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1. Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix

Author

Marena Trinidad, Xinying Hong, Steven Froelich, Jessica Daiker, James Sacco, Hong Phuc Nguyen, Madelynn Campagna, Dean Suhr, Teryn Suhr, Jonathan H. LeBowitz, Michael H. Gelb, and Wyatt T. Clark

Subjects
Metachromatic leukodystrophy, Genotype–phenotype relationship, Newborn screening, Mass spectrometry, Phenotype, Mutation, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by mutations in the arylsulfatase A gene (ARSA) and categorized into three subtypes according to age of onset. The functional effect of most ARSA mutants remains unknown; better understanding of the genotype–phenotype relationship is required to support newborn screening (NBS) and guide treatment. Results We collected a patient data set from the literature that relates disease severity to ARSA genotype in 489 individuals with MLD. Patient-based data were used to develop a phenotype matrix that predicts MLD phenotype given ARSA alleles in a patient’s genotype with 76% accuracy. We then employed a high-throughput enzyme activity assay using mass spectrometry to explore the function of ARSA variants from the curated patient data set and the Genome Aggregation Database (gnomAD). We observed evidence that 36% of variants of unknown significance (VUS) in ARSA may be pathogenic. By classifying functional effects for 251 VUS from gnomAD, we reduced the incidence of genotypes of unknown significance (GUS) by over 98.5% in the overall population. Conclusions These results provide an additional tool for clinicians to anticipate the disease course in MLD patients, identifying individuals at high risk of severe disease to support treatment access. Our results suggest that more than 1 in 3 VUS in ARSA may be pathogenic. We show that combining genetic and biochemical information increases diagnostic yield. Our strategy may apply to other recessive diseases, providing a tool to address the challenge of interpreting VUS within genotype–phenotype relationships and NBS.

Published
2023
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2. Galactosylceramidase deficiency and pathological abnormalities in cerebral white matter of Krabbe disease

Author

Diego Iacono, Shunsuke Koga, Hui Peng, Arulmani Manavalan, Jessica Daiker, Monica Castanedes-Casey, Nicholas B. Martin, Aimee R. Herdt, Michael H. Gelb, Dennis W. Dickson, and Chris W. Lee

Subjects
Krabbe disease, Globoid cell leukodystrophy, Galactosylceramidase, Oligodendrocyte, Psychosine, Cerebral white matter, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Krabbe Disease (KD) is an autosomal recessive disorder that results from loss-of-function mutations in the GALC gene, which encodes lysosomal enzyme galactosylceramidase (GALC). Functional deficiency of GALC is toxic to myelin-producing cells, which leads to progressive demyelination in both the central and peripheral nervous systems. It is hypothesized that accumulation of psychosine, which can only be degraded by GALC, is a primary initiator of pathologic cascades. Despite the central role of GALC in KD pathomechanism, investigations of GALC deficiency at a protein level are largely absent, due in part, to the lack of sensitive antibodies in the field. Leveraging two custom antibodies that can detect GALC at endogenous levels, we demonstrated that GALC protein is predominantly localized to oligodendrocytes in cerebral white matter of an infant brain, consistent with its functional role in myelination. Mature GALC could also be quantitatively detected as a 26 kDa band by western blotting and correlated to enzyme activity in brain tissues. The p.Ile562Thr polymorphic variant, which is over-represented in the KD population, was associated with reduced mature GALC protein and activity. In three infantile KD cases, homozygous null mutations in GALC lead to deficiency in total GALC protein and activity. Interestingly, although GALC activity was absent, normal levels of total GALC protein were detected by a sandwich ELISA using our custom antibodies in a later-onset KD brain, which suggests that the assay has the potential to differentiate infantile- and later-onset KD cases. Among the infantile KD cases, we quantified a 5-fold increase in psychosine levels, and observed increased levels of acid ceramidase, a key enzyme for psychosine production, and hyperglycosylated lysosomal-associated membrane protein 1, a marker for lysosomal activation, in periventricular white matter, a major pathological brain region, when compared with age-matched normal controls. While near complete demyelination was observed in these cases, we quantified that an early-infantile case (age of death at 10 months) had about 3-fold increases in both globoid cells, a pathological hallmark for KD, and CD8-positive T lymphocytes, a pathological marker for multiple sclerosis, in the white matter when compared with a slower progressing infantile case (age of death at 21 months), which suggests a positive correlation between clinical severity and neuropathology. Taken together, our findings have advanced the understanding of GALC protein biology in the context of normal and KD brain white matter. We also revealed new neuropathological changes that may provide insights to understand KD pathogenesis.

Published
2022
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3. Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots

Author

Martin Sadilek, Warunee Dansithong, C. Ronald Scott, Nicole Ruiz-Schultz, Xinying Hong, Stevie Norcross, Michael H. Gelb, Arun Kumar, Teryn R. Suhr, Maria L. Escolar, Jessica Daiker, and Andreas Rohrwasser

Subjects
0301 basic medicine, medicine.medical_specialty, Newborn screening, Arylsulfatase A, Spots, business.industry, Extramural, Leukodystrophy, 030105 genetics & heredity, medicine.disease, Screening algorithm, complex mixtures, Gastroenterology, Metachromatic leukodystrophy, 03 medical and health sciences, 030104 developmental biology, Internal medicine, medicine, business, Dried blood, Genetics (clinical)
Abstract

Purpose Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA), which results in the accumulation of sulfatides. Newborn screening for MLD may be considered in the future as innovative treatments are advancing. We carried out a research study to assess the feasibility of screening MLD using dried blood spots (DBS) from de-identified newborns. Methods To minimize the false-positive rate, a two-tier screening algorithm was designed. The primary test was to quantify C16:0-sulfatide in DBS by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The screening cutoff was established based on the results from 15 MLD newborns to achieve 100% sensitivity. The secondary test was to measure the ARSA activity in DBS from newborns with abnormal C16:0-sulfatide levels. Only newborns that displayed both abnormal C16:0-sulfatide abundance and ARSA activity were considered screen positives. Results A total of 27,335 newborns were screened using this two-tier algorithm, and 2 high-risk cases were identified. ARSA gene sequencing identified these two high-risk subjects to be a MLD-affected patient and a heterozygote. Conclusion Our study demonstrates that newborn screening for MLD is highly feasible in a real-world scenario with near 100% assay specificity.

Published
2021
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4. Toward newborn screening of cerebrotendinous xanthomatosis: results of a biomarker research study using 32,000 newborn dried blood spots

Author

Jie Duan, Albert H. Bootsma, Jessica Daiker, Xinying Hong, Michael H. Gelb, Andrea E. DeBarber, Frédéric M. Vaz, John Y.L. Chiang, Hidde H. Huidekoper, Martin Sadilek, Pediatrics, Laboratory Genetic Metabolic Diseases, AGEM - Inborn errors of metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Personalized Medicine, and APH - Methodology

Subjects
Cerebrotendinous Xanthomatosis, Article, Neonatal Screening, Liquid chromatography–mass spectrometry, Tandem Mass Spectrometry, CYP27A1, Medicine, Humans, Dried blood, Genetics (clinical), Newborn screening, Spots, business.industry, newborn screening, Infant, Newborn, Xanthomatosis, Cerebrotendinous, cerebrotendinous xanthomatosis, Molecular biology, Biomarker (medicine), biomarker, biomarker ratio, business, Glucuronide, Biomarkers, Chromatography, Liquid
Abstract

Purpose: Cerebrotendinous xanthomatosis (CTX) is a treatable hereditary disorder caused by the deficiency of sterol 27-hydroxylase, which is encoded by the CYP27A1 gene. Different newborn screening biomarkers for CTX have been described, including 7α,12α-dihydroxy-4-cholesten-3-one (7α12αC4), 5β-cholestane-3α,7α,12α,25-tetrol glucuronide (GlcA-tetrol), the ratio of GlcA-tetrol to tauro-chenodeoxycholic acid (t-CDCA) (GlcA-tetrol/t-CDCA), and the ratio of tauro-trihydroxycholestanoic acid (t-THCA) to GlcA-tetrol (t-THCA/GlcA-tetrol). We set out to evaluate these screening methods in a research study using over 32,000 newborn dried blood spots (DBS). Methods: Metabolites were extracted from DBS with methanol containing internal standard, which was then quantified by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Results: The measurement of 7α12αC4 was complicated by isobaric interferences and was discontinued. A total of 32,737 newborns were screened based on the GlcA-tetrol concentration in DBS. GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios were also calculated. Newborns displaying both elevated GlcA-tetrol and GlcA-tetrol/t-CDCA ratio were considered to be screen positives. The t-THCA/GlcA-tetrol ratio was used to further distinguish CTX screen positives from Zellweger Spectrum Disorder (ZSD) screen positives. Only one newborn displayed both elevated GlcA-tetrol concentration in DBS and a typical CTX biochemical profile. This newborn was interpreted as a CTX-affected patient as CYP27A1 gene sequencing identified two known pathogenic variants. Conclusion: The results indicate that both GlcA-tetrol and the GlcA-tetrol/t-CDCA ratio are excellent CTX biomarkers suitable for newborn screening. By characterizing the relationship of GlcA-tetrol, t-CDCA, and t-THCA as secondary markers, 100% assay specificity can be achieved.

Published
2020

5. Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots

Author

Xinying, Hong, Jessica, Daiker, Martin, Sadilek, Nicole, Ruiz-Schultz, Arun Babu, Kumar, Stevie, Norcross, Warunee, Dansithong, Teryn, Suhr, Maria L, Escolar, C, Ronald Scott, Andreas, Rohrwasser, and Michael H, Gelb

Subjects
Neonatal Screening, Tandem Mass Spectrometry, Infant, Newborn, Humans, Leukodystrophy, Metachromatic, Cerebroside-Sulfatase, Chromatography, Liquid
Abstract

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA), which results in the accumulation of sulfatides. Newborn screening for MLD may be considered in the future as innovative treatments are advancing. We carried out a research study to assess the feasibility of screening MLD using dried blood spots (DBS) from de-identified newborns.To minimize the false-positive rate, a two-tier screening algorithm was designed. The primary test was to quantify C16:0-sulfatide in DBS by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The screening cutoff was established based on the results from 15 MLD newborns to achieve 100% sensitivity. The secondary test was to measure the ARSA activity in DBS from newborns with abnormal C16:0-sulfatide levels. Only newborns that displayed both abnormal C16:0-sulfatide abundance and ARSA activity were considered screen positives.A total of 27,335 newborns were screened using this two-tier algorithm, and 2 high-risk cases were identified. ARSA gene sequencing identified these two high-risk subjects to be a MLD-affected patient and a heterozygote.Our study demonstrates that newborn screening for MLD is highly feasible in a real-world scenario with near 100% assay specificity.

Published
2020

6. Leukocyte and Dried Blood Spot Arylsulfatase A Assay by Tandem Mass Spectrometry

Author

Maria L. Beltran-Quintero, Xinying Hong, Alan Finglas, Michael H. Gelb, Omar Sherbini, Giancarlo la Marca, Joanne Kurtzberg, Fabiola De Mattia, Maria L. Escolar, Arun Kumar, Francesca Fumagalli, Roberta Damiano, Adeline Vanderver, Martin Sadilek, Alessandro Aiuti, Maria Luisa Della Bona, Teryn R. Suhr, Jessica Daiker, Amy Waldman, Valeria Calbi, Sarah Woidill, Amber Olsen, Laura Adang, Fan Yi, Hong, Xinying, Kumar, Arun Babu, Daiker, Jessica, Yi, Fan, Sadilek, Martin, De Mattia, Fabiola, Fumagalli, Francesca, Calbi, Valeria, Damiano, Roberta, Bona, Maria Della, 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, and Gelb, Michael H

Subjects
Arylsulfatase A, Multiple Sulfatase Deficiency Disease, 010402 general chemistry, Tandem mass spectrometry, 01 natural sciences, Article, Analytical Chemistry, Multiple sulfatase deficiency, Tandem Mass Spectrometry, medicine, Leukocytes, Humans, Cerebroside-Sulfatase, chemistry.chemical_classification, Newborn screening, Sulfoglycosphingolipids, biology, Molecular Structure, 010401 analytical chemistry, Leukodystrophy, Metachromatic, medicine.disease, Molecular biology, 0104 chemical sciences, Dried blood spot, Metachromatic leukodystrophy, Enzyme, chemistry, biology.protein, Dried Blood Spot Testing, Antibody, Chromatography, Liquid
Abstract

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays were developed to measure arylsulfatase A (ARSA) activity in leukocytes and dried blood spot (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 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 patient and for monitoring the efficacy of therapeutic treatments. On the other hand, ARSA activity was measured in DBS for the first time without an antibody. Currently, this new ARSA DBS assay serves as a second-tier test following the sulfatide measurement in DBS in our large-scale de-identified pilot study for the screening of MLD. This leads to an elimination of most of the false positives identified by the sulfatide assay. We are also evaluating its potential utility as the first-tier test for the newborn screening of MLD.

Published
2020

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