congruence between the participating five laboratories was achieved using the psychosine DBS calibrators. This allowed application of disease-specific reference ranges obtained by the reference laboratory with the most extensive data by the other reference laboratories. Congruence between multiple reference laboratories in the measurement of the absolute concentration of biomarkers in DBS (and by extension other samples) is possible by the use of a common set of DBS calibrators. Full article
(This article belongs to the Special Issue Newborn Screening and Follow-Up Diagnostic Testing for Krabbe Disease)
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Review

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10 pages, 375 KiB  
Review
Advances in the Diagnosis and Treatment of Krabbe Disease
by David A Wenger, Paola Luzi and Mohammad A. Rafi
Int. J. Neonatal Screen. 2021, 7(3), 57; https://doi.org/10.3390/ijns7030057 - 18 Aug 2021
Cited by 9 | Viewed by 3724
Abstract
Krabbe disease is an autosomal recessive leukodystrophy caused by pathogenic variants in the galactocerebrosidase (GALC) gene. GALC activity is needed for the lysosomal hydrolysis of galactosylceramide, an important component of myelin. While most patients are infants, older patients are also diagnosed. Starting in [...] Read more.
Krabbe disease is an autosomal recessive leukodystrophy caused by pathogenic variants in the galactocerebrosidase (GALC) gene. GALC activity is needed for the lysosomal hydrolysis of galactosylceramide, an important component of myelin. While most patients are infants, older patients are also diagnosed. Starting in 1970, a diagnosis could be made by measuring GALC activity in leukocytes and cultured cells. After the purification of GALC in 1993, the cDNA and genes were cloned. Over 260 disease-causing variants as well as activity lowering benign variants have been identified. While some pathogenic variants can be considered “severe,” others can be considered “mild.” The combination of alleles determines the type of Krabbe disease a person will have. To identify patients earlier, newborn screening (NBS) has been implemented in several states. Low GALC activity in this screening test may indicate a diagnosis of Krabbe disease. Second tier testing as well as neuro-diagnostic studies may be required to identify those individuals needing immediate treatment. Treatment of pre-symptomatic or mildly symptomatic patients at this time is limited to hematopoietic stem cell transplantation. Treatment studies using the mouse and dog models have shown that combining bone marrow transplantation with intra-venous gene therapy provides the best outcomes in terms of survival, behavior, and preservation of normal myelination in the central and peripheral nervous systems. With earlier diagnosis of patients through newborn screening and advances in treatment, it is hoped that more patients will have a much better quality of life. Full article
(This article belongs to the Special Issue Newborn Screening and Follow-Up Diagnostic Testing for Krabbe Disease)
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Other

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7 pages, 670 KiB  
Case Report
Low Psychosine in Krabbe Disease with Onset in Late Infancy: A Case Report
by Camille S. Corre, Dietrich Matern, Joan E. Pellegrino, Carlos A. Saavedra-Matiz, Joseph J. Orsini and Robert Thompson-Stone
Int. J. Neonatal Screen. 2021, 7(2), 28; https://doi.org/10.3390/ijns7020028 - 28 May 2021
Cited by 4 | Viewed by 2831
Abstract
Krabbe disease (KD) is a rare inherited neurodegenerative disorder caused by a deficiency in galactocerebrosidase enzyme activity, which can present in early infancy, requiring an urgent referral for hematopoietic stem cell transplantation, or later in life. Newborn screening (NBS) for KD requires identification [...] Read more.
Krabbe disease (KD) is a rare inherited neurodegenerative disorder caused by a deficiency in galactocerebrosidase enzyme activity, which can present in early infancy, requiring an urgent referral for hematopoietic stem cell transplantation, or later in life. Newborn screening (NBS) for KD requires identification and risk-stratification of patients based on laboratory values to predict disease onset in early infancy or later in life. The biomarker psychosine plays a key role in NBS algorithms to ascertain probability of early-onset disease. This report describes a patient who was screened positive for KD in New York State, had a likely pathogenic genotype, and showed markedly reduced enzyme activity but surprisingly low psychosine levels. The patient ultimately developed KD in late infancy, an outcome not clearly predicted by existing NBS algorithms. It remains critical that psychosine levels be evaluated alongside genotype, enzyme activity levels, and the patient’s evolving clinical presentation, ideally in consultation with experts in KD, in order to guide diagnosis and plans for monitoring. Full article
(This article belongs to the Special Issue Newborn Screening and Follow-Up Diagnostic Testing for Krabbe Disease)
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