Newborn Screening for Krabbe Disease-Illinois Experience: Role of Psychosine in Diagnosis of the Disease.

Khaja Basheeruddin,Pearlie Gardley,Fran Balster,Rong Shao,Laura Ashbaugh

doi:10.3390/ijns7020024

Khaja Basheeruddin, Pearlie Gardley + Show 3 more

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https://doi.org/10.3390/ijns7020024

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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 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.

Highlights

The State of Illinois initiated newborn screening (NBS) for Krabbe disease (KD; globoid cell leukodystrophy; OMIM 245200) in December 2017 by measuring galactocerebrosidase (GALC; EC 3.2.1.46) activity in dried blood spots (DBSs)
Pompe disease and Mucopolysaccharidosis I (MPS I) are the only two lysosomal diseases included on the federal Recommended Uniform Newborn Screening Panel (RUSP) by the Advisory Committee on Heritable Disorders in Newborns and Children of the Department of Health and Human Services
Infants having a single pathogenic mutation or one copy of the 30-kb deletion were identified as carriers (23%) and follow-up was not recommended for both VUSand carrier-assigned categories

Summary

Introduction

The State of Illinois initiated newborn screening (NBS) for Krabbe disease (KD; globoid cell leukodystrophy; OMIM 245200) in December 2017 by measuring galactocerebrosidase (GALC; EC 3.2.1.46) activity in dried blood spots (DBSs). Pompe disease and Mucopolysaccharidosis I (MPS I) are the only two lysosomal diseases included on the federal Recommended Uniform Newborn Screening Panel (RUSP) by the Advisory Committee on Heritable Disorders in Newborns and Children of the Department of Health and Human Services In addition to these recommended LSDs, several states have started mandatory statewide testing for KD, initiated primarily as a result of parent advocacy [4,5]. The non-specific reduction in enzyme activity due to the presence of many known pseudodeficiency variants in vitro using the current artificial substrates is common, with no clinical evidence of disease These variants, if inherited as homozygous mutations or in trans with a disease-causing mutation, do not cause disease. IKD cannot be excluded if gene sequencing reveals the presence of only one pathogenic mutation because of uncertainty of missing other possible disease-causing mutations in GALC exon sequencing

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