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Fabry disease is an X-linked lysosomal storage disorder caused by reduced activity or absence of the alpha-galactosidase A enzyme resulting in systemic accumulation of glycosphingolipids. End-stage renal disease (ESRD) is a late-stage manifestation of Fabry disease, typically presenting in the fifth decade of life, but is very rare in childhood. Here we present a case of an 11-year-old boy with classical Fabry disease presenting with ESRD requiring haemodialysis and transplant. Diagnosis was confirmed by renal biopsy, GLA mutation and low alpha-galactosidase A levels. He has an unusual genotype, hemizygous for the c.1000–11T>A intronic variant and positive for the pseudodeficiency allele D313Y. Due to the possibility of very early and accelerated disease progression, Fabry disease should be considered as a possible diagnosis in unexplained renal failure in males from a younger age.

Aims To evaluate the impact of the COVID-19 pandemic on the lysosomal disorders unit (LSDU) at Royal Free London NHS Foundation Trust (RFL), a highly specialised national service for diagnosis and management of adults with lysosomal storage disorders (LSD). Methods Review of home care enzyme replacement therapy (ERT) and emergency care, and Covid-19 shielding categories as per UK government guidance. New clinical pathways developed to manage patients safely during the pandemic; staff wellbeing initiatives described. Results LSDU staff redeployed and/or had additional roles to support increased needs of hospitalised Covid-19 patients. During the first lockdown in March 2020, 286 of 602 LSD patients were shielding; 72 of 221 had home care enzyme replacement therapy (ERT) infusions interrupted up to 12 weeks. During the pandemic, there was a 12% reduction in home care nursing support required, with patients learning to self-cannulate or require support for cannulation only. There were no increased adverse clinical events during this period. Twenty-one contracted covid-19 infection, with one hospitalised and no Covid-19 related deaths. In 2020, virtual clinics increased by 88% (video and/or telephone) compared to 2019. RFL well-being initiatives supported all staff. Conclusions We provide an overview of the impact of the COVID-19 pandemic on staff and patients attending a highly specialised rare disease service. As far as we are aware, this is the first detailed narrative on the challenges and subsequent rapid adaptations made, both as part of a large organisation and as a specialist centre. Lessons learnt could be translated to other rare disease services and ensure readiness for any future pandemic. This article is protected by copyright. All rights reserved.

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

Fabry disease (FD) is a treatable X linked lysosomal storage disorder with a wide phenotypic spectrum. There is a scarcity of published data on the burden of FD in India. This study evaluates the clinical and molecular spectrum of Indian patients with FD. In this multicentric study involving 10 tertiary referral centers in India, we analyzed the clinical course and genotype of 54 patients from 37 families. Family screening identified 19 new patients (35%) from 12 index cases. Then, 33 GLA gene variants were identified in 49/54 (90.7%) which included 11 novel and 22 known pathogenic variants. Of the 54 patients in our cohort, 40 patients had “classical” and 10 patients had a “nonclassical” presentation. The symptoms and signs included kidney dysfunction in 38/54 (70.3%), neuropathic pain in 34/54 (62.9%), left ventricular hypertrophy in 22/49 (44.8%) and stroke in 5/54 (9.2%). Female heterozygotes were 10/54 (18.5%) of whom 2 were index cases. There was a significant delay in reaching the diagnosis of 11.7 years. Enzyme replacement therapy was initiated in 28/54 (51.8%) patients with significant improvement of neuropathic pain and gastrointestinal symptoms. This study highlights the clinical presentation and mutational spectrum of FD in India and suggests that family screening and screening of high‐risk groups (hypertrophic cardiomyopathy, idiopathic chronic renal failure and cryptogenic stroke) could be the most cost‐effective strategies for early identification of FD.

The outcome of 110 patients with paediatric onset mucopolysaccharidosis II (MPS II) since the commercial introduction of enzyme replacement therapy (ERT) in England in 2007 is reported. Median length of follow up was 10 years 3 months (range = 1 y 2 m to 18 years 6 month). 78 patients were treated with ERT, 18 had no ERT or disease modifying treatment 7 had haematopoietic stem cell transplant, 4 experimental intrathecal therapy and 3 were lost to follow up. There is clear evidence of improved survival (median age of death of ERT treated (n = 16) = 15.13 years (range = 9.53 to 20.58 y), and untreated (n = 17) = 11.43 y (0.5 to 19.13 y) p = .0005). Early introduction of ERT improved respiratory outcome at 16 years, the median FVC (% predicted) of those in whom ERT initiated8 years = 69% (range = 34-86%) and 48% (25-108) (p = .045) in those started8 years. However, ERT appears to have minimal impact on hearing, carpal tunnel syndrome or progression of cardiac valvular disease. Cardiac valvular disease occurred in 18/46 (40%), with progression occurring most frequently in the aortic valve 13/46 (28%). The lack of requirement for neurosurgical intervention in the first 8 years of life suggests that targeted imaging based on clinical symptomology would be safe in this age group after baseline assessments. There is also emerging evidence that the neurological phenotype is more nuanced than the previously recognized dichotomy of severe and attenuated phenotypes in patients presenting in early childhood.

Objective To investigate the safety and efficacy of N-acetyl-l-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann–Pick disease type C (NPC) patients. Methods In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6–12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. Results 33 subjects aged 7–64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. Clinicaltrials.gov identifier NCT03759639.

Fabry disease is a rare, X-linked lysosomal storage disorder that begins in childhood with a wide variety of symptoms, including neuropathic pain, gastrointestinal abnormalities, and skin abnormalities. Despite the substantial impact of these symptoms on children's quality of life (QOL), systematic QOL analysis of Japanese pediatric Fabry disease patients has been limited. Therefore, to evaluate the QOL of Japanese pediatric Fabry disease patients using standardized and disease-specific scales, we used the Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ), which was developed by the Fabry Outcome Survey.The FPHPQ was translated in accordance with the Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes. A back-translated version was reviewed twice by the original lead author of FPHPQ to confirm the conceptual equivalence. The questionnaire was then validated by cognitive debriefing, and distributed to pediatric Fabry disease patients in Japan.Questionnaire responses were obtained from eight patients. The mean scores on the FPHPQ were 11.0 (± 11.43) for heat-associated pain, 5.5 (± 4.60) for cold-associated pain, and 14.8 (± 5.97) for abdominal pain and fatigue. In addition, heat-associated pain negatively correlated with physical well-being, whereas cold-associated pain positively correlated with good friendships.We established the Japanese version of the FPHPQ to assess the QOL of pediatric Fabry disease patients. The internal consistency and partial criterion-related validity of the Japanese version were confirmed. Analysis of a larger number of patients should be performed in the future to further validate the outcomes of this study.

Background: Mucopolysaccharidosis type III (MPS III, Sanfilippo disease) is a life-limiting recessive lysosomal storage disorder caused by a deficiency in the enzymes involved in degrading glycosaminoglycan heparan sulfate. MPS III is characterized by progressive deterioration of the central nervous system. Respiratory tract infections have been reported as frequent and as the most common cause of death, but gastrointestinal (GI) manifestations have not been acknowledged as a cause of concern. The aim of this study was to determine the incidence of GI problems as a primary cause of death and to review GI symptoms reported in published studies. Methods: Causes of death from 221 UK death certificates (1957–2020) were reviewed and the literature was searched to ascertain reported GI symptoms. Results: GI manifestations were listed in 5.9% (n = 13) of death certificates. Median (IQR) age at death was 16.7 (5.3) years. Causes of death included GI failure, GI bleed, haemorrhagic pancreatitis, perforation due to gastrostomies, paralytic ileus and emaciation. Twenty-one GI conditions were reported in 30 studies, mostly related to functional GI disorders, including diarrhoea, dysphagia, constipation, faecal incontinence, abdominal pain/distension and cachexia. Conclusions: GI manifestations may be an under-recognized but important clinical feature of MPS III. Early recognition of GI symptoms and timely interventions is an important part of the management of MPS III patients.

Background and aims For children with heterozygous familial hypercholesterolaemia (HeFH), European guidelines recommend consideration of statin therapy by age 8–10 years for those with a low density lipoprotein cholesterol (LDL-C) >3.5 mmol/l, and dietary and lifestyle advice. Here we compare the characteristics and lipid levels in HeFH children from Norway, UK, Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods Fully-anonymized data were analysed at the London centre. Differences in registration and on treatment characteristics were compared by standard statistical tests. Results Data was obtained from 3064 children. The median age at diagnosis differed significantly between countries (range 3–11 years) reflecting differences in diagnostic strategies. Mean (SD) LDL-C at diagnosis was 5.70 (±1.4) mmol/l, with 88% having LDL-C>4.0 mmol/l. The proportion of children older than 10 years at follow-up who were receiving statins varied significantly (99% in Greece, 56% in UK), as did the proportion taking Ezetimibe (0% in UK, 78% in Greece). Overall, treatment reduced LDL-C by between 28 and 57%, however, in those >10 years, 23% of on-treatment children still had LDL-C>3.5 mmol/l and 66% of those not on a statin had LDL-C>3.5 mmol/l. Conclusions The age of HeFH diagnosis in children varies significantly across 8 countries, as does the proportion of those >10 years being treated with statin and/or ezetimibe. Approximately a quarter of the treated children and almost three quarters of the untreated children older than 10 years still have LDL-C concentrations over 3.5 mmol/l. These data suggest that many children with FH are not receiving the full potential benefit of early identification and appropriate lipid-lowering treatment according to recommendations., Graphical abstract Image 1, Highlights • The age of HeFH diagnosis varies significantly between 8 European countries. • The proportion of HeFH children being treated varies across 8 European countries. • A quarter of FH children on statins have LDL-C above the target (>3.5 mmol/L). • Many FH children are not getting the full benefit of early diagnosis and treatment.

This consensus statement on the management of children and young people with heterozygous familial hypercholesterolaemia (FH) addresses management of paediatric FH in the UK, identified by cascade testing when a parent is diagnosed with FH and for those diagnosed following incidental lipid tests. Lifestyle and dietary advice appropriate for children with FH; suggested low density lipoprotein cholesterol (LDL-C) targets and the most appropriate lipid-lowering therapies to achieve these are discussed in this statement of care. Based on the population prevalence of FH as ~1/250 and the UK paediatric population, there are approximately 50,000 FH children under 18 years. Currently only about 550 of these children and young people have been identified and are under paediatric care.

Purpose Following the publication of 5-year agalsidase alfa enzyme replacement therapy (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed. Patients and methods FOS (ClinicalTrials.gov identifier: NCT03289065) data (April 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment start (baseline) for patients with ≥3 measurements, including baseline and year 10. Results Median (range) age (years) of the evaluable treated renal cohort at treatment start was 48.8 (17.9-67.3) for females (n=62), 34.4 (18.0-66.8) for males (n=90). With eGFR ≥60 mL/min/1.73 m2 at baseline, mean (95% CI) rate of eGFR change (eGFR/year) over 10 years was relatively stable in females (n=52; -0.55 [-1.12, +0.01]) and slightly declined in males (n=79; -1.99 [-2.45, -1.54]). With impaired kidney function (eGFR 48 g/m2.7 in females, >50 g/m2.7 in males) at baseline, mean (95% CI) LVMI/year slightly increased over 10 years in females (n=18; +1.51 [+0.91, +2.12]) and males (n=14; +0.87 (+0.19, +1.55). Without LVH at baseline, mean (95% CI) LVMI/year was stable in females (n=16; +0.52 [-0.13, +1.17]) and males (n=21; +0.57 [+0.02, +1.13]) over 10 years. Conclusion Agalsidase alfa-treated patients with 10-year FOS data and preserved kidney function and/or normal LVMI at baseline remained largely stable; those with decreased kidney function or LVH at baseline experienced modest declines in renal function and/or increases in LVMI.

Autosomal Dominant Familial Hypercholesterolaemia (FH) is the commonest inherited disorder of lipoprotein metabolism. Untreated monogenic FH caused by mutations in the LDLR, APOB or PCSK9 genes result in early onset cardiovascular death (below the age of 60 years). In the UK the prevalence of heterozygous FH is 1 in 270 and homozygous FH is 160,000 approximately. The introduction of statins nearly three decades ago has altered the natural history of FH, with a significant reduction of cardiovascular related morbidity and mortality. There is increasing evidence that early childhood interventions such as lifestyle choices, healthy eating and commencing statins by the age of 10 years would potentially prevent early onset cardiovascular disease and mortality in monogenic FH. The medium term safety of statins in children has been demonstrated. The UK paediatric FH register data has shown that children with FH are less obese than the normal population and the register aims to monitor the longer-term safety of statins in children with FH. Child-parent screening would potentially benefit the child and enables identifying a parent with FH, before the onset of a life threatening cardiovascular event. In addition, genetic cascade testing of relatives of an affected individual has been shown to be highly cost effective. We review the current literature with brief updates on genetics, the UK paediatric FH register data, published recommendations for the management of homozygous and heterozygous FH, lipid lowering therapies in children and screening for FH in childhood.

Background Gaucher disease (GD) is a rare lysosomal storage disorder classically subdivided into type 1 (non-neuronopathic) GD, and types 2 and 3 (neuronopathic) GD. It is typically characterized by clinical manifestations including anemia, thrombocytopenia, hepatosplenomegaly, bone lesions, and (in more severe forms) neurological impairment. However, less-commonly reported and often under-recognized manifestations exist, which potentially have a significant impact on patient outcomes. Greater efforts are needed to understand, recognize, and manage these manifestations. Objectives This review provides a synthesis of published information about three under-recognized GD manifestations (pulmonary involvement, lymphadenopathy, and Gaucheroma) and recommends diagnostic, management, and treatment strategies based on the available literature and author experience. The authors aim to raise awareness about these serious, progressive, and sometimes life-threatening conditions, which are often diagnosed late in life. Conclusions Little is known about the incidence, pathophysiology, prognostic factors, and optimal management of pulmonary involvement, lymphadenopathy, and Gaucheroma in patients with GD. Enzyme replacement therapy (ERT) has shown limited efficacy for the prevention and treatment of these manifestations. More research is needed to evaluate the potential effect of substrate reduction therapy (SRT) with glucosylceramide synthase (GCS) inhibitors, and to develop additional approaches to treat these GD manifestations. Improvements in data collection registries and international data-sharing are required to better understand the impact of these manifestations on GD patients, help develop effective management strategies, and, ultimately, improve patient outcomes.

Background and aims: Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Methods: Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. Results: Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10-16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10-16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). Conclusions: The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH. Highlights: LDLR mutations are the most common cause of familial hypercholesterolaemia (FH) in children from 8 European countries; Overall, 279 different LDLR mutations were found in 2531 FH children; The frequency of APOB p.(Arg3527Gln) varied significantly over the 8 countries; APOB-FH was less severe than LDLR-FH for low density lipoprotein-cholesterol (LDL-C) concentration and family onset of coronary heart disease (CHD). The European Register is supported by a grant from the International Atherosclerosis Society (Pfizer number 24052829). The UK register is supported by funds from the British Heart Foundation (BHF); HEART UK, Cardiac Network Co-ordinating Group Wales and the Royal College of Physicians. SEH is a BHF Professor and is funded by PG08/008, and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. MF is funded by the Fondation Leducq Transatlantic Networks of Excellence Program grant (no. 14 CVD03). MV is supported by the Ministry of Health, Czechia, project No. 64165, General University Hospital in Prague. TF and LT are supported by the Ministry of Health, Czechia, grant number NU20-02-00261. The Austrian FH register has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Portuguese FH Study has been supported by grants from the Portuguese Science and Technology Foundation and grants from the Portuguese Cardiology Society. AMM was supported by the Portuguese Science and Technology Foundation, grant number SFRH/BD/113,017/2015. The study sponsors had no role in study design, the collection, analysis, and interpretation of data, the writing of the report or the decision to submit the manuscript for publication. No honorarium, grant, or other form of payment was given to anyone to produce the manuscript. info:eu-repo/semantics/publishedVersion

BackgroundLysosomal storage disorders (LSDs) are rare genetic disorders, with heterogeneous clinical manifestations and severity. Treatment options, such as enzyme replacement therapy (ERT), substrate replacement therapy, and pharmacological chaperone therapy, are available for several LSDs, including Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (mucopolysaccharidosis type II [MPS II]). However, patients in some countries face challenges accessing treatments owing to limited availability of locally licensed, approved drugs.MethodsThe Takeda LSD Charitable access program aims to meet the needs of individuals with GD, FD or MPS II with the greatest overall likelihood of benefit, in selected countries, through donation of ERT to nonprofit organizations, and support for medical capacity-building as well as family support via independent grants. Long-term aims of the program are to establish sustainable healthcare services delivered by local healthcare providers for patients with rare metabolic diseases. Patients receiving treatment through the program are monitored regularly, and their clinical data and progress are reviewed annually by an independent medical expert committee (MEC). The MEC also selects patients for enrollment completely independent from the sponsoring company.ResultsAs of 31 August, 2019, 199 patients from 13 countries were enrolled in the program; 142 with GD, 41 with MPS II, and 16 with FD. Physicians reported improvements in clinical condition for 147 (95%) of 155 patients with follow-up data at 1 year.ConclusionsThe response rate for follow-up data at 1 year was high, with data collected for > 90% of patients who received ERT through the program showing clinical improvements in the majority of patients. These findings suggest that the program can benefit selected patients previously unable to access disease-specific treatments. Further innovative solutions and efforts are needed to address the challenges and unmet needs of patients with LSDs and other rare diseases around the world.

BackgroundNiemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative disorder characterized by symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in observational case studies and animal and cellular models of NPC. Therefore, the effects of the active L-enantiomer, N-acetyl-L-leucine (NALL, Sponsor Code IB1001) were evaluated in paediatric and adult patients with NPC.MethodsWe conducted a 9-center, multinational, open-label, rater-blinded Phase 2 study to assess the safety and efficacy of NALL for the treatment of pediatric (≥ 6 years) and adult patients with NPC (IB1001-201 clinical trial). Eligible patients were assessed during three study phases: a baseline period (with or without a study run-in), a 6-week treatment period (dosage of NALL 4 g/d in patients aged ≥13 years; weight tiered doses for patients aged 6-12 years based on approximately 0.1 g/kg/day), and a 6-week post-treatment washout period. The primary outcome was based on the Clinical Impression of Change in Severity (CI-CS) assessment (assessed on a 7-point Likert scale) performed by blinded, centralized raters who compared videos of patients performing a pre-defined primary anchor test (either the 8-Meter Walk Test (8MWT) or 9-Hole Peg Test of the Dominant Hand (9HPT-D)) at different study periods. Secondary outcomes included the cerebellar function evaluations, namely the Scale for Assessment and Rating of Ataxia (SARA), the Spinocerebellar Ataxia Functional Index (SCAFI), and the Clinical Global Impression Scales (CGI) as well as the EuroQol-5D/VAS.ResultsThirty-three subjects aged 7 to 64 years with a confirmed diagnosis of NPC were enrolled according to the trial protocol between 04 September 2019 and 30 January 2020. Thirty-two patients were included in the modified intention-to-treat analysis. IB1001 met its CI-CS primary endpoint (mean difference 0.86 ((90% CI 0.25,1.75, p=0.029). IB1001 also met secondary endpoints, including improvement during treatment on the SARA scale (mean difference −1.19 (90% CI −1.8, −0.5, p=0.001)), investigator’s CGI-C assessment (mean difference from baseline to the end of treatment 0.6 (90% CI 0.5, 1.0, pp=0.002)) and investigator’s CGI-C assessment (washout mean difference −0.5 (90% CI −1.0, 0.0, p=0.006). IB1001 was well-tolerated with no treatment related serious adverse reactions occurring.ConclusionsConsistent with its pharmacological action, IB1001 rapidly improved symptoms, functioning, and quality of life in 6-weeks, the clinical effect of which was lost after the 6-week, post-treatment washout period. High consistency and statistical significance between the primary and secondary endpoints demonstrate a clear, clinically meaningful improvement with IB1001. IB1001 was well-tolerated and no drug-related serious adverse events were reported, demonstrating a favorable risk/benefit profile for the treatment of NPC (Funded by IntraBio; ClinicalTrials.gov number, NCT03759639; EudraCT number 2018-004331-71).

Background Cardiac involvement in Fabry Disease (FD) occurs prior to left ventricular hypertrophy (LVH) and is characterized by low myocardial native T1 with storage reflected by cardiovascular magnetic resonance (CMR) and ECG changes. Objectives We hypothesize that a pre-storage myocardial phenotype might occur even earlier, prior to T1 lowering. Methods FD patients and age, sex and heart rate matched healthy controls underwent same-day ECG with advanced analysis and multiparametric CMR (cines, global longitudinal strain [GLS], T1 and T2 mapping, stress perfusion [myocardial blood flow, MBF] and late gadolinium enhancement [LGE]). Results 114 Fabry patients (46±13 years, 61% female) and 76 controls (49±15 years, 50% female) were included. In pre-LVH FD (n=72, 63%), a low T1 (n=32/72, 44%) was associated with a constellation of ECG and functional abnormalities compared to normal T1 FD patients and controls. However, pre-LVH FD with normal T1 (n=40/72, 56%) also had abnormalities compared to controls: reduced GLS (−18±2 vs −20±2%, P Conclusions FD has a measurable myocardial phenotype pre-LVH and pre-detectable myocyte storage with microvascular dysfunction, subtly impaired GLS and altered atrial depolarization and ventricular repolarization intervals. Proposed stages of cardiac involvement Funding Acknowledgement Type of funding source: None

PURPOSE OF REVIEW All guidelines for the management of heterozygous familial hypercholesterolaemia in children and young people recommend statins to lower LDL-cholesterol (LDL-C) concentrations, to reduce the individual's adult risk of developing cardiovascular disease (CVD). Here, we review recent findings regarding the efficacy and safety of the use of stains in childhood. RECENT FINDINGS As expected from their safety profile in adults, there is no evidence from short-term trials or long-term follow-up that statin use in children is associated with any adverse effects on growth, pubertal development or muscle or liver toxicity. Long-term follow-up indicates benefits with respect to lower CVD rates. Factors that influence adherence are discussed, as is the role of the underlying genetic causes for hypercholesterolaemia and of variation at other genes in determining the LDL-C-lowering effect. SUMMARY Based on the good safety profile, and the expert opinion guidelines, clinicians should consider prescribing statins for children with hypercholesterolaemia from the age of at least 10 years (and earlier if CVD risk is particularly high in the family). Uptitrating statin dosage and the use of additional lipid-lowering therapies should be considered so that LDL-C concentrations are lowered to recommended targets.

The initiation of enzyme-replacement therapy prior to the occurrence of substantial and irreversible organ damage in patients with Fabry disease is of critical importance. The Fabry Outcome Survey is an international disease registry of patients with a confirmed diagnosis of Fabry disease. In this study, data from the Fabry Outcome Survey were used for the assessment of the risks for cardiovascular and renal events in patients who received agalsidase alfa treatment.Eligible patients were males and females aged ≥18 years with Fabry disease treated with agalsidase alfa. Cardiovascular events included myocardial infarction, left ventricular hypertrophy (LVH), heart failure, arrhythmia, conduction abnormality, and cardiac surgery. Renal events included dialysis, transplantation, and renal failure. Kaplan-Meier curves and log-rank tests were used for comparing event-free probabilities and time to first cardiovascular or renal event, from agalsidase alfa initiation to a maximum of 120 months, in patients with LVH versus normal left ventricular mass index (LVMI; ≤50 g/mAmong the 560 patients (269 males; 291 females) with available LVMI data, 306 (55%) had LVH and 254 (45%) had normal LVMI at baseline. The risk for a cardiovascular event was higher in the subgroup with LVH versus normal LVMI at baseline (hazard ratio [HR] = 1.57; 95% CI, 1.21-2.05; P 0.001), but the risk for a renal event was similar between the 2 subgroups (HR = 1.90; 95% CI, 0.94-3.85; P = 0.074). Among the 1093 patients (551 males; 542 females) with available eGFR data, 433 (40%) had a low eGFR and 660 (60%) had a normal eGFR at baseline. The subgroup with a low eGFR at baseline had a significantly higher risk for a cardiovascular event (HR = 1.33; 95% CI, 1.04-1.70; P = 0.021) or a renal event (HR = 5.88; 95% CI, 2.73-12.68; P 0.001) compared with patients with a normal eGFR at baseline.In the present study, the presence of LVH and/or reduced renal function at agalsidase alfa initiation was associated with a significantly higher risk for a cardiovascular or renal event, indicating that cardiovascular and renal pathologies in Fabry disease may be inter-related. Early initiation of agalsidase alfa treatment prior to the onset of severe organ damage may improve outcomes. ClinicalTrials.gov identifier: NCT03289065.

Gaucher disease is an inborn error of metabolism resulting from the deficiency of the enzyme glucocerebrosidase and consequent accumulation of glucocerebroside within the lysosomes of macrophages. The clinical presentation is very diverse, depending on the age of onset and the severity of the disease, and results from the progressive infiltration of lipid-laden cells in various organs. Common manifestations of Gaucher disease include enlarged liver and/or spleen (hepatosplenomegaly), bone marrow disease (pancytopenia) and bone abnormalities, which are extremely variable and can affect multiple skeletal sites. While bone involvement of long bones and vertebrae is a well-recognised feature of Gaucher disease, jawbone involvement is less commonly noted. Here, we describe a case of a 63-year-old patient with type 1 Gaucher disease with a history of long-term use of bisphosphonates and who had presented with dental pain, with subsequent investigations confirming the radiological features of jaw involvement in Gaucher disease, including periodontal disease.