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Abstract: The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by defects in the enzymes involved in the degradation of glycosaminoglycans. Hurler syndrome (MPS I) and Sanfilippo syndrome (MPS III) are among the more common diseases in the group, each occurring with an incidence of approximately 1 in 100,000. We present a case of siblings, born of a consanguineous union, affected with both MPS I and MPS IIIa. The diagnoses were confirmed with fibroblast enzyme assays and sequence analysis of the genes, which identified homozygous mutations in IDUA and SGSH. We discuss their clinical features and course and examine the psychosocial aspects of their case, specifically, the decision-making process that the medical team and family faced regarding treatment with enzyme replacement therapy. [Copyright &y& Elsevier]

Current newborn screening programs for Pompe disease (PD) and mucopolysaccharidosis type I (MPS I) suffer from a high false positive rate and long turnaround time for clinical follow up. This study aimed to develop a novel proteomics-based assay for rapid and accurate second-tier screening of PD and MPS I. A fast turnaround assay would enable the identification of severe cases who need immediate clinical follow up and treatment. We developed an immunocapture coupled with mass spectrometry-based proteomics (Immuno-SRM) assay to quantify GAA and IDUA proteins in dried blood spots (DBS) and buccal swabs. Sensitivity, linearity, reproducibility, and protein concentration range in healthy control samples were determined. Clinical performance was evaluated in known PD and MPS I patients as well as pseudodeficiency and carrier cases. Using three 3.2 mm punches (~13.1 μL of blood) of DBS, the assay showed reproducible and sensitive quantification of GAA and IDUA. Both proteins can also be quantified in buccal swabs with high reproducibility and sensitivity. Infantile onset Pompe disease (IOPD) and severe MPS I cases are readily identifiable due to the absence of GAA and IDUA, respectively. In addition, late onset Pompe disease (LOPD) and attenuated MPS I patients showed much reduced levels of the target protein. By contrast, pseudodeficiency and carrier cases exhibited significant higher target protein levels compared to true patients. Direct quantification of endogenous GAA and IDUA peptides in DBS by Immuno-SRM can be used for second-tier screening to rapidly identify severe PD and MPS I patients with a turnaround time of <1 week. Such patients could benefit from immediate clinical follow up and possibly earlier treatment. [ABSTRACT FROM AUTHOR]

The standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD. We identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children. All six IOPD patients (4 males/2 females) had been treated with ERT for 12–15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9–15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing. Among a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline. [ABSTRACT FROM AUTHOR]