This project seeks to apply biomarkers for mucopolysaccharidoses (MPS) to the development of an innovative newborn screening (NBS) system for this group of lysosomal storages diseases. Background: MPS are caused by excessive accumulation of glycosaminoglycans (GAGs) from a deficiency of enzyme activity catalyzing their degradation. There are 11 known enzyme deficiencies that give rise to seven distinct forms of MPS with an overall incidence of approximately 1 out of 25,000 live births that indicates approximately 200 newborn patients per year in the Unites States. The accumulation of undegraded storage material in lysosomes causes different clinical syndromes. Generally, the clinical conditions progress if untreated, leading to irreversible developmental delay, systemic skeletal deformities and/or early death. These MPS disorders are potentially treatable with enzyme replacement therapy or hematopoietic stem cell transplantation. The quality of life for MPS patients treated with these therapies dramatically improves when treatment begins at an early stage. Early detection (through NBS) will allow maximum therapeutic benefit of these and other novel therapies. However, conventional laboratory screening methods for MPS are designed to measure urinary total GAGs (heparan sulfate: HS, keratan sulfate: KS, dermatan sulfate: DS, chondroitin sulfate: CS) and cannot be applied to NBS blood samples. We describe a two-tiered approach to NBS for MPS by using high performance liquid chromatography tandem mass spectrometry (LC/MS/MS). The first-tier screen will identify an """"""""at increased risk"""""""" population for all types of MPS based on simultaneous assay of specific GAG markers (DS, HS and KS) using dried blood spots. The subsequent second-tier individual enzyme assays provide definitive diagnosis. Challenges: Since cost-effectiveness is a key for NBS, a highly efficient, sensitive, specific and inexpensive screening method is required. The cost of screening each type of MPS would be high and prohibitive as the incidence rates range from about 1:100,000 births to less than 1:2,000,000 births. However, screening for MPS as a group with a combined incidence of about 1:25,000 births would be comparable to other genetic disorders currently targeted by existing screening programs. The new LC/MS/MS method enables the simultaneous detection of a group of MPS and is promising for NBS. Perspective in proposed research plan: We will establish a NBS method for MPS with simultaneous determination of three major GAGs (DS, HS and KS) as biomarkers. In addition to the NBS application we will measure GAGs as biomarkers for assessing disease severity and monitoring the effects of evolving therapies over a long clinical course.

Public Health Relevance

Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism caused by deficiency of lysosomal enzyme activities, leading to accumulation of glycosaminoglycans (a chain of sugars) such as dermatan sulfate, heparan sulfate, chondroitin sulfate, and keratan sulfate in multiple organs causing systemic bone deformities, enlarged abdominal organs, hearing loss, valvular heart disease, mental retardation and early death. Our research proposal addresses development of a novel newborn screening method for MPS that enables early diagnosis and potential treatment, preventing serious irreversible damage and leading to a better quality of life. We propose to perform a newborn screening pilot study for MPS to evaluate our innovative method.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
Urv, Tiina K
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Saint Louis University
Schools of Medicine
Saint Louis
United States
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Stapleton, Molly; Kubaski, Francyne; Mason, Robert W et al. (2017) Presentation and Treatments for Mucopolysaccharidosis Type II (MPS II; Hunter Syndrome). Expert Opin Orphan Drugs 5:295-307
Kubaski, Francyne; Suzuki, Yasuyuki; Orii, Kenji et al. (2017) Glycosaminoglycan levels in dried blood spots of patients with mucopolysaccharidoses and mucolipidoses. Mol Genet Metab 120:247-254
Kubaski, Francyne; Yabe, Hiromasa; Suzuki, Yasuyuki et al. (2017) Hematopoietic Stem Cell Transplantation for Patients with Mucopolysaccharidosis II. Biol Blood Marrow Transplant 23:1795-1803
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Kubaski, Francyne; Kecskemethy, Heidi H; Harcke, H Theodore et al. (2016) Bone mineral density in mucopolysaccharidosis IVB. Mol Genet Metab Rep 8:80-84

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