Residual α-l-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients

Oussoren, Esmée; Keulemans, J. L. M.; Diggelen, O. P. van; Oemardien, Linda F.; Timmermans, Remco; Ploeg, Ans T. van der; Ruijter, George J. G.

doi:10.1016/j.ymgme.2013.05.016

Cited by 44 publications

(54 citation statements)

References 27 publications

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“…Clinical improvement, despite relatively low engraftment, should not be surprising. Studies in fibroblasts from MPS-I patients with different phenotypes and different genetic backgrounds confirmed that tiny differences in residual enzyme activity are related to important clinical differences 33 . Several studies on HSCT in MPS-IH reported improvements in cardiopulmonary function, hearing and vision, and preservation of neurocognitive function 9,14,34 .…”

Section: Discussionmentioning

confidence: 93%

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome

Saute

Souza

Poswar

et al. 2016

Arq. Neuro-Psiquiatr.

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Hematopoietic stem cell transplantation (HSCT) is the only available treatment for the neurological involvement of disorders such as late-onset metachromatic leukodystrophy (MLD), mucopolysaccharidosis type I-Hurler (MPS-IH), and X-linked cerebral adrenoleukodystrophy (CALD). Objective To describe survival and neurological outcomes after HSCT for these disorders. Methods Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated. Results Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT. Conclusion Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor.

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Section: Discussionmentioning

confidence: 93%

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome

Saute

Souza

Poswar

et al. 2016

Arq. Neuro-Psiquiatr.

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“…This therapeutic threshold can differ significantly for different diseases. For example, it is estimated that 30–35% of normal CFTR activity is required for a therapeutic improvement in CF (68, 112), 20–30% of normal dystrophin function is required for attenuation of DMD (20, 91), and only 0.4–1% of the α-L-iduronidase enzyme activity is required to alleviate MPS I-H (16, 96). Also, the threshold for correction can differ in various tissues in individuals with the same disease and between the same tissues in different patients.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Therapeutics Based on Stop Codon Readthrough

Keeling

Xue

Gunn

et al. 2014

Annu. Rev. Genom. Hum. Genet.

263

273

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Nonsense suppression therapy encompasses approaches aimed at suppressing translation termination at in-frame premature termination codons (PTCs, also known as nonsense mutations) to restore deficient protein function. In this review, we examine the current status of PTC suppression as a therapy for genetic diseases caused by nonsense mutations. We discuss what is currently known about the mechanism of PTC suppression as well as therapeutic approaches under development to suppress PTCs. The approaches considered include readthrough drugs, suppressor tRNAs, PTC pseudouridylation, and inhibition of nonsense-mediated mRNA decay. We also discuss the barriers that currently limit the clinical application of nonsense suppression therapy and suggest how some of these difficulties may be overcome. Finally, we consider how PTC suppression may play a role in the clinical treatment of genetic diseases caused by nonsense mutations.

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“…To improve phenotype prediction, an algorithm was proposed to detect severe MPS I patients on the basis of clinical and biochemical data in the first month of life [39]. Moreover, an improved assay of IDUA activity in fibroblasts from skin biopsies of newborn MPS I patients allowed the accurate quantification of residual enzymatic activity that may be useful to predict MPS I phenotype severity [40]. However, these innovative and promising approaches to differentiating patients through the measure of residual enzymatic activity are feasible tests only if performed in a research laboratory with well-recognized expertise in the field.…”

Section: Introductionmentioning

confidence: 99%

Open issues in Mucopolysaccharidosis type I-Hurler

Parini

Deodato

Rocco

et al. 2017

Orphanet J Rare Dis

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Mucopolysaccharidosis I-Hurler (MPS I-H) is the most severe form of a metabolic genetic disease caused by mutations of IDUA gene encoding the lysosomal α-L-iduronidase enzyme. MPS I-H is a rare, life-threatening disease, evolving in multisystem morbidity including progressive neurological disease, upper airway obstruction, skeletal deformity and cardiomyopathy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the gold standard for the treatment of MPS I-H in patients diagnosed and treated before 2-2.5 years of age, having a high rate of success. Beyond the child's age, other factors influence the probability of treatment success, including the selection of patients, of graft source and the donor type employed. Enzyme replacement therapy (ERT) with human recombinant laronidase has also been demonstrated to be effective in ameliorating the clinical conditions of pre-transplant MPS I-H patients and in improving HSCT outcome, by peri-transplant co-administration. Nevertheless the long-term clinical outcome even after successful HSCT varies considerably, with a persisting residual disease burden. Other strategies must then be considered to improve the outcome of these patients: one is to pursue early pre-symptomatic diagnosis through newborn screening and another one is the identification of novel treatments. In this perspective, even though newborn screening can be envisaged as a future attractive perspective, presently the best path to be pursued embraces an improved awareness of signs and symptoms of the disorder by primary care providers and pediatricians, in order for the patients' timely referral to a qualified reference center. Furthermore, sensitive new biochemical markers must be identified to better define the clinical severity of the disease at birth, to support clinical judgement during the follow-up and to compare the effects of the different therapies. A prolonged neuropsychological follow-up of post-transplant cognitive development of children and residual disease burden is needed. In this perspective, the reference center must guarantee a multidisciplinary followup with an expert team. Diagnostic and interventional protocols of reference centers should be standardized whenever possible to allow comparison of clinical data and evaluation of results. This review will focus on all these critical issues related to the management of MPS I-H.

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Residual α-l-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients

Cited by 44 publications

References 27 publications

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome

Therapeutics Based on Stop Codon Readthrough

Open issues in Mucopolysaccharidosis type I-Hurler

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