Enzyme replacement therapies (ERTs) approved for Fabry disease require infusions every 2 weeks (E2W). Pegunigalsidase alfa, a PEGylated ERT with a prolonged half-life vs. other ERTs, may allow extension of the dosing interval to every 4 weeks (E4W). BRIGHT F51 (NCT03614234) is an ongoing phase III, open-label extension study evaluating long-term efficacy and safety of pegunigalsidase alfa 2 mg/kg E4W in adults with Fabry disease previously treated with agalsidase alfa or beta E2W for ≥ 3 years who completed one year of pegunigalsidase alfa treatment in the BRIGHT study. This interim analysis reports results following 3–5 years of treatment (cutoff date December 31, 2022). Twenty-nine patients were enrolled. Median (interquartile range [IQR]) annualized eGFR slope during treatment was ‒2.2 (‒2.9; ‒1.1) mL/min/1.73 m2/year (males: ‒2.4 [‒2.9; ‒1.0, n = 23]; females: ‒1.8 [‒2.4; ‒1.3, n = 6]; anti-drug antibody [ADA]-positive: ‒2.6 [‒4.0; ‒1.7, n = 9 all male]; ADA-negative: ‒1.8 [‒2.7; ‒0.6, n = 20]). Median (IQR) change in plasma lyso-Gb3 from baseline to Week 208 was 3.2 (‒3.9; 8.5, n = 17) nM in males; concentrations remained low and stable in females. Overall, 51/477 treatment-emergent adverse events in 13 patients (45

The sphingolipidoses Fabry disease, Gaucher disease and Acid sphingomyelinase deficiency (ASMD) are the three most common lysosomal storage diseases for which treatment is currently available. Timely diagnosis with estimation of the disease severity and possibilities of follow-up of patients, whether or not under therapy, is crucial for providing good care and for the prevention of possible lethal complications. With this research we provide an efficient and sensitive detection method; its implementation in clinical practice could optimize the diagnosis and follow-up of patients with Gaucher, Fabry and ASMD. This detection method on dried blood spots (DBS) was validated according to the international Clinical and Laboratory Standards Institute (CLSI) guidelines, looking at reproducibility, linearity, carry-over and lower limit of quantification. Analogously, validation and subsequent comparison of the method validation results using another matrix, the Capitainer blood sampling cards (Capitainers), was fulfilled. The results showed that this detection method is fully applicable clinically when using DBS as well as Capitainers. In addition, even additional improvements of some validation parameters were found when using the Capitainers. Twenty-six patient samples and fifteen healthy samples were analyzed for case finding control. All patient cases were detected without ambiguity. We present a high-resolution mass spectrometry method that provides an accurate analysis for targeted screening, aiming for improved/accelerated diagnosis when added in the diagnostic pathway and monitoring of Fabry, Gaucher and ASMD in DBS as well as in Capitainers, with the main advantages of a small volume of blood samples, guaranteeing stability and easy transportation from the collection site to the laboratory.

Palliative care should be an integral part of follow-up for patients with life-limiting/life-threatening conditions, irrespective of age and diagnosis. Many patients with inherited metabolic disorders (IMD) have palliative care needs due to multi-systemic conditions without curative treatment options. To map the organisation and accessibility of palliative care across European IMD expert centres, and to explore the experiences of IMD physicians with palliative care, the European Reference Network for Hereditary Metabolic Disorders (MetabERN) invited physicians from all 103 member institutions to participate in a survey covering various aspects of palliative care. Ninety-two physicians from 63 institutions in 23 countries participated. A national plan or strategy for palliative care had been established in most countries (87%). Both children (91%) and adults (89%) had access to palliative care services. Most paediatric (86%) and many adult IMD physicians (67%) used advance care planning. A total of 284 referrals to palliative care were reported, mostly IMD patients with lysosomal and mitochondrial disorders, and neurological, respiratory, cognitive and gastrointestinal comorbidities. However, during the past 5 years, the majority of physicians (60%) had referred 20% or fewer of their deceased patients to palliative care. Although palliative care is available in most European IMD expert centres, only a small proportion of deceased IMD patients has been referred. The findings of this study indicate both a misconception and underutilisation of modern palliative care services. Addressing existing barriers is essential, and both IMD physicians and patients may need more information about available palliative care services and up-to-date indications for referral.

Acid Sphingomyelinase Deficiency (ASMD) is a lysosomal storage disorder that can lead to severe complications if not promptly treated. This case aims to highlight the critical importance of early awareness of ASMD and to introduce, for the first time in the literature, a new and highly effective treatment option for children.

Introduction Le pegunigalsidase alfa est une thérapie enzymatique de remplacement (TER) approuvée pour la maladie de Fabry à la dose de 1mg/kg administrée par voie intraveineuse toutes les deux semaines (T2S). Afin d’alléger le fardeau du calendrier d’administration T2S, le schéma posologique alternatif de 2mg/kg toutes les quatre semaines (T4S) a été étudié dans l’essai BRIGHT/F50 et son extension (BRIGHT-F51/CLI-06657AA1-03). Matériels et méthodes Afin d’explorer l’expérience des patients avec la pegunigalsidase alfa administrée T4S, les sujets enrôlés dans l’essai BRIGHT-F51 ont été invités à participer à l’étude qualitative transversale PEOPLE axée sur les résultats centrés sur le patient tels que les signes/symptômes et l’impact sur la qualité de vie (QdV). 17/29 entretiens ont été réalisés en suivant un guide d’entretien semi-structuré. Le codage des transcriptions des entretiens a été effectué à l’aide du logiciel d’analyse qualitative MAXQDA. Résultats En décrivant leur expérience, les patients ont signalé 54 signes/symptômes uniques (par exemple, fatigue, diminution de la transpiration et douleur dans les extrémités) et 24 impacts uniques sur la QdV. Les répercussions sur les activités de la vie quotidienne et la productivité au travail ou à l’école sont les concepts les plus fréquemment signalés comme affectant “gravement” la qualité de vie des patients. Les patients ont également été invités à décrire les avantages ou les inconvénients de l’horaire T4S par rapport à l’horaire T2S. L’horaire T4S a été perçu comme plus pratique et permettant aux patients de mieux gérer leur temps et leurs activités et d’être plus productifs. L’horaire T4S est également perçu comme permettant aux patients de mener une vie plus normale. Les patients ont également attribué l’amélioration de la qualité de vie à l’atténuation de certains signes/symptômes (par exemple, la fatigue, la diarrhée et les douleurs aux extrémités) qu’ils associaient à l’efficacité du médicament. En outre, l’avantage de ne pas avoir sommeil en raison de l’absence de prise d’antihistaminique avant la perfusion a été mentioné par les patients. Pour la plupart des patients, ces avantages l’emportent sur l’inconvénient d’une durée de perfusion plus longue que celle de le TER précédent. Conclusion Dans l’ensemble, les points de vue des patients de cette étude mettent en évidence les avantages et l’amélioration de la qualité de vie associés au traitement par la pegunigalsidase alfa administré en 4heures.

BackgroundLeft ventricular (LV) hypertrophy is a common clinical finding. Differential diagnosis includes Fabry disease, a rare and progressive, but treatable storage disease caused by deficiency of alpha-galactosidase A. However, diagnosis of Fabry is often hampered by its clinical heterogeneity, LV hypertrophy phenocopies and unawareness of the clinician.MethodsThis review summarises clinical data, family history, electrocardiogram (ECG) and imaging (echocardiogram and cardiovascular magnetic resonance (CMR)) characteristics to differentiate aetiologies of LV hypertrophy including clues for the diagnosis of Fabry.ResultsLV hypertrophy is a consequence of pressure overload mostly, but differential diagnosis includes hypertrophic cardiomyopathy and infiltrative diseases. Clinical data, ECG, type and degree of LV hypertrophy, functional and tissue characteristics differ among aetiologies. LV hypertrophy in Fabry is progressive and mostly concentric but may copy any hypertrophic cardiomyopathy. Dependent on residual alfa-galactosidase A enzyme activity, degree of LV hypertrophy in Fabry may vary. Initially, low myocardial CMR T1-map values are calculated. At a later stage, midwall late gadolinium enhancement of the inferolateral LV wall may occur. Global longitudinal strain may be depressed in the inferolateral wall. Voltage criteria for LV hypertrophy and short PQ interval are common. Right ventricular (RV) hypertrophy is frequent. In addition, multisystemic symptoms including neuropathic pain, hypohidrosis, proteinuria, renal insufficiency and familial young stroke are pointing to Fabry.ConclusionsLV hypertrophy should raise suspicion of Fabry disease, especially if LV hypertrophy is unexplained and/or associated with RV hypertrophy. In Fabry, LV hypertrophy may be heterogeneous and mimic any hypertrophic cardiomyopathy. ECG, multisystemic symptoms and imaging may provide clues for Fabry.

Pegunigalsidase alfa, a PEGylated α-galactosidase A enzyme replacement therapy (ERT) for Fabry disease, has a longer plasma half-life than other ERTs administered intravenously every 2 weeks (E2W). BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks. Primary objective assessed safety, including number of treatment-emergent adverse events (TEAEs). Thirty patients were enrolled (24 males); 23 previously received agalsidase beta. Pegunigalsidase alfa plasma concentrations remained above the lower limit of quantification throughout the 4-week dosing interval. Thirty-three of 182 TEAEs (in 9 patients) were considered treatment-related; all were mild/moderate. No patients developed de novo anti-drug antibodies (ADAs). In the efficacy analysis (n = 29), median (inter-quartile range) eGFR change from baseline over 52 weeks was -1.9 (-5.9; 1.8) mL/min/1.73 m2 (n = 28; males [n = 22]: -2.4 [-5.2; 3.2]; females [n = 6]: -0.7 [-9.2; 2.0]). Overall, median eGFR slope was -1.9 (-8.3; 1.9) mL/min/1.73 m2/year (ADA-negative [n = 20]: -1.2 [-6.4; 2.6]; ADA-positive [n = 9]: -8.4 [-11.6; -1.0]). Lyso-Gb3 concentrations were low and stable in females, with a slight increase in males (9/24 ADA-positive). The BRIGHT study results suggest that 2 mg/kg pegunigalsidase alfa E4W is tolerated well in stable adult patients with Fabry disease. Due to the low number of patients in this study, more research is needed to demonstrate the effects of pegunigalsidase alfa given E4W. Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W. TAKE-HOME MESSAGE: Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by a deficiency of the lysosomal hydrolase α-L-iduronidase. MPS I is characterized by a broad range of disease manifestations. This includes devastating neurocognitive and bone manifestations and a short life expectancy in severely affected MPS I patients. Neurocognitive manifestations are typically limited in more attenuated MPS I, but patients may still suffer from severe somatic and bone manifestations. Severe MPS I patients are primarily treated with hematopoietic stem cell transplantation (HSCT) and more attenuated patients with enzyme replacement therapy. HSCT should be initiated before irreversible disease manifestations, preferably before 9 months, but may be initiated in patients up to 2 years. Early diagnosis of MPS I is challenging at best, and newborn screening (NBS) has already been initiated in several countries to diagnose and treat patients early. This article summarizes the history, benefits, methods and challenges that have to be addressed before NBS can be used most effectively.

Background: Gaucher's and Fabry's disease are two of the most common treatable lysosomal storage diseases, and have a wide spectrum of clinical symptoms. Early detection is important, because timely initiation of treatments can improve the disease status and prevent complications. However disease manifestations develop in childhood, diagnosis is delayed until adulthood partly due to the limitations of the currently used diagnostic pathway. The aim of this research is to develop and validate a multiplex assay and defining reference ranges, which do not exist at this moment, to improve and facilitate the entire diagnostic work up and enable treatment in an earlier stage of disease. Methods and findings: Biomarkers glucosylsphingosine (GlcSph) and globotriaosylsphingosine (Lyso-Gb3) were detected and quantified using LC-MS/MS on dried blood spots. We developed an improved and new extraction method that allowed to measure GlcSph and Lyso-Gb3 in a multiplex analytical platform. After validation of the method, samples of 1480 individuals with normal enzymatic activity were collected to determine age and gender-related reference ranges.Our combination method showed a good linearity, precision, accuracy and limit of quantification with lack of carry-over following the specific international CLSI guidelines. The suggested protocol is robust, efficient, sensitive, specific, comprehensive and relatively cheap in order to accelerate the diagnostic process for both lysosomal storage diseases. The samples, with normal enzymatic activity, defined statistical relevant and clinical correct reference ranges for each specific age group by gender. Conclusion: We report a multiplex LC-MS/MS method and relevant reference ranges that are appropriate for the targeted screening, diagnosis and follow-up of Fabry and Gaucher disease.

Childhood fasting intolerance is a life-threatening problem associated with various inborn errors of metabolism. Plasma acylcarnitines reflect fatty acid oxidation and help determine fasting intolerance etiology. Pediatric reference values of plasma acylcarnitines upon fasting are not available, complicating interpretation of stress samples.Retrospective analysis of supervised clinical fasting studies between 01/2005-09/2012. Exclusion criteria involved patients with (suspected) disorders, repeated tests or incomplete results. Remaining children were grouped according to age: group A (≤24 months), B (25-84 months) and C (≥85 months). Median and 2.5th to 97.5th percentiles of basic metabolic parameters and acylcarnitines were determined at start and end of testing on the ward and analyzed for significant differences (p<0.05).Out of 127 fasting studies, 48 were included: group A (n=13), B (n=23) and C (n=12). Hypoglycemia occurred in 21%. Children from group C demonstrated significantly higher end glucose concentrations while end ketone body concentrations were significantly lower compared to younger children. In all groups, free carnitine and C3-carnitine significantly decreased upon fasting, while C2-, C6-, C12:1-, C12-, C14:1-, C14-, C16:1- and C16-carnitine significantly increased. End concentrations of C6-, C12:1-, C12-, C14:1-, C14-, C16:1-, C16- and C18:1-carnitine were significantly lower in children ≥85 months compared to younger children.Fasting-induced counter-regulatory mechanisms to maintain energy homeostasis are age-dependent. This influences the changes in basic metabolic parameters and acylcarnitine profiles. Our data enable improved interpretation of the individual fasting response and may support assessment of minimal safe fasting times or treatment responses in patients.

We report a unique case of an infant with a severe dilated cardiomyopathy as the clinical presentation of sialidosis type II (OMIM 256550), a rare autosomal recessive inherited lysosomal storage disease that is characterized by partial or complete deficiency of α-neuraminidase, following mutations in the gene neuraminidase 1 (NEU1), located on the short arm of chromosome 6 (6p21.3). Accumulation of metabolic intermediates leads to severe morbidity, especially myoclonus, gait disturbances, cherry-red macules with secondary loss of visual acuity, impaired color vision and night blindness, and sometimes additional neurological findings such as seizures. Dilated cardiomyopathies are characterized by dilation and impaired contraction of the left or both ventricles, whereas most of the metabolic cardiomyopathies are hypertrophic forms appearing with diastolic dysfunction and, in case of lysosomal storage diseases, often associated with valvular thickening and prolapse. Cardiac manifestations in systemic storage disorders are common although rarely described in mucolipidoses. In mucolipidosis type 2 or I-cell disease only three cases were presented with severe dilated cardiomyopathy and endocardial fibroelastosis in infancy, as opposed to sialidosis type II, by which to the best of our knowledge no presentation of dilated cardiomyopathy was previously reported in literature.

To learn what mothers know about newborn bloodspot screening (NBS), the procedure, and the sources used, a pilot study was performed. An online questionnaire was developed, with the first part focused on characteristics and the NBS procedure, and the second on knowledge, information sources, and health care providers (HCPs). This questionnaire was accessible until 200 answers were received. The characteristics of respondents were representative for the population. Mothers gave verbal consent in 69.5% of cases, 12.5% did not, and 18% stated that no consent was requested. The ‘knowledge’ part contained 12 closed questions, five multiple-choice questions on sources, and assessments (5-point Likert scores) of the information transfer. The mean knowledge level was 7.2/12. Screening concepts (consequences, likelihood, sensitivity, carrier) and absence of notification of normal findings were well known. The fact that NBS is not compulsory was poorly known, and post-analysis sample handling procedures were poorly understood. Key HCPs were midwifes (80.5%) and nurses (38.5%). When the leaflet (44%) was provided, the majority read it. Mean Likert scores were 3.36, 3.38, 3.11 and 3.35 for clarity, timing appropriateness, sufficiency, and usefulness. The knowledge level and consent practices were reasonably good. Key HCP were midwives and nurses, the leaflets were supporting. This should enable a quality improvement program to a sustainable NBS program in Flanders.

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal storage disorder caused by biallelic pathogenic variants in the gene encoding arylsulfatase A. Disease onset is variable (with late infantile, early and late juvenile, and adult forms) and treatment options depend on age and disease symptoms at onset. In the past, allo-hematopoietic stem cell transplantation (allo-HSCT) has been the best treatment option, following strict selection criteria. The outcome however is variable and morbidity remains high. This paved the way to the development of new treatment options, some of them aiming to be curative. In the light of this changing therapeutic field, newborn screening is becoming a valuable option. This narrative review aims to describe the outcome of allo-HSCT in the different MLD disease forms, and, in addition, reviews new treatment options. Finally, the shift of the field towards newborn screening for MLD is discussed.

Chimeric antigen receptor T (CAR-T)-cell, an adaptive immune therapy is approved for patients with acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Its use and subsequent toxicities are expected to rise in the coming years. The main toxicities are cytokine release syndrome, hemophagocytic lymphohistiocytosis and immune effector cell associated neurotoxicity syndrome. Cytokine release syndrome is observed in up to 40% of patients. Almost 20% of patient suffer from acute kidney injury after CAR-T cell infusion. Associated factors are high-grade cytokine release syndrome, a prior autologous or allogeneic stem cell transplantation andrequirement of intensive care unit. Several mechanisms may contribute to the occurrence of acute kidney injury after CAR-T infusion: hypoperfusion during cytokine release syndrome, cytokine injury, T cell infiltration, tumor lysis syndrome and sepsis-induced injury. Kidney injury is associated with substantial increase in morbi-mortality.