Different diseases, different needs: Patient preferences for gene therapy in lysosomal storage disorders, a probabilistic threshold technique survey.

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.

Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement.

Fabry disease (FD, OMIM #301500) is caused by pathogenic GLA gene (OMIM #300644) variants, resulting in a deficiency of the α-galactosidase A enzyme with accumulation of its substrate globotriaosylceramide and its derivatives. The phenotype of FD is highly variable, with distinctive disease features and course in classical male patients but more diverse and often nonspecific features in non-classical and female patients. FD-specific therapies have been available for approximately two decades, yet establishing robust evidence for long-term effectiveness remains challenging. This review aims to identify the factors contributing to this lack of robust evidence for the treatment of FD with enzyme replacement therapy (ERT) (agalsidase-alfa and -beta and pegunigalsidase alfa) and chaperone therapy (migalastat). Major factors that have been identified are study population heterogeneity (concerning sex, age, phenotype, disease stage) and differences in study design (control groups, outcomes assessed), as well as the short duration of studies. To address these challenges, we advocate for patient matching to improve control group compatibility in future FD therapy studies. We recommend international collaboration and harmonization, facilitated by an independent FD registry. We propose a stepwise approach for evaluating the effectiveness of novel treatments, including recommendations for surrogate outcomes and required study duration.

Monocyte and macrophage profiles in patients with inherited long-chain fatty acid oxidation disorders.

Patients with inherited disorders of the long-chain fatty acid oxidation (lcFAO) machinery present with a heterogeneous profile of disease manifestations and aggravation of symptoms is often triggered by inflammatory activation. Monocytes and macrophages are innate immune cells that play a major role in the onset and resolution of inflammation. These cells undergo metabolic rewiring upon activation including the regulation of the FAO rate. The rewiring of FAO and the effect of lcFAO disorders (lcFAOD) on human monocyte and macrophage phenotype and function remain largely unknown. Here, we performed extensive phenotyping of circulating monocytes and analyzed plasma cytokine levels in 11 lcFAOD patients and 11 matched control subjects. In patients with lcFAOD, we observed induced plasma levels of the inflammatory cytokines IL-1ß and IL-6, and enhanced CD206 and CD62L surface marker expression in circulating monocyte subsets. To mimic the most common lcFAOD very-long-chain acyl-CoA dehydrogenase disorder (VLCADD), we used siRNA-mediated knockdown of the ACADVL gene (encoding VLCAD) in macrophages derived from healthy volunteers. Hereby, we found that siVLCAD affected IL-4-induced alternative macrophage activation while leaving LPS responses and cellular metabolism intact. In the same line, monocyte-derived macrophages from lcFAOD patients had elevated levels of the IL-4-induced alternative macrophage markers CD206 and CD200R. Still, they did not show major metabolic defects or changes in the LPS-induced inflammatory response. Our results indicate that monocytes and macrophages from lcFAOD patients present no major inflammatory or metabolic differences and show that IL-4-induced surface markers are intertwined with lcFAO in human macrophages.

Redefining the phenotype of alpha-methylacyl-CoA racemase (AMACR) deficiency.

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.

Framework for Multistakeholder Patient Registries in the Field of Rare Diseases: Focus on Neurogenetic Diseases.

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.

Riboflavin transporter deficiency in young adults unmasked by dietary changes.

Riboflavin transporter deficiency (RTD) is a genetic disorder of reduced riboflavin (vitamin B2) uptake that causes progressive, multifocal neurological dysfunction. Most patients present in early childhood; if patients present later in life, symptoms usually develop more gradually. We report three previously healthy young adults, who developed rapidly progressive neurological symptoms after decreasing dietary intake of meat and dairy. After a diagnostic odyssey, the diagnosis of a riboflavin transporter deficiency was made. Treatment with high dose oral riboflavin (20-40 mg/kg/day) partially reversed symptoms. This case series highlights that reduced riboflavin intake as a result of dietary changes can unmask RTD at a later age. We emphasize the importance of early recognition of this progressive and potentially lethal disease and show that timely treatment with high dose riboflavin is highly effective.

Newborn screening in metachromatic leukodystrophy - European consensus-based recommendations on clinical management.

INTRODUCTION: Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder resulting from arylsulfatase A enzyme deficiency, leading to toxic sulfatide accumulation. As a result affected individuals exhibit progressive neurodegeneration. Treatments such as hematopoietic stem cell transplantation (HSCT) and gene therapy are effective when administered pre-symptomatically. Newborn screening (NBS) for MLD has recently been shown to be technically feasible and is indicated because of available treatment options. However, there is a lack of guidance on how to monitor and manage identified cases. This study aims to establish consensus among international experts in MLD and patient advocates on clinical management for NBS-identified MLD cases. METHODS: A real-time Delphi procedure using eDELPHI software with 22 experts in MLD was performed. Questions, based on a literature review and workshops, were answered during a seven-week period. Three levels of consensus were defined: A) 100%, B) 75-99%, and C) 50-74% or >75% but >25% neutral votes. Recommendations were categorized by agreement level, from strongly recommended to suggested. Patient advocates participated in discussions and were involved in the final consensus. RESULTS: The study presents 57 statements guiding clinical management of NBS-identified MLD patients. Key recommendations include timely communication by MLD experts with identified families, treating early-onset MLD with gene therapy and late-onset MLD with HSCT, as well as pre-treatment monitoring schemes. Specific knowledge gaps were identified, urging prioritized research for future evidence-based guidelines. DISCUSSION: Consensus-based recommendations for NBS in MLD will enhance harmonized management and facilitate integration in national screening programs. Structured data collection and monitoring of screening programs are crucial for evidence generation and future guideline development. Involving patient representatives in the development of recommendations seems essential for NBS programs.

The management and clinical outcomes of pregnancies in women with urea cycle disorders: A review of the literature and results of an international survey.

An increasing number of women with urea cycle disorders (UCDs) are reaching child-bearing age and becoming pregnant. Improved diagnostics and increased awareness of inherited metabolic diseases has also led to more previously undetected women being diagnosed with a UCD during or shortly after pregnancy. Pregnancy increases the risk of acute metabolic decompensation with hyperammonemia-which can occur in any trimester, and/or the postpartum period, and may lead to encephalopathy, psychosis, coma, and even death, if not diagnosed promptly and treated appropriately. There are also (theoretical) concerns that a maternal UCD, or its treatment, may cause potential risks for the unborn child. Currently evidence on management and outcome of pregnancies in UCDs is limited to case reports and there are no clear guidelines. In order to inform management and investigate outcomes of pregnancies in women with a UCD, we performed a retrospective review of published cases and analyzed data collected from an international online survey. We conclude that, although risk during the intra- and postpartum period exists, multidisciplinary management by an experienced team and a prospective plan usually result in successful pregnancy, labor, delivery, and postpartum period. No deaths were reported in mothers managed accordingly. With the exception of male neonates with Ornithine Transcarbamylase deficiency, the clinical outcome of children born to mothers with UCDs appears positive, although follow-up is limited. The outcome for women presenting with a first acute metabolic decompensation during pregnancy or postpartum is less favorable. Deaths were associated with diagnostic delay/late management of hyperammonemia in previously undiagnosed women.

Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study.

BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676.

Inherited metabolic disorders in adults: systematic review on patient characteristics and diagnostic yield of broad sequencing techniques (exome and genome sequencing).

Background/Objectives: The timely diagnosis of inherited metabolic disorders (IMD) is essential for initiating treatment, prognostication and genetic testing of relatives. Recognition of IMD in adults is difficult, because phenotypes are different from those in children and influenced by symptoms from acquired conditions. This systematic literature review aims to answer the following questions: (1) What is the diagnostic yield of exome/genome sequencing (ES/GS) for IMD in adults with unsolved phenotypes? (2) What characteristics do adult patients diagnosed with IMD through ES/GS have? Methods: A systematic search was conducted using the following search terms (simplified): "Whole exome sequencing (WES)," "Whole genome sequencing (WGS)," "IMD," "diagnostics" and the 1,450 known metabolic genes derived from ICIMD. Data from 695 articles, including 27,702 patients, were analyzed using two different methods. First, the diagnostic yield for IMD in patients presenting with a similar phenotype was calculated. Secondly, the characteristics of patients diagnosed with IMD through ES/GS in adulthood were established. Results: The diagnostic yield of ES and/or GS for adult patients presenting with unexplained neurological symptoms is 11% and for those presenting with dyslipidemia, diabetes, auditory and cardiovascular symptoms 10, 9, 8 and 7%, respectively. IMD patients diagnosed in adulthood (n = 1,426), most frequently portray neurological symptoms (65%), specifically extrapyramidal/cerebellar symptoms (57%), intellectual disability/dementia/psychiatric symptoms (41%), pyramidal tract symptoms/myelopathy (37%), peripheral neuropathy (18%), and epileptic seizures (16%). The second most frequently observed symptoms were ophthalmological (21%). In 47% of the IMD diagnosed patients, symptoms from multiple organ systems were reported. On average, adult patients are diagnosed 15 years after first presenting symptoms. Disease-related abnormalities in metabolites in plasma, urine or cerebral spinal fluid were identified in 40% of all patients whom underwent metabolic screening. In 52% the diagnosis led to identification of affected family members with the same IMD. Conclusion: ES and/or GS is likely to yield an IMD diagnosis in adult patients presenting with an unexplained neurological phenotype, as well as in patients with a phenotype involving multiple organ systems. If a gene panel does not yield a conclusive diagnosis, it is worthwhile to analyze all known disease genes. Further prospective research is needed to establish the best diagnostic approach (type and sequence of metabolic and genetic test) in adult patients presenting with a wide range of symptoms, suspected of having an IMD. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42021295156.

Newborn screening for primary carnitine deficiency: who will benefit? - a retrospective cohort study.

BACKGROUND: Newborn screening (NBS) programmes identify a wide range of disease phenotypes, which raises the question whether early identification and treatment is beneficial for all. This study aims to answer this question for primary carnitine deficiency (PCD) taking into account that NBS for PCD identifies newborns with PCD and also until then undiagnosed mothers. METHODS: We investigated clinical, genetic (variants in SLC22A5 gene) and functional (carnitine transport activity in fibroblasts) characteristics of all referred individuals through NBS (newborns and mothers) and clinically diagnosed patients with PCD (not through NBS). Disease phenotype in newborns was predicted using data from PCD mothers and cases published in literature with identical SLC22A5 variants. RESULTS: PCD was confirmed in 19/131 referred newborns, 37/82 referred mothers and 5 clinically diagnosed patients. Severe symptoms were observed in all clinically diagnosed patients, 1 newborn and none of the mothers identified by NBS. PCD was classified as severe in all 5 clinically diagnosed patients, 3/19 newborns and 1/37 mothers; as benign in 8/19 newborns and 36/37 mothers and as unknown in 8/19 newborns. Carnitine transport activity completely separated severe phenotype from benign phenotype (median (range): 4.0% (3.5-5.0)] vs 26% (9.5-42.5), respectively). CONCLUSION: The majority of mothers and a significant proportion of newborns with PCD identified through NBS are likely to remain asymptomatic without early treatment. Conversely, a small proportion of newborns with predicted severe PCD could greatly benefit from early treatment. Genetic variants and carnitine transport activity can be used to distinguish between these groups.

Early Risk Stratification for Natural Disease Course in Fabry Patients Using Plasma Globotriaosylsphingosine Levels.

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.

A qualitative study on the perspectives of mothers who had been diagnosed with primary carnitine deficiency through newborn screening of their child.

BACKGROUND: Primary carnitine deficiency is an inborn error of metabolism, which can lead to life-threating complications early in life. Low carnitine levels can be detected by newborn bloodspot screening (NBS). However, NBS can also identify, mostly asymptomatic, mothers with primary carnitine deficiency. To identify mothers' needs and areas for improving screening practice, this study explored the experiences with, and opinions on primary carnitine deficiency screening in NBS among women diagnosed through NBS of their newborn. METHODS: Twelve Dutch women were interviewed, 3-11 years after diagnosis. Data were analysed using a thematic approach. RESULTS: Four main themes were derived: 1) psychological impact of primary carnitine deficiency diagnosis, 2) becoming a patient and "patient-in-waiting", 3) information issues and care provision, and 4) primary carnitine deficiency as part of the NBS panel. Mothers shared that they did not experience major psychological distress of the diagnosis. They did experience (recall) various emotions following the initial abnormal NBS result, including fear and anxiety as well as relief, and emotions regarding their own diagnosis, including uncertainty about health risks and treatment effectiveness. Some felt a patient-in-waiting. Many participants experienced a lack of information, especially shortly after receiving the abnormal NBS result. All shared the belief that screening for primary carnitine deficiency in NBS is beneficial for the newborn, and, given the information they received, also considered the knowledge beneficial for their own health. CONCLUSIONS: Psychological burden following diagnosis was experienced by women as limited, although the experienced lack of information amplified feelings of uncertainty and anxiety. Most mothers believed that benefits of knowing about primary carnitine deficiency outweighed the disadvantages. Mothers' perspectives should be incorporated in policy-making about primary carnitine deficiency in NBS.

ECG Changes during Adult Life in Fabry Disease: Results from a Large Longitudinal Cohort Study.

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.

Patients' view on gene therapy development for lysosomal storage disorders: a qualitative study.

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.

Recurrent metabolic alkalosis following ketone body treatment of adult mitochondrial trifunctional protein deficiency: A case report.

Recent studies have reported the potential for the therapeutic use of ketones in the form of ketone salts (KSs) in pediatric patients with fatty acid oxidation disorders (FAODs). We report a case of ketone salt administration in an adult patient with mitochondrial trifunctional protein deficiency (MTPD), an ultra-rare inborn error of the fatty acid metabolism. This patient was treated with oral KSs during an episode of sepsis of unknown origin. Before KS supplementation was initiated, he had developed severe rhabdomyolysis as well as a respiratory insufficiency that did not respond to emergency treatment aimed at stabilizing the metabolic decompensation by promoting anabolism. Therefore, KS supplementation was attempted twice to support his energy production and help regain metabolic stability. In both instances, KS supplementation led to a considerable metabolic alkalosis, which prompted its discontinuation. This adverse event could have been caused by an increase in extracellular sodium load due to KS administration. Therefore, the clinical applicability of KSs in adults may be limited. Alternative chemical forms of beta-hydroxybutyrate (ßHB), such as ketone esters, might provide a more acceptable safety profile for future research into the therapeutic benefits of ketone body supplementation in adult patients with FAODs.

Mind the B2: Life-Threatening Neonatal Complications of a Strict Vegan Diet during Pregnancy.

An increasing number of women of reproductive age follow vegan diets. Because vegan diets are deficient in a number of essential nutrients, guidelines address the necessity of supplementations such as iron, zinc, and vitamin B12. However, the risk of riboflavin (vitamin B2) deficiency is not properly addressed. We report a case of a male neonate with a life-threatening hypoglycaemia and lactic acidosis due to severe riboflavin deficiency. The mother followed a strict vegan diet with intermittent use of supplements (folic acid, vitamin B12, vitamin D, omega 3). This case highlights the importance of adequate counselling of all pregnant women adhering to vegan diets to ensure sufficient intake of essential nutrients and vitamins, including riboflavin.