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Background: Gene therapy is currently in development for several monogenetic diseases including lysosomal storage disorders. Limited evidence is available on patient preferences for gene therapy in this population. In this study, we compare gene therapy-related risk tolerance between people affected by three lysosomal storage diseases currently faced with different therapeutic options and prognoses., Methods: A survey including the probabilistic threshold technique was developed in which respondents were asked to choose between gene therapy and the current standard of care. The attributes included to establish participants' risk tolerance were previously identified in focus groups of affected people or their representatives, namely: risk of mild side effects, severe side effects, the need for additional medication, and the likelihood of long-term effectiveness. The survey was distributed among people receiving outpatient care for type 1 Gaucher disease (good prognosis with current treatment options), Fabry disease (varying prognosis with current treatment options, XY-genotype on average more severely affected than XX), and parents representing people with severe forms of mucopolysaccharidosis type III A/B (poor prognosis, no disease-specific therapy available)., Results: A total of 85 surveys were completed (15 Gaucher disease respondents, 62 Fabry disease respondents (17 self-identifying male), eight parents of ten people with mucopolysaccharidosis type III). Disease groups with higher disease severity trended towards higher risk tolerance: Gaucher disease respondents were most cautious and predominantly preferred the current standard of care as opposed to MPS III representatives who were more risk tolerant. Respondents with Fabry disease were most heterogeneous in their risk tolerance, with male participants being more risk tolerant than female participants. Long-term effectiveness was the attribute in which respondents tolerated the least risk., Conclusions: People affected by a lysosomal storage disease associated with a poorer prognosis and less effective current treatment options trended towards more risk tolerance when choosing between gene therapy and the current standard of care. This study shows the importance of involvement of patient preferences before and during the development process of new treatment modalities such as gene therapy for rare diseases, to ensure that innovative therapies align with the wishes and needs of people affected by these diseases., (© 2024. The Author(s).)

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.

Background: Alpha-methylacyl-CoA racemase (AMACR) deficiency is a rare peroxisomal enzyme deficiency caused by biallelic variants in the AMACR gene. This deficiency leads to the accumulation of toxic bile acid intermediates (R)-trihydroxycholestenoic acid (THCA) and (R)-dihydroxycholestenoic acid (DHCA) and pristanic acid. With less than 20 patients described in literature, the phenotype of AMACR deficiency is poorly defined and no data on the natural history are available., Results: Here we describe a cohort of 12 patients (9 adults and 3 children) with genetically confirmed AMACR deficiency (median age at diagnosis 56 years, range 3-69), followed for an average of 6 years (between 2015 and 2023). Five novel pathogenic variants are described. In 5/9 adult patients, retinitis pigmentosa was detected at a median age of 45 years (range 30-61). The median delay to diagnosis of AMACR deficiency after the diagnosis of retinitis pigmentosa was 24 years (range 0-33). All adult patients subsequently developed neurological signs and symptoms after the age of 40 years; most frequently neuropathy, ataxia and cognitive decline with prior normal cognitive functioning. One patient presented with a stroke-like episode. All adult patients showed a typical MRI pattern involving the thalami and gray matter structures of the pons and midbrain. One patient had a hepatocellular carcinoma at the time of the AMACR deficiency diagnosis and two patients suffered from gallstones. All three included children had elevated liver transaminases as single presenting sign and showed no brain MRI abnormalities., Conclusion: AMACR deficiency can be considered as an adult slowly progressive disease with a predominant neurological phenotype. The main signs comprise retinitis pigmentosa, neuropathy, ataxia and cognitive decline; stroke-like episodes may occur. Recognition of typical MRI abnormalities may facilitate prompt diagnosis. In addition, there is a risk of liver fibrosis/cirrhosis and hepatocellular carcinoma in these patients, requiring active monitoring., (© 2024. The Author(s).)

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare lysosomal storage disease with a broad spectrum of manifestations ranging from severe neuropathic forms to attenuated, chronic visceral forms. Manifestations of the chronic visceral subtype are variable and encompass different degrees of hepatosplenomegaly, pulmonary disease and dyslipidemia. The aim of this study was to provide insights into the natural course of adult patients with the chronic visceral subtype. Based on these insights, we proposed tentative criteria for initiation and follow-up of enzyme replacement therapy (ERT). The data of 23 adult patients were collected in a prospective study. Clinical, genetic and demographic data, plasma measurements, abdominal imaging, pulmonary imaging, pulmonary function tests and quality of life questionnaires were collected. Stability of disease based on several clinical, biochemical and radiological markers (i.e., spleen volume, platelet levels, liver volume, alanine aminotransferase [ALT] levels, diffusion capacity of the lungs for carbon monoxide [DLCO] chitotriosidase activity and lysosphingomyelin [LSM]) was assessed. Cardiovascular risk was estimated based on sex, age, smoking, systolic blood pressure and lipid profile. Quality of life was evaluated with the 36-Item Short Form Health Survey and the Health Assessment Questionnaire. Median follow-up was 6.1 years (range 1.3-19.5 years). The most common manifestations were splenomegaly (100%), decreased high-density lipoprotein cholesterol (HDL-C) plasma levels (83%), (signs of) steatosis measured with transient elastography (82%), thrombocytopenia (64%), hepatomegaly (52%) and decreased diffusion capacity (45%). The majority of markers remained stable during follow-up. Twelve patients showed progression of disease: four for spleen volume, two for liver volume, three for DLCO, seven for chitotriosidase activity and three for LSM. One patient showed progression of disease based on four markers, although this patient did not report any problems at the last visit. Cardiovascular risk was estimated and was increased in half of the patients older than 40 years. Patient-reported quality of life did not differ from the general population, but differences in median 36-Item Short Form Health Survey (SF-36) scores of patients with severe pulmonary involvement and those of patients without pulmonary involvement were observed. Tentative criteria for initiation and effect of therapy were proposed. In conclusion, the chronic visceral subtype of ASMD showed a predominantly stable disease course in this cohort. We propose that ERT should be initiated on an individual basis and only in case of progression or symptomatic disease. Collection and analysis of real world data are necessary to refine start, stop and follow-up criteria in the future., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Amiodarone and mexiletine are used for ventricular arrhythmias, for which a combination therapy of both anti-arrhythmic drugs (AADs) is not uncommon. Therapeutic drug monitoring (TDM) can be beneficial for clinical guidance of therapy, especially to correctly identify adverse events. Desethylamiodarone, the active metabolite of amiodarone, accumulates over time and is associated with serious adverse events. Therefore, simultaneous TDM for amiodarone, desethylamiodarone and mexiletine is advantageous in clinical practice. The presented LC-MS/MS method was validated for selectivity, matrix effect, linearity, accuracy, precision, carry-over and stability. The method was continuously evaluated during eight months of clinical use. The method was shown to be linear within the measured range of 0.1 to 10 mg/L for each component. The matrix effect was considered negligible. No interfering responses were found for amiodarone, desethylamiodarone and the isotopic-labeled internal standards. A constant and reproducible within-run contribution of 45.3 %, originating from the system, was identified for mexiletine. The systemic contribution to the peak area of the lowest quantifiable concentration of mexiletine affected the selectivity and carry-over effect measurements. Multiple measurements showed that regression adjusted concentrations were accurate and reproducible, indicating calibration correction was applicable. Sample stability was found to be within limits for all storage conditions and freeze-thaw cycles. Furthermore, long-term method evaluation with external controls resulted in stable measurements with a percentage coefficient of variance between 1.3 % and 6.3 %. The presented practical and reliable method is applicable for clinical TDM and will allow clinical practitioners to guide drug therapy of amiodarone and mexiletine., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.E.M. Hollak reports financial support was provided by Nationale Postcode Loterij. P.G. Postema reports a relationship with Dutch Heart Foundation that includes: funding grants. P.G. Postema is a member of the Scientific Advisory Group on Cardiovascular Issues (SAG-CVS) of the EMA since 2021 If there are other authors, they 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To illustrate the financial consequences of implementing different managed entry agreements (managed entry agreements for the Dutch healthcare system for autologous gene therapy atidarsagene autotemcel [Libmeldy]), while also providing a first systematic guidance on how to construct managed entry agreements to aid future reimbursement decision making and create patient access to high-cost, one-off potentially curative therapies., Methods: Three payment models were compared: (1) an arbitrary 60% price discount, (2) an outcome-based spread payment with discounts, and (3) an outcome-based spread payment linked to a willingness to pay model with discounts. Financial consequences were estimated for full responders (A), patients responding according to the predicted clinical pathway presented in health technology assessment reports (B), and unstable responders (C). The associated costs for an average patient during the time frame of the payment agreement, the total budget impact, and associated benefits expressed in quality-adjusted life-years of the patient population were calculated., Results: When patients responded according to the predicted clinical pathway presented in health technology assessment reports (scenario B), implementing outcome-based reimbursement models (models 2 and 3) had lower associated budget impacts while gaining similar benefits compared with the discount (scenario 1, €8.9 million to €6.6 million vs €9.2 million). In the case of unstable responders (scenario C), costs for payers are lower in the outcome-based scenarios (€4.1 million and €3.0 million, scenario 2C and 3C, respectively) compared with implementing the discount (€9.2 million, scenario 1C)., Conclusions: Outcome-based models can mitigate the financial risk of reimbursing atidarsagene autotemcel. This can be considerably beneficial over simple discounts when clinical performance was similar to or worse than predicted., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section. The views expressed in this article are the personal views of the authors. They may not be understood or quoted as being made on behalf of or reflecting the position of the agencies or organizations with which the authors are affiliated., (Copyright © 2024. Published by Elsevier Inc.)

Rationale: Gaucher disease (GD), an autosomal recessive lysosomal storage disease, results from GBA1 variants causing glucocerebrosidase (GCase) deficiency. While enzyme replacement therapy (ERT) helps with systemic symptoms, neurological complications in GD2 and GD3 persist due to the blood-brain-barrier (BBB) limiting ERT efficacy. Ambroxol, a BBB-permeable chaperone, enhances GCase activity. Our review explores high-dose ambroxol's therapeutic potential, both preclinical and clinical, in GD2 and GD3., Methods: PubMed was searched for studies published before March 2023, including clinical, animal, and in vitro studies focusing on the effect of high-dose ambroxol in GD2 and GD3. A narrative synthesis was performed., Results: Nine in vitro, three animal, and eight clinical studies were included, demonstrating varied responses to ambroxol across diverse outcome measures. In vitro and animal studies demonstrated reduced endoplasmatic reticulum stress due to the relocation of GCase from the ER to the lysosomes. In vitro cell lines exhibited varying degrees of increased GCase activity. Clinical trials observed reduced lyso-GL1 levels in plasma (41-89%) and cerebrospinal fluid (CSF) (26-97%), alongside increased GCase activity in GD3 patients. Ambroxol exhibited varying effects on neurological outcomes and development. No severe adverse events were reported., Conclusion: High-dose ambroxol shows promise in managing neurological manifestations in GD3, albeit with uncertainties resulting from genetic heterogeneity and variable response. Further clinical trials, are essential for elucidating dosage-response relationships and refining treatment outcomes and strategies for neuronopathic GD., Competing Interests: Declaration of competing interest CH has participated in clinical trials supported by Sanofi, Protalix and Idorsia. She receives no personal fees from commercial parties. MB has participated in clinical trials supported by Intrabio (not Gaucher related). She receives no personal fees from commercial parties., (Copyright © 2024. Published by Elsevier Inc.)

An ongoing global shortage of verteporfin (Visudyne ® ) limits the treatment possibilities for several chorioretinal diseases, including central serous chorioretinopathy, choroidal hemangioma, and polypoidal choroidal vasculopathy. Verteporfin is required to perform photodynamic therapy in these ocular diseases. Therefore, the current situation has a substantial impact on eye care worldwide. The worldwide supply of verteporfin appears to be manufactured by a single factory, which is situated in the United States. The distribution of verteporfin is done by different companies for different regions of the world. Official communication on the shortage by the responsible companies has been scarce and over the past years several promises with regards to resolution of the shortage have not been fulfilled. The delivery of new batches of verteporfin is at irregular intervals, unpredictable, and may not be fairly balanced between different regions or countries in the world. To ensure a fair distribution of available verteporfin within a country, several measures can be taken. In the Netherlands, a national committee, consisting of ophthalmologists, is in place to arrange this. On the European level, the European Union and European Medicine Agency have plans to monitor medicine shortages more closely and to intervene if necessary. With a more intensified monitoring and regulation of medicine supplies, future impending shortages may be prevented. Remarkably, the amount of medicine shortages is increasing, having a significant and sometimes irreversible impact on patient care. Thus, efforts should be undertaken to minimize the consequences and, whenever possible, to prevent future medicine shortages., (© 2024. The Author(s).)

Off-label repurposing of empagliflozin allows pathomechanism-based treatment of neutropenia/neutrophil-dysfunction in glycogen storage disease type Ib (GSDIb). From a value-based healthcare (VBHC) perspective, we here retrospectively studied patient-reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity-analysis, and systematic benefit-risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality-of-life-scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony-stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between € 6482-14 190 (NL) and € 1281-41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between € 75 062-225 716 (NL) and € 37 697-231 790 (AT), based on conservative assumptions. The systematic benefit-risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit-risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems., (© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Classical galactosemia (CG) is an autosomal recessive disorder of galactose metabolism. Despite early initiation of a galactose-restricted diet, patients develop long-term complications including cognitive impairment. There is an ongoing debate whether the cognitive impairment in CG is stable throughout life or progresses with age. Earlier cross-sectional and longitudinal studies regarding intelligence suggest stability, but longitudinal neuropsychological studies focusing on specific cognitive functions are limited. Therefore, the aim of this study is to assess cognitive change over time in adult CG-patients. Ten adult patients with normal to borderline intelligence (mean age 33 years, range 22-49; IQ≥70 or independent work- or living situation) were assessed twice with a mean time interval of 3 years and 9 months (range 1023-1575 days). The neuropsychological assessments covered information processing speed, executive functioning, verbal fluency, and visuospatial functioning. Results showed that there was no significant decline or improvement in test scores on all neuropsychological measures except a decline on the Trail Making Test-A ( p  = 0.048). However, this group-level difference was subject to "regression to the mean" and was not endorsed by significant change in test scores measuring the same cognitive domain. Moreover, no specific pattern of reliable change (RCI > -1.96) was present on specific measures or within individual patients. This explorative study performed in 10 adult CG-patients with normal to borderline intelligence revealed no cognitive change on several cognitive domains. This implies that the subset of adults with a normal to borderline IQ in their early and middle adulthood are cognitively stable., Competing Interests: Merel E. Hermans, Gert J. Geurtsen, and Annet M. Bosch declare that they have no conflict of interest. Carla E.M. Hollak declares that she is involved in premarketing studies of Sanofi and Idorsia., (© 2024 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Objective: Classical galactosemia (CG) is an inborn error of galactose metabolism. Many CG patients suffer from long-term complications including poor cognitive functioning. There are indications of social dysfunction but limited evidence in the literature. Therefore, this study aims to improve our understanding of social competence in CG by investigating social cognition, neurocognition and emotion regulation., Methods: A comprehensive (neuro)psychological test battery, including self and proxy questionnaires, was administered to CG patients without intellectual disability. Social cognition was assessed by facial emotion recognition, Theory of Mind and self-reported empathy. Standardised results were compared to normative data of the general population., Results: Data from 23 patients (aged 8-52) were included in the study. On a group level, CG patients reported satisfaction with social roles and no social dysfunction despite the self-report of lower social skills. They showed deficits in all aspects of social cognition on both performance tests (emotion recognition and Theory of Mind) and self-report questionnaires (empathy). Adults had a lower social participation than the general population. Parents reported lower social functioning, less adaptive emotion regulation and communication difficulties in their children. Individual differences in scores were present., Conclusion: This study shows that CG patients without intellectual disability are satisfied with their social competence, especially social functioning. Nevertheless, deficits in social cognition are present in a large proportion of CG patients. Due to the large variability in scores and discrepancies between self- and proxy-report, an individually tailored, comprehensive neuropsychological assessment including social cognition is advised in all CG patients. Treatment plans need to be customised to the individual patient.

Dietary or nutritional management strategies are the cornerstone of treatment for many inborn errors of metabolism (IEMs). Though a vital part of standard of care, the products prescribed for this are often not formally registered as medication. Instead, they are regulated as food or as food supplements, impacting the level of oversight as well as reimbursed policies. This scoping literature review explores the European regulatory framework relevant to these products and its implications for current clinical practice. Searches of electronic databases (PubMed, InfoCuria) were carried out, supplemented by articles identified by experts, from reference lists, relevant guidelines and case-law by the European Court of Justice. In the European Union (EU), nutritional therapy products are regulated as food supplements, food for special medical purposes (FSMPs) or medication. The requirements and level of oversight increase for each of these categories. Relying on lesser-regulated food products to treat IEMs raises concerns regarding product quality, safety, reimbursement and patient access. In order to ascertain whether a nutritional therapy product functions as medication and thus could be classified as such, we developed a flowchart to assess treatment characteristics (benefit, pharmacological attributes, and safety) with a case-based approach. Evaluating nutritional therapy products might reveal a justifiable need for a pharmaceutical product. A flowchart can facilitate systematically distinguishing products that function medication-like in the management of IEMs. Subsequently, finding and implementing appropriate solutions for these products might help improve the quality, safety and accessibility including reimbursement of treatment for IEMs., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background and Purpose: White matter lesions are commonly found in patients with Fabry disease. Existing studies have shown elevated diffusivity in healthy-appearing brain regions that are commonly associated with white matter lesions, suggesting that DWI could help detect white matter lesions at an earlier stage This study explores whether diffusivity changes precede white matter lesion formation in a cohort of patients with Fabry disease undergoing yearly MR imaging examinations during a 5-year period., Materials and Methods: T1-weighted anatomic, FLAIR, and DWI scans of 48 patients with Fabry disease (23 women; median age, 44 years; range, 15-69 years) were retrospectively included. White matter lesions and tissue probability maps were segmented and, together with ADC maps, were transformed into standard space. ADC values were determined within lesions before and after detection on FLAIR images and compared with normal-appearing white matter ADC. By means of linear mixed-effects modeling, changes in ADC and ΔADC (relative to normal-appearing white matter) across time were investigated., Results: ADC was significantly higher within white matter lesions compared with normal-appearing white matter ( P  < .01), even before detection on FLAIR images. ADC and ΔADC were significantly affected by sex, showing higher values in men (60.1 [95% CI, 23.8-96.3] ×10 -6 mm 2 /s and 35.1 [95% CI, 6.0-64.2] ×10 -6 mm 2 /s), respectively. ΔADC increased faster in men compared with women (0.99 [95% CI, 0.27-1.71] ×10 -6 mm 2 /s/month). ΔADC increased with time even when only considering data from before detection (0.57 [95% CI, 0.01-1.14] ×10 -6 mm 2 /s/month)., Conclusions: Our results indicate that in Fabry disease, changes in diffusion precede the formation of white matter lesions and that microstructural changes progress faster in men compared with women. These findings suggest that DWI may be of predictive value for white matter lesion formation in Fabry disease., (© 2023 by American Journal of Neuroradiology.)

Background: Fabry disease is a very heterogeneous X-linked lysosomal storage disease. Disease manifestations in the kidneys, heart, and brain vary greatly, even between patients of the same sex and with the same disease classification (classical or nonclassical). A biomarker with a strong association with the development of disease manifestations is needed to determine the need for Fabry-specific treatment and appropriate frequency of follow-up because clinical manifestations of the disorder may take decennia to develop., Methods: We investigated the levels of plasma lysoGb3 levels over time and its association with disease manifestations and disease course in 237 untreated patients with Fabry disease (median age 42 years, 38% male) using linear mixed-effect models., Results: LysoGb3 levels are stable over time in plasma of untreated patients with Fabry disease. Higher levels of lysoGb3 were associated with steeper decline in eGFR ( P = 0.05) and a faster increase in albuminuria (measured as the urinary albumin-to-creatinine ratio, P < 0.001), left ventricular mass (measured on echocardiography, P < 0.001), left atrial volume index ( P = 0.003), and Fazekas score ( P = 0.003). In addition, regardless of age, higher lysoGb3 levels were associated with higher relative wall thickness ( P < 0.001) and unfavorable functional markers on echocardiography, including septal mitral annular early diastolic velocity (e', P < 0.001) and the ratio of early transmitral velocity (E) to e' (E/e', P = 0.001)., Conclusions: In an individual patient with Fabry disease, the plasma lysoGb3 level reached a specific level in early childhood which, in the absence of Fabry-specific treatment, remained stable throughout life. The level of lysoGb3 in untreated patients was associated with nearly all Fabry-specific disease manifestations, regardless of the sex of the patient., (Copyright © 2023 by the American Society of Nephrology.)

Medicine development for rare diseases, including inborn errors of metabolism (IEMs) is challenging. Many academic innovations fail to reach the patient, either by stranding in the translational stage or due to suboptimal patient access related to pricing or uncertain effectiveness. Expanding and solidifying the role of the academic in public-private partnerships (PPPs) may present an innovative solution to help overcome these complexities. This narrative review explores the literature on traditional and novel collaborative approaches to medicine development for rare diseases and analyzes examples of PPPs, with a specific focus on IEMs. Several academic institutions have introduced guidelines for socially responsible licensing of innovations for private development. The PPP model offers a more integrative approach toward academic involvement of medicine development. By sharing risks and rewards, failures in the translational stage can be mutually absorbed. If socially responsible terms are not included, however, high pricing can impede patient access. Therefore, we propose a framework for socially responsible PPPs aimed at medicine development for metabolic disorders. This socially responsible PPP framework could stimulate successful and accessible medicine development for IEMs as well as other rare diseases if the establishment of such collaborations includes terms securing joint data ownership and evidence generation, fast access, and socially responsible pricing., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Acid sphingomyelinase deficiency (ASMD) is a rare LSD characterized by lysosomal accumulation of sphingomyelin, primarily in macrophages. With the recent availability of enzyme replacement therapy, the need for biomarkers to assess severity of disease has increased. Glycoprotein non-metastatic protein B (GPNMB) plasma levels were demonstrated to be elevated in Gaucher disease. Given the similarities between Gaucher disease and ASMD, the hypothesis was that GPNMB might be a potential biochemical marker for ASMD as well. Plasma samples of ASMD patients were analyzed and GPNMB plasma levels were compared to those of healthy volunteers. Visceral disease severity was classified as severe when splenic, hepatic and pulmonary manifestations were all present and as mild to moderate if this was not the case. Median GPNMB levels in 67 samples of 19 ASMD patients were 185 ng/ml (range 70-811 ng/ml) and were increased compared to 10 healthy controls (median 36 ng/ml, range 9-175 ng/ml, p < 0.001). Median plasma GPNMB levels of ASMD patients with mild to moderate visceral disease compared to patients with severe visceral disease differed significantly and did not overlap (respectively 109 ng/ml, range 70-304 ng/ml and 325 ng/ml, range 165-811 ng/ml, p < 0.001). Correlations with other biochemical markers of ASMD (i.e. chitotriosidase activity, CCL18 and lysosphingomyelin, respectively R = 0.28, p = 0.270; R = 0.34, p = 0.180; R = 0.39, p = 0.100) and clinical parameters (i.e. spleen volume, liver volume, diffusion capacity and forced vital capacity, respectively R = 0.59, p = 0.061, R = 0.5, p = 0.100, R = 0.065, p = 0.810, R = -0.38, p = 0.160) could not be established within this study. The results of this study suggest that GPNMB might be suitable as a biomarker of visceral disease severity in ASMD. Correlations between GPNMB and biochemical or clinical markers of ASMD and response to therapy have to be studied in a larger cohort., Competing Interests: Declaration of Competing Interest ML, LV, MB and JA have no competing interests to declare. EE is involved in a pre-marketing study with Sanofi Genzyme. CH is involved in premarketing studies with Sanofi Genzyme, Protalix, Cheisi and Idorsia. BS was involved in pre-marketing studies with Protalix, Cheisi and Sanofi Genzyme. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2023. Published by Elsevier Inc.)

Background: Classical galactosemia (CG), an inborn error of galactose metabolism, results in long-term complications including cognitive impairment and movement disorders, despite early diagnosis and dietary treatment. Two decades ago, lower motor-, cognitive- and social health related quality of life (HRQoL) was demonstrated in pediatric and adult patients. Since then, the diet has been relaxed, newborn screening was implemented and new international guidelines resulted in major changes in follow-up. The aim of this study was to assess HRQoL of CG by means of online self- and/or proxy-HRQoL-questionnaires focusing on the main areas of concern of CG (i.e. anxiety, depression, cognition, fatigue, social- and upper extremity function) within the patient-reported outcomes measurement information system (PROMIS®) and generic HRQoL-questionnaires (TAPQOL, TACQOL, TAAQOL)., Results: Data of 61 Dutch patients (aged 1-52 years) were collected and compared to available Dutch or US reference populations. On the PROMIS-questionnaires, children reported more fatigue (P = 0.044), lower function in upper extremities (P = 0.021), more cognitive difficulties (P = 0.055, d = 0.56) and higher anxiety (P = 0.063, d = 0.52) than reference children although the latter findings remained non-significant. Parents of CG patients reported lower quality of peer relationships of their children (P < 0.001). Both children and parents reported lower cognitive functioning (P = 0.005, P = 0.010) on the TACQOL. Adults reported on PROMIS domains lower cognitive functioning (P = 0.030), higher anxiety (P = 0.004) and more fatigue (P = 0.026). Cognitive difficulties were reported on the TAAQOL by adults (P < 0.001), as well as physical-, sleeping and social difficulties., Conclusions: CG remains to impact the HRQoL of pediatric and adult patients negatively on several domains including cognition, anxiety, motor function and fatigue. A lower social health was mainly reported by parents, and not by patients themselves. The Covid-19 pandemic might have amplified the results on anxiety although higher levels of anxiety fit pre-pandemic findings. The reported fatigue is a new finding in CG. Because the effect of lockdown fatigue could not be eliminated and fatigue is a frequent finding in patients with chronic disorders, future studies are warranted. Clinicians and researchers should be attentive to both pediatric and adult patients, and the age-dependent difficulties they might encounter., (© 2023. The Author(s).)

Background and Objective: Fabry disease (FD) is a rare lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (aGal A). Since 2001, two different enzyme replacement therapies have been authorized, with agalsidase beta being used in most parts of the Western world. Currently, biosimilars of several expensive enzyme therapies are under development to improve their accessibility for patients. We present the preclinical results of the development of a biosimilar to agalsidase beta., Methods: Produced in a Chinese hamster ovary (CHO)-cell system, the biosimilar aGal A Biosidus (AGABIO), was compared with agalsidase beta with respect to amino acid sequence, glycosylation, specific α-galactosidase activity, stability in plasma, and effects on cultured human Fabry fibroblasts and Fabry mice., Results: AGABIO had the same amino acid composition and similar glycosylation, enzymatic activity, and stability as compared with agalsidase beta. After uptake in fibroblasts, α-galactosidase A activity increased in a dose-dependent manner, with maximum uptake observed after 24 h, which remained stable until at least 48 h. Both enzymes were localized to lysosomes. Reduction of accumulated globotriaosylceramide (Gb3) and lysoGb3 in cultured Fabry fibroblasts by AGABIO and agalsidase beta showed comparable dose-response curves. In Fabry knockout mice, after a single injection, both enzymes were rapidly cleared from the plasma and showed equal reductions in tissue and plasma sphingolipids. Repeated dose studies in rats did not raise any safety concerns. Anti-drug antibodies from patients with FD treated with agalsidase beta showed equal neutralization activity toward AGABIO., Conclusion: These findings support the biosimilarity of AGABIO in comparison with agalsidase beta. The clinical study phase is currently under development., (© 2023. The Author(s).)

Background: Time to reimbursement (TTR) of new anticancer medicines differs between countries and contributes to unequal access. We aimed to investigate TTR of new anticancer medicines and explore factors influencing the reimbursement process in seven high-income European countries., Materials and Methods: We carried out a retrospective case study of anticancer medicines with European Union Market Access (EU-MA) and a positive Committee for Medicinal Products for Human Use opinion from 2016 until 2021 with subsequent national reimbursement approval (NRA). The National Health Technology Assessment (HTA) and reimbursement websites of Germany, France, UK, the Netherlands, Belgium, Norway and Switzerland were used to identify TTR, defined as time from EU-MA to NRA. Additionally, we investigated medication-, country-, indication- and pharma-related factors potentially influencing TTR., Results: Thirty-five medicines were identified for which TTR ranged from -81 days to 2320 days (median 407 days). At data cut-off, 16 (46%) were reimbursed in all seven countries. Overall, the shortest TTR was in Germany (median 3 days, all medicines reimbursed <5 days). The time limit for reimbursement of 180 days stated by the Council of European Communities after the EU-MA (EU Transparency Directive) was met for 100% of included medicines in Germany, 51% in France, 29% in the UK and the Netherlands, 14% in Switzerland, 6% in Norway and 3% in Belgium. The TTR was significantly different between countries (P < 0.001). In multivariate analysis, factors associated with shorter TTR were higher gross domestic product (GDP), absence of a pre-assessment procedure and submission by a big pharmaceutical company., Conclusions: TTR of anticancer medicines varies significantly between seven high-income European countries and leads to inequality in access. Among explored medication-, country-, indication- and pharma-related factors we found that a high GDP, the absence of a pre-assessment procedure and submission by big pharmaceutical companies were associated with shorter TTR., Competing Interests: Role of the funder The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclosure HCP and CEMH are members of the platform ‘Medicine for Society’ (see funding), CEMH reports to be involved in pre-marketing studies with Genzyme, Protalix and Idorsia. HWML declared a consultant or advisory role: Amphera, AstraZeneca, Beigene, BMS, Daiichy-Sankyo, Dragonfly, Eli Lilly, MSD, Nordic Pharma, Servier and a research funding and/or medication supply: Bayer, BMS, Celgene, Janssen, Incyte, Eli Lilly, MSD, Nordic Pharma, Philips, Roche, Servier; and a speaker role: Astellas, Benecke, Daiichy-Sankyo, JAAP, Medtalks, Novartis, Travel Congress Management B.V. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pharmacy compounding of medicines is an essential part of patient care as it enables pharmacists to provide customized pharmaceutical care when no suitable commercial medicine is available. A distinction is made between individual preparations (on prescription for one patient) and stock preparations (for larger groups). Pharmacy compounded medicines can be of added value when specific pharmaceutical care is required, a commercial medicine is unavailable, or for use in clinical scientific research. A number of preconditions require attention to preserve pharmacy compounding in the future. Pharmacists should share technical knowledge on raw materials and pharmacy compounding more, and it is important that medicine development is retained as a basic skill in the education programme. Rational pharmacy compounded medicines should be eligible for reimbursement, taking room for innovation and research in consideration when determining tariffs. This is essential to ensure responsible implementation of pharmacy compounded medicines to improve healthcare availability and affordability.

Background : Novel or repurposed medicines for rare diseases often emerge from fundamental research or empirical findings in academia. However, researchers may be insufficiently aware of the possibilities and requirements to bring novel medicinal treatment options to the patient. This paper aims to provide an easily applicable, comprehensive roadmap designed for academic researchers to make medicines for rare diseases available for patients by addressing the relevant regulatory frameworks, including marketing authorization and alternative routes. Methods : Key points of the regulatory chapters "Placing on the Market" and "Scope" of Directive 2001/83/EC relating to medicinal products for human use were summarized. Provisions in EU directives regarding blood products, radiopharmaceuticals, and herbal and homeopathic medicinal products were excluded. Cross-referencing to other provisions was included. European case-law was retrieved from the InfoCuria database to exemplify the implications of alternative routes. Results : Medicines may only be placed on the market with a valid marketing authorization. To obtain such authorization in Europe, a "Common Technical Document" comprising reports on quality and non-clinical and clinical studies must be submitted to a "competent authority", a national medicine agency or the European Medicines Agency. Timely interaction of academic researchers with regulators via scientific advice may lead to better regulatory alignment and subsequently a higher chance for approval of academic inventions. Furthermore, reimbursement by national payers could be essential to ensure patient access. Apart from the marketing authorization route, we identified multiple alternative routes to provide (early) access. These include off-label use, named-patient basis, compassionate use, pharmacy compounding, and hospital exemption for Advanced Therapy Medicinal Products. Discussion : Aligning academic (non-)clinical studies on rare diseases with regulatory and reimbursement requirements may facilitate fast and affordable access. Several alternative routes exist to provide (early) pharmaceutical care at a national level, but case-law demonstrates that alternative routes should be interpreted strictly and for exceptional situations only. Academics should be aware of these routes and their requirements to improve access to medicines for rare diseases., Competing Interests: CH is involved in pre-marketing research with Sanofi, Protalix, and Idorsia, outside the submitted work. NR, SB, BJ, NS, HP, SV, and CH are members of platform “Medicijn voor de Maatschappij”. This is an academic initiative that aims to support sustainable access to medicines for rare diseases. SV teaches Clinical Development at Paul Janssen Futurelab Leiden for academic and industry professionals. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rosenberg, van den Berg, Stolwijk, Jacobs, Post, Pasmooij, de Visser and Hollak.)

Bile acid synthesis defects (BASDs) comprise a group of rare diseases that can be severely disabling. Bile acid supplementation with 5 to 15 mg/kg cholic acid (CA) has been hypothesized to decrease endogenous bile acid production, stimulate bile secretion, and improve bile flow and micellar solubilization, thereby improving the biochemical profile and potentially slowing down disease progression. Currently, CA treatment is unavailable in the Netherlands, and CA capsules were compounded by the Amsterdam UMC Pharmacy from CA raw material. This study aims to determine the pharmaceutical quality and stability of the pharmacy compounded CA capsules. Pharmaceutical quality tests were performed on 25 mg and 250 mg CA capsules according to general monographs of the European Pharmacopoeia 10th ed. For the stability study, the capsules were stored under long-term conditions (25 °C ± 2 °C/60% ± 5% RH) and accelerated conditions (40 °C ± 2 °C/75% ± 5% RH). Samples were analyzed at 0, 3, 6, 9 and 12 months. The findings demonstrate that the pharmacy compounded CA capsules within a range of 25-250 mg that complied with the European regulations in regard to product quality and safety. The pharmacy compounded CA capsules are suitable for use in patients with BASD, as clinically indicated. With its simple formulation, pharmacies are provided a guidance on product validation and stability testing when commercial CA capsules are unavailable.

Background: Fabry disease (FD) is an X-linked, lysosomal storage disorder leading to severe cardiomyopathy in a significant proportion of patients. To identify ECG markers that reflect early cardiac involvement and disease progression, we conducted a long term retrospective study in a large cohort of FD patients. Methods: A total of 1995 ECGs from 133 patients with classical FD (64% females, 80% treated with enzyme replacement therapy), spanning 20 years of follow-up, were compared to ECGs from 3893 apparently healthy individuals. Generalized linear mixed models were used to evaluate the effect of age, FD and sex on: P-wave duration, PR-interval, QRS-duration, QTc, Cornell index, spatial QRS-T angle and frontal QRS-axis. Regression slopes and absolute values for each parameter were compared between FD patients and control subjects. Results: At a younger age (<40 years), the Cornell index was higher and frontal QRS-axis more negative in FD patients compared to controls ( p < 0.05). For the other ECG parameters, the rate of change, more than the absolute value, was greater in FD patients compared to controls ( p < 0.05). From the fifth decade (men) or sixth (women) onwards, absolute values for P-wave duration, QRS-duration, QTc and spatial QRS-T angle were longer and higher in FD patients compared to control subjects. Conclusions: ECG abnormalities indicative of FD are age and sex dependent. Tracking the rate of change in ECG parameters could be a good way to detect disease progression, guiding treatment initiation. Moreover, monitoring ECG changes in FD can be used to evaluate the effectiveness of treatment.

Aims: While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically endangered. Here we aim to demonstrate the effectiveness and safety of mexiletine in the treatment of patients with (recurrent) ventricular arrhythmias, emphasizing the absolute necessity of its accessibility., Methods and Results: Studies were included in this systematic review (PROSPERO, CRD42020213434) if the efficacy or safety of mexiletine in any dose was evaluated in patients at risk for (recurrent) ventricular arrhythmias with or without comparison with alternative treatments (e.g. placebo). A systematic search was performed in Ovid MEDLINE, Embase, and in the clinical trial registry databases ClinicalTrials.gov and ICTRP. Risk of bias were assessed and tailored to the different study designs. Large heterogeneity in study designs and outcome measures prompted a narrative synthesis approach. In total, 221 studies were included reporting on 8970 patients treated with mexiletine. Age ranged from 0 to 88 years. A decrease in ventricular arrhythmias of >50% was observed in 72% of the studies for pre-mature ventricular complexes, 64% for ventricular tachycardia, and 33% for ventricular fibrillation. Electrocardiographic effects of mexiletine were small; only in a subset of patients with primary arrhythmia syndromes, a relative (desired) QTc decrease was reproducibly observed. As for adverse events, gastrointestinal complaints were most frequently observed (33% of the patients)., Conclusions: In this systematic review, we present all the currently available knowledge of mexiletine in patients at risk for (recurrent) ventricular arrhythmias and show that mexiletine is both effective and safe., Competing Interests: Conflict of interest: P.G.P. is a member of the Scientific Advisory Group on Cardiovascular Issues (SAG-CVS) of the EMA since 2021. C.E.M.H. is involved in pre-marketing research with Sanofi, Protalix, and Idorsia, outside the submitted work. N.R., N.S., S.B., V.W., B.J., and C.E.M.H. are members of the platform ‘Medicijn voor de Maatschappij’. This is an academic initiative that aims to support sustainable access to medicines for rare diseases, including mexiletine. V.W. reports personal fees from Fair Medicine Foundation, personal fees from Patient One, outside the submitted work., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Since July 2021, a worldwide shortage of verteporfin (Visudyne®) occurred: an essential medicine required for photodynamic therapy (PDT). PDT with verteporfin has a broad range of indications in ophthalmology, including chronic central serous chorioretinopathy, polypoidal choroidal vasculopathy and choroidal haemangioma. For these disorders, PDT is either the first-choice treatment or regarded as a major treatment option., Materials and Methods: A questionnaire was sent to key opinion leaders in the field of medical retina throughout the world, to assess the role of PDT in their country and the effects of the shortage of verteporfin. In addition, information on the application of alternative treatments during shortage of verteporfin was obtained, to further assess the impact of the shortage., Results: Our questionnaire indicated that the shortage of verteporfin had a major impact on ophthalmic care worldwide and was regarded to be a serious problem by most of our respondents. However, even though there is ample evidence to support the use of PDT in several chorioretinal diseases, we found notable differences in its use in normal patient care throughout the world. Various alternative management strategies were noted during the verteporfin shortage, including lowering the dose of verteporfin per patient, the use of alternative treatment strategies and the use of a centralized system for allocating the remaining ampoules of verteporfin in some countries., Conclusion: The shortage of verteporfin has had a large effect on the care of ophthalmic patients across the world and may have resulted in significant and irreversible vision loss. Mitigation strategies should be developed in consultation with all stakeholders to avoid future medication shortages of verteporfin and other unique ophthalmic medications. These strategies may include mandatory stock keeping, compulsory licensing to an alternative manufacturer or incentivizing the development of competition, for example through novel public-private partnerships., (© 2022 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Classical galactosemia (CG) is one of the more frequent inborn errors of metabolism affecting approximately 1:40.000 people. Despite a life-saving galactose-restricted diet, patients develop highly variable long-term complications including intellectual disability and movement disorders. The pathophysiology of these complications is still poorly understood and development of new therapies is hampered by a lack of valid prognostic biomarkers. Multi-omics approaches may discover new biomarkers and improve prediction of patient outcome. In the current study, (semi-)targeted mass-spectrometry based metabolomics and lipidomics were performed in erythrocytes of 40 patients with both classical and variant phenotypes and 39 controls. Lipidomics did not show any significant changes or deficiencies. The metabolomics analysis revealed that CG does not only compromise the Leloir pathway, but also involves other metabolic pathways including glycolysis, the pentose phosphate pathway, and nucleotide metabolism in the erythrocyte. Moreover, the energy status of the cell appears to be compromised, with significantly decreased levels of ATP and ADP. This possibly is the consequence of two different mechanisms: impaired formation of ATP from ADP possibly due to reduced flux though the glycolytic pathway and trapping of phosphate in galactose-1-phosphate (Gal-1P) which accumulates in CG. Our findings are in line with the current notion that the accumulation of Gal-1P plays a key role in the pathophysiology of CG not only by depletion of intracellular phosphate levels but also by decreasing metabolite abundance downstream in the glycolytic pathway and affecting other pathways. New therapeutic options for CG could be directed towards the restoration of intracellular phosphate homeostasis., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Introduction: Several new treatment modalities are being developed for lysosomal storage disorders (LSDs), including gene therapy. As the currently available treatment options and their influence on disease progression differ greatly within the spectrum of LSDs, willingness to undergo gene therapy might vary among patients with LSDs and/or their representatives. The width of the LSD spectrum is illustrated by the differences between type 1 Gaucher disease, Fabry disease and Mucopolysaccharidosis type III (MPS III). For type 1 Gaucher and Fabry disease several therapies are available, resulting in a near normal or improved, but individually varying, prognosis. No treatment options are available for MPS III., Aim: To identify factors influencing patients' and/or their representatives' decisions regarding undergoing gene therapy., Methods: Focus group discussions and semi-structured interviews were conducted with patients with type 1 Gaucher disease, Fabry disease and MPS III. Parents of MPS III patients were included as patients' representatives., Results: Nine Gaucher patients, 23 Fabry patients, two adult MPS III patients and five parents of MPS III patients participated in the study. The five main themes that arose were: outcome of gene therapy, risks and side effects, burden of gene therapy treatment, current situation and ethical aspects. Participants' views ranged from hesitance to eagerness to undergo gene therapy, which seemed to be mostly related to disease severity and currently available treatment options. Severe disease, limited treatment options and limited effectiveness of current treatment augmented the willingness to choose gene therapy. Gaucher and Fabry patients deemed the burden of treatment important. Fabry and MPS III patients and parents considered outcome important, suggesting hope for improvement. When asked to rank the factors discussed in the focus group discussions, Gaucher patients ranked outcome low, which could indicate a more cautious attitude towards gene therapy., Conclusion: This study underlines the importance of exploring patients' needs and expectations before using limited resources in the development of therapies for patient groups of which a significant subset may not be willing to undergo that specific therapy., (© 2022. The Author(s).)

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: A rare subset of vitamin B6 responsive seizure disorders does not respond to pyridoxine, and requires the active form of vitamin B6, pyridoxal-5'-phosphate (PLP), to maintain seizure control. Patients with PLP-responsive seizures are dependent on chronic PLP treatment, yet no licensed PLP product is available. PLP food supplements, a product category regulated less stringently than medication, may prove of insufficient effectiveness and safety. Here we describe and discuss three patient scenarios which illustrate this conundrum., Methods: Medical and laboratory records were reviewed with retrospective extraction for three unrelated patients who suffered complications during treatment with PLP food supplements., Results: - Two cases of PNPO deficiency and one case of PLP-dependent epileptic encephalopathy without a (genetic) diagnosis are reported. These patients are critically dependent on PLP for seizure control and have suffered complications due to insufficient quality of these food supplements during the course of treatment. Complications include the occurrence of seizures following the administration of suspected low quality PLP, inactive PLP due to light exposure, a PLP intoxication, resisting administration and post-administration vomiting as a result of the ingestion of large amounts of capsules per day., Conclusion: - This case series illustrates that the reliance on food supplements as anti-seizure therapy is not without risk. The treatment of PLP-dependent seizures exemplifies that PLP is administered as medication, thus there is a clear need for licensed vitamin products of pharmaceutical quality., (© 2022 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background & Aims: Glycogen storage disease type Ia (GSDIa) is an inborn error of carbohydrate metabolism caused by pathogenic variants in the glucose-6-phosphatase catalytic subunit 1 ( G6PC1 ) gene and is associated with hepatocellular adenoma (HCA) formation. Data on risk factors for HCA occurrence in GSDIa are scarce. We investigated HCA development in relation to sex, G6PC1 genotype, and serum triglyceride concentration (TG)., Methods: An observational study of patients with genetically confirmed GSDIa ≥12 years was performed. Patients were categorised for sex; presence of 2, 1, or 0 predicted severe G6PC1 variant (PSV); and median TG during childhood (<12 years; stratified for above/below 5.65 mmol/L, i.e. 500 mg/dl)., Results: Fifty-three patients (23 females) were included, of which 26 patients developed HCA at a median (IQR) age of 21 (17-25) years. At the age of 25 years, 48% of females and 30% of males had developed HCA (log-rank p  = 0.045). Two-thirds of patients with GSDIa carried 2 PSVs, 20% carried 1, and 13% carried none. Neither the number of PSVs nor any specific G6PC1 variants were associated with HCA occurrence. Childhood TG was 3.4 (3.0-4.2) mmol/L in males vs . 5.6 (4.0-7.9) mmol/L in females ( p  = 0.026). Childhood TG >5.65 mmol/L was associated with HCA development at younger age, compared with patients with childhood TG <5.65 mmol/L (18 vs . 33 years; log-rank p  = 0.001). Cox regression analysis including TG, sex, and TG-sex interaction correction revealed childhood TG >5.65 mmol/L as an independent risk factor for HCA development (hazard ratio [HR] 6.0; 95% CI 1.2-29.8; p  = 0.028)., Conclusions: In patients with GSDIa, high childhood TG was associated with an increased risk of HCA, and earlier onset of HCA development, independent of sex-associated hypertriglyceridaemia, and G6PC1 genotype., Lay Summary: Glycogen storage disease type Ia (GSDIa) is a rare, inherited metabolic disease that can be complicated by liver tumours (hepatocellular adenomas), which in turn may cause bleeding or progress to liver cancer. Risk factors associated with hepatocellular adenoma formation in patients with GSDIa are largely unknown. In our study, we found that high serum triglyceride concentrations during childhood, but not specific genetic variants, were associated with increased risk of hepatocellular adenoma diagnosis later in life., Competing Interests: There are no conflicts of interest to be reported. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Background: Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions., Results: Three distinct sets of data elements were defined by the 13-member expert panel. The minimal set (n = 13) contained demographics and basic disease characteristics. The core set (n = 55) included functional status scores in terms of motor, manual, speech and eating abilities, and causal and supportive treatment characteristics. Health-related quality of life scores were included that were also deemed necessary for HTA. The optional set (n = 31) contained additional clinical aspects, such as findings at neurological examination, detailed motor function, presence of peripheral neuropathy, gall bladder involvement and micturition., Conclusion: Using a modified Delphi procedure with physicians from the main expert centers, consensus was reached on a core set of data that can be collected retrospectively and prospectively. With this consensus-based approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments., (© 2022. The Author(s).)

Background: Enzyme replacement therapy (ERT) slows disease progression of Fabry disease (FD), especially when initiated before the onset of irreversible organ damage. However, with the clinically asymptomatic progression of renal, cardiac and cerebral disease manifestations spanning decades, optimal timing of ERT initiation remains unclear., Methods: In this cross-sectional retrospective study, seven male FD patients with a classical disease phenotype (cFD) who started treatment with agalsidase-beta in childhood were evaluated after 10 years of treatment (median age at evaluation 24 years, range 14-26). Cardiac imaging (echocardiography and MRI), electrophysiological and biochemical data of these patients were compared to those of untreated male cFD patients (n = 23, median age 22 years, range 13-27)., Results: Albuminuria was less common and less severe in treated patients (albumin to creatinine ratio, ACR 0-8.8 mg/mmol, median 0.4) compared to untreated patients (ACR 0-248 mg/mmol, median 3.7, p = 0.02). The treated group had a lower left ventricular mass, measured using echocardiography (median 80 g/m 2 versus 94 g/m 2 , p = 0.02) and MRI (median 53 g/m 2 versus 68 g/m 2 , p = 0.02). Myocardial fibrosis was absent in all included patients. eGFR was normal in all treated patients whereas 7/23 (30%) of untreated patients had abnormal eGFR. Cerebral manifestations did not differ., Conclusions: Start of treatment with ERT before age 16, in male cFD patients is associated with reduced occurrence of renal and cardiac manifestations of FD, as assessed by intermediate endpoints. Confirmation that this approach delays or even prevents renal failure and cardiac events requires another decade of follow-up., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)