Biomarker analysis of Morquio syndrome: identification of disease state and drug responsive markers

Martell, Lisa Argento; Lau, Kelly; Mei, Miranda; Burnett, Vicki L.; Decker, Celeste; Foehr, Erik D

doi:10.1186/1750-1172-6-84

Cited by 26 publications

(16 citation statements)

References 24 publications

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“…Recently, LC-MS/MS analysis of keratan sulfate derived disaccharides in plasma and urine of MPS IV patients was described [31,32]. Incubation of DBS with keratanase could be used to analyze keratan sulfate storage, due to MPS IV, in newborn DBS.…”

Section: Discussionmentioning

confidence: 99%

Heparan sulfate and dermatan sulfate derived disaccharides are sensitive markers for newborn screening for mucopolysaccharidoses types I, II and III

Ruijter

Wagemans

et al. 2012

Molecular Genetics and Metabolism

103

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Section: Discussionmentioning

confidence: 99%

Heparan sulfate and dermatan sulfate derived disaccharides are sensitive markers for newborn screening for mucopolysaccharidoses types I, II and III

Ruijter

Wagemans

et al. 2012

Molecular Genetics and Metabolism

103

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“…Subjects indicated pain location on a body diagram. uKS was measured by liquid chromatography tandem mass spectroscopy and normalized using urinary creatinine [Martell et al, 2011]. Blood samples for pharmacokinetic analysis were obtained at weeks 0 and 23 within 15 min prior to dosing, 60 and 120 min after the start of the infusion, at the end of the infusion, and 5, 15, 30, 60, 120, and 180 min post‐infusion.…”

Section: Methodsmentioning

confidence: 99%

Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double‐blind, pilot study

Burton

Berger

Lewis

et al. 2015

American J of Med Genetics Pt A

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The primary treatment outcomes of a phase 2, randomized, double‐blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6‐min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3‐min stair climb test [3MSCT]), exercise capacity (cardio‐pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty‐five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0–4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain. © 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

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“…3 While there is no currently approved treatment for MPS IV A, enzyme replacement therapy, where patients are injected weekly with recombinant enzyme, is in Phase III clinical trials. 4 …”

Section: Introductionmentioning

confidence: 99%

The Structure of Human GALNS Reveals the Molecular Basis for Mucopolysaccharidosis IV A

Rivera-Colón

Schutsky

Kita

et al. 2012

Journal of Molecular Biology

107

111

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Lysosomal enzymes catalyze the breakdown of macromolecules in the cell. In humans, loss of activity of a lysosomal enzyme leads to an inherited metabolic defect known as a lysosomal storage disorder. The human lysosomal enzyme galactosamine-6-sulfatase (GALNS, also known as N-acetylgalactosamine-6-sulfatase and GalN6S; E.C. 3.1.6.4) is deficient in patients with the lysosomal storage disease mucopolysaccharidosis IV A (also known as MPS IV A and Morquio A). Here we report the three-dimensional structure of human GALNS, determined by x-ray crystallography at 2.2 Å resolution. The structure reveals a catalytic gem diol nucleophile derived from modification of a cysteine side chain. The active site of GALNS is a large, positively charged trench suitable for binding polyanionic substrates such as keratan sulfate and chondroitin-6-sulfate. Enzymatic assays on the insect cell-expressed human GALNS indicate activity against synthetic substrates and inhibition by both substrate and product. Mapping 120 MPS IV A missense mutations onto the structure reveals that a majority of mutations affect the hydrophobic core of the structure, indicating that most MPS IV A cases result from misfolding of GALNS. Comparison of the structure of GALNS to paralogous sulfatases shows a wide variety of active site geometries in the family, but strict conservation of the catalytic machinery. Overall, the structure and the known mutations establish the molecular basis for MPS IV A and for the larger MPS family of diseases.

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Biomarker analysis of Morquio syndrome: identification of disease state and drug responsive markers

Cited by 26 publications

References 24 publications

Heparan sulfate and dermatan sulfate derived disaccharides are sensitive markers for newborn screening for mucopolysaccharidoses types I, II and III

Heparan sulfate and dermatan sulfate derived disaccharides are sensitive markers for newborn screening for mucopolysaccharidoses types I, II and III

Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double‐blind, pilot study

The Structure of Human GALNS Reveals the Molecular Basis for Mucopolysaccharidosis IV A

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