Mucopolysaccharidosis type IH (MPS IH) is a lysosomal disease caused by insufficient L-iduronidase (IDUA), resulting in progressive accumulation of glycosaminoglycans (GAGs) in the central nervous system (CNS). Hematopoietic cell transplantation (HCT) replaces IDUA through cellular cross-correction, stabilizing the CNS. Intravenous (i.v.) enzyme replacement therapy (ERT) is also effective at reducing GAG accumulation; however, it is thought to inefficiently cross the blood-brain barrier. To compare the effect of i.v. ERT on GAG degradation in the CNS with the effect of brain-penetrant therapy, i.e., HCT, we measured cerebrospinal fluid (CSF) GAG non-reducing ends in patients with MPS IH who were ERT-naive (n = 33), received i.v. ERT prior to HCT (n = 34), or underwent HCT (n = 26). We found that CSF GAGs (cGAGs) were 33%-65% lower in patients exposed to i.v. ERT. One year after HCT, cGAGs declined to their lowest levels. There was no difference in cGAG levels between patients treated with i.v. ERT for 52 weeks after HCT and those treated for only 8 weeks after HCT. In summary, i.v. ERT can lead to a significant decrease in cGAGs prior to HCT, indicating that i.v. ERT may affect CNS biomarkers, which reach their lowest levels with a brain-penetrant therapy.

Non-coronary artery systemic arterial aneurysms (SAAs) are rare and an under-reported sequelae of Kawasaki disease (KD). We hypothesize that practices regarding SAA screening and management vary widely among experts and published literature. A survey was sent to members of the International KD Registry regarding their experiences and practices with SAAs in KD patients. For comparison, a systematic scoping review was conducted using PRISMA methodology, from which 25 reports with 83 patients were included. Results from each were compared. Surveys were completed by 48 (56

Mucopolysaccharidosis type I (MPS I) is a rare metabolic disorder caused by deficiency of a-L-iduronidase (IDUA), resulting in glycosaminoglycan (GAG) accumulation and multisystemic disease. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy, but these do not address all manifestations of the disease. We infused MPS I mice with an adeno-associated virus 9 (AAV9)-IDUA vector (RGX-111) at doses from 107 to 1010 vector genomes (vg) via intrathecal (IT), intravenous (IV), and intrathecal+intravenous (IT+IV) routes of administration. In mice administered doses <= 109 vg IT or <= 108 vg IV, there was no therapeutic benefit, while in mice administered 109 vg IV, there was a variable increase in IDUA activity with inconclusive neurocognitive and cardiac assessments. However, at the 1010 vg dose, we observed substantial metabolic correction, with restored IDUA levels and normalized tissue GAGs for all treatment groups. Aortic insufficiency was mostly normalized, neurologic deficit was prevented, and microcomputed tomography (micro-CT) analysis showed normalization of skeletal parameters. Histologic analysis showed minimal GAG storage and lysosomal pathology. We thus report a minimal effective dose of 1010 vg (5 x 1011 per kg) RGX-111 for IV and IT routes of administration in MPS I mice, which prevented neurocognitive deficit, cardiac insufficiency, and skeletal manifestations, as a model for genetic therapy of human MPS I.

Mucopolysaccharidosis type I is an inborn error of glycosaminoglycan catabolism with phenotypes ranging from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes). Cardiovascular involvement is common and contributes significantly to morbidity and mortality. We conducted a retrospective analysis of the prevalence and natural history of cardiac abnormalities in treatment-naïve individuals enrolled in the international Mucopolysaccharidosis Type I Registry. Interrogation of echocardiography data (presence of cardiac valve regurgitation and/or stenosis; measurements of left ventricular chamber dimensions in diastole and systole, diastolic left ventricular posterior wall and interventricular septal thicknesses and ventricular systolic function (shortening fraction)) showed that mitral regurgitation was the most common and earliest finding for individuals with both severe (58.3%, median age 1.2 years) and attenuated (74.2%, median age 8.0 years) disease. Left-sided valve stenosis was also common in individuals with attenuated disease (mitral 30.3%; aortic 25%). Abnormal ventricular wall and septal thickness (Z-scores ≥2) were observed early in both phenotypes. Z-scores for diastolic left ventricular posterior wall and interventricular septal thicknesses increased with age in the severe phenotype (annualised slopes of 0.2777 [p = 0.037] and 0.3831 [p = 0.001], respectively); a similar correlation was not observed in the attenuated phenotype (annualised slopes of -0.0401 [p = 0.069] and -0.0029 [p = 0.875], respectively). Decreased cardiac ventricular systolic function (defined as shortening fraction <28%) was uncommon but, when noted, was more frequent in infants with the severe phenotype. While cardiac abnormalities occur early in both severe and attenuated mucopolysaccharidosis type I, the pattern of valve dysfunction and progression of ventricular abnormalities vary by phenotype.

Existe una elevada variabilidad en la información documental dirigida a los pacientes, que muestra distintos contenidos, formatos y presentación.Conocer la percepción de seguridad de los pacientes atendidos en el Hospital Comarcal de Melilla (HCML) y valorar la calidad de los documentos mediante los criterios de adaptación del instrumento International Patient Decision Aid Standards (IPDAS).Estudio descriptivo de los documentos entregados a pacientes del HCML, mediante encuesta de valoración de la percepción de seguridad, una clasificación de los documentos y análisis del grado de cumplimiento de los criterios IPDAS.La información durante la estancia de los pacientes en el HCML, su participación en la toma de decisiones y la información sobre la medicación no superaron el valor medio de la escala de aceptación. Solo 40 documentos fueron objeto de estudio (de 131 recogidos), por ser de autoría propia y se clasificaron, siguiendo las definiciones de la RAE, en instrucciones (20), recomendaciones (14) y guías (6). De ellos, solo el 27,5% ostentó alguna imagen institucional.En el análisis de su contenido, según los criterios IPDAS, se observó un porcentaje global de cumplimiento de ítems del 24,1% en instrucciones, el 24,8% en recomendaciones y el 61,5% en guías.La percepción de la seguridad de los pacientes manifestada por la encuesta y su valoración según los criterios IPDAS nos proporcionan una posibilidad de mejora importante dentro de la organización. Además, la calidad de la documentación sanitaria dirigida a pacientes puede ayudar a la toma de decisiones.There is a high variability in the level of information intended for patients, with different content, format and presentation.To determine the perceived safety of the patients treated at the Country Hospital of Melilla (HCML) and to assess the quality of the documents using criteria adapted to the «International Patient Decision Aid Standards» (IPDAS).Descriptive study of the documents given to patients by the HCML. They included questionnaires on perceived safety, classification of the documents, and the level of adherence to the IPDAS criteria.The Information given to patients during their stay in the HCML, their participation in decision-making, and the information about medication, did not exceed the average on the acceptance scale. Only 40 documents were studied (of the 131 collected), on being published in-house, and were classified, following the definitions of the RAE, into instructions (20), recommendations (14) and guidelines (6). Of these, only the 27.5% showed hospital logo.In the content analysis according to the IPDAS criteria, there was an overall adherence rate of 24.1% in instructions, 24.8% in recommendations, and 61.5% in guidelines.The perception of patient safety expressed in the questionnaire, and its assessment according IPDAS criteria, shows there may be a significant improvement within the organization. Furthermore, the quality of patient documentation provided can help decision making.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a late systemic inflammatory response to a recent mild or asymptomatic coronavirus disease of 2019 infection. The pathophysiology is incompletely understood but it often features significant coagulopathy along with cardiac and endothelial dysfunction. Endothelial inflammation has been primarily described in acute coronavirus disease of 2019 infection, with less characterization in MIS-C. Here we describe novel findings of nearly universal severe and prolonged factor VIII (FVIII) and von Willebrand factor antigen elevations in an institutional cohort of patients with MIS-C ages younger than or 21 years old (N=31). All patients had elevated acute phase reactants and D-dimer at presentation and met published criteria for MIS-C. FVIII was high at presentation in 97% of patients but continued to rise during the ensuing weeks of treatment to a mean 429%, peaking on median day 17 of illness as an outpatient. FVIII levels were >600% in multiple patients. von Willebrand factor antigen was measured less frequently but showed similar trends. These escalations occurred amidst resolving cardiac dysfunction and acute phase reactant normalization and despite patients receiving multimodal anti-inflammatory treatments and aspirin and enoxaparin thromboprophylaxis. No thrombotic events occurred. Endothelial dysfunction represented by very elevated FVIII levels may persist longer than other acute phase reactants may reflect.

Omalizumab, an anti-IgE monoclonal antibody, is administered by injection once or twice monthly in offices and clinics. It offers a potential alternative intervention for patients with allergic asthma that is not well controlled because of recalcitrant poor adherence to inhaled corticosteroid therapy.To assess the effect of omalizumab therapy by measuring airway responsiveness to adenosine, a marker of allergic airway inflammation, and resource use.Patients (N = 17) aged 6 to 26 years (mean age, 16.4 years) with poorly controlled persistent allergic asthma, less than 50% adherence to inhaled corticosteroid therapy, a forced expiratory volume in 1 second (FEV1) of 60% predicted or higher, and adenosine provocation concentration that caused a decrease in FEV1 of 20% (PC20) of 60 mg/mL or less were randomized to receive 4 months of omalizumab or placebo in a double-blind, crossover trial with a 3- to 4-month washout between treatments. Patients were instructed to continue taking inhaled corticosteroids throughout the study. The PC20 was measured before and after each period.Fifteen patients completed the study. The mean baseline PC20 was 14.1 mg/mL (95% CI, 10.8–18.4 mg/mL). The fold change PC20 was 0.9 (95% CI, 0.5–1.7) during placebo and 3.1 (95% CI, 1.6–6.2) during omalizumab treatment; the estimated ratio was 3.4 (95% CI, 1.2–9.3; P = .02). Six patients required one or more short courses of oral corticosteroids for asthma exacerbations during placebo, but none required this intervention during omalizumab. During the study, the median prescription refills for inhaled corticosteroids was 0.15 (95% CI, 0.00–0.33) canisters per month.Omalizumab therapy is an alternative for patients with more severe poorly controlled asthma in whom adherence does not improve with conventional interventions.clinicaltrials.gov Identifier: NCT00133042.

BACKGROUND:Severe mucopolysaccharidosis type I, (MPS IH) is a rare inherited lysosomal disorder resulting in progressive storage of proteoglycans (GAGs) in central nervous system and somatic tissues and, if left untreated, causing death within the first decade of life. Hematopoietic cell transplantation (HCT) arrests many of the features of MPS IH but carries a 10-15% risk of mortality. Decreased cardiac function can occur in MPS IH and increase the risk of HCT. METHODS:Retrospective chart review was performed to determine the long-term outcome of individuals evaluated for HCT with MPS IH who had decreased cardiac function as measured by cardiac echocardiogram (echo) and ejection fraction (EF) of <50% at the time of initial evaluation. RESULTS:Six patients ranging in age from 1 week to 21 months (median: 4 months) had EFs ranging from 25 to 47% (median: 32%) at diagnosis and were initiated on enzyme replacement therapy (ERT) with improvement in EF in three patients by 5 months. The remaining three patients continued to have EFs <50% and continuous milrinone infusion was added in the pre-HCT period. On average, milrinone infusion was able to be discontinued post-HCT, prior to hospital discharge, within a mean of 37 days. Five patients survived HCT and are alive today with normal EFs. One patient receiving milrinone died of sepsis during HCT with a normal EF. CONCLUSION:Decreased cardiac systolic function in infants with MPS IH that fails to normalize with ERT alone may benefit from the addition of continuous milrinone infusion during HCT.

Novel therapies for Hurler syndrome aim to cross the blood–brain barrier (BBB) to target neurodegeneration by degrading glycosaminoglycans (GAG). BBB penetration has been assumed with decreased cerebrospinal fluid (CSF) GAG, yet little is known about CSF GAG without brain‐targeting therapies. We compared pre‐transplant CSF GAG in patients who were treatment naïve (n = 19) versus receiving standard non‐BBB penetrating enzyme replacement therapy (ERT, n = 12). In the ERT versus treatment naïve groups, CSF GAG was significantly lower across all content assayed, raising questions about using CSF GAG decrements to show BBB penetration. Future studies should compare GAG reduction in standard versus novel therapies. ANN NEUROL 2023;94:1182–1186

Introduction: Kawasaki disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 show considerable clinical overlap making differentiation challenging. Hypothesis: Cardiac biomarkers can differentiate KD from MIS-C. Methods: The International KD Registry enrolled 2566 contemporaneous KD, MIS-C and acute COVID-19 pediatric patients from 39 sites in 8 countries from January 2020 through January 2022. The study population included MIS-C patients meeting CDC criteria with confirmed or probable COVID-19 infection, and KD patients meeting AHA guideline criteria without COVID-19 infection. Included patients had to have at least one measurement of NTproBNP or troponin I. KD and MIS-C patients were compared, to assess factors associated with cardiac biomarkers and cardiac outcomes. Receiver operating characteristic curves were used to determine cut points differentiating KD from MIS-C. Results: Of 779 patients with KD, 168 had NTproBNP (median 381 ng/L) and 173 had troponin I (median <10 ug/L) assessed at presentation, while of 1207 patients with MIS-C, 427 had NTproBNP (median 1850 ng/L; p<0.001 vs KD) and 522 had troponin I (median 12.7 ug/L; p<0.001) assessed. Baseline NTproBNP and troponin were correlated mildly (r=0.09; p=0.05) and were associated with older age and higher creatinine levels. Lower LV ejection fraction (LVEF) was associated with MIS-C (vs KD), but not with baseline or peak troponin levels after adjusting for age and creatinine levels. Lower LVEF was significantly associated with higher baseline and peak NTproBNP levels after adjusting for diagnosis and age. Higher peak coronary artery Z score was associated with KD vs MIS-C, but neither cardiac biomarker. Baseline troponin I >10 ug/L predicted MIS-C vs KD with a sensitivity of 57% and specificity of 74% (c-statistic 0.61), and baseline NTproBNP >1600 ng/L with a sensitivity of 54% and specificity of 75% (c-statistic 0.69). Conclusions: Higher baseline troponin I and NTproBNP levels are more predictive of MIS-C compared to KD. Lower LVEF, more common with MIS-C, was associated with higher NTproBNP but not troponin I levels, and coronary artery involvement, more common in KD, was not associated with either cardiac biomarker.