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1.
Prague Med Rep ; 125(3): 239-255, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39171551

RESUMO

The correct diagnosis is fundamental for the appropriate treatment to be employed in a particular pathology. The best treatment is not the one that solves only local problems, fragmenting the patient, and therefore, it is necessary to integrate the entire systemic condition of the individual before initiating any local treatment. This context inevitably requires dentistry to participate in a multidisciplinary approach, where the role of the dentist is expanded in concepts that encompass ethics, human dignity, and professional valorization. This article describes a clinical case of a patient with mucopolysaccharidosis type I, whose treatment of cystic lesions present in the mandible was exclusively performed through marsupialisation. The objective of this study is to demonstrate, within the complexity of this rare syndrome, the difficulties of diagnosis and the need for evaluation of the patient beyond the limits of the oral cavity, as well as to report two cases of large dentigerous cysts, surgically treated conservatively through marsupialisation, without the need for re-approach for enucleation and without recurrences over a 20-year period.


Assuntos
Cisto Dentígero , Mucopolissacaridose I , Humanos , Cisto Dentígero/cirurgia , Cisto Dentígero/diagnóstico , Mucopolissacaridose I/complicações , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/terapia , Masculino , Doenças Mandibulares/cirurgia , Doenças Mandibulares/diagnóstico , Feminino
2.
Sci Transl Med ; 16(745): eadi8214, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38691622

RESUMO

Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.


Assuntos
Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I , Humanos , Mucopolissacaridose I/terapia , Mucopolissacaridose I/patologia , Mucopolissacaridose I/genética , Masculino , Feminino , Pré-Escolar , Lactente , Resultado do Tratamento , Células-Tronco Hematopoéticas/metabolismo , Criança , Osso e Ossos/patologia , Imageamento por Ressonância Magnética
3.
Mol Ther ; 32(6): 1643-1657, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38582963

RESUMO

Gene therapy in hematopoietic stem and progenitor cells (HSPCs) shows great potential for the treatment of inborn metabolic diseases. Typical HSPC gene therapy approaches rely on constitutive promoters to express a therapeutic transgene, which is associated with multiple disadvantages. Here, we propose a novel promoterless intronic gene editing approach that triggers transgene expression only after cellular differentiation into the myeloid lineage. We integrated a splicing-competent eGFP cassette into the first intron of CD11b and observed expression of eGFP in the myeloid lineage but minimal to no expression in HSPCs or differentiated non-myeloid lineages. In vivo, edited HSPCs successfully engrafted in immunodeficient mice and displayed transgene expression in the myeloid compartment of multiple tissues. Using the same approach, we expressed alpha-L-iduronidase (IDUA), the defective enzyme in Mucopolysaccharidosis type I, and observed a 10-fold supraendogenous IDUA expression exclusively after myeloid differentiation. Edited cells efficiently populated bone marrow, blood, and spleen of immunodeficient mice, and retained the capacity to secrete IDUA ex vivo. Importantly, cells edited with the eGFP and IDUA transgenes were also found in the brain. This approach may unlock new therapeutic strategies for inborn metabolic and neurological diseases that require the delivery of therapeutics in brain.


Assuntos
Edição de Genes , Células-Tronco Hematopoéticas , Íntrons , Células Mieloides , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição , Transgenes , Animais , Edição de Genes/métodos , Camundongos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células Mieloides/metabolismo , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genética , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/metabolismo , Diferenciação Celular/genética , Terapia Genética/métodos , Iduronidase/genética , Iduronidase/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Expressão Gênica , Linhagem da Célula/genética , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Transplante de Células-Tronco Hematopoéticas/métodos , Mucopolissacaridose I/terapia , Mucopolissacaridose I/genética
4.
JCI Insight ; 9(5)2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38456506

RESUMO

Dysostosis multiplex is a major cause of morbidity in Hurler syndrome (mucopolysaccharidosis type IH [MPS IH], OMIM #607014) because currently available therapies have limited success in its prevention and reversion. Unfortunately, the elucidation of skeletal pathogenesis in MPS IH is limited by difficulties in obtaining bone specimens from pediatric patients and poor reproducibility in animal models. Thus, the application of experimental systems that can be used to dissect cellular and molecular mechanisms underlying the skeletal phenotype of MPS IH patients and to identify effective therapies is highly needed. Here, we adopted in vitro/in vivo systems based on patient-derived bone marrow stromal cells to generate cartilaginous pellets and bone rudiments. Interestingly, we observed that heparan sulphate accumulation compromised the remodeling of MPS IH cartilage into other skeletal tissues and other critical aspects of the endochondral ossification process. We also noticed that MPS IH hypertrophic cartilage was characterized by dysregulation of signaling pathways controlling cartilage hypertrophy and fate, extracellular matrix organization, and glycosaminoglycan metabolism. Our study demonstrates that the cartilaginous pellet-based system is a valuable tool to study MPS IH dysostosis and to develop new therapeutic approaches for this hard-to-treat aspect of the disease. Finally, our approach may be applied for modeling other genetic skeletal disorders.


Assuntos
Disostoses , Mucopolissacaridose I , Animais , Humanos , Criança , Mucopolissacaridose I/genética , Mucopolissacaridose I/patologia , Mucopolissacaridose I/terapia , Iduronidase/genética , Iduronidase/metabolismo , Medula Óssea/patologia , Reprodutibilidade dos Testes
5.
Mol Ther ; 32(3): 609-618, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38204164

RESUMO

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.


Assuntos
Mucopolissacaridose I , Humanos , Mucopolissacaridose I/terapia , Mucopolissacaridose I/tratamento farmacológico , Iduronidase/efeitos adversos , Iduronidase/genética , Iduronidase/metabolismo , Encéfalo/metabolismo , Barreira Hematoencefálica/metabolismo , Receptores da Transferrina/genética , Heparitina Sulfato/metabolismo
6.
Transplant Cell Ther ; 29(11): 707.e1-707.e4, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37582469

RESUMO

Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder characterized by the deficiency of the alpha-L-iduronidase enzyme necessary for the degradation of glycosaminoglycans (GAG) in the lysosome. Hurler syndrome is the most severe form of MPS I, manifesting as multiorgan dysfunction, cognitive delay, and death, usually within ten years if left untreated. Hematopoietic stem cell transplantation (HSCT) is the optimal treatment option, providing a permanent solution to enzyme deficiency and halting cognitive decline; however, the HSCT complications transplantation-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD) are known risk factors for bloodstream infection (BSI). BSI is a serious complication of HSCT, contributing to poor outcomes and transplantation-related morbidity. There are little data evaluating BSI after HSCT in the Hurler syndrome population. We performed a retrospective analysis of patients with Hurler syndrome who underwent HSCT at our center between 2013 and 2020 to determine the incidence of BSI within the first year post-transplantation. Patient BSI data were collected through the first year post-HSCT. Variables including patient demographics and transplantation-related characteristics were collected, including information on BSI and mortality. Twenty-five patients with a total of 28 HSCTs were included in the analysis; the majority (n = 17; 68%) were male, with a median age of 1.1 years (interquartile range, .35 to 1.44 years) at the time of transplantation. The most common graft source was cord blood (n = 15; 54%), followed by bone marrow (n = 13; 46%), with the majority from matched unrelated donors (n = 14; 52%) and mismatched unrelated donors (n = 13; 44%). Sixteen BSIs were diagnosed in 12 patients (48%). Most infections (n = 7; 43.8%) were diagnosed in the first 20 days post-transplantation, with fewer infections observed at later time points. Seven of the 9 Hurler patients diagnosed with TA-TMA (78%) also had a BSI. The incidence rate of BSIs in Hurler patients (n = 12; 48%) was higher than the rates reported in the general pediatric HSCT population at 1-year post-transplantation (15% to 35%). Given the high rate of both TA-TMA and a BSI in Hurler patients, we suspect a possible correlation between the 2. Additionally, due to the time it takes for GAG levels to normalize post-HSCT in Hurler patients, it is reasonable to suspect that the high BSI rates in these patients are linked to their Hurler diagnosis. These findings bring awareness to possible disease-related factors contributing to high BSI rates in the Hurler population post-HSCT.


Assuntos
Doenças Transmissíveis , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I , Sepse , Humanos , Masculino , Criança , Feminino , Mucopolissacaridose I/complicações , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/terapia , Incidência , Estudos Retrospectivos , Doenças Transmissíveis/etiologia , Sepse/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos
7.
Sci Rep ; 13(1): 12716, 2023 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-37543633

RESUMO

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disorder that causes syndromes characterized by physiological dysfunction in many organs and tissues. Despite the recognizable morphological and behavioral deficits associated with MPS I, neither the underlying alterations in functional neural connectivity nor its restoration following gene therapy have been shown. By employing high-resolution resting-state fMRI (rs-fMRI), we found significant reductions in functional neural connectivity in the limbic areas of the brain that play key roles in learning and memory in MPS I mice, and that adeno-associated virus (AAV)-mediated gene therapy can reestablish most brain connectivity. Using logistic regression in MPS I and treated animals, we identified functional networks with the most alterations. The rs-fMRI and statistical methods should be translatable into clinical evaluation of humans with neurological disorders.


Assuntos
Mucopolissacaridose I , Humanos , Animais , Camundongos , Mucopolissacaridose I/genética , Mucopolissacaridose I/terapia , Encéfalo/diagnóstico por imagem , Terapia Genética/métodos , Mapeamento Encefálico/métodos , Imageamento por Ressonância Magnética
8.
Cells ; 12(13)2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37443816

RESUMO

The main approach used in the current therapy of mucopolysaccharidosis (MPS) is to reduce the levels of glycosaminoglycans (GAGs) in cells, the deposits considered to be the main cause of the disease. Previous studies have revealed significant differences in the expression of genes encoding proteins involved in many processes, like those related to actin filaments, in MPS cells. Since the regulation of actin filaments is essential for the intracellular transport of specific molecules, the process which may affect the course of MPSs, the aim of this study was to evaluate the changes that occur in the actin cytoskeleton and focal adhesion in cells derived from patients with this disease, as well as in the MPS I mouse model, and to assess whether they could be potential therapeutic targets for different MPS types. Western-blotting, flow cytometry and transcriptomic analyses were employed to address these issues. The levels of the key proteins involved in the studied processes, before and after specific treatment, were assessed. We have also analyzed transcripts whose levels were significantly altered in MPS cells. We identified genes whose expressions were changed in the majority of MPS types and those with particularly highly altered expression. For the first time, significant changes in the expression of genes involved in the actin cytoskeleton structure/functions were revealed which may be considered as an additional element in the pathogenesis of MPSs. Our results suggest the possibility of using the actin cytoskeleton as a potential target in therapeutic approaches for this disease.


Assuntos
Mucopolissacaridoses , Mucopolissacaridose I , Animais , Camundongos , Adesões Focais/metabolismo , Polimerização , Mucopolissacaridoses/terapia , Mucopolissacaridose I/terapia , Mucopolissacaridose I/metabolismo , Citoesqueleto de Actina/metabolismo
9.
Mol Genet Metab ; 139(4): 107651, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37473537

RESUMO

Mucopolysaccharidosis Type I (MPSI) is a rare inherited lysosomal storage disease that arises due to mutations in the IDUA gene. Defective alpha-L-iduronidase (IDUA) enzyme is unable to break down glucosaminoglycans (GAGs) within the lysosomes and, as a result, there is systemic accumulation of undegraded products in lysosomes throughout the body leading to multi-system disease. Here, we characterised the skeletal/craniofacial, neuromuscular and behavioural outcomes of the MPSI Idua-W392X mouse model. We demonstrate that Idua-W392X mice have gross craniofacial abnormalities, showed signs of kyphosis, and show signs of hypoactivity compared to wild-type mice. X-ray imaging analysis revealed significantly shorter and wider tibias and femurs, significantly wider snouts, increased skull width and significantly thicker zygomatic arch bones in Idua-W392X female mice compared to wild-type mice at 9 and 10.5 months of age. Idua-W392X mice display decreased muscle strength, especially in the forelimbs, which is already apparent from 3 months of age. Female Idua-W392X mice display hypoactivity in the open-field test from 9 months of age and anxiety-like behaviour at 10 months of age. As these behaviours have been identified in Hurler children, the MPSI Idua-W392X mouse model may be important for the investigation of new therapeutic approaches for MPSI-Hurler.


Assuntos
Doenças por Armazenamento dos Lisossomos , Mucopolissacaridose I , Criança , Camundongos , Feminino , Humanos , Animais , Mucopolissacaridose I/terapia , Iduronidase/genética , Iduronidase/uso terapêutico , Fenótipo , Ansiedade
10.
Cornea ; 42(8): 992-999, 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-36857777

RESUMO

PURPOSE: Mucopolysaccharidoses (MPSs) are a rare group of lysosomal storage disorders characterized by the accumulation of incompletely degraded glycosaminoglycans (GAGs) in multiple organ systems, including the eye. Visual loss occurs in MPS predominantly due to corneal clouding. Despite the success of enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) in improving many systemic manifestations of MPS, less is known about their effect on corneal clouding. This study prospectively analyses the effect of both ERT and HSCT on corneal clouding using objective measures over time. METHODS: This is a prospective longitudinal observational study. Corneal clouding was assessed in each participant using slitlamp, digital slit-lamp photographs, and an iris camera (Corneal Opacification Measure [COM] and the Pentacam system). RESULTS: Data were collected for 65 participants: 39 MPS I (Hurler), 5 MPS II (Hunter), 12 MPS IV (Morquio), and 9 MPS VI (Maroteaux-Lamy). Follow-up data are available for 45 participants (29 MPS I, 3 MPS II, 6 MPS IV, and 7 MPS VI). CONCLUSIONS: This study found corneal clouding to be stable in most participants with MPS I, II, IV, and VI over a follow-up period of 5 to 75 months (median of 30 months) when measured with clinical corneal grading systems, graded digital slit-lamp images, and iris camera COMs. For those with Pentacam densitometry measures, there was a progression of corneal clouding, on average, in those with MPS I and MPS VI. There was no apparent difference in progression of corneal clouding between patients who were on ERT, HSCT, or no treatment.


Assuntos
Doenças da Córnea , Opacidade da Córnea , Mucopolissacaridoses , Mucopolissacaridose I , Humanos , Estudos Prospectivos , Mucopolissacaridoses/complicações , Mucopolissacaridoses/terapia , Opacidade da Córnea/diagnóstico , Opacidade da Córnea/etiologia , Doenças da Córnea/diagnóstico , Doenças da Córnea/etiologia , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/terapia , Terapia de Reposição de Enzimas/métodos
12.
J Inherit Metab Dis ; 46(2): 348-357, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36601751

RESUMO

Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disease caused by α-L-iduronidase enzyme deficiency, resulting in glycosaminoglycan (GAG) accumulation in various cell types, including ocular tissues. Ocular manifestations in humans are common with significant pathological changes including corneal opacification, retinopathy, optic nerve swelling and atrophy, and glaucoma. Available treatments for MPS I are suboptimal and there is limited to no effect in treating the ocular disease. The goal of this study was to characterize the clinical and pathological features of ocular disease in a line of MPS I affected dogs, including changes not previously reported. A total of 22 dogs were studied; 12 MPS I were affected and 10 were unaffected. A subset of each underwent complete ophthalmic examination including slit lamp biomicroscopy, indirect ophthalmoscopy, rebound tonometry, and ultrasonic pachymetry. Globes were evaluated microscopically for morphological changes and GAG accumulation. Clinical corneal abnormalities in affected dogs included edema, neovascularization, fibrosis, and marked stromal thickening. Intraocular pressures were within reference interval for affected and unaffected dogs. Microscopically, vacuolated cells containing alcian blue positive inclusions were detected within the corneal stroma, iris, ciliary body, sclera, and optic nerve meninges of affected dogs. Ganglioside accumulation was identified by luxol fast blue staining in rare retinal ganglion cells. Increased lysosomal integral membrane protein-2 expression was demonstrated within the retina of affected animals when compared to unaffected controls. Results of this study further characterize ocular pathology in the canine model of MPS I and provide foundational data for future therapeutic efficacy studies.


Assuntos
Oftalmopatias , Doenças por Armazenamento dos Lisossomos , Mucopolissacaridose I , Doenças Retinianas , Humanos , Cães , Animais , Mucopolissacaridose I/terapia , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Glicosaminoglicanos/metabolismo , Iduronidase/uso terapêutico
13.
Hum Gene Ther ; 34(1-2): 8-18, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36541357

RESUMO

The mucopolysaccharidoses (MPS) are a group of recessively inherited conditions caused by deficiency of lysosomal enzymes essential to the catabolism of glycosaminoglycans (GAG). MPS I is caused by deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA), while MPS II is caused by a lack of iduronate-2-sulfatase (IDS). Lack of these enzymes leads to early mortality and morbidity, often including neurological deficits. Enzyme replacement therapy has markedly improved the quality of life for MPS I and MPS II affected individuals but is not effective in addressing neurologic manifestations. For MPS I, hematopoietic stem cell transplant has shown effectiveness in mitigating the progression of neurologic disease when carried out in early in life, but neurologic function is not restored in patients transplanted later in life. For both MPS I and II, gene therapy has been shown to prevent neurologic deficits in affected mice when administered early, but the effectiveness of treatment after the onset of neurologic disease manifestations has not been characterized. To test if neurocognitive function can be recovered in older animals, human IDUA or IDS-encoding AAV9 vector was administered by intracerebroventricular injection into MPS I and MPS II mice, respectively, after the development of neurologic deficit. Vector sequences were distributed throughout the brains of treated animals, associated with high levels of enzyme activity and normalized GAG storage. Two months after vector infusion, treated mice exhibited spatial navigation and learning skills that were normalized, that is, indistinguishable from those of normal unaffected mice, and significantly improved compared to untreated, affected animals. We conclude that cognitive function was restored by AAV9-mediated, central nervous system (CNS)-directed gene transfer in the murine models of MPS I and MPS II, suggesting that gene transfer may result in neurodevelopment improvements in severe MPS I and MPS II when carried out after the onset of cognitive decline.


Assuntos
Disfunção Cognitiva , Iduronato Sulfatase , Mucopolissacaridose II , Mucopolissacaridose I , Doenças do Sistema Nervoso , Humanos , Animais , Camundongos , Idoso , Qualidade de Vida , Mucopolissacaridose II/genética , Mucopolissacaridose II/terapia , Mucopolissacaridose I/genética , Mucopolissacaridose I/terapia , Sistema Nervoso Central/metabolismo , Iduronidase/genética , Iduronidase/metabolismo , Iduronato Sulfatase/genética , Disfunção Cognitiva/metabolismo , Glicosaminoglicanos/metabolismo , Modelos Animais de Doenças
14.
Bone Marrow Transplant ; 58(3): 295-302, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36494569

RESUMO

Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8-16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation (n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I , Adulto , Humanos , Mucopolissacaridose I/terapia , Seguimentos , Estudos Retrospectivos , Terapia Genética , Iduronidase/uso terapêutico
15.
Genes (Basel) ; 13(8)2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35893030

RESUMO

Mucopolysaccharidosis type I (MPS I) is a rare inherited lysosomal disorder caused by deficiency of the α-L-iduronidase enzyme, resulting in the progressive accumulation of glycosaminoglycans (GAGs), which interfere with the normal function of multiple tissues and organs. The clinical phenotype includes characteristic facial features, hepatosplenomegaly, dysostosis multiplex, umbilical and inguinal hernias, progressive cognitive deficits with corresponding hydrocephalus, and neuropathology. Untreated children do not survive into the second decade. The common cardiac phenotype seen in MPS I and other MPS types includes valve thickening and dysfunction, conduction abnormalities, coronary artery disease, and cardiomyopathy-usually seen later in the disease course. A 15-month-old ex-35-weeker who presented with cardiomyopathy and left ventricular failure at the age of three weeks is presented here. Early evaluation and diagnosis with the help of newborn screening (NBS), followed by treatment with enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), resulted in improvement of his cardiopulmonary status. In MPS I, an early cardiac phenotype is uncommon. Based on the evidence from the literature review for early neonatal cardiac phenotype, we propose that all infants with abnormal newborn screening for MPS I should receive cardiac screening with echocardiogram and NT-proB-type natriuretic peptide (BNP) during the initial evaluation.


Assuntos
Cardiomiopatias , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I , Terapia de Reposição de Enzimas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/genética , Mucopolissacaridose I/terapia , Fenótipo , Doenças Raras/tratamento farmacológico
16.
Artigo em Inglês | MEDLINE | ID: mdl-35619307

RESUMO

BACKGROUND: Mucopolysaccharidosis-1H (Hurler syndrome, MPS-1H) is the most severe form of a lysosomal storage disorder (LSD) caused by variants in IDUA, encoding alpha- L-iduronidase (IDUA). MPS-1H is also associated with various degrees of skeletal defects due to the accumulation of partially degraded glycosaminoglycans (GAGs) in the lysosomes of connective tissue cells. The efficacy of hematopoietic stem cell transplantation (HSCT) and enzymatic replacement therapy (ERT) on MPS-1H skeletal manifestations is still considered unsatisfactory. CASE PRESENTATION: We report the case of a young girl, who manifested significant changes in bone remodeling markers and osteoclastogenesis potential after HSCT combined with ERT. She received ERT and underwent two HSCTs. The skeletal alterations at the time of diagnosis showed a trend toward improvement of both mobility and radiological features after HSCT. We observed the highest levels of Receptor activator of nuclear factor-kappa-Β ligand (RANKL) and RANK/osteoprotegerin (OPG) ratio at diagnosis and during ERT, consistently with spontaneous osteoclastogenesis. Conversely, after the successful HSCT with ongoing ERT, the highest levels of osteocalcin were observed and all markers of bone formation and resorption improved. CONCLUSION: The combination therapy of ERT and HSCT was effective in reducing osteoclast activity and increasing osteoblast activity, and these changes were according to the child's bone phenotype, IDUA activity, and Glycosaminoglycan (GAG) trends. These results represent one of the few pieces of human evidence in this context.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Doenças por Armazenamento dos Lisossomos , Mucopolissacaridose I , Criança , Feminino , Humanos , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/metabolismo , Mucopolissacaridose I/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Terapia de Reposição de Enzimas/métodos , Remodelação Óssea
17.
Int J Mol Sci ; 23(9)2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35563175

RESUMO

Mucopolysaccharidosis type I (MPS I) is a rare monogenic disease in which glycosaminoglycans' abnormal metabolism leads to the storage of heparan sulfate and dermatan sulfate in various tissues. It causes its damage and impairment. Patients with the severe form of MPS I usually do not live up to the age of ten. Currently, the therapy is based on multidisciplinary care and enzyme replacement therapy or hematopoietic stem cell transplantation. Applying gene therapy might benefit the MPS I patients because it overcomes the typical limitations of standard treatments. Nanoparticles, including nanoemulsions, are used more and more in medicine to deliver a particular drug to the target cells. It allows for creating a specific, efficient therapy method in MPS I and other lysosomal storage disorders. This article briefly presents the basics of nanoemulsions and discusses the current state of knowledge about their usage in mucopolysaccharidosis type I.


Assuntos
Mucopolissacaridose II , Mucopolissacaridose I , Terapia de Reposição de Enzimas , Terapia Genética , Glicosaminoglicanos/metabolismo , Heparitina Sulfato/metabolismo , Humanos , Mucopolissacaridose I/genética , Mucopolissacaridose I/terapia , Mucopolissacaridose II/genética
19.
Mol Genet Metab ; 136(1): 22-27, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35304037

RESUMO

BACKGROUND: A physical symptom score (PSS) for the mucopolysaccharidosis (MPS) disorders has been developed to quantitate the somatic burden of disease across multiple organ systems. Studies have demonstrated the sensitivity and its relationship to age, IQ and adaptive functioning of the PSS in older children. With the onset of newborn screening, there is an increased need to characterize the somatic symptoms in the earliest stages of life, especially for young children under 36 months of age. Consequently, a new scale, Infant Physical Symptom Score (IPSS), was developed to score physical symptoms in infants and toddlers. OBJECTIVE: Part I. To create a measure to quantify somatic burden in patients with MPS disorders under 36 months of age. The IPSS assess outcomes and changes in somatic disease in individuals with MPS disorders diagnosed very early in life. Part II. To determine the relationship between IPSS and other measures to evaluate its validity and utility, a) we evaluated the relationship between the IPSS and PSS in the same patients with MPS I over time to determine if the two scales are measuring the same concepts, and b) we evaluated the association between IPSS and a functional adaptive measure over time with a focus on the age at first treatment (under 36 months) to determine if the IPSS has predictive value. METHODS: Part I. The Infant Physical Symptom Score (IPSS) for the infant population in MPS disorders was established using data from 39 patients enrolled in the Lysosomal Disease Network longitudinal MPS I study (U54NS065768). All of these patients had Hurler syndrome (MPS IH) and underwent hematopoietic stem cell transplant (HSCT) at the University of Minnesota. Items for the IPSS were selected by reviewing CRFs prepared for the MPS I longitudinal study and examining medical records of these patients prior to HSCT based on the knowledge gained from the development of the PSS. Part II. Of those 39 patients, a subset of 19 were all seen 9 to 12 years post HSCT. Having retrospectively calculated their IPSS prior to HSCT, we categorized them by age at HSCT, and examined their most recent PSS along with Composite and Daily Living Skills scores on the Vineland Adaptive Behavior Scales - Second Edition (VABS-II). RESULTS AND CONCLUSION: The total score on the IPSS collected prior to transplant differed by patient's age at transplant, as expected in this progressive condition. Those transplanted at ≤12 months of age had a mean score of 7.4, which was significantly lower, suggesting less somatic disease burden, compared to those transplanted at >12 to ≤24 months (mean 11.8) and > 24 to ≤36 months (mean 13.6). Higher IPSS reflects more evidence of somatic disease burden and lower IPSS reflects less evidence of disease burden. Nine to 12 years later, the severity level as measured by the PSS was comparable to severity on the IPSS suggesting that the two scales are measuring similar concepts. Retrospectively calculated pre-transplant IPSS were negatively associated with higher VABS-II Composite scores 9-12 years later (p value-0.015) and to a lesser extent Daily Living Skills scores (p value-0.081). We conclude that the IPSS appears to be a useful approach to quantifying the somatic disease burden of MPS IH patients under 36 months of age.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Mucopolissacaridose I/complicações , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/terapia , Estudos Retrospectivos
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