Measuring what matters: Why and how to include patient reported outcomes in clinical care and research on inborn errors of metabolism

Patient reported outcomes (PROs) are generally defined as ‘any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else’. A broader definition of PRO also includes ‘any information on the outcomes of health care obtained directly from patients without modification by clinicians or other health care professionals’. Following this approach, PROs encompass subjective perceptions of patients on how they function or feel not only in relation to a health condition but also to its treatment as well as concepts such as health‐related quality of life (HrQoL), information on the functional status of a patient, signs and symptoms and symptom burden. PRO measurement instruments (PROMs) are mostly questionnaires and inform about what patients can do and how they feel. PROs and PROMs have not yet found unconditional acceptance and wide use in the field of inborn errors of metabolism. This review summarises the importance and usefulness of PROs in research, drug legislation and clinical care and informs about quality standards, development, and potential methodological shortfalls of PROMs. Inclusion of PROs measured with high‐quality, well‐selected PROMs into clinical care, drug legislation, and research helps to identify unmet needs, improve quality of care, and define outcomes that are meaningful to patients. The field of IEM should open to new methodological approaches such as the definition of core sets of variables including PROs to be systematically assessed in specific metabolic conditions and new collaborations with PRO experts, such as psychologists to facilitate the systematic collection of meaningful data

Explaining juvenile idiopathic arthritis to paediatric patients using illustrations and easy-to-read texts: improvement of disease knowledge and adherence to treatment

INTRODUCTION Juvenile idiopathic arthritis (JIA) is the leading chronic rheumatic disease in childhood. To achieve adherence to therapy, in-depth understanding of disease and treatment options are important. OBJECTIVE Development of specifically designed illustrations and standardised, easy-to-read texts for children and adolescents with JIA. Education materials were tested for comprehensibility and content validity. We hypothesised that children would be able to increase their knowledge about JIA after presentation of materials. METHODS The illustrations were designed by a graphic artist and the informative texts consecutively transformed to easy-to-read language. The materials appear as a modular system to allow individualized information for each patient. The illustrations and texts were tested for knowledge gain and improvement of self-efficacy in children affected by JIA/ rheumatic diseases and controls. Health-related quality of life (HRQoL) was tested as an overall assessment of patients' well-being. RESULTS 46 controls (71% female) and 38 patients (48% female) with a median age of 11 years were tested in a standardised setting. In both groups knowledge gain was significant (controls: t (44) = 11.08, p < 0.001, d = 1.65; patients: t (37) = 7.48, p < 0.001, d = 1.21). The control group had a significantly higher enhancement of disease knowledge compared to patients' group (p = .046) The follow-up testing was only performed in one school class (20 controls) due to Covid-19 pandemic with significant improvement compared to the pre-test results (p = .002). The enhancement of self-efficacy through the teaching session was significantly higher in the patients' group. No impairment of HRQoL was seen. CONCLUSION Explaining juvenile rheumatic diseases and therapeutic strategies is an important task in paediatric rheumatology. To avoid incomprehensible explanations in medical jargon, illustrations and easy-to-read texts were developed. Standardised presentation of the newly created materials resulted in a significant improvement of disease knowledge in patients and controls in addition to an enhancement of self-efficacy in patients

Evaluation of Implementation, Adaptation and Use of the Recently Proposed Urea Cycle Disorders Guidelines

BACKGROUND Implementation of guidelines and assessment of their adaptation is not an extensively investigated process in the field of rare diseases. However, whether targeted recipients are reached and willing and able to follow the recommendations has significant impact on the efficacy of guidelines. In 2012, a guideline for the management of urea cycle disorders (UCDs) has been published. We evaluate the efficacy of implementation, adaptation, and use of the UCD guidelines by applying different strategies. METHODS (i) Download statistics from online sources were recorded. (ii) Facilities relevant for the implementation of the guidelines were assessed in pediatric units in Germany and Austria. (iii) The guidelines were evaluated by targeted recipients using the AGREE instrument. (iv) A regional networking-based implementation process was evaluated. RESULTS (i) Download statistics revealed high access with an increase in downloads over time. (ii) In 18% of hospitals ammonia testing was not available 24/7, and emergency drugs were often not available. (iii) Recipient criticism expressed in the AGREE instrument focused on incomplete inclusion of patients' perspectives. (iv) The implementation process improved the availability of ammonia measurements and access to emergency medication, patient care processes, and cooperation between nonspecialists and specialists. CONCLUSION Interest in the UCD guidelines is high and sustained, but more precise targeting of the guidelines is advisable. Surprisingly, many hospitals do not possess all facilities necessary to apply the guidelines. Regional network and awareness campaigns result in the improvement of both facilities and knowledge

FBXL4-Related Mitochondrial DNA Depletion Syndrome 13 (MTDPS13): A Case Report With a Comprehensive Mutation Review

Mitochondrial DNA depletion syndromes (MTDPS) are a group of rare genetic disorders caused by defects in multiple genes involved in mitochondrial DNA (mtDNA) maintenance. Among those, FBXL4 mutations result in the encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13; OMIM #615471), which commonly presents as a combination of failure to thrive, neurodevelopmental delays, encephalopathy, hypotonia, and persistent lactic acidosis. We report here the case of a Lebanese infant presenting to us with profound neurodevelopmental delays, generalized hypotonia, facial dysmorphic features, and extreme emaciation. Whole-exome sequencing (WES) showed the girl as having MTDPS13 with an underlying FBXL4 missense mutation that has been previously reported only twice in unrelated individuals (c.1303C &gt; T). Comprehensive literature search marked our patient as being the 94th case of MTDPS13 reported to date worldwide, and the first from Lebanon. We include at the end of this report a comprehensive mutation review table of all the pathological FBXL4 mutations reported in the literature, using it to highlight, for the first time, a possible founder effect of Arab origins to the disorder, being most prevalent in patients of Arab descent as shown in our mutation table. Finally, we provide a direct comparison of the disorder's clinical manifestations across two unrelated patients harboring the same disease-causing mutation as our patient, emphasizing the remarkable variability in genotype-to-phenotype correlation characteristic of the disease

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire

Purpose: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). Methods: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. Results: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. Conclusion: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib. Keywords: GSD Ib; Glycogen storage disease type Ib; Neutropenia; SGLT2 inhibitors; SLC37A

A retrospective study on disease management in children and adolescents with phenylketonuria during the Covid-19 pandemic lockdown in Austria

BACKGROUND In classical phenylketonuria (PKU) phenylalanine (Phe) accumulates due to functional impairment of the enzyme phenylalanine hydroxylase caused by pathogenic variants in the PAH gene. PKU treatment prevents severe cognitive impairment. Blood Phe concentration is the main biochemical monitoring parameter. Between appointments and venous blood sampling, Austrian PKU patients send dried blood spots (DBS) for Phe measurements to their centre. Coronavirus disease-19 (COVID-19), caused by the SARS CoV-2 virus, was classified as a pandemic by the World Health Organization in March 2020. In Austria, two nationwide lockdowns were installed during the first and second pandemic wave with variable regional and national restrictions in between. This retrospective questionnaire study compared the frequency of Phe measurements and Phe concentrations during lockdown with the respective period of the previous year in children and adolescents with PKU and explored potential influencing factors. RESULTS 77 patients (30 female, 47 male; mean age 12.4 [8-19] years in 2020) from five centres were included. The decline of venous samples taken on appointments in 2020 did not reach significance but the number of patients with none or only one DBS tripled from 4 (5.2%) in 2019 to 12 (15.6%) in 2020. Significantly more patients had a decline than a rise in the number of DBS sent in between 2019 and 2020 (p < 0.001; Chi$^{2}$ = 14.79). Especially patients ≥ 16 years sent significantly less DBS in 2020 (T = 156, p = 0.02, r = 0.49). In patients who adhered to DBS measurements, Phe concentrations remained stable. Male or female sex and dietary only versus dietary plus sapropterin treatment did not influence frequency of measurements and median Phe. CONCLUSION During the COVID pandemic, the number of PKU patients who stopped sending DBS to their metabolic centre increased significantly, especially among those older than 16 years. Those who kept up sending DBS maintained stable Phe concentrations. Our follow-up system, which is based on DBS sent in by patients to trigger communication with the metabolic team served adherent patients well. It failed, however, to actively retrieve patients who stopped or reduced Phe measurements

Caregiver burden, and parents' perception of disease severity determine health-related quality of life in paediatric patients with intoxication-type inborn errors of metabolism.

Background Living with a non-acute (phenylketonuria) or acute (e.g. urea cycle disorders, organic acidurias) intoxication-type inborn error of metabolism (IT-IEM) can have a substantial impact on health-related quality of life (HrQoL) of paediatric patients and their families. Parents take primary responsibility for treatment monitoring and experience worry and fear about their child's health status. Quantitative evidence on parental psychological factors which may influence the HrQoL of patients with IT-IEM are sparse to non-existent. Methods In this multicenter survey study 50 parents of IT-IEM patients (ages 5-19) assessed the severity of their child's disease, reported on caregiver burden, and proxy-rated their child's HrQoL. Additionally, 35 patient self-reports on HrQoL were obtained (n = 16 female patients, n = 19 male patients). Multiple linear regressions were conducted to examine the predictive power of child age, sex, medical diagnosis type (acute / non-acute), parental perceived disease severity and caregiver burden on patients' HrQoL. Mediation analyses were used to investigate the relation of caregiver burden and parental ratings of disease severity with patients' HrQoL. Results Significant regression models for self-reported [F(5,34) = 10.752, p < .001, R 2 adj.. = 0.59] and parent proxy reported HrQoL [F(5,49) = 20.513, p < .001, R 2 adj.. = 0.67] emerged. High caregiver burden and perceived disease severity predicted significantly lower patient self- and proxy-reported HrQoL while type of diagnosis (acute versus non-acute) did not. Female sex predicted significantly lower self-reported HrQoL. High caregiver burden was the mediating factor between high perceived severity of the child's disease and lower proxy- by parent rated HrQoL. Conclusion Detecting elevated burden of care and providing support for parents seems crucial to prevent adverse consequences for their children's HrQoL. Intervention studies are needed, to assess which support programs are most efficient

100 years of inherited metabolic disorders in Austria-A national registry of minimal birth prevalence, diagnosis, and clinical outcome of inborn errors of metabolism in Austria between 1921 and 2021

Inherited metabolic disorders (IMDs) are a heterogeneous group of rare disorders characterized by disruption of metabolic pathways. To date, data on incidence and prevalence of IMDs are limited. Taking advantage of a functioning network within the Austrian metabolic group, our registry research aimed to update the data of the "Registry for Inherited Metabolic Disorders" started between 1985 and 1995 with retrospectively retrieved data on patients with IMDs according to the Society for the Study of Inborn Errors of Metabolism International Classification of Diseases 11 (SSIEM ICD11) catalogue. Included in this retrospective register were 2631 patients with an IMD according to the SSIEM ICD11 Classification, who were treated in Austria. Thus, a prevalence of 1.8/10 000 for 2020 and a median minimal birth prevalence of 16.9/100 000 (range 0.7/100 000-113/100 000) were calculated for the period 1921 to February 2021. We detected a male predominance (m:f = 1.2:1) and a mean age of currently alive patients of 17.6 years (range 5.16 months-100 years). Most common diagnoses were phenylketonuria (17.7%), classical galactosaemia (6.6%), and biotinidase deficiency (4.2%). The most common diagnosis categories were disorders of amino acid and peptide metabolism (819/2631; 31.1%), disorders of energy metabolism (396/2631; 15.1%), and lysosomal disorders (395/2631; 15.0%). In addition to its epidemiological relevance, the "Registry for Inherited Metabolic Disorders" is an important tool for enhancing an exchange between care providers. Moreover, by pooling expertise it prospectively improves patient treatment, similar to pediatric oncology protocols. A substantial requirement for ful filling this goal is to regularly update the registry and provide nationwide coverage with inclusion of all medical specialties

Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection

Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies

Postauthorization safety study of betaine anhydrous

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013–2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0–9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation