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1.
J Cardiothorac Surg ; 16(1): 141, 2021 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-34030701

RESUMEN

BACKGROUND: The Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI) is a rare, inherited metabolic disease that results in progressive tissue accumulation of dermatan-sulfated glycosaminoglycans and inflammatory consequences that almost always affects the heart valves. From the anesthesia point of view, managing the airway and ventilation might be a serious challenge due to specific features of the syndrome. Additionally, it is more than probable that the surgical team will perform a non-straightforward procedure. CASE PRESENTATION: A 42-year-old male with Maroteaux-Lamy syndrome was referred to our department with shortness of breath, due to severe aortic stenosis, and at least moderate mitral valve regurgitation. The patient was initially scheduled for aortic valve replacement. After multiple attempts with video assisted laryngoscopy, the endotracheal intubation was achieved with the aid of fiberoptic bronchoscopy, while the ventilation succeeded only with laryngeal mask. The somatic features of the syndrome that made the anesthesia induction extremely difficult, also affected the surgical procedure. Suboptimal exposure of the mitral valve, patch enlargement of the aortic root to host the bigger possible prosthesis, and the hard decision to replace the mitral valve even with a marginal indication were the intraoperative challenges for the surgical team. Finally, the patient underwent a successful double valve replacement with aortic root enlargement and 18 months postoperatively remains improved. CONCLUSION: Patients with Maroteaux-Lamy syndrome represent a challenge for both anesthesiologists and cardiac surgeons. The whole team should be well prepared to deal with difficulties in airway management, ventilation and surgical valve exposure. The cardiac surgeon should be ready to offer additional procedures and even replace "prematurely" a moderately diseased valve in order to avoid a dangerous reoperation. The limited knowledge on the natural history of the Maroteaux-Lamy syndrome valvulopathy and the difficulties in anesthesia induction support this approach.


Asunto(s)
Anestesia , Estenosis de la Válvula Aórtica/cirugía , Implantación de Prótesis de Válvulas Cardíacas , Insuficiencia de la Válvula Mitral/cirugía , Mucopolisacaridosis VI/complicaciones , Adulto , Humanos , Intubación Intratraqueal , Masculino
2.
BMC Ophthalmol ; 21(1): 214, 2021 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-33985463

RESUMEN

BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is a rare autosomal recessive inherited disease caused by mutations in the arylsulfatase B (ARSB) gene. MPS VI is a multisystemic disease resulting from a deficiency in arylsulfatase B causing an accumulation of glycosaminoglycans in the tissues and organs of the body. In this report, we present the case of a 16-year-old Chinese male who presented with vision loss caused by corneal opacity. MPS VI was confirmed by genetic diagnosis. CASE PRESENTATION: A 16-year-old Chinese male presented with a one-year history of binocular vision loss. The best-corrected visual acuity was 0.25 in the right eye and 0.5 in the left eye. Although slit-lamp examination revealed corneal opacification in both eyes, the ocular examinations of his parents were normal. At the same time, the patient presented with kyphotic deformity, short stature, joint and skeletal malformation, thick lips, long fingers, and coarse facial features. Genetic assessments revealed that ARSB was the causative gene. Compound heterozygous missense mutations were found in the ARSB gene, namely c.1325G > A (p. Thr442Met) (M1) and c.1197G > C (p. Phe399Leu) (M2). Genetic diagnosis confirmed that the patient had MPS VI. CONCLUSIONS: This paper reports a case of MPS VI confirmed by genetic diagnosis. MPS VI is a multisystem metabolic disease, with corneal opacity as a concomitant ocular symptom. As it is difficult for ophthalmologists to definitively diagnose MPS VI, genetic testing is useful for disease confirmation.


Asunto(s)
Mucopolisacaridosis VI , N-Acetilgalactosamina-4-Sulfatasa , Adolescente , China , Humanos , Masculino , Mucopolisacaridosis VI/diagnóstico , Mucopolisacaridosis VI/genética , Mutación , Mutación Missense , N-Acetilgalactosamina-4-Sulfatasa/genética
6.
Mol Genet Metab ; 133(1): 94-99, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33678523

RESUMEN

Patients with mucopolysaccharidosis type VI (MPS VI) present with a wide range of disease severity and clinical manifestations, with significant functional impairment and shortened lifespan. Enzyme replacement therapy (ERT) with galsulfase has been shown to improve clinical and biochemical parameters including patient survival, quality of life and growth. The present study is a resurvey of 34 Brazilian MPS VI patients with rapidly progressive disease (classical phenotype) who initiated ERT with galsulfase under five years of age and had been on ERT until data collection in 2019, with few exceptions (n = 4 patients who died before 2019). Anthropometric measures, urinary glycosaminoglycans, and data regarding cardiac, orthopedic, neurologic, sleep apnea, hearing and ophthalmologic outcomes were filled in by specialists. Pubertal development, clinical complications, hospitalizations, and surgeries were also assessed. In this resurvey study, treatment with galsulfase has shown to be safe and well tolerated in MPS VI patients who initiated ERT under the age of 5 years and who have been undergoing ERT for approximately 10 years. Mortality rate suggests that early initiation of ERT may have a positive impact on patients' survival, improving but not preventing disease progression and death. MPS VI patients on ERT also showed improved growth velocity and the pubertal development was normal in all surviving patients. Follow-up data on pneumonia and hospitalization suggest that early ERT may have a protective effect against major respiratory complications. Cardiac valve disease progressed since their prior evaluation and spinal cord compression was observed in a large number of patients, suggesting that these disease complications were not modified by ERT.


Asunto(s)
Cognición/efectos de los fármacos , Terapia de Reemplazo Enzimático , Mucopolisacaridosis VI/terapia , N-Acetilgalactosamina-4-Sulfatasa/genética , Adolescente , Brasil/epidemiología , Niño , Preescolar , Femenino , Glicosaminoglicanos/orina , Humanos , Masculino , Mucopolisacaridosis VI/enzimología , Mucopolisacaridosis VI/patología , Mucopolisacaridosis VI/orina , N-Acetilgalactosamina-4-Sulfatasa/uso terapéutico , Fenotipo , Calidad de Vida , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapéutico , Índice de Severidad de la Enfermedad
7.
Mol Genet Metab ; 133(1): 100-108, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33775523

RESUMEN

OBJECTIVE: Long-term outcomes of patients with mucopolysaccharidosis (MPS) VI treated with galsulfase enzyme replacement therapy (ERT) since infancy were evaluated. METHODS: The study was a multicenter, prospective evaluation using data from infants with MPS VI generated during a phase 4 study (ASB-008; Clinicaltrials.govNCT00299000) and clinical data collected ≥5 years after completion of the study. RESULTS: Parents of three subjects from ASB-008 (subjects 1, 2, and 4) provided written informed consent to participate in the follow-up study. One subject was excluded as consent was not provided. Subjects 1, 2, and 4 were aged 0.7, 0.3, and 1.1 years, respectively, at initiation of galsulfase and 10.5, 7.9, and 10.5 years, respectively, at follow-up. All subjects had classical MPS VI based on pre-treatment urinary glycosaminoglycans and the early onset of clinical manifestations. At follow-up, subject 4 had normal stature for age; subjects 1 and 2 had short stature, but height remained around the 90th percentile of growth curves for untreated classical MPS VI. Six-minute walk distance was normal for age/height in subjects 1 (550 m) and 4 (506 m), and reduced for subject 2 (340 m). Subject 2 preserved normal respiratory function, while percent predicted forced vital capacity and forced expiratory volume in 1 s decreased over time in the other subjects. Skeletal dysplasia was already apparent in all subjects at baseline and continued to progress. Cardiac valve disease showed mild progression in subject 1, mild improvement in subject 4, and remained trivial in subject 2. All subjects had considerably reduced pinch and grip strength at follow-up, but functional dexterity was relatively normal for age and there was limited impact on activities of daily living. Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) results showed that subjects 2 and 4 had numerous fine and gross motor competencies. Corneal clouding progressed in all subjects, while progression of hearing impairment was variable. Liver size normalized from baseline in subjects 1 and 4, and remained normal in subject 2. CONCLUSION: Very early and continuous ERT appears to slow down the clinical course of MPS VI, as shown by preservation of endurance, functional dexterity, and several fine and gross motor competencies after 7.7-9.8 years of treatment, and less growth impairment or progression of cardiac disease than could be expected based on the patients' classical phenotype. ERT does not seem to prevent progression of skeletal or eye disease in the long term.


Asunto(s)
Condroitinsulfatasas/genética , Terapia de Reemplazo Enzimático , Mucopolisacaridosis VI/terapia , N-Acetilgalactosamina-4-Sulfatasa/genética , Actividades Cotidianas , Niño , Preescolar , Estudios de Seguimiento , Glicosaminoglicanos/orina , Humanos , Lactante , Masculino , Mucopolisacaridosis VI/genética , Mucopolisacaridosis VI/patología , Proteínas Recombinantes/genética , Pruebas de Función Respiratoria
8.
Rev. cient. odontol ; 9(1): e051, ene.-mar. 2021. ilus
Artículo en Español | LILACS, LIPECS | ID: biblio-1254403

RESUMEN

La mucopolisacaridosis tipo VI, también conocida como síndrome de Maroteaux-Lamy, es un trastorno lisosómico autosómico recesivo, causado por la deficiencia de la enzima arilsulfatasa B, lo que conduce a la acumulación de dermatán sulfato en los tejidos y su excreción urinaria. La deposición de mucopolisacáridos genera un trastorno progresivo que afecta a múltiples órganos y que, a menudo, resulta en la muerte a temprana edad. Esta enfermedad tiene varias manifestaciones orales, entre las que destacan las complicaciones dentales, que pueden ser graves e incluir folículos similares a quistes dentígeros, maloclusiones, defectos condilares e hiperplasia gingival, además de características clínicas como cuello corto, opacidad corneal, macroglosia y agrandamiento del cráneo, dimensión anteroposterior larga y mano en garra. Se presenta el caso de un paciente de 14 meses de edad que acudió a consulta de odontopediatría por episodios de fiebre, bajo peso e hiperplasia gingival severa. El examen físico evidenció facies tosca, cuello corto, pectus excavatus, manos con disminución en agarre y retardo en el neurodesarrollo. El examen intraoral halló retardo de la erupción dental, hiperplasia gingival generalizada y paladar con poco crecimiento transversal. El examen radiográfico detectó órganos dentarios incluidos y mala posición en el sector anterior, molares superiores dentro del seno maxilar y caninos inferiores rotados. El paciente fue remitido a medicina para exámenes bioquímicos y genéticos para definir el diagnóstico. La bioquímica reveló MPS tipo VI, lo que fue confirmado mediante prueba molecular. Las manifestaciones clínicas en este caso corresponden a la forma clínica de progresión rápida reportada en estos pacientes: talla baja, malformaciones esqueléticas y alteraciones a nivel oral. Los niños con MPS VI grave comienzan temprano y progresan rápidamente, las radiografías óseas y la medición de GAG en orina son útiles para el diagnóstico con actividad de la enzima ARSB y genética. Es necesario fortalecer el conocimiento en odontología y la población en general sobre las características clínicas de mucopolisacáridos tipo VI para tener un diagnóstico temprano y un mejor manejo de patologías en estos pacientes. (AU)


Mucopolysaccharidosis type VI, also known as Maroteaux-Lamy syndrome, is an autosomal recessive lysosomal disorder, due to the deficiency of the enzyme arylsulfatase B that leads to the accumulation of dermatan sulfate in the tissues and its urinary excretion. Mucopolysaccharide deposition leads to a progressive disorder affecting multiple organs that often results in death at a young age. This disease has several oral manifestations, among which dental complications can be serious and include follicles similar to dentigerous cysts, malocclusions, condylar defects and gingival hyperplasia, in addition to a short neck, corneal opacity, macroglossia, skull enlargement, anteroposterior dimension long, claw hand is some of the clinical features. A case of a 14-month-old patient is presented, who attended a pediatric dentistry consultation for episodes of fever, low weight, severe gingival hyperplasia. Physical examination revealed coarse facies, short neck, pectus excavatus, hands with decreased grip, and neurodevelopmental delay. On intraoral examination, dental eruption delayed, generalized gingival hyperplasia, palate with little transverse growth. On radiographic examination, dental organs included and poor position in the anterior sector, upper molars within the maxillary sinus, rotated lower canines. He is referred to medicine for biochemical tests and genetics for diagnosis. Detailed biochemistry MPS type VI, confirmed by molecular testing. The clinical manifestations in this case correspond to the clinical form of rapid progression reported in these patients. They report: short stature, skeletal malformations and alterations at the oral level. Children with severe MPS VI start early and progress rapidly, bone radiographs and urine GAG measurement are helpful for diagnosis with genetic and ARSB enzyme activity. It is necessary to strengthen the knowledge in dentistry and the general population about the clinical characteristics of type VI mucopolysaccharides in order to have an early diagnosis and management of pathologies in these patients. (AU)


Asunto(s)
Humanos , Femenino , Lactante , Arilsulfatasas , Mucopolisacaridosis VI , Dermatán Sulfato , Hiperplasia Gingival , Glicosaminoglicanos
10.
Anim Genet ; 51(6): 982-986, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32985704

RESUMEN

Mucopolysaccharidosis (MPS) VI is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-4-sulfatase, also called arylsulfatase B (ARSB, EC 3.1.6.12). Dogs with MPS VI show progressive predominantly oculoskeletal signs homologous to those in human and feline patients. We report herein two pathogenic ARSB gene variants in Miniature Pinscher and Miniature Schnauzer dogs with MPS VI and a genotyping survey in these breeds. All exons and adjacent regions of the ARSB gene were sequenced from three affected Miniature Pinschers and three affected Miniature Schnauzers. Allelic discrimination assays were used for genotyping. A missense variant (NM_001048133.1:c.910G>A) was found in exon 5 of MPS VI-affected Miniature Pinschers that is predicted to result in a deleterious amino acid substitution of a highly conserved glycine to arginine (NP_001041598.1:p.Gly304Arg). In MPS VI-affected Miniature Schnauzers, a 56 bp deletion (NM_001048133.1:c.-24_32del) was found at the junction of exon 1 and its upstream region, predicting no enzyme synthesis. All clinically affected Miniature Pinschers and Miniature Schnauzers were homozygous for the respective variants, and screened healthy dogs in each breed were either heterozygous or homozygous for the wt allele. Whereas the Miniature Pinscher variant seemed to occur commonly (0.133 allele frequency), the Miniature Schnauzer variant was presumed to be rare. In conclusion, two breed-specific pathogenic ARSB gene variants were identified in Miniature Pinscher and Miniature Schnauzer dogs with MPS VI, allowing for genotyping and informed breeding to prevent the production of affected offspring.


Asunto(s)
Enfermedades de los Perros/genética , Perros/genética , Mucopolisacaridosis VI/genética , N-Acetilgalactosamina-4-Sulfatasa/genética , Animales , Cruzamiento , Exones , Frecuencia de los Genes , Homocigoto , Mutación Missense
11.
Int J Mol Sci ; 21(14)2020 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-32664626

RESUMEN

Perturbations of glycosaminoglycan metabolism lead to mucopolysaccharidoses (MPS)-lysosomal storage diseases. One type of MPS (type VI) is associated with a deficiency of arylsulfatase B (ARSB), for which we previously established a cellular model using pulmonary artery endothelial cells with a silenced ARSB gene. Here, we explored the effects of silencing the ARSB gene on the growth of human pulmonary artery smooth muscle cells in the presence of different concentrations of dermatan sulfate (DS). The viability of pulmonary artery smooth muscle cells with a silenced ARSB gene was stimulated by the dermatan sulfate. In contrast, the growth of pulmonary artery endothelial cells was not affected. As shown by microarray analysis, the expression of the arylsulfatase G (ARSG) in pulmonary artery smooth muscle cells increased after silencing the arylsulfatase B gene, but the expression of genes encoding other enzymes involved in the degradation of dermatan sulfate did not. The active site of arylsulfatase G closely resembles that of arylsulfatase B, as shown by molecular modeling. Together, these results lead us to propose that arylsulfatase G can take part in DS degradation; therefore, it can affect the functioning of the cells with a silenced arylsulfatase B gene.


Asunto(s)
Dermatán Sulfato/metabolismo , Miocitos del Músculo Liso/enzimología , N-Acetilgalactosamina-4-Sulfatasa/fisiología , Secuencia de Aminoácidos , Arilsulfatasas/biosíntesis , Arilsulfatasas/química , Arilsulfatasas/genética , Dominio Catalítico , Dermatán Sulfato/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Silenciador del Gen , Humanos , Modelos Moleculares , Mucopolisacaridosis VI/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , N-Acetilgalactosamina-4-Sulfatasa/química , Especificidad de Órganos , Unión Proteica , Conformación Proteica , Arteria Pulmonar/citología , ARN Mensajero/biosíntesis , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Análisis de Matrices Tisulares , Regulación hacia Arriba
12.
Mol Genet Metab ; 130(4): 255-261, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32563631

RESUMEN

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of rare, inherited metabolic diseases that result from a deficiency in one of several lysosomal enzymes essential for stepwise glycosaminoglycan (GAG) degradation, leading to GAG accumulation and widespread cellular pathology and clinical disease. Although disease presentation is heterogeneous, the clinical hallmarks are largely comparable across several MPS subtypes. Extensive data have shown that the level of urinary GAG (uGAG) excretion above normal is strongly correlated with disease severity and clinical outcomes in MPS diseases. Thus, change in uGAG excretion may have significant value as a potential primary endpoint in clinical trials of MPS diseases that are too rare to study using traditional clinical endpoints. METHODS: A retrospective medical chart review was undertaken of patients with MPS I, II, and VI who had been treated long term with enzyme replacement therapy (ERT). The relationship between uGAG reduction and clinical outcomes relevant to the major clinical manifestations of these MPS diseases was evaluated. A multi-domain responder index (MDRI) score was calculated, measuring the following 4 domains: 6-min walk test, pulmonary function, growth rate, and Clinician Global Impression of Change. For each domain, a minimal important difference (MID) was defined based on published information of these outcome measures in MPS and other diseases. RESULTS: Of the 50 patients evaluated, 18 (36%) had MPS I, 23 (46%) had MPS II, and 9 (18%) had MPS VI. Forty-two were clinical practice patients and 8 had participated in clinical trials. Across all MPS subtypes, the mean (± SD) uGAG level at baseline was 66.0 ± 51.5 mg/mmol creatinine (n = 48) and there was a mean reduction of 54.6% following ERT. Analysis of the MDRI score based on the MID defined for each domain showed a greater magnitude of improvement in patients with increased uGAG reduction when compared with those patients with lower uGAG reduction for all assessed uGAG thresholds, and a trend toward a higher likelihood of positive mean MDRI score in patients with a uGAG reduction ≥40%. CONCLUSIONS: In this retrospective study, uGAG reduction was associated with long-term clinical outcomes as assessed by a number of approaches, supporting the use of uGAG reduction as a biomarker primary endpoint.


Asunto(s)
Biomarcadores/orina , Terapia de Reemplazo Enzimático/métodos , Glicosaminoglicanos/orina , Mucopolisacaridosis II/patología , Mucopolisacaridosis I/patología , Mucopolisacaridosis VI/patología , N-Acetilgalactosamina-4-Sulfatasa/uso terapéutico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Mucopolisacaridosis I/enzimología , Mucopolisacaridosis I/terapia , Mucopolisacaridosis I/orina , Mucopolisacaridosis II/enzimología , Mucopolisacaridosis II/terapia , Mucopolisacaridosis II/orina , Mucopolisacaridosis VI/enzimología , Mucopolisacaridosis VI/terapia , Mucopolisacaridosis VI/orina , Pronóstico , Estudios Retrospectivos
13.
Int J Pediatr Otorhinolaryngol ; 135: 110137, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32502916

RESUMEN

OBJECTIVES: The mucopolysaccharidoses (MPS) are inherited lysosomal storage disorders with multisystemic and highly variable clinical manifestation. ENT symptoms are common and early signs of MPS. The most common ENT diagnoses are chronic/recurrent rhinosinusitis, acute otitis media, otitis media with effusion, hearing loss and airway obstruction. METHODS: A single-centre retrospective chart review of 61 patients (36 M/25F) with different MPS subtypes (MPS I (n = 15), MPS II (n = 10), MPS III (n = 17), MPS IV (n = 15) and MPS VI (n = 4)) was conducted. The age of ENT presentation and frequency of ENT symptoms, surgeries and their distribution among MPS subtypes was studied. The relationship between ENT presentation, first ENT surgery and the age of diagnosis was also evaluated. RESULTS: Median age at the first ENT manifestation was 2.8 years, median age at MPS diagnosis 4.1 years. The great majority of patients (90%) manifested at least one ENT diagnosis; often before the diagnosis of MPS (75%). Chronic/recurrent rhinosinusitis was the most prevalent ENT diagnosis (77%), followed by upper airway obstruction (65%) and hearing loss (53%). Chronic/recurrent rhinosinusitis was the first ENT symptom to appear (median age 2.2 years), followed by otitis media with effusion (3.7 years) and hearing loss (4.5 years). At least one ENT surgery was performed in 57% of patients; in 69% before MPS diagnosis was established. Median age of the first ENT surgery was 4.1 years. ENT symptoms and surgical procedures were earliest present in MPS II. CONCLUSIONS: Our study documents high and early occurrence of various otolaryngologic symptoms in MPS and thus highlights the role of ENT specialist in prompt diagnosis of these rare diseases and their long-term management.


Asunto(s)
Obstrucción de las Vías Aéreas/etiología , Pérdida Auditiva/etiología , Mucopolisacaridosis/complicaciones , Rinitis/etiología , Sinusitis/etiología , Adolescente , Factores de Edad , Niño , Preescolar , Enfermedad Crónica , Femenino , Humanos , Lactante , Masculino , Mucopolisacaridosis/diagnóstico , Mucopolisacaridosis I/complicaciones , Mucopolisacaridosis I/diagnóstico , Mucopolisacaridosis II/complicaciones , Mucopolisacaridosis II/diagnóstico , Mucopolisacaridosis III/complicaciones , Mucopolisacaridosis III/diagnóstico , Mucopolisacaridosis IV/complicaciones , Mucopolisacaridosis IV/diagnóstico , Mucopolisacaridosis VI/complicaciones , Mucopolisacaridosis VI/diagnóstico , Otitis Media con Derrame/etiología , Procedimientos Quirúrgicos Otorrinolaringológicos , Estudios Retrospectivos , Adulto Joven
14.
PLoS One ; 15(5): e0233032, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32413051

RESUMEN

Mucopolysaccharidoses are a class of lysosomal storage diseases, characterized by enzymatic deficiency in the degradation of specific glycosaminoglycans (GAG). Pathological accumulation of excess GAG leads to multiple clinical symptoms with systemic character, most severely affecting bones, muscles and connective tissues. Current therapies include periodic intravenous infusion of supplementary recombinant enzyme (Enzyme Replacement Therapy-ERT) or bone marrow transplantation. However, ERT has limited efficacy due to poor penetration in some organs and tissues. Here, we investigated the potential of the ß-D-xyloside derivative odiparcil as an oral GAG clearance therapy for Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). In vitro, in bovine aortic endothelial cells, odiparcil stimulated the secretion of sulphated GAG into culture media, mainly of chondroitin sulphate (CS) /dermatan sulphate (DS) type. Efficacy of odiparcil in reducing intracellular GAG content was investigated in skin fibroblasts from MPS VI patients where odiparcil was shown to reduce efficiently the accumulation of intracellular CS with an EC50 in the range of 1 µM. In vivo, in wild type rats, after oral administrations, odiparcil was well distributed, achieving µM concentrations in MPS VI disease-relevant tissues and organs (bone, cartilage, heart and cornea). In MPS VI Arylsulphatase B deficient mice (Arsb-), after chronic oral administration, odiparcil consistently stimulated the urinary excretion of sulphated GAG throughout the treatment period and significantly reduced tissue GAG accumulation in liver and kidney. Furthermore, odiparcil diminished the pathological cartilage thickening observed in trachea and femoral growth plates of MPS VI mice. The therapeutic efficacy of odiparcil was similar in models of early (treatment starting in juvenile, 4 weeks old mice) or established disease (treatment starting in adult, 3 months old mice). Our data demonstrate that odiparcil effectively diverts the synthesis of cellular glycosaminoglycans into secreted soluble species and this effect can be used for reducing cellular and tissue GAG accumulation in MPS VI models. Therefore, our data reveal the potential of odiparcil as an oral GAG clearance therapy for MPS VI patients.


Asunto(s)
Glicosaminoglicanos/metabolismo , Glicósidos/uso terapéutico , Mucopolisacaridosis VI/tratamiento farmacológico , Mucopolisacaridosis VI/metabolismo , Administración Oral , Animales , Bovinos , Células Cultivadas , Sulfatos de Condroitina , Dermatán Sulfato/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Glicósidos/administración & dosificación , Glicósidos/farmacocinética , Humanos , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Mucopolisacaridosis VI/genética , Ratas , Ratas Sprague-Dawley
15.
Int J Mol Sci ; 21(6)2020 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-32188102

RESUMEN

Mucopolysaccharidoses (MPSs) are rare lysosomal storage diseases caused by the accumulation of undegraded glycosaminoglycans in cells and tissues. The effectiveness of early intervention for MPS has been reported. Multiple-assay formats using tandem mass spectrometry have been developed. Here, we developed a method for simultaneous preparation and better measurement of the activities of five enzymes involved in MPSs, i.e., MPS I, MPS II, MPS IIIB, MPS IVA, and MPS VI, which were validated using 672 dried blood spot samples obtained from healthy newborns and 23 patients with MPS. The mean values of the enzyme activities and standard deviations in controls were as follows: α-iduronidase (IDUA), 4.19 ± 1.53 µM/h; iduronate-2-sulfatase (I2S), 8.39 ± 2.82 µM/h; N-acetyl-α-glucosaminidase (NAGLU), 1.96 ± 0.57 µM/h; N-acetylgalactosamine-6-sulfatase (GALNS), 0.50 ± 0.20 µM/h; and N-acetylgalactosamine-4-sulfatase (ARSB), 2.64 ± 1.01 µM/h. All patients displayed absent or low enzyme activity. In MPS I, IIIB, and VI, each patient group was clearly separated from controls, whereas there was some overlap between the control and patient groups in MPS II and IVA, suggesting the occurrence of pseudo-deficiencies. Thus, we established a multiplex assay for newborn screening using liquid chromatography tandem mass spectrometry, allowing simultaneous pretreatment and measurement of five enzymes relevant to MPSs.


Asunto(s)
Cromatografía Liquida/métodos , Pruebas de Enzimas/métodos , Mucopolisacaridosis/enzimología , Mucopolisacaridosis/metabolismo , Espectrometría de Masas en Tándem/métodos , Glicosaminoglicanos , Humanos , Iduronidasa , Recién Nacido , Mucopolisacaridosis I/sangre , Mucopolisacaridosis II/sangre , Mucopolisacaridosis III/sangre , Mucopolisacaridosis IV/sangre , Mucopolisacaridosis VI/sangre , Tamizaje Neonatal/métodos
16.
Clin Radiol ; 75(6): 441-447, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32061396

RESUMEN

AIM: To describe the magnetic resonance imaging (MRI) findings of the cervical spine of patients with mucopolysaccharidosis type VI (MPS VI) and correlate them with clinical manifestations. MATERIALS AND METHODS: This is a cross-sectional study involving 12 patients with MPS VI. A limited neurological examination was undertaken in each patient including Tinel's test, assessment of muscle tone, and the evaluation of deep tendon reflexes. Additionally, each patient underwent cervical spine MRI to evaluate platybasia, odontoid dysplasia, periodontoid soft-tissue thickening, spinal canal stenosis, myelopathy, basilar invagination, platyspondyly, and reduction of nasopharyngeal airway. RESULTS: Nine patients were male (75%). The average age was 12.5 (±3.5 years). Tinel's test was negative in all patients. No muscle tone abnormalities were observed. Approximately 48% of the tested reflexes were considered abnormal, 10 of which (8.3%) were pathological occurring in five different patients (41.6%). At MRI, all patients showed periodontoid soft-tissue thickening and cervical spinal stenosis; six showed spinal cord compression and two showed myelopathy. Odontoid hypoplasia and basilar invagination were observed in nine patients. All patients with cervical stenosis on MRI had abnormal reflexes; however, only two of the six patients with evidence of cord compression on MRI had abnormal reflexes on clinical examination. CONCLUSIONS: The present study of 12 patients with MPS VI demonstrated that a normal neurological examination cannot confidently exclude potential cord compression in patients with this condition. MRI may aid in the timely identification of cervical spine abnormalities, and potentially play a role in lessening morbidity and mortality in patients with MPS.


Asunto(s)
Vértebras Cervicales/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Mucopolisacaridosis VI/diagnóstico por imagen , Compresión de la Médula Espinal/diagnóstico por imagen , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Examen Neurológico
17.
BMC Med Genet ; 21(1): 37, 2020 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-32075597

RESUMEN

BACKGROUND: The Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome (OMIM 253200) is an autosomal recessive lysosomal disorder, caused by the deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (also known as arylsulfatase B) due to mutations of the ARSB gene. Cardiologic features are well recognized, and are always present in MPS VI patients. Generally, the onset and the progression of the cardiologic symptoms are insidious, and just a few patients have developed a rapidly progressive disease. Cardiac involvement in MPS VI is a common and progressive feature. For MPS patients, cardiac evaluations are recommended every 1 to 2 years, including blood pressure measurement, electrocardiography and echocardiography. However, congestive heart failure and valvular surgical repair are not frequently seen, and if so, they are performed in adults. Here we report on an atypical MPS VI case with ascites fetalis and a rapidly progressive cardiac disease. CASE PRESENTATION: A 6-month-old Brazilian male, only child of a Brazilian healthy non-consanguineous couple. During pregnancy, second trimester ultrasonography observed fetal ascites and bilateral hydrocele. Physical exam at 6 months-old revealed a typical gibbus deformity and MPS was suspected. Biochemical investigation revealed a diagnosis of MPS type VI, confirmed by molecular test. Baseline echocardiogram revealed discrete tricuspid regurgitation and a thickened mitral valve with posterior leaflet prolapse, causing moderate to severe regurgitation. The patient evolved with mitral insufficiency and congestive heart failure, eventually requiring surgical repair by the first year of age. CONCLUSIONS: We report the first case of MPS VI whose manifestations started in the prenatal period with fetal ascites, with severe cardiac valvular disease that eventually required early surgical repair. Moreover, in MPS with neonatal presentation, including fetal hydrops, besides MPS I, IVA and VII, clinicians should include MPS VI in the differential diagnosis.


Asunto(s)
Insuficiencia Cardíaca/genética , Corazón/fisiopatología , Mucopolisacaridosis VI/genética , N-Acetilgalactosamina-4-Sulfatasa/genética , Ascitis , Brasil/epidemiología , Progresión de la Enfermedad , Corazón/diagnóstico por imagen , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Lactante , Masculino , Mucopolisacaridosis VI/diagnóstico por imagen , Mucopolisacaridosis VI/fisiopatología , Mutación , Fenotipo
18.
Am J Med Genet A ; 182(3): 469-483, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31926052

RESUMEN

Several studies have been published on the frequency of the mucopolysaccharidoses (MPS) in different countries. The objective of the present study was to estimate the birth prevalence (BP) of MPS in Brazil. MPS diagnosis registered at MPS-Brazil Network and in Instituto Vidas Raras were reviewed. BP was estimated by (a) the number of registered patients born between 1994 and 2015 was divided by the number of live births (LBs), and (b) a sample of 1,000 healthy individuals was tested for the most frequent variant in IDUA gene in MPS I (p.Trp402Ter) to estimate the frequency of heterozygosity and homozygosity. (a) The BP based on total number of LBs was (cases per 100,000 LBs): MPS overall: 1.25; MPS I: 0.24; MPS II: 0.37; MPS III: 0.21; MPS IV: 0.14; MPS VI: 0.28; MPS VII: 0.02. (b) The overall frequency of p.Trp402Ter was 0.002. Considering the frequency of heterozygotes for the p.Trp402Ter IDUA variant in the RS state, the frequency of this variant among MPS I patients and the relative frequency of the different MPSs, we estimated the birth prevalence of MPS in total and of each MPS type, as follows: MPS overall: 4.62; MPS I: 0.95; MPS II: 1.32; MPS III: 0.56; MPS IV: 0.57; MPS VI: 1.02; MPS VII: 0.05. This study provided original data about BP and relative frequency of the MPS types, in Brazil, based on the frequency of the commonest IDUA pathogenic variant and in the records of two large patient databases.


Asunto(s)
Iduronidasa/genética , Mucopolisacaridosis/genética , Brasil/epidemiología , Femenino , Humanos , Iduronidasa/sangre , Nacimiento Vivo , Masculino , Mucopolisacaridosis/sangre , Mucopolisacaridosis/epidemiología , Mucopolisacaridosis/patología , Mucopolisacaridosis I/sangre , Mucopolisacaridosis I/epidemiología , Mucopolisacaridosis I/genética , Mucopolisacaridosis II/sangre , Mucopolisacaridosis II/epidemiología , Mucopolisacaridosis II/genética , Mucopolisacaridosis III/sangre , Mucopolisacaridosis III/epidemiología , Mucopolisacaridosis III/genética , Mucopolisacaridosis VI/sangre , Mucopolisacaridosis VI/epidemiología , Mucopolisacaridosis VI/genética , Mutación/genética
19.
Colomb Med (Cali) ; 51(3): e213996, 2020 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-33402755

RESUMEN

Objective: To assess the functional independence of a group of patients with mucopolysaccharidosis using the Functional Independence Measure as a tool that accomplishes this purpose. Methods: This is a cross-sectional study of patients with mucopolysaccharidosis. Our data was collected between June 2015 and July 2016. In addition to history of present illness and physical examination each study participant was asked to answer a questionnaire to specifically evaluate their functional independence using the functional independence measure. the internal consistency of the functional independence measure was assessed using Cronbach's alpha coefficient. Results: We collected data on 20 patients with mucopolysaccharidosis. The average age was 10.8 (8.67-13.03) years, the average weight was 23.6 (19.91-27.37) kg and the average height was 1 (0.83-1.17) m. The most prevalent type of mucopolysaccharidosis in the study was type VI (n= 14). The average total functional independence measure score was 104.4 (97.61-111.19), the average for the mobility domain was 73.50 (68.22-78.78) and the average for the cognitive function domain was 30.90 (28.68-33.13). The internal consistency of the entire questionnaire was 0.859, with values of 0.966 for the mobility domain and 0.624 for the cognitive function domain. Conclusion: The lowest functional independence measure scores were obtained in the following sub-domains: self-care, locomotion and cognitive function. The functional independence measure questionnaire demonstrated internal consistency for the evaluation of functional independence in patients with mucopolysaccharidosis, being able to value all the affected sub-domains separately.


Asunto(s)
Cognición/fisiología , Estado Funcional , Mucopolisacaridosis/fisiopatología , Adolescente , Estatura , Peso Corporal , Niño , Intervalos de Confianza , Estudios Transversales , Femenino , Humanos , Locomoción , Masculino , Limitación de la Movilidad , Mucopolisacaridosis I/fisiopatología , Mucopolisacaridosis II/fisiopatología , Mucopolisacaridosis VI/fisiopatología , Autocuidado
20.
Rev. méd. (La Paz) ; 25(2): 58-64, Jul. Dic., 2019.
Artículo en Español | LILACS | ID: biblio-1102699

RESUMEN

El síndrome de Maroteaux-Lamy es una de las mucopolisacaridosis menos frecuente, con una incidencia aproximada de 0.36 a 1.30 por cada 100,000 nacidos vivos. Causado por una mutación en el gen ARSB, que produce la deficiencia enzimática de arilsulfatasa Bocasionando acumulación de dermatán sulfato en las células. Clínicamente, los pacientes presentan afectación multiorgánica progresiva. En este trabajo presentamos tres pacientes de origen boliviano no emparentados con MPS VI. Adicionalmente revisamos 38 casos de pacientes con MPS VI reportados en literatura.


Asunto(s)
Mucopolisacaridosis VI
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