Challenges in Newborn Screening for Mucopolysaccharidosis Type I: A Case Study
Biochemical/Metabolic and Therapeutics
-
Primary Categories:
-
Secondary Categories:
Introduction
Mucopolysaccharidosis Type I (MPS I) was added to the recommended uniform screening panel (RUSP) in 2016. Since then, an increasing number of patients have been diagnosed during the newborn period and are receiving early treatments such as enzyme replacement therapy and bone marrow transplants for severe cases. However, many patients also receive inconclusive positive newborn screening (NBS) results, which can complicate clinical management and lead to uncertainty for both healthcare providers and families. We present a case of a positive NBS for MPS I with inconclusive follow-up testing and the associated challenges.
Case Presentation
We present a case of a Hispanic male who presented with a positive NBS for MPS I. First-tier test for enzyme activity in IDUA was 1.013 (cut-off ≥ 1.7802 umol/L/h). Second-tier testing showed a homozygous variant in IDUA: c.952T>C (p.Tyr318His), which was classified as of uncertain significance.
Diagnostic Workup
The confirmatory enzyme activity for IDUA was low, with 0.06 nmol/h/mg (cut-off >=2.06) in leukocytes. Follow-up testing included GAGs (LC-MS/MS) in blood spot, which were normal, with dermatan sulfate at 118 nmol/L (cut-off ≤ 130), heparan sulfate at 66 nmol/L (cut-off < 95), and total keratan sulfate at 872 nmol/L (≤ 1900). Total NREs in urine were elevated, with total heparan sulfate at 1.964 mg/mmol CRT (reference 0.149-1.582), elevated I0S0 at 0.043 mg/mmol CRT (reference ≤ 0.010), and elevated I0S6 at 0.368 mg/mmol CRT (reference ≤ 0.030).
The patient has four older sisters, and genetic testing was offered; three of them were found to have the same genotype. Two of the three had negative blood spot GAGs, while one sister exhibited elevated dermatan sulfate. All three had mildly elevated total GAGs and heparan sulfate in urine, as measured by MS/MS, with only one having normal dermatan sulfate levels in urine.
Treatment and Management
Further evaluation to better characterize the phenotype included ophthalmology assessments, skeletal surveys, and echocardiograms, all reported as normal. The only significant finding was that one of the sisters exhibited short stature and mild learning difficulties, prompting a referral to endocrinology for further assessment.
Outcome and Follow-Up
Given the positive NBS, the homozygous status for a variant of uncertain significance (VUS), multiple asymptomatic family members with the same genotype, and inconclusive biochemical testing, a shared decision was made to continue monitoring for symptoms. Enzyme replacement therapy was withheld given the consideration of risk versus benefits in asymptomatic patients.
Discussion
NBS for lysosomal storage disorders (LSD) presents several challenges, including pseudodeficiencies, variants of uncertain significance (VUS), and mild phenotypes where treatment burden may exceed the benefits. In this case, we could not determine if the identified variant indicates mild Scheie disease, a pseudodeficiency, or a biochemical phenotype. As RUSP expands, more patients have had positive NBS results, often accompanied by inconclusive biochemical tests, concerns raised for late-onset presentations, and VUS, particularly among minority populations.
Conclusion
This case highlights the critical need for better classification and management strategies for LSD, to ensure appropriate interventions are made for affected individuals while minimizing unnecessary treatment for asymptomatic patients.
Mucopolysaccharidosis Type I (MPS I) was added to the recommended uniform screening panel (RUSP) in 2016. Since then, an increasing number of patients have been diagnosed during the newborn period and are receiving early treatments such as enzyme replacement therapy and bone marrow transplants for severe cases. However, many patients also receive inconclusive positive newborn screening (NBS) results, which can complicate clinical management and lead to uncertainty for both healthcare providers and families. We present a case of a positive NBS for MPS I with inconclusive follow-up testing and the associated challenges.
Case Presentation
We present a case of a Hispanic male who presented with a positive NBS for MPS I. First-tier test for enzyme activity in IDUA was 1.013 (cut-off ≥ 1.7802 umol/L/h). Second-tier testing showed a homozygous variant in IDUA: c.952T>C (p.Tyr318His), which was classified as of uncertain significance.
Diagnostic Workup
The confirmatory enzyme activity for IDUA was low, with 0.06 nmol/h/mg (cut-off >=2.06) in leukocytes. Follow-up testing included GAGs (LC-MS/MS) in blood spot, which were normal, with dermatan sulfate at 118 nmol/L (cut-off ≤ 130), heparan sulfate at 66 nmol/L (cut-off < 95), and total keratan sulfate at 872 nmol/L (≤ 1900). Total NREs in urine were elevated, with total heparan sulfate at 1.964 mg/mmol CRT (reference 0.149-1.582), elevated I0S0 at 0.043 mg/mmol CRT (reference ≤ 0.010), and elevated I0S6 at 0.368 mg/mmol CRT (reference ≤ 0.030).
The patient has four older sisters, and genetic testing was offered; three of them were found to have the same genotype. Two of the three had negative blood spot GAGs, while one sister exhibited elevated dermatan sulfate. All three had mildly elevated total GAGs and heparan sulfate in urine, as measured by MS/MS, with only one having normal dermatan sulfate levels in urine.
Treatment and Management
Further evaluation to better characterize the phenotype included ophthalmology assessments, skeletal surveys, and echocardiograms, all reported as normal. The only significant finding was that one of the sisters exhibited short stature and mild learning difficulties, prompting a referral to endocrinology for further assessment.
Outcome and Follow-Up
Given the positive NBS, the homozygous status for a variant of uncertain significance (VUS), multiple asymptomatic family members with the same genotype, and inconclusive biochemical testing, a shared decision was made to continue monitoring for symptoms. Enzyme replacement therapy was withheld given the consideration of risk versus benefits in asymptomatic patients.
Discussion
NBS for lysosomal storage disorders (LSD) presents several challenges, including pseudodeficiencies, variants of uncertain significance (VUS), and mild phenotypes where treatment burden may exceed the benefits. In this case, we could not determine if the identified variant indicates mild Scheie disease, a pseudodeficiency, or a biochemical phenotype. As RUSP expands, more patients have had positive NBS results, often accompanied by inconclusive biochemical tests, concerns raised for late-onset presentations, and VUS, particularly among minority populations.
Conclusion
This case highlights the critical need for better classification and management strategies for LSD, to ensure appropriate interventions are made for affected individuals while minimizing unnecessary treatment for asymptomatic patients.