RESUMEN

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.

Asunto(s)

Quiste Dentígero , Mucopolisacaridosis I , Humanos , Quiste Dentígero/cirugía , Quiste Dentígero/diagnóstico , Mucopolisacaridosis I/complicaciones , Mucopolisacaridosis I/diagnóstico , Mucopolisacaridosis I/terapia , Masculino , Enfermedades Mandibulares/cirugía , Enfermedades Mandibulares/diagnóstico , Femenino

RESUMEN

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by a deficiency of glycosaminoglycan (GAG) catalytic enzymes, resulting in an accumulation of unprocessed or partly degraded GAGs in different tissues, including bones and joints. Notably, skeletal and joint abnormalities may be the first complaint that prompts patients to seek medical attention, especially in the milder forms of the disease. To our knowledge, there are no prior imaging reports that have documented capsuloligamentous thickening in patients with MPS on MRI. In this study, we present four cases of patients with clinically and genetically confirmed diagnosis of type II MPS, encompassing seven MRI examination of different joints, including cervical spine, hip, wrist, knee, and shoulder. All of the patients were male, aged between 14 and 35 years, and exhibited varying degrees of joint stiffness in the clinical examination and carpal tunnel syndrome in cases of the wrist joint was affected. None of the patients had a history of surgical procedures on the affected joint, other metabolic or deposit diseases, or sports activity practice. The MRI revealed significant capsuloligamentous and retinaculum thickening, up to eight times greater than the normal capsular thickness reported in the literature.

Asunto(s)

Síndrome del Túnel Carpiano , Artropatías , Mucopolisacaridosis , Mucopolisacaridosis I , Humanos , Masculino , Adolescente , Adulto Joven , Adulto , Femenino , Mucopolisacaridosis/diagnóstico por imagen , Mucopolisacaridosis/complicaciones , Artropatías/etiología , Imagen por Resonancia Magnética , Vértebras Cervicales , Mucopolisacaridosis I/complicaciones , Mucopolisacaridosis I/diagnóstico

RESUMEN

OBJECTIVE: To report on the first 3 years of mucopolysaccharidosis type I (MPS I) newborn screening (NBS) in the large and diverse state of California. STUDY DESIGN: The California Genetic Disease Screening Program began universal NBS for MPS I on August 29, 2018. The screening uses a 2-tiered approach: an α-L-iduronidase (IDUA) enzyme activity assay followed by DNA sequencing for variants in the IDUA gene. RESULTS: As of August 29, 2021, 1 295 515 California newborns were screened for MPS I. In tier 1 of screening, 329 (0.025%) had an IDUA enzyme measurement below the cutoff and underwent tier-2 IDUA DNA sequencing. After tier 2, 146 (0.011%) newborns were screen positive, all of whom were referred to a metabolic Special Care Center for follow-up. After long-term follow-up, 7 cases were resolved as severe MPS I (Hurler syndrome) and 2 cases as attenuated MPS I for an MPS I birth prevalence of 1/143 946. DNA sequencing identified 107 unique IDUA variants among a total of 524 variants; 65% were known pseudodeficiency alleles, 25% were variants of uncertain significance, and 10% were pathogenic variants. CONCLUSIONS: As a result of a 2-tiered NBS approach, 7 newborns diagnosed with Hurler syndrome had received early treatment for MPS I. Continuation of California's long-term follow-up program will be crucial for further understanding the complex genotype-phenotype relationships of MPS I.

Asunto(s)

Mucopolisacaridosis I , Humanos , Recién Nacido , Mucopolisacaridosis I/diagnóstico , Mucopolisacaridosis I/genética , Tamizaje Neonatal , Iduronidasa/genética , Pruebas Genéticas , Alelos

RESUMEN

Mucopolysaccharidosis type I (MPS I) is caused by alpha-L-iduronidase deficiency encoded by the IDUA gene. Therapy with CRISPR/Cas9 is being developed for treatment, however a detailed investigation of off-target effects must be performed. This study aims to evaluate possible off-targets for a sgRNA aiming to correct the most common variant found in MPS I patients (p.Trp402*). A total of 272 potential off-target sequences was obtained and 84 polymorphic sites were identified in these sequences with a frequency equal to or greater than 1% in at least one of the populations. In the majority of cases, polymorphic sites decrease the chance of off-target cleavage and a new PAM was created, which indicates the importance of such analysis. This study highlights the importance of screening off-targets in a population-specific context using Mucopolysaccharidosis type I as an example of a problem that concerns all therapeutic treatments. Our results can have broader applications for other targets already clinically in use, as they could affect CRISPR/Cas9 safety and efficiency.

Asunto(s)

Proteína 9 Asociada a CRISPR , Sistemas CRISPR-Cas , Edición Génica , Mucopolisacaridosis I/terapia , Simulación por Computador , Edición Génica/métodos , Marcación de Gen/métodos , Humanos , Mucopolisacaridosis I/genética , Polimorfismo Genético

RESUMEN

BACKGROUND: Mucopolysaccharidosis type I (MPS I) is an inherited disease caused by deficiency of the enzyme alpha-l-iduronidase (IDUA). MPS I affects several tissues, including the brain, leading to cognitive impairment in the severe form of the disease. Currently available treatments do not reach the brain. Therefore, in this study, we performed nasal administration (NA) of liposomal complexes carrying two plasmids encoding for the CRISPR/Cas9 system and for the IDUA gene targeting the ROSA26 locus, aiming at brain delivery in MPS I mice. METHODS: Liposomes were prepared by microfluidization, and the plasmids were complexed to the formulations by adsorption. Physicochemical characterization of the formulations and complexes, in vitro permeation, and mucoadhesion in porcine nasal mucosa (PNM) were assessed. We performed NA repeatedly for 30 days in young MPS I mice, which were euthanized at 6 months of age after performing behavioral tasks, and biochemical and molecular aspects were evaluated. RESULTS: Monodisperse mucoadhesive complexes around 110 nm, which are able to efficiently permeate the PNM. In animals, the treatment led to a modest increase in IDUA activity in the lung, heart, and brain areas, with reduction of glycosaminoglycan (GAG) levels in serum, urine, tissues, and brain cortex. Furthermore, treated mice showed improvement in behavioral tests, suggesting prevention of the cognitive damage. CONCLUSION: Nonviral gene editing performed through nasal route represents a potential therapeutic alternative for the somatic and neurologic symptoms of MPS I and possibly for other neurological disorders.

Asunto(s)

Mucopolisacaridosis I , Animales , Encéfalo/metabolismo , Sistemas CRISPR-Cas/genética , Edición Génica , Iduronidasa/genética , Iduronidasa/metabolismo , Ratones , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/terapia , Plásmidos

RESUMEN

We developed a brain and spine magnetic resonance scoring system based on a magnetic resonance assessment of 9 patients with mucopolysaccharidosis type I-Hurler who underwent hematopoietic stem-cell transplantation. The score is reliable and correlates with long-term clinical and cognitive outcome in patients with mucopolysaccharidosis type I-Hurler.

Asunto(s)

Encéfalo/diagnóstico por imagen , Mucopolisacaridosis I/diagnóstico por imagen , Médula Espinal/diagnóstico por imagen , Adolescente , Encéfalo/patología , Niño , Preescolar , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Imagen por Resonancia Magnética , Masculino , Mucopolisacaridosis I/patología , Mucopolisacaridosis I/cirugía , Neuroimagen , Estudios Retrospectivos , Médula Espinal/patología

RESUMEN

Introducción: el síndrome de Hurler es la forma más grave de la mucopolisacaridosis I. El depósito de heparán y dermatán sulfato en las meninges favorece el desarrollo de hidrocefalia y, a su vez, de meningoencefaloceles. Caso clínico: se describe el caso de una paciente de 23 años con este síndrome y un encefalocele nasosinusal intervenido mediante cirugía endoscópica nasosinusal y posterior refuerzo mediante un colgajo pericraneal. Discusión: el abordaje endoscópico de los meningoencefaloceles nasales ha crecido notablemente en los últimos años debido a una tasa de éxito elevada tanto para la eliminación de dicha lesión, como para el adecuado control de la fístula de líquido cefalorraquídeo consecuente. Conclusiones: actualmente, la cirugía endoscópica nasosinusal es una herramienta muy útil para el tratamiento de patologías de base de cráneo y reduce la morbilidad causada por el abordaje transcraneal.

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Introduction: Hurler syndrome is the most severe version of mucopolysaccharidosis I. The storage of dermatan and heparin sulfate in meninges allows the development of hydrocephalus and meningoencephaloceles. Case report: We report a 23-year-old female with this syndrome and a sinonasal encephalocele operated by endoscopic sinonasal surgery and subsequent pericranial flap as support. Discussion: Endoscopic sinonasal surgery has grown in last years in relation with treatment of sinonasal meningoencephaloceles due to a high rate of success removing the lesion and closing the subsequent cerebrospinal fluid fistula. Conclusion: Currently, the endoscopic sinonasal surgery has become a useful tool in the management of skull base pathologies, and reduces the morbidity due to a transcranial approach.

Asunto(s)

Humanos , Mucopolisacaridosis I , Colgajos Quirúrgicos , Encefalocele

RESUMEN

Se describen como desafíos actuales en mucopolisacaridosis I la necesidad de una clasificación adecuada, vinculándola a las indicaciones terapéuticas; el diagnóstico temprano desde la pesquisa neonatal, sus ventajas y dificultades hasta la sospecha clínica de las formas grave y atenuada; el cuidado de la patología espinal y oftalmológica, desde el diagnóstico, el seguimiento y el tratamiento; las reacciones alérgicas por terapia de reemplazo enzimático, su diagnóstico y tratamiento. Por último, la transición hacia el cuidado adulto

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Here we describe the current challenges of mucopolysaccharidosis type I: the need for an adequate classification, establishing its relationship to therapeutic indications; an early diagnosis, from neonatal screening, its advantages and barriers, to clinical suspicion of severe and attenuated forms; spinal and eye disease care, from diagnosis to follow-up and treatment; allergic reactions caused by enzyme replacement therapy, their diagnosis and treatment. And lastly, transition to adult care

Asunto(s)

Humanos , Masculino , Femenino , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Mucopolisacaridosis I/diagnóstico , Mucopolisacaridosis I/terapia , Tamizaje Neonatal , Mucopolisacaridosis I/clasificación , Oftalmopatías/diagnóstico , Oftalmopatías/terapia , Transición a la Atención de Adultos , Hipersensibilidad/diagnóstico , Hipersensibilidad/terapia

RESUMEN

Here we describe the current challenges of mucopolysaccharidosis type I: the need for an adequate classification, establishing its relationship to therapeutic indications; an early diagnosis, from neonatal screening, its advantages and barriers, to clinical suspicion of severe and attenuated forms; spinal and eye disease care, from diagnosis to follow-up and treatment; allergic reactions caused by enzyme replacement therapy, their diagnosis and treatment. And lastly, transition to adult care.

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Se describen como desafíos actuales en mucopolisacaridosis I la necesidad de una clasificación adecuada, vinculándola a las indicaciones terapéuticas; el diagnóstico temprano desde la pesquisa neonatal, sus ventajas y dificultades hasta la sospecha clínica de las formas grave y atenuada; el cuidado de la patología espinal y oftalmológica, desde el diagnóstico, el seguimiento y el tratamiento; las reacciones alérgicas por terapia de reemplazo enzimático, su diagnóstico y tratamiento. Por último, la transición hacia el cuidado adulto.

Asunto(s)

Hipersensibilidad , Mucopolisacaridosis I , Adulto , Terapia de Reemplazo Enzimático , Humanos , Recién Nacido , Mucopolisacaridosis I/tratamiento farmacológico , Mucopolisacaridosis I/terapia , Tamizaje Neonatal

RESUMEN

Background: Mucopolysaccharidoses (MPS) are a group of rare illnesses caused by deficient activity of enzymes requiredfor degradation of glycosaminoglycans (GAGs). Each type of MPS is caused by mutations in one of the genes that encodethe 11 acid hydrolases involved in this degradation process, which are present in the lysosomes. Progressive accumulationof GAGs in the lysosomes result in cellular dysfunction and multisystemic clinical signs, with consequent decrease in quality of life and lifespan of the affected patients. The objective of the present work is to report a case of MPS type I in a dog.Case: A mixed-breed male dog of approximately 2-month-old weighing 2.5 kg was referred to Hospital Veterinário deUberaba with a distended abdomen. At the clinical examination, the patient exhibited a regular nutritional status, pale mucous membranes, 7% dehydration, an arterial pulse rate of 120 beats per minute, a respiratory rate of 40 breaths per minute,and a heart rate of 120 beats per minute. There were increased abdominal volume and tension, and hepatosplenomegaly.The abdominal percussion exam produced a dull tone. Additional findings included muscular atrophy, increased volume inthe metaphyseal areas of the thoracic and pelvic limbs, valgus limb deformity in the thoracic limbs, and instability of thehip joint. Radiographic examination revealed a series of bone alterations such as reduced vertebral bodies, a generalizeddecrease in radiopacity, thin cortical areas in long bones, narrowing of the pelvic canal, and marked deformation and irregularities in acetabular and epiphyseal (both proximal and distal) areas of the femurs and tibias. Ankylosis of the tibiotarsal andtarsometatarsal joints was also observed. There was also loss of trabecular structure and irregularities on the surfaces of allepiphyses of the bones, epiphyseal lines markedly open, and bones that were...(AU)

Asunto(s)

Animales , Masculino , Perros , Perros , Mucopolisacaridosis I/veterinaria , Leucocitosis/veterinaria , Radiografía/veterinaria , Huesos/anomalías

RESUMEN

Dados los avances sobre mucopolisacaridosis Icon posterioridad al consenso publicado en la Argentina por un grupo de expertos en 2008, se revisan recomendaciones respecto a estudios genéticos, seguimiento cardiológico, cuidado de la vía aérea, alertas sobre aspectos auditivos, de la patología espinal y neurológica. Se hace revisión de la terapéutica actual y se enfatiza en la necesidad de un diagnóstico y tratamiento precoces, así como de un seguimiento interdisciplinario

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Considering the advances made on mucopolysaccharidosis type I after the consensus study published by a group of experts in Argentina in 2008, recommendations about genetic testing, cardiological follow-up, airway care, hearing impairment detection, spinal and neurological conditions, as well as current treatments, were reviewed. Emphasis was placed on the need for early diagnosis and treatment, as well as an interdisciplinary follow-up

Asunto(s)

Humanos , Mucopolisacaridosis I/diagnóstico , Mucopolisacaridosis I/terapia , Pediatría , Mucopolisacaridosis I/etiología , Mucopolisacaridosis I/genética , Cuidados Posteriores

RESUMEN

Objetivo: Describir las características bucales prevalentes de pacientes argentinos con mucopolisacaridosis (MPS) atendidos en el Servicio de Odontología del Hospital Nacional "Prof. Alejandro Posadas". Materiales y métodos: Se consideraron las historias clínicas de 19 pacientes con diagnóstico de MPS. Se registraron la edad, el sexo, el lugar de residencia, el tipo de MPS y la presencia de retraso madurativo. La muestra estuvo constituida por 13 niños (6,7±3 años) y 6 adultos (26±9 años): 2 eran mujeres (1 con MPS tipo I; 1 con MPS tipo IV A) y 17 eran hombres (15 con MPS tipo 2; 1 con MPS tipo 1; 1 con MPS tipo III); 13 de los pacientes presentaban discapacidad intelectual. Se evaluaron: tipo de dentición, oclusión, macroglosia, hipoplasias del esmalte, tipo de respiración predominante, clase molar y tratamiento realizado. Resultados: Ambos casos con MPS I presentaban mordida abierta anterior y giroversión dental, y solo uno de estos, diastemas, microdoncia, hipoplasias del esmalte, macroglosia y respiración bucal. De los 15 pacientes con MPS II, 11 presentaban mordida abierta anterior (73%), 3 mordida cruzada posterior (20%), 5 giroversión dental (33%), 11 diastemas (73%), 3 retraso en la erupción (20%), 4 hiperplasia gingival (26%), 13 macroglosia (87%), 7 hipoplasias del esmalte (47%), 2 microdoncia (13%), 9 respiración bucal (60%). Se registraron 5 pacientes con clase molar I (33%), 3 con clase molar II (20%), 3 con clase molar III (20%) y en 3 casos no se pudo evaluar (20%). En el paciente con MPS tipo III se halló mordida abierta anterior, diastemas, retraso en la erupción, macroglosia, respiración bucal y clase molar II; y en el caso de MPS tipo IV A, mordida abierta anterior, diastemas, hiperplasia gingival, macroglosia y clase molar II. El 90% de los pacientes requirió tratamiento odontológico (AU)

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Aim: To identify the most prevalent oral manifestations of 19 Argentine patients with mucopolysaccharidos (MPS) attending the Dentistry Service of the National Posadas Hospital. Materials and methods: The medical records of 19 patients diagnosed with MPS were considered. Age, sex, place of residence, type of MPS, and presence of maturational delay were recorded. The sample consisted of 13 children (6.7 ± 3 years) and 6 adults (26 ± 9 years): 2 were women (1 with MPS type I; 1 with MPS type IV A) and 17 were men (15 with MPS type 2; 1 with MPS type 1; 1 with MPS type III); 13 of the patients had intellectual disabilities. The following were evaluated: type of dentition, occlusion, macroglossia, enamel hypoplasia, predominant type of respiration, molar class and treatment performed Results: Both cases with MPS I presented anterior open bite and dental gyroversion, and only one of these, diastemas, microdontia, enamel hypoplasia, macroglossia and mouth respiration. Of the 15 patients with MPS II, 11 presented anterior open bite (73%), 3 posterior crossbite (20%), 5 dental gyroversion (33%), 11 diastemas (73%), 3 delayed eruption (20%), 4 gingival hyperplasia (26%), 13 macroglossia (87%), 7 enamel hypoplasia (47%), 2 microdontia (13%), 9 mouth breathing (60%). 5 patients with molar class I (33%), 3 with molar class II (20%), 3 with molar class III (20%) and in 3 cases it could not be evaluated (20%). In the patient with type III MPS, anterior open bite, diastemas, delayed eruption, macroglossia, mouth breathing and molar class II were found; and in the case of type IV A MPS, anterior open bite, diastemas, gingival hyperplasia, macroglossia and molar class II. 90% of the patients required dental treatment. Conclusion: The most observed oral manifestations were macroglossia (84.2%) and anterior open bite (73%) (AU)

Asunto(s)

Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Manifestaciones Bucales , Mucopolisacaridosis II/patología , Mucopolisacaridosis I/patología , Mucopolisacaridosis III/patología , Argentina , Epidemiología Descriptiva , Estudios Transversales , Mordida Abierta/epidemiología , Servicio Odontológico Hospitalario/estadística & datos numéricos , Distribución por Edad y Sexo , Macroglosia/epidemiología , Maloclusión/epidemiología

RESUMEN

Considering the advances made on mucopolysaccharidosis type I after the consensus study published by a group of experts in Argentina in 2008, recommendations about genetic testing, cardiological follow-up, airway care, hearing impairment detection, spinal and neurological conditions, as well as current treatments, were reviewed. Emphasis was placed on the need for early diagnosis and treatment, as well as an interdisciplinary follow-up.

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Dados los avances sobre mucopolisacaridosis I con posterioridad al consenso publicado en la Argentina por un grupo de expertos en 2008, se revisan recomendaciones respecto a estudios genéticos, seguimiento cardiológico, cuidado de la vía aérea, alertas sobre aspectos auditivos, de la patología espinal y neurológica. Se hace revisión de la terapéutica actual y se enfatiza en la necesidad de un diagnóstico y tratamiento precoces, así como de un seguimiento interdisciplinario.

Asunto(s)

Mucopolisacaridosis I , Argentina , Consenso , Humanos , Mucopolisacaridosis I/diagnóstico , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/terapia

RESUMEN

BACKGROUND: Mucopolysaccharidosis type I (MPS I) is an inherited disorder caused by α-L-iduronidase (IDUA) deficiency. The available treatments are not effective in improving all signs and symptoms of the disease. OBJECTIVE: In the present study, we evaluated the transfection efficiency of repeated intravenous administrations of cationic nanoemulsions associated with the plasmid pIDUA (containing IDUA gene). METHODS: Cationic nanoemulsions were composed of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(amino[polyethylene glycol]- 2000) (DSPE-PEG), 1,2-dioleoyl-sn-glycero-3-trimethylammonium propane (DOTAP), medium- chain triglycerides, glycerol, and water and were prepared by high-pressure homogenization and were repeatedly administered to MPS I mice for IDUA production and gene expression. RESULTS: A significant increase in IDUA expression was observed in all organs analyzed, and IDUA activity tended to increase with repeated administrations when compared to our previous report when mice received a single administration of the same dose. In addition, GAGs were partially cleared from organs, as assessed through biochemical and histological analyzes. There was no presence of inflammatory infiltrate, necrosis, or signs of an increase in apoptosis. Furthermore, immunohistochemistry for CD68 showed a reduced presence of macrophage cells in treated than in untreated MPS I mice. CONCLUSION: These sets of results suggest that repeated administrations can improve transfection efficiency of cationic complexes without a significant increase in toxicity in the MPS I murine model.

Asunto(s)

Mucopolisacaridosis I , Animales , Terapia Genética , Iduronidasa/genética , Ratones , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/terapia , Plásmidos , Transfección

RESUMEN

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by alpha-L-iduronidase (IDUA) deficiency, an enzyme responsible for glycosaminoglycan degradation. Musculoskeletal impairment is an important component of the morbidity related to the disease, as it has a major impact on patients' quality of life. To understand how this disease affects bone structure, morphological, biomechanical and histological analyses of femurs from 3- and 6-month-old wild type (Idua +/+) and MPS I knockout mice (Idua -/-) were performed. Femurs from 3-month-old Idua -/- mice were found to be smaller and less resistant to fracture when compared to their age matched controls. In addition, at this age, the femurs presented important alterations in articular cartilage, trabecular bone architecture, and deposition of type I and III collagen. At 6 months of age, femurs from Idua -/- mice were more resistant to fracture than those from Idua +/+. Our results suggest that the abnormalities observed in bone matrix and articular cartilage in 3-month-old Idua -/- animals caused bone tissue to be less flexible and more likely to fracture, whereas in 6-month-old Idua -/- group the ability to withstand more load before fracturing than wild type animals is possibly due to changes in the bone matrix.

Asunto(s)

Iduronidasa/metabolismo , Mucopolisacaridosis I/metabolismo , Mucopolisacaridosis I/patología , Animales , Fenómenos Biomecánicos/fisiología , Colágeno/metabolismo , Modelos Animales de Enfermedad , Femenino , Fémur/enzimología , Fémur/metabolismo , Fémur/patología , Iduronidasa/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mucopolisacaridosis I/enzimología

RESUMEN

Mucopolysaccharidosis type I is a rare autosomal recessive genetic disease caused by deficient activity of α-L-iduronidase. As a consequence of low or absent activity of this enzyme, glycosaminoglycans accumulate in the lysosomal compartments of multiple cell types throughout the body. Mucopolysaccharidosis type I has been classified into 3 clinical subtypes, ranging from a severe Hurler form to the more attenuated Hurler-Scheie and Scheie phenotypes. Over 200 gene variants causing the various forms of mucopolysaccharidosis type I have been reported. DNA isolated from dried blood spot was used to sequencing of all exons of the IDUA gene from a patient with a clinical phenotype of severe mucopolysaccharidosis type I syndrome. Enzyme activity of α-L-iduronidase was quantified by fluorimetric assay. Additionally, a molecular dynamics simulation approach was used to determine the effect of the Ser633Trp mutation on the structure and dynamics of the α-L-iduronidase. The DNA sequencing analysis and enzymatic activity shows a c.1898C>G mutation associated a patient with a homozygous state and α-L-iduronidase activity of 0.24 µmol/L/h, respectively. The molecular dynamics simulation analysis shows that the p.Ser633Trp mutation on the α-L-iduronidase affect significant the temporal and spatial properties of the different structural loops, the N-glycan attached to Asn372 and amino acid residues around the catalytic site of this enzyme. Low enzymatic activity observed for p.Ser633Trp variant of the α-L-iduronidase seems to lead to severe mucopolysaccharidosis type I phenotype, possibly associated with a perturbation of the structural dynamics in regions of the enzyme close to the active site.

Asunto(s)

Anomalías Múltiples/genética , Dermatán Sulfato/química , Heparitina Sulfato/química , Iduronidasa/química , Mucopolisacaridosis I/genética , Mutación Puntual , Anomalías Múltiples/enzimología , Anomalías Múltiples/patología , Anomalías Múltiples/terapia , Dominio Catalítico , Cristalografía por Rayos X , Dermatán Sulfato/metabolismo , Terapia de Reemplazo Enzimático/métodos , Expresión Génica , Heparitina Sulfato/metabolismo , Humanos , Iduronidasa/genética , Iduronidasa/metabolismo , Lactante , Masculino , Simulación de Dinámica Molecular , Mucopolisacaridosis I/enzimología , Mucopolisacaridosis I/patología , Mucopolisacaridosis I/terapia , Análisis de Componente Principal , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Especificidad por Sustrato

RESUMEN

Background: Mucopolysaccharidoses (MPS) are a group of rare illnesses caused by deficient activity of enzymes requiredfor degradation of glycosaminoglycans (GAGs). Each type of MPS is caused by mutations in one of the genes that encodethe 11 acid hydrolases involved in this degradation process, which are present in the lysosomes. Progressive accumulationof GAGs in the lysosomes result in cellular dysfunction and multisystemic clinical signs, with consequent decrease in quality of life and lifespan of the affected patients. The objective of the present work is to report a case of MPS type I in a dog.Case: A mixed-breed male dog of approximately 2-month-old weighing 2.5 kg was referred to Hospital Veterinário deUberaba with a distended abdomen. At the clinical examination, the patient exhibited a regular nutritional status, pale mucous membranes, 7% dehydration, an arterial pulse rate of 120 beats per minute, a respiratory rate of 40 breaths per minute,and a heart rate of 120 beats per minute. There were increased abdominal volume and tension, and hepatosplenomegaly.The abdominal percussion exam produced a dull tone. Additional findings included muscular atrophy, increased volume inthe metaphyseal areas of the thoracic and pelvic limbs, valgus limb deformity in the thoracic limbs, and instability of thehip joint. Radiographic examination revealed a series of bone alterations such as reduced vertebral bodies, a generalizeddecrease in radiopacity, thin cortical areas in long bones, narrowing of the pelvic canal, and marked deformation and irregularities in acetabular and epiphyseal (both proximal and distal) areas of the femurs and tibias. Ankylosis of the tibiotarsal andtarsometatarsal joints was also observed. There was also loss of trabecular structure and irregularities on the surfaces of allepiphyses of the bones, epiphyseal lines markedly open, and bones that were...

Asunto(s)

Masculino , Animales , Perros , Perros , Mucopolisacaridosis I/veterinaria , Leucocitosis/veterinaria , Huesos/anomalías , Radiografía/veterinaria

RESUMEN

OBJECTIVE: Early diagnosis and treatment initiation are important factors for successful treatment of mucopolysaccharidosis type I (MPS I). The purpose of this observational study was to assess whether age at diagnosis and time to first treatment for individuals with MPS I have improved over the last 15 years. STUDY DESIGN: Data from the MPS I Registry (NCT00144794) for individuals with attenuated or severe disease who initiated therapy with laronidase enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT) between 1 January 2003 and 31 December 2017 were included. RESULTS: Data were available for 740 individuals with attenuated (n=291) or severe (n=424) MPS I (unknown n=25). Median age at diagnosis for attenuated disease did not change over time and ranged between 4.5 and 6 years of age while the median duration from diagnosis to first ERT decreased from 5.6 years before/during 2004 to 2.4 months in 2014-2017. For severe MPS I treated with HSCT, median age at diagnosis was less than 1 year and median time to first treatment was less than 3 months throughout the 15-year observation period. CONCLUSIONS: Times to diagnosis and HSCT initiation for individuals with severe MPS I were consistent over time. For individuals with attenuated MPS I, the time to ERT initiation after diagnosis has improved substantially in the last 15 years, but median age at diagnosis has not improved. Efforts to improve early diagnosis in attenuated MPS I are needed to ensure that patients receive appropriate treatment at the optimal time.

Asunto(s)

Diagnóstico Tardío/estadística & datos numéricos , Mucopolisacaridosis I/diagnóstico , Mucopolisacaridosis I/terapia , Tiempo de Tratamiento/estadística & datos numéricos , Niño , Preescolar , Progresión de la Enfermedad , Terapia de Reemplazo Enzimático/métodos , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Masculino , Mucopolisacaridosis I/genética , Sistema de Registros , Estudios Retrospectivos , Índice de Severidad de la Enfermedad

RESUMEN

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by mutations in the IDUA gene, that codifies the alpha-L-iduronidase enzyme, which deficiency leads to storage of glycosaminoglycans, with multiple clinical manifestations. One of the leading causes of death in MPS I patients are cardiac complications such as cardiac valve thickening, conduction abnormalities, myocardial dysfunction, and cardiac hypertrophy. The mechanism leading to cardiac dysfunction in MPS I is not entirely understood. In a previous study, we have demonstrated that losartan and propranolol improved the cardiac function in MPS I mice. Thus, we aimed to investigate whether the pathways influenced by these drugs may modulate the cardiac remodeling process in MPS I mice. According to our previous observation, losartan and propranolol restore the heart function, without altering valve thickness. MPS I mice presented reduced activation of AKT and ERK1/2, increased activity of cathepsins, but no alteration in metalloproteinase activity was observed. Animals treated with losartan showed a reduction in cathepsin activity and restored ERK1/2 activation. While both losartan and propranolol improved heart function, no mechanistic evidence was found for propranolol so far. Our results suggest that losartan or propranolol could be used to ameliorate the cardiac disease in MPS I and could be considered as adjuvant treatment candidates for therapy optimization.

Asunto(s)

Cardiopatías/patología , Losartán/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mucopolisacaridosis I/tratamiento farmacológico , Remodelación Ventricular/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Ecocardiografía , Femenino , Cardiopatías/tratamiento farmacológico , Cardiopatías/genética , Iduronidasa/genética , Sistema de Señalización de MAP Quinasas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/patología , Mutación

RESUMEN

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by a mutation in the IDUA gene, which codes α-L-iduronidase (IDUA), a lysosomal hydrolase that degrades two glycosaminoglycans (GAGs): heparan sulfate (HS) and dermatan sulfate (DS). GAGs are macromolecules found mainly in the extracellular matrix and have important signaling and structural roles which are essential to the maintenance of cell and tissue physiology. Nondegraded GAGs accumulate in various cell types, which characterizes MPS I as a multisystemic progressive disease. Many tissues and vital organs have been described in MPS I models, but there is a lack of studies focused on their effects on the reproductive tract. Our previous studies indicated lower sperm production and morphological damage in the epididymis and accessory glands in male MPS I mice, despite their ability to copulate and to impregnate females. Our aim was to improve the testicular characterization of the MPS I model, with a specific focus on ultrastructural observation of the different cell types that compose the seminiferous tubules and interstitium. We investigated the testicular morphology of 6-month-old male C57BL/6 wild-type (Idua+/+) and MPS I (Idua-/-) mice. We found vacuolated cells widely present in the interstitium and important signs of damage in myoid, Sertoli and Leydig cells. In the cytoplasmic region of Sertoli cells, we found an increased number of vesicles with substrates under digestion and a decreased number of electron-dense vesicles similar to lysosomes, suggesting an impaired flux of substrate degradation. Conclusions: Idua exerts an important role in the morphological maintenance of the seminiferous tubules and the testicular interstitium, which may influence the quality of spermatogenesis, having a greater effect with the progression of the disease.

Asunto(s)

Glicosaminoglicanos/genética , Enfermedades por Almacenamiento Lisosomal/genética , Mucopolisacaridosis I/genética , Células de Sertoli/patología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Células Intersticiales de Cajal/metabolismo , Células Intersticiales de Cajal/patología , Células Intersticiales del Testículo/metabolismo , Células Intersticiales del Testículo/patología , Enfermedades por Almacenamiento Lisosomal/metabolismo , Enfermedades por Almacenamiento Lisosomal/patología , Masculino , Ratones , Mucopolisacaridosis I/metabolismo , Mucopolisacaridosis I/patología , Mutación/genética , Células de Sertoli/metabolismo , Espermatozoides/metabolismo , Espermatozoides/patología