Newborn Screening for Hunter Disease: A Small-Scale Feasibility Study

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression.

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“…5, 6 The evidence of oxidative stress early in pathogenesis makes early diagnosis in severe MPSII patients of the utmost importance. 25 …”

Section: Discussionmentioning

confidence: 99%

Glial degeneration with oxidative damage drives neuronal demise in MPSII disease

et al. 2016

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“…However, because the samples were de-identified, no clinical follow-up was possible, and molecular genetic confirmation was not performed. 67 …”

Section: Newborn Screening For Mucopolysaccharidosis Type IImentioning

confidence: 97%

Newborn screening for lysosomal storage disorders

Matern

Gavrilov

Oglesbee

et al. 2015

Seminars in Perinatology

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“…Several MPS-subtypes have specific enzyme replacement therapy available, and there are many indications that MPS patients treated at an early age do better than those treated later in life (Auclair et al, 2003; McGill et al, 2010; Gabrielli et al, 2010; Schulze-Frenking et al, 2011; Baldo et al, 2013; Poe et al, 2014; Muenzer J, 2014; Tomatsu et al, 2016). Newborn screening programs for MPSs using dried blood spots (DBS) were proposed in 2001 and high-throughput technologies such as tandem mass spectrometry (MS/MS) are now under investigation (Meikle et al, 2006; Gelb et al, 2006; Wolfe et al, 2011; de Ruijter et al, 2012; Spacil et al, 2013; Scott et al, 2013; Lin et al, 2013; Tomatsu et al, 2013; Tomatsu et al, 2014; Shimada et al, 2014a; Liao et al, 2014; Gucciardi et al, 2014; Ruijter et al, 2014; Gelb et al, 2015; Hopkins et al, 2015). Methods currently under development include assays for activity of deficient enzymes (Gelb et al, 2015; Hopkins et al, 2015), measurement of accumulated GAGs (Oguma et al, 2007; Tomatsu et al, 2013; Lawrence et al, 2012, 2014).…”

Section: Introductionmentioning

confidence: 99%

Newborn screening for mucopolysaccharidoses: a pilot study of measurement of glycosaminoglycans by tandem mass spectrometry

Kubaski

Mason

Nakatomi

et al. 2016

J of Inher Metab Disea

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BACKGROUND Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism that are progressive and usually result in irreversible in skeletal, visceral and/or brain damage, highlighting a need for early diagnosis. METHODS This pilot study analyzed 2,862 dried blood spots (DBS) from newborns and 14 DBS from newborn patients with MPS (MPS I, n = 7; MPS II, n = 2; MPS III, n = 5). Disaccharides were produced from polymer GAGs by digestion with chondroitinase B, heparitinase, and keratanase II. Heparan sulfate (0S, NS), dermatan sulfate (DS) and mono- and di-sulfated KS were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Median absolute deviation (MAD) was used to determine cutoffs to distinguish patients from controls. Cutoffs were defined as median + 7× MAD from general newborns. RESULTS The cutoffs were as follows: HS-0S> 90ng/mL; HS-NS> 23 ng/mL, DS> 88 ng/mL; mono-sulfated KS> 445 ng/mL; di-sulfated KS> 89 ng/mL and ratio di-KS in total KS> 32%. All MPS I and II samples were above the cutoffs for HS-0S, HS-NS and DS, and all MPS III samples were above cutoffs for HS-0S and HS-NS. The rate of false positives for MPS I and II was 0.03% based on a combination of HS-0S, HS-NS, and DS, and for MPS III was 0.9% based upon a combination of HS-0S and HS-NS. CONCLUSIONS Combination of levels of two or more different GAGs improves separation of MPS patients from unaffected controls, indicating that GAG measurements are potentially valuable biomarkers for newborn screening for MPS.

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Newborn Screening for Hunter Disease: A Small-Scale Feasibility Study

Abstract: Hunter disease (Mucopolysaccharidosis type II, MPS II) is an X-linked lysosomal storage disorder caused by deficiency of iduronate-

Cited by 18 publications

References 25 publications

Glial degeneration with oxidative damage drives neuronal demise in MPSII disease

Glial degeneration with oxidative damage drives neuronal demise in MPSII disease

Newborn screening for lysosomal storage disorders

Newborn screening for mucopolysaccharidoses: a pilot study of measurement of glycosaminoglycans by tandem mass spectrometry

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