The Morquio A Clinical Assessment Program: Baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects

Harmatz, Paul; Mengel, Karl Eugen; Giugliani, Roberto; Valayannopoulos, Vassili; Lin, Shuan Pei; Parini, Rossella; Guffon, Nathalie; Burton, Barbara K.; Hendriksz, Christian J.; Mitchell, John; Martins, Ana María; Jones, Simon A.; Guelbert, Norberto; Vellodi, Ashok; Hollak, Carla E. M.; Slasor, Peter; Decker, Celeste

doi:10.1016/j.ymgme.2013.01.021

Cited by 129 publications

(249 citation statements)

References 40 publications

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“…The 6MWT is a multi‐systemic test, though improvement may not be demonstrated in this endpoint in each individual benefiting from treatment due to the heterogeneity of the disease and variable impact of ERT on outcomes. Results of the 3MSCT also showed that patients in this study had a relatively high level of function, with the number of stairs climbed per minute at baseline being more than twice that seen in the phase 3 and MorCAP studies [Harmatz et al, 2013; Hendriksz et al, [Link]]. After 24 weeks of treatment, the 3MSCT showed a numerical improvement at the higher dose, but not at the lower dose, though there was a high degree of variability at both baseline and outcomes among subjects for this test.…”

Section: Discussionsupporting

confidence: 61%

“…Moreover, as previously indicated, the study was not powered to detect significant differences between doses. uKS has been suggested to be a biomarker of clinical severity in Morquio A syndrome [Harmatz et al, 2013], but no clear link between treatment‐induced uKS changes and clinical efficacy could be established in clinical studies thus far.…”

Section: Discussionmentioning

confidence: 99%

“…This accumulation causes cellular and organ dysfunction leading to the progressive development of an array of clinical manifestations. Most apparent are the musculoskeletal and joint issues, including short‐trunk dwarfism and chest, spine, hip, knee, and ankle abnormalities, atlantoaxial instability, and wrist hypermobility [Harmatz et al, 2013; Hendriksz et al, 2015a]. Common non‐skeletal manifestations include cardiorespiratory compromise, spinal cord compression, corneal clouding, hearing loss, hepatosplenomegaly, and dental abnormalities [Harmatz et al, 2013; Hendriksz et al, 2013; Hendriksz et al, 2015a].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Mucopolysaccharidoses IV A, better known as Morquio-A syndrome, is a rare disease that represents one of the multi-organic and progressive diseases with the most severe musculoskeletal system involvement (1,2). It has a wide clinical spectrum, that may not be easy to recognize from other non-systemic skeletal dysplasias, which represents a challenge in diagnosis in young patients (3,4).…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of Morquio-A patients in Mexico: How far are we from prompt diagnosis?

Colmenares-Bonilla

Esquitin-Garduño

2017

IRDR

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“…Patients with a classic (severe) form of MPS IVA have a unique systemic skeletal dysplasia including short-trunk dwarfism, kyphoscoliosis, coxa valga, odontoid hypoplasia, abnormal gait, joint mobility problems, restriction of chest wall movement, and a life span of 20-30 years if an appropriate orthopedic intervention is unavailable. Patients with an attenuated form have a milder skeletal involvement, and most have normal life span (Dũng et al 2013;Yasuda et al 2013;Tomatsu et al 2011Tomatsu et al , 2012aTomatsu et al , 2013aNorthover et al 1996;Montaño et al 2007Montaño et al , 2008Suzuki et al 2001;Hendriksz et al 2013;M€ ollmann et al 2013;Harmatz et al 2013). Patients with MPS IVB show a milder phenotype of skeletal dysplasia than patients with the severe form of MPS IVA.…”

Section: Introductionmentioning

confidence: 99%

Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

et al. 2014

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Keratan sulfate (KS) is a storage material in mucopolysaccharidosis IV (MPS IV). However, no detailed analysis has been reported on subclasses of KS: monosulfated KS and di-sulfated KS. We established a novel method to distinguish and quantify mono-and di-sulfated KS using liquid chromatography-tandem mass spectrometry and measured both KS levels in various specimens.Di-sulfated KS was dominant in shark cartilage and rat serum, while mono-sulfated KS was dominant in bovine cornea and human serum. Levels of both mono-and di-sulfated KS varied with age in the blood and urine from control subjects and patients with MPS II and IVA. The mean levels of both forms of KS in the plasma/serum from patients with MPS II, IVA, and IVB were elevated compared with that in age-matched controls. Di-sulfated KS provided more significant difference between MPS IVA and the age-matched controls than mono-sulfated KS. The ratio of di-sulfated KS to total KS in plasma/serum increased with age in control subjects and patients with MPS II but was age independent in MPS IVA patients. Consequently, this ratio can discriminate younger MPS IVA patients from controls. Levels of monoand di-sulfated KS in urine of MPS IVA and IVB patients were all higher than age-matched controls for all ages studied.In conclusion, the level of di-sulfated KS and its ratio to total KS can distinguish control subjects from patients with MPS II, IVA, and IVB, indicating that di-sulfated KS may be a novel biomarker for these disorders. Abbreviations

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The Morquio A Clinical Assessment Program: Baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects

Cited by 129 publications

References 40 publications

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

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

Diagnosis of Morquio-A patients in Mexico: How far are we from prompt diagnosis?

Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

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