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Whybra C, Kampmann C, Krummenauer F, Ries M, Mengel E, Miebach E, Baehner F, Kim K, Bajbouj M, Schwarting A, Gal A, Beck M. The Mainz Severity Score Index: a new instrument for quantifying the Anderson–Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Anderson–Fabry disease (AFD) is an X-linked disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A. The availability of enzyme replacement therapy (ERT) for this debilitating condition has led to the need for a convenient and sensitive instrument to monitor clinical effects in an individual patient. This study aimed to develop a scoring system – the Mainz Severity Score Index (MSSI) – to measure the severity of AFD and to monitor the clinical course of the disease in response to ERT. Thirty-nine patients (24 males and 15 females) with AFD were assessed using the MSSI immediately before and 1 year after commencing agalsidase alfa ERT. Control data were obtained from 23 patients in whom AFD was excluded. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases. The MSSI indicated that, although more men than women had symptoms classified as severe, overall, the median total severity scores were not significantly different between male and female patients. One year of ERT with agalsidase alfa led, in all patients, to a significant (p < 0.001) reduction in MSSI score (by a median of nine points). This study has shown that the MSSI score may be a useful, specific measure for objectively assessing the severity of AFD and for monitoring ERT-related treatment effects. [ABSTRACT FROM AUTHOR]

Background and Purpose: Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late-onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT., Methods: The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in-person meeting, three rounds of discussion and voting to provide a consensus recommendation., Results: The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient-by-patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion-associated reactions. Switching of ERT should be discussed on a patient-by-patient shared-decision basis. If there are severe, unmanageable infusion-associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six-monthly European Pompe Consortium muscle function assessments are recommended., Conclusions: The triple-S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six-monthly long-term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Acid sphingomyelinase deficiency (ASMD) is a rare, lysosomal storage disease with limited evidence on its natural history. This retrospective, medical record abstraction study aimed to characterize the natural history of ASMD (types B and A/B) during childhood and adolescence. Recruiting sites were European centers (i.e., France, Germany, Italy, and the United Kingdom) from the ASCEND-Peds trial (NCT02292654); these sites were targeted because of the rarity of ASMD and specialized care provided at these centers. The study population comprised ASMD trial patients (before exposure to treatment) and ASMD non-trial participants who were managed at the same trial sites. Overall, 18 patients were included (11 trials; 7 non-trials; median [Q1; Q3] age at ASMD diagnosis: 2.5 [1.0; 4.0] years). Median follow-up duration was 10.0 years. Frequently reported medical conditions were hepatobiliary (17 [94.4%]) and blood and lymphatic system disorders (16 [88.9%]). Adenoidectomy (3 [16.7%]) was the most commonly reported surgical procedure; gastroenteritis (5 [27.8%]) was the most frequently reported infection, and epistaxis (6 [33.3%]) was the most commonly reported bleeding event. Abnormal spleen (16 [88.9%]) and liver (15 [83.3%]) size and respiratory function (8 [44.4%]) were commonly reported during physical examination. Overall, 11 (61.1%) patients were hospitalized; 6 (33.3%) patients had emergency room visits. Findings were consistent with published literature and support the current understanding of natural history of ASMD., Competing Interests: Declaration of competing interest Eugen Mengel received research grants, speakers' fees, and consulting honoraria from Sanofi, Orphazyme, Takeda, Cyclo Therapeutics, Idorsia, JCR, Denali, Amicus, and Avrobio. Maurizio Scarpa received funds for research and honoraria from Sanofi, Takeda, Chiesi, Ultragenyx, Amicus, Azafaros, BioMarin, and Orchard. Nathalie Guffon received some fees from Sanofi, Chiesi, and Ultragenyx as an expert in Advisory Board and is an employee of Reference Center for Inherited Metabolic Disorders that received a grant for clinical trials (Sanofi, Chiesi, BioMarin, Takeda, and JCR). Simon A Jones received speaker's and consultancy fees from Sanofi and BioMarin. Vishal Goriya and Carly Rodriguez reported being employed by IQVIA, which received funding from Sanofi for this research. Valerie Dyevre, Jérôme Msihid, Maja Gasparic, and Ruth Pulikottil-Jacob are employees of Sanofi and may hold stocks and/or stock options in the company. Lubomyra Nalysnyk holds stocks in Sanofi. Fernando Laredo was an employee of Sanofi at the time of this research., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, potentially fatal lysosomal storage disease that exhibits a broad spectrum of clinical phenotypes. There is a need to expand the knowledge of disease mortality and morbidity in Germany because of limited information on survival analysis in patients with chronic ASMD (type B or type A/B)., Methods: This observational, multicentre, retrospective cohort study was conducted using medical records of patients with the first symptom onset/diagnosis of ASMD type B or type A/B between 1st January 1990 and 31st July 2021 from four German medical centres. Eligible medical records were abstracted to collect data on demographic characteristics, medical history, hospitalisation, mortality, and causes of death from disease onset to the last follow-up/death. Survival outcomes were estimated using the Kaplan-Meier analysis. Standardised mortality ratio (SMR) was also explored., Results: This study included 33 chart records of patients with ASMD type B (n = 24) and type A/B (n = 9), with a median (interquartile range [IQR]) age of 8.0 [3.0-20.0] years and 1.0 [1.0-2.0] years, respectively, at diagnosis. The commonly reported manifestations were related to spleen (100.0%), liver (93.9%), and respiratory (77.4%) abnormalities. Nine deaths were reported at a median [IQR] age of 17.0 [5.0-25.0] years, with 66.7% of overall patients deceased at less than 18 years of age; the median [IQR] age at death for patients with ASMD type B (n = 4) and type A/B (n = 5) was 31.0 [11.0-55.0] and 9.0 [4.0-18.0] years, respectively. All deaths were ASMD-related and primarily caused by liver or respiratory failures or severe progressive neurodegeneration (two patients with ASMD type A/B). The median (95% confidence interval [CI]) overall survival age since birth was 45.4 (17.5-65.0) years. Additionally, an SMR [95% CI] analysis (21.6 [9.8-38.0]) showed that age-specific deaths in the ASMD population were 21.6 times more frequent than that in the general German population., Conclusions: This study highlights considerable morbidity and mortality associated with ASMD type B and type A/B in Germany. It further emphasises the importance of effective therapy for chronic ASMD to reduce disease complications., (© 2024. The Author(s).)

Background: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DL CO ), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment., Results: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DL CO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DL CO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event., Conclusion: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691., (© 2023. The Author(s).)

Background: Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed diagnosis and barriers to good care. There are no published national or international consensus guidelines for the diagnosis and management of patients with ASMD. For these reasons, we have developed clinical guidelines that defines standard of care for ASMD patients., Methods: The information contained in these guidelines was obtained through a systematic literature review and the experiences of the authors in their care of patients with ASMD. We adopted the Appraisal of Guidelines for Research and Evaluation (AGREE II) system as method of choice for the guideline development process., Results: The clinical spectrum of ASMD, although a continuum, varies substantially with subtypes ranging from a fatal infantile neurovisceral disorder to an adult-onset chronic visceral disease. We produced 39 conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. In addition, these guidelines have identified knowledge gaps that must be filled by future research., Conclusion: These guidelines can inform care providers, care funders, patients and their carers about best clinical practice and leads to a step change in the quality of care for patients with ASMD with or without enzyme replacement therapy (ERT)., (© 2023. The Author(s).)

Gaucher disease type 3 is a chronic neuronopathic disorder with wide-ranging effects, including hepatosplenomegaly, anaemia, thrombocytopenia, skeletal disease and diverse neurological manifestations. Biallelic mutations in GBA1 reduce lysosomal acid β-glucosidase activity, and its substrates, glucosylceramide and glucosylsphingosine, accumulate. Enzyme replacement therapy and substrate reduction therapy ameliorate systemic features of Gaucher disease, but no therapies are approved for neurological manifestations. Venglustat is an investigational, brain-penetrant, glucosylceramide synthase inhibitor with potential to improve the disease by rebalancing influx of glucosylceramide with impaired lysosomal recycling. The Phase 2, open-label LEAP trial (NCT02843035) evaluated orally administered venglustat 15 mg once-daily in combination with maintenance dose of imiglucerase enzyme replacement therapy during 1 year of treatment in 11 adults with Gaucher disease type 3. Primary endpoints were venglustat safety and tolerability and change in concentration of glucosylceramide and glucosylsphingosine in CSF from baseline to Weeks 26 and 52. Secondary endpoints included change in plasma concentrations of glucosylceramide and glucosylsphingosine, venglustat pharmacokinetics in plasma and CSF, neurologic function, infiltrative lung disease and systemic disease parameters. Exploratory endpoints included changes in brain volume assessed with volumetric MRI using tensor-based morphometry, and resting functional MRI analysis of regional brain activity and connectivity between resting state networks. Mean (SD) plasma venglustat AUC0-24 on Day 1 was 851 (282) ng•h/ml; Cmax of 58.1 (26.4) ng/ml was achieved at a median tmax 2.00 h. After once-daily venglustat, plasma concentrations (4 h post-dose) were higher compared with Day 1, indicating ∼2-fold accumulation. One participant (Patient 9) had low-to-undetectable venglustat exposure at Weeks 26 and 52. Based on mean plasma and CSF venglustat concentrations (excluding Patient 9), steady state appeared to be reached on or before Week 4. Mean (SD) venglustat concentration at Week 52 was 114 (65.8) ng/ml in plasma and 6.14 (3.44) ng/ml in CSF. After 1 year of treatment, median (inter-quartile range) glucosylceramide decreased 78% (72, 84) in plasma and 81% (77, 83) in CSF; median (inter-quartile range) glucosylsphingosine decreased 56% (41, 60) in plasma and 70% (46, 76) in CSF. Ataxia improved slightly in nine patients: mean (SD, range) total modified Scale for Assessment and Rating of Ataxia score decreased from 2.68 [1.54 (0.0 to 5.5)] at baseline to 1.55 [1.88 (0.0 to 5.0)] at Week 52 [mean change: -1.14 (95% CI: -2.06 to -0.21)]. Whole brain volume increased slightly in patients with venglustat exposure and biomarker reduction in CSF (306.7 ± 4253.3 mm3) and declined markedly in Patient 9 (-13894.8 mm3). Functional MRI indicated stronger connectivity at Weeks 26 and 52 relative to baseline between a broadly distributed set of brain regions in patients with venglustat exposure and biomarker reduction but not Patient 9, although neurocognition, assessed by Vineland II, deteriorated in all domains over time, which illustrates disease progression despite the intervention. There were no deaths, serious adverse events or discontinuations. In adults with Gaucher disease type 3 receiving imiglucerase, addition of once-daily venglustat showed acceptable safety and tolerability and preliminary evidence of clinical stability with intriguing but intrinsically inconsistent signals in selected biomarkers, which need to be validated and confirmed in future research., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12-17 year], nine children [6-11 year], and seven infants/early child [1-5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DL CO ), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores., Results: All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p < 0.0001) and mean percent-predicted-DL CO increased by 46.6% (p < 0.0001) in nine patients who performed the test at baseline. Lipid profiles and elevated liver transaminase levels that improved or normalized by 1 year remained stable. Mean height Z-scores improved in all age groups (mean change from baseline 1.17, P < 0.0001)., Conclusion: Olipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year. Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704 ., (© 2022. The Author(s).)

Purpose: Gangliosidoses are a group of inherited neurogenetic autosomal recessive lysosomal storage disorders usually presenting with progressive macrocephaly, developmental delay, and regression, leading to significant morbidity and premature death. A quantitative definition of the natural history would support and enable clinical development of specific therapies., Methods: Single disease registry of 8 gangliosidoses (NCT04624789). Cross-sectional analysis of baseline data in N = 26 patients. Primary end point: disease severity assessed by the 8-in-1 score. Secondary end points: first neurologic sign or symptom observed (1) by parents and (2) by physicians, diagnostic delay, as well as phenotypical characterization. Tertiary end points: neurologic outcomes (development, ataxia, dexterity) and disability., Results: The 8-in-1 score quantitatively captured severity of disease. Parents recognized initial manifestations (startle reactions) earlier than physicians (motor developmental delay and hypotonia). Median diagnostic delay was 3.16 (interquartile range 0.69-6.25) years. In total, 8 patients presented with late-infantile phenotypes., Conclusion: Data in this registry raise awareness of these rare and fatal conditions to accelerate diagnosis, inform counseling of afflicted families, define quantitative end points for clinical trials, and can serve as historical controls for future therapeutic studies. We provide further insight into the rare late-infantile phenotype for G M2 -gangliosidosis. Longitudinal follow up is planned., Competing Interests: Conflict of Interest M.R., G.M., L.A.-K., Y.A., and S.D. declare no conflict of interest. F.Q. and B.H. are volunteering members of the patients’ organization “Hand in Hand against Tay-Sachs and Sandhoff disease” that financially supported this study. M.B. received honoraria from Takeda. E.M. received research grants and consultation fees and speakers’ honoraria from Sanofi Genzyme, Amicus Therapeutics, Takeda Pharmaceutical Company Limited, Orphazyme, Prevail Therapeutics, Idorsia Pharmaceuticals Ltd, Sio Gene Therapies, and Taysha Gene Therapies., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Acid sphingomyelinase deficiency (ASMD) is caused by pathogenic variants in the SMPD1 gene. This chronic, progressive, and potentially fatal condition requires prompt specialist care. The diagnosis of ASMD can be delayed or missed if patients that harbor the Q294K mutation undergo enzyme activity assessments that employ synthetic fluorometric substrates. Two case studies are presented, which illustrate the spectrum of disease in patients with a compound heterozygous Q294K pathogenic variant and the impact of false normal ASM activity results., Competing Interests: YA and EM have received speaker honoraria from Sanofi. There are no other no competing interests., (© 2022 The Authors.)

Purpose: This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults., Methods: A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics., Results: Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, P = .0004), spleen volume (39% decrease vs 0.5% increase, P < .0001), and liver volume (28% vs 1.5% decreases, P < .0001). Splenomegaly-related score decreased in both groups (P = .64). Other clinical outcomes improved in the olipudase alfa group compared with the placebo group. There were no treatment-related serious adverse events or adverse event-related discontinuations. Most adverse events were mild., Conclusion: Olipudase alfa was well tolerated and associated with significant and comprehensive improvements in disease pathology and clinically relevant endpoints compared with placebo in adults with ASMD., Competing Interests: Conflict of Interest M.W.: has received travel reimbursement and consulting fees from Sanofi Genzyme. A.B.: received honoraria for lectures, advisory boards, meetings, and travel support from Sanofi Genzyme and Takeda Shire. R.G.: has received honoraria, consulting fees, speaker fees, and travel reimbursement from Sanofi Genzyme. R.L.: has received consulting fees and travel reimbursement from Sanofi Genzyme. P.M.: has received consulting fees, speaker fees, and travel reimbursement from Sanofi Genzyme. E.M.: has received consulting fees and honoraria from Sanofi Genzyme. Employees of Sanofi Genzyme (or were at the time of the study) and own stock in the company: Y.C., S.F., B.L.T., A.Z., M.K., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

GM2 and GM1 gangliosidoses are genetic, neurodegenerative lysosomal sphingolipid storage disorders. The earlier the age of onset, the more severe the clinical presentation and progression, with infantile, juvenile and late-onset presentations broadly delineated into separate phenotypic subtypes. Gene and substrate reduction therapies, both of which act directly on sphingolipidosis are entering clinical trials for treatment of these disorders. Simple to use biomarkers for disease monitoring are urgently required to support and expedite these clinical trials. Here, lysosphingolipid and protein biomarkers of sphingolipidosis and neuropathology respectively, were assessed in plasma samples from 33 GM2 gangliosidosis patients, 13 GM1 gangliosidosis patients, and compared to 66 controls. LysoGM2 and lysoGM1 were detectable in 31/33 GM2 gangliosidosis and 12/13 GM1 gangliosidosis patient samples respectively, but not in any controls. Levels of the axonal damage marker Neurofilament light (NF-L) were highly elevated in both GM2 and GM1 gangliosidosis patient plasma samples, with no overlap with controls. Levels of the astrocytosis biomarker Glial fibrillary acidic protein (GFAP) were also elevated in samples from both patient populations, albeit with some overlap with controls. In GM2 gangliosidosis patient plasma NF-L, Tau, GFAP and lysoGM2 were all most highly elevated in infantile onset patients, indicating a relationship to severity and phenotype. Plasma NF-L and liver lysoGM2 were also elevated in a GM2 gangliosidosis mouse model, and were lowered by treatment with a drug that slowed disease progression. These results indicate that lysosphingolipids and NF-L/GFAP have potential to monitor pharmacodynamics and pathogenic processes respectively in GM2 and GM1 gangliosidoses patients., Competing Interests: RW, HF, MS, MG, DS, CS and PG are current or past employees of Idorsia pharmaceuticals which has an interest in developing pharmaceuticals for the treatment of lysosomal storage disorders., (© 2022 The Authors.)

Introduction: Inconsistent associations of leptin and adiponectin with bone mineral characteristics in puberty and adolescence have been reported. We aimed to examine the associations between leptin to adiponectin ratio (LAR) in puberty and bone mineral characteristics at the age of 18 years in healthy males., Materials and Methods: 88 white Caucasian boys were investigated at T1 (mean age 12.1 years), T2 (14.0 years) and T3 (18.0 years). Serum leptin and adiponectin were measured and LAR was calculated at T1, T2 and T3, bone mineral density (BMD) and bone mineral apparent density (BMAD) for total body and lumbar spine (LS) at T1 and T3. Spearman correlation coefficient and partial correlation analyses were used to describe the associations between mean pubertal LAR and BMD at T3., Results: Mean pubertal LAR was negatively correlated with both LS BMD (r = -0.23; P < 0.05) and LS BMAD at T3 (r = -0.33; P < 0.05). These associations remained significant also in partial correlation analysis after controlling for total body fat percentage, total testosterone, HOMA-IR and physical activity at T1 (r = -0.31; P < 0.05 and r = -0.41; P < 0.05 respectively)., Conclusion: LAR in puberty is negatively associated with lumbar spine BMD and lumbar spine BMAD at the age of 18 years., Competing Interests: The 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., (© 2021 The Authors.)

Background: Niemann-Pick disease type C (NPC) is a debilitating condition that impacts patients' and caregivers' quality of life (QOL) and reduces the patient's life expectancy. Since there is little qualitative research from the perspective of patients and family caregivers, this study explored the impact of NPC on patients' and caregivers' daily lives to understand the burden of disease., Results: A survey of caregivers for patients with NPC and adult patients with NPC (n = 49; patient age: 13 months-65 years) assessed NPC severity, importance of NPC symptoms, and how symptoms impacted patients' and caregivers' activities of daily living (ADLs) and health-related QOL (HRQOL). Follow-up interviews with a subset of survey participants (n = 28) explored the ranking of NPC symptom importance and impact on ADLs and HRQOL. Findings indicated that the most important manifestations of NPC were ambulation, swallowing, speech, fine motor skills, and cognition, which were those that had the most significant impact on ADLs and HRQOL. A wide range of ADLs were affected by NPC, mainly eating/drinking and the ability to perform daily tasks, including self-care, communicating, participating in school or work, and moving indoors as well as outside the home. Along with these impacts, there was an increased risk of experiencing dangerous or life-threatening situations leading to loss of patient independence and additional caregiver burden, often requiring changes in lifestyle such as giving up work. All aspects of patients' and caregivers' HRQOL were affected. Participants reported feelings of social isolation, loss of enjoyment in activities (patients), and feelings of sadness or worry (caregivers)., Conclusions: Ambulation, swallowing, speech, fine motor skills, and cognition are important manifestations of NPC. ADLs and HRQOL were impaired in the majority of patients as well as their caregivers. The findings were independent of current age, age of onset of symptoms, and level of NPC disease-related disability; however, the impact increased at higher levels of disease disability. Knowing the impact of NPC on patients and caregivers is important for understanding the lived experience of NPC and for identifying potential areas of support., (© 2021. The Author(s).)

The purpose of this investigation was to study whether prolonged competitive rhythmic gymnastics training influenced bone mineral accrual in premenarcheal girls. Eighty-nine girls (45 rhythmic gymnasts [RG] and 44 untrained controls [UC]) between 7 and 9 years of age were recruited and measured annually for four years (not all participants were measured at every occasion). Dual energy x-ray absorptiometry was used to assess the development of whole body (WB), femoral neck (FN) and lumbar spine (LS) bone mineral content (BMC). In addition, body composition, blood adipokine and jumping performance characteristics were obtained. For longitudinal analyses, hierarchical mixed-effects models were constructed to predict differences in the development of WB, FN and LS BMC between RG and UC groups, while accounting for differences in body composition, blood adipokine and jumping performance values. It appeared that from 8 years of age, RG had lower (p < 0.05) fat mass and leptin values, and higher (p < 0.05) jumping performance measures in comparison with UC girls. Hierarchical mixed-effects models demonstrated that RG had 71.9 ± 12.0, 0.23 ± 0.11 and 1.39 ± 0.42 g more (p < 0.05) WB, FN and LS BMC, respectively, in comparison with UC girls. In addition, WB, FN and LS BMC increased more (p < 0.05) between 7 to 12 years of age in RG girls in comparison with UC. In conclusion, these findings suggest that the prolonged exposure to competitive rhythmic gymnastics trainings in premenarcheal girls is associated with greater bone mineral accrual despite lower body fat mass and leptin values., (© Journal of Sports Science and Medicine.)