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Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare, X-linked lysosomal storage disease caused by reduced activity of iduronate-2-sulfatase (I2S), with subsequent cellular accumulation of the glycosaminoglycans (GAGs), heparan sulfate, and dermatan sulfate (DS). DS is a major component of the extracellular matrix of heart valves, which can be affected in MPS II. We investigated the natural history of valve disease in MPS II and the impact of long-term intravenous enzyme replacement therapy (ERT) with recombinant I2S (idursulfase). In total, 604 cardiac examinations were assessed from serial follow-up of 80 male patients (49 neuronopathic). Valve disease was classified according to standard practice from hemodynamic features evident from echocardiography. The natural history group comprised 48 patients (up to 14.8 years of follow-up; median, 2.6 years; 24 patients started ERT during the study); 56 patients were treated (up to 14.2 years of follow-up; median, 6.2 years). Lifetime GAG burden (calculated from urinary GAG measurements) correlated significantly with the degree of valve disease. Onset of moderate-to-severe valve disease was significantly delayed in treated (median age at onset, 29.1 ± 2 [95% CI: 25.2-32.9] years; Kaplan-Meier estimation) versus untreated patients (17.6 ± 1 [95% Cl: 15.8-19.4] years; p < 0.0001). Cox regression modeling found that long-term ERT reduced the probability of developing severe valve disease (χ 2 , 32.736; significant after 5 years of ERT). Overall, this study found that valve disease severity in MPS II correlates with GAG burden and that progression is delayed by long-term ERT., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Competing Interests: Competing Interests C Tackaberry is a director and employee of Clinithink and also a shareholder. No other competing interests from any author to disclose.

Objective: Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown., Methods: Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial "Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)" was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions., Results: In sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect., Conclusions: KST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance., Competing Interests: Declaration of competing interest Jens Jordan receives grants from Novo-Nordisk, Boehringer-Ingelheim, NASA and ESA as well as honoraria from Menarini and Berlin Chemie. He participates in boards of Novo-Nordisk, Theravance, ESH, EFAS and DGLRM and is the co-founder of Eternygen GmbH. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

High-affinity allergen-specific IgE is essential for the severe allergic anaphylaxis response. High-affinity Abs are formed by successive rounds of selection of Ag-specific B cells in the germinal center (GC); however, several studies have shown that IgE+ GC B cells are impaired in their ability to undergo selection in the GC. A pathway, known as the "indirect switching pathway" for IgE, has been described whereby Ag-specific B cells initially switch to the IgG1 isotype and undergo affinity selection in the GC, with a secondary switch to the IgE isotype after affinity selection. In previous work, using a food allergy model in mice, we investigated how high-affinity IgE develops in the GC, but we did not test the indirect switching model. In this study, we analyzed the importance of the indirect switching pathway by constructing IgG1-cre Bcl6-fl/fl mice. In these mice, once B cells switch to IgG1, they delete Bcl6 and thus cannot enter or persist in the GC. When we tested IgG1-cre Bcl6-fl/fl mice with our food allergy model, we found that, as expected, IgG1 Abs had decreased affinity, but unexpectedly, the affinity of IgE for allergen was unchanged. IgG1-cre Bcl6-fl/fl mice underwent anaphylaxis in response to allergen, consistent with the formation of high-affinity IgE. Thus, in a food allergy response, high-affinity IgE can be efficiently formed in the absence of indirect switching to IgG1, either by direct selection of IgE+ GC B cells or indirect selection of IgM+ GC B cells that later switch to IgE., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Importance: Parent-child play is a beneficial and meaningful co-occupation. Therapists who want to optimize parent-child play for Latino- and Latina-American dyads need valid, reliable measures to assess caregiver playfulness in addition to preexisting measures of child playfulness., Objective: To evaluate data collected from Latino-American caregivers with the Scale of Parental Playfulness Attitude (PaPA), a 28-item parent self-report to determine its construct validity, internal reliability, and cross-cultural validity., Design: Quantitative exploratory design applying a latent-trait psychometric model., Setting: Online survey., Participants: Convenience sample of 50 Spanish-speaking parents from the mainland United States recruited via snowballing (88% mothers, ages 24-47 yr; M = 34.8 yr; 82% first-generation Americans). The inclusion criteria were age ≥18 yr; literate in Spanish; primary caregiver to a child age 2.5-7 yr. Data from an existing sample of 50 parents dwelling in Puerto Rico were used to examine cross-cultural validity., Outcomes and Measures: Rasch analysis demonstrated evidence for adequate construct validity: positive point-measure correlations, 93% fit of items, logical item hierarchy, and good progression of the rating scale. Range and mean for parent playfulness exceeded those of the items; principal-components analysis revealed one contrast of 4.46 eigenvalues, bringing unidimensionality into question. Evidence suggested excellent internal reliability (person-reliability index = 0.85, strata = 3.55) and good cross-cultural validity (25 of 28 items formed a similar hierarchy for parents dwelling in the mainland United States and Puerto Rico)., Conclusions and Relevance: Although the PaPA can be used to assess caregiver playfulness with culturally diverse Latino-American dyads, further research is required. What This Article Adds: This study provides evidence for the construct validity and internal reliability of a tool that measures parent playfulness in the context of parent-child play. The PaPA is an important tool for occupational therapists working with Latino-American families., (Copyright © 2023 by the American Occupational Therapy Association, Inc.)

Background: Lysosomal Storage Diseases (LSD) are rare and multisytemic diseases which are caused by lysosomal enzyme deficiencies leading into accumulation of waste products due to an interruption in the decomposition process. Due to the low prevalence and therefore limited disease awareness as well as the fact that LSD patients present with unspecific symptoms the final diagnosis is often made after a long delay. The aim of this German-wide survey was to characterize the period between onset of symptoms and final diagnosis regarding e.g. self-perceived health, symptom burden and false diagnoses for patients with selected LSDs (Fabry disease (FD), Gaucher disease (GD) and Mucopolysaccharidosis type II (MPS II)., Methods: The study was conducted as a telephone based cross-sectional survey. All patients living in Germany with a confirmed diagnosis of FD, GD or MPS II were eligible to participate. The questionnaire was provided in advance in order to enable the participants to prepare for the interview. Only descriptive analyses were carried out. Single analyses were not carried out for all three patient groups due low case numbers., Results: Of the overall population, 39 patients have been diagnosed with FD, 19 with GD and 11 with MPS II with the majority of patients being index patients. The majority of FD patients reported their current health status as "satisfactory" or better (79.5%). Self-perceived health status was observed to be at least stable or improving for the majority of FD patients compared to the year prior to diagnosis. The most frequently reported symptoms for patients with FD were paraesthesias (51.3%), whereas patients with GD reported a tendency for bleeding, blue spots or coagulation disorder (63.2%) as well as hepatomegaly and/or splenomegaly (63.2%) as the most commonly appearing symptoms. The number of patients reporting misdiagnoses was n = 5 (13.5%) for patients with FD and n = 5 (27.8%) for patients with GD. The median duration of the diagnostic delay was 21.0 years for FD, 20.0 years for GD and 2.0 years for MPS II., Conclusions: This study showed that self-perceived status of health for patients might improve once the final correct diagnoses has been made and specific treatment was available. Furthermore, it was observed that diagnostic delay is still high in Germany for a relevant proportion of affected patients. Further challenges in the future will still be to increase awareness for these diseases across the entire healthcare sector to minimize the diagnostic delay., Competing Interests: Eugen Mengel received consulting fees and speakers honoraria from Sanofi Genzyme, Alexion, Orphazyme and Prevail. Eugen Mengel also received honoraria from Shire Deutschland GmbH to contribute his clinical expertise to this study. Jens Gaedeke has received honoraria from Amicus Therapeutics, Novartis, Sanofi, Roche. Jens Gaedeke also received honoraria from Shire Deutschland GmbH to contribute his clinical expertise to this study. Jörg Reinke received honoraria from BioMarin Pharmaceutical Inc., Genzyme, and Actelion. Jörg Reinke also received honoraria from Shire Deutschland GmbH to contribute his clinical expertise to this study. Holger Gothe is employed by IGES Institut GmbH; Simon Krupka and Christoph Ohlmeier were employed by IGES Institut GmbH at the time the study was performed. IGES Institut GmbH received funding from Shire Deutschland GmbH for the execution of the study and manuscript preparation. Anja Lachmann is employed by Shire Deutschland GmbH. These commercial affiliations do not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Purpose: We retrospectively assessed bone and visceral manifestations in patients with Gaucher disease type 1 (GD1) with whole-body magnetic resonance imaging (WB-MRI) to determine the effects of different timing in initiating long-term enzyme replacement therapy., Materials and Methods: In 17 patients with GD1, we performed 2 WB-MRI examinations at a median interval of 13 months. Patients had received enzyme replacement therapy with alglucerase/imiglucerase for a median of 13 years prior to the first examination. MRI results were retrospectively stratified based on treatment initiation into 2 groups: "early" (age ≤12 years, median 5 years) and "late" (during adulthood, median 32 years). We evaluated occurrence of irreversible avascular necroses (AVN) and applied several semi-quantitative scores, including the Bone-Marrow-Burden (BMB) score, the Düsseldorf-Gaucher score (DGS), the Vertebra-Disc-Ratio (VDR), and the Gaucher disease type 1 Severity Scoring System (GD-DS3)., Results: MRI assessments showed no AVN in the "early" group. AVN were observed in 2 patients of the "late" group; one also had a splenic Gaucheroma. The follow-up examinations showed slight improvements in the BMB-score, DGS, and VDR, with similar tendencies in both treatment groups. The GD-DS3 score only improved in "late" group., Conclusion: This retrospective study supported the ongoing clinical value of enzyme replacement therapy with alglucerase/imiglucerase, as WB-MRI-based scores stayed constant or slightly improved even after long-term treatment. Secondary complications were only observed in the late treatment group. Our results suggest that "early initiation" of enzyme replacement therapy may protect the bone., Competing Interests: The authors declare that no conflicts of interest besides those mentioned in the acknowledgements exist., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: To evaluate the function of the oculomotor and vestibular systems and to correlate these findings with the clinical status of patients with Gaucher disease type 3 (GD3). The goal of this cross-sectional and longitudinal study was to find oculomotor biomarkers for future clinical trials., Methods: Twenty-six patients with GD3 were assessed for eligibility and 21 were able to perform at least one task. Horizontal and vertical reflexive saccades, smooth pursuit, gaze-holding, optokinetic nystagmus, and horizontal vestibulo-ocular reflex (VOR) were examined by video-oculography/video-head impulse test and compared concurrently with 33 healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA), the modified Severity Scoring Tool (mSST), and Grooved Pegboard Test (GPT) were administered to assess overall neurological function. Eleven patients were also re-assessed after 1 year., Results: Nine out of 17 patients exhibited gaze-holding deficits. One patient had upbeat nystagmus. Three patients presented with bilateral abducens palsy in combination with central oculomotor disorders, suggesting a bilateral involvement of the abducens nucleus. Horizontal angular VOR gain was reduced in all patients (0.66 ± 0.37) compared with controls (1.1 ± 0.11, p  < 0.001). Most strongly correlated with clinical rating scales were peak velocity of downward saccades (SARA: ρ = -0.752, p  < 0.0005; mSST: ρ = -0.611, p  = 0.003; GPT: ρ = -0.649, p  = 0.005) and duration of vertical saccades (SARA: ρ = 0.806, p  < 0.001; mSST: ρ = 0.700, p  < 0.0005; GPT: ρ = 0.558, p  = 0.02) together with the VOR gain (SARA: ρ = -0.63, p  = 0.016; mSST: ρ = -0.725, p  = 0.003; GPT: ρ = -0.666, p  = 0.004). Vertical smooth pursuit gain decreased significantly at follow-up., Interpretation: This study shows neuronal degeneration of the brainstem and cerebellum with combined involvement of both supranuclear and nuclear oculomotor structures and the vestibular system in GD3. We also identified oculomotor parameters that correlate with the neurological status and can be used as biomarkers in future clinical trials.