Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients

Bhalla, Akhil; Ravi, Ritesh; Fang, Meng; Arguello, Annie; Davis, Sonnet S.; Chiu, Chi-Lu; Blumenfeld, Jessica; Nguyen, Hoang; Earr, Timothy; Wang, Junhua; Astarita, Giuseppe; Zhu, Yuda; Fiore, Damian; Scearce‐Levie, Kimberly; Diaz, Dolores; Cahan, Heather; Troyer, Matthew D.; Harris, Jeffrey M.; Escolar, Maria L.

doi:10.3390/ijms21155188

Cited by 15 publications

(10 citation statements)

References 51 publications

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“…ERT has significantly lowered the risk of death in patients with MPS II [31,[191][192][193] and has had a beneficial effect on many of the biochemical and systemic manifestations, including reduced urinary GAG excretion levels, decreased volumes of liver and spleen, and increased cardiopulmonary function and average walking distance (Table 4) [194,195]. However, it is believed that the enzyme does not cross the blood-brain barrier (BBB) and is, therefore, not likely to have an effect on CNS disease among severely affected patients [196][197][198].…”

Section: Treatmentmentioning

confidence: 99%

Differences in MPS I and MPS II Disease Manifestations

Hampe

Yund

Orchard

et al. 2021

IJMS

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Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

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Section: Treatmentmentioning

confidence: 99%

Differences in MPS I and MPS II Disease Manifestations

Hampe

Yund

Orchard

et al. 2021

IJMS

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“…Neuroinflammation is a common hallmark of neuronopathic LSDs (12) and has been reported in mouse models of MPS II (11,13,14) and in patients with MPS II (15)(16)(17)(18). To determine if ETV:IDS reduces neuroinflammation, we analyzed brain tissue sections immunostained for a marker of responsive microglia, CD68.…”

Section: Resultsmentioning

confidence: 99%

“…Nf-L measured in CSF and serum is considered a sensitive marker of neuronal damage ( 19 ) that is elevated in patients with neuronopathic MPS II ( 15 ) as well as in Ids -KO TfR mu/hu mice ( 11 ). In this mouse model, Nf-L levels in the CSF were increased as early as 3 months of age and continued to rise with disease progression ( Supplemental Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome

Arguello¹,

Meisner²,

Thomsen³

et al. 2021

JCI Insight

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“…Based on this evidence, plasma levels of NfL have already been investigated and found to be elevated in patients affected by two neurodegenerative lysosomal disorders: mucopolysaccharidosis II and neuronal ceroid lipofuscinosis type 2 [ 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

“…Given the reports of elevated NfL levels in CSF or plasma in genetic, inflammatory, and other neurodegenerative diseases [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ], NfL in body fluids appears to be a general, not disease-specific, but sensitive marker of neurodegeneration due to the loss of neurons and axons. This has led to the present study on the possible role of NfL in plasma as a biomarker for the neurological disease associated with NPCD.…”

Section: Introductionmentioning

confidence: 99%

Plasma Neurofilament Light (NfL) in Patients Affected by Niemann–Pick Type C Disease (NPCD)

Dardis

Pavan

Fabris

et al. 2021

JCM

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(1) Background: Niemann–Pick type C disease (NPCD) is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. The clinical presentation is characterized by visceral and neurological involvement. Apart from a small group of patients presenting a severe perinatal form, all patients develop progressive and fatal neurological disease with an extremely variable age of onset. Different biomarkers have been identified; however, they poorly correlate with neurological disease. In this study we assessed the possible role of plasma NfL as a neurological disease-associated biomarker in NPCD. (2) Methods: Plasma NfL levels were measured in 75 healthy controls and 26 patients affected by NPCD (24 NPC1 and 2 NPC2; 39 samples). (3) Results: Plasma NfL levels in healthy controls correlated with age and were significantly lower in pediatric patients as compared to adult subjects (p = 0.0017). In both pediatric and adult NPCD patients, the plasma levels of NfL were significantly higher than in age-matched controls (p < 0.0001). Most importantly, plasma NfL levels in NPCD patients with neurological involvement were significantly higher than the levels found in patients free of neurological signs at the time of sampling, both in the pediatric and the adult group (p = 0.0076; p = 0.0032, respectively). Furthermore, in adults the NfL levels in non-neurological patients were comparable with those found in age-matched controls. No correlations between plasma NfL levels and NPCD patient age at sampling or plasma levels of cholestan 3β-5α-6β-triol were found. (4) Conclusions: These data suggest a promising role of plasma NfL as a possible neurological disease-associated biomarker in NPCD.

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Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients

Cited by 15 publications

References 51 publications

Differences in MPS I and MPS II Disease Manifestations

Differences in MPS I and MPS II Disease Manifestations

Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome

Plasma Neurofilament Light (NfL) in Patients Affected by Niemann–Pick Type C Disease (NPCD)

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