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Fabry disease (FD) is a multi-organ disorder associated with severe physical and psychological impairments, particularly in adulthood. To date, comprehensive data on the psychological burden of FD are lacking. The present study assessed quality of life (QOL) in a representative cohort of adults with FD.Patient-reported outcome measures were retrospectively analyzed in 86 adults with FD (49.6±16.6 years; 62.8% female) and compared to adults with congenital heart defects (ACHD) which is another lifelong disease and affliction. QOL was assessed using the European Quality of Life 5 Dimensions 5 Levels questionnaire (EQ-5D-5L).Subjects affected by FD reported an overall reduced QOL (EQ-VAS: 71.8±20.0). Most frequently reported complaints occurred within the dimensions pain/discomfort (69.7%), daily activities (48.9%) and anxiety/depression (45.4%). Compared to ACHD, individuals with FD scored significantly lower in the areas of pain/discomfort, usual activities and mobility (all P0.05). Older age and female sex were particularly associated with diminished QOL (P=0.05).Patients with FD are at high risk for impaired QOL. They require additional support to cope with disease-related challenges. Increased attention should be directed towards improving their subjective well-being to potentially increase their QOL and long-term health outcomes.

IntroductionMucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases caused by different enzyme deficiencies that lead to accumulation of glycosaminoglycans (GAGs) in lysosomes and the extracellular matrix. This storage-induced inflammation is a key driver of cytopathology in MPS, and pharmacological immunomodulation can improve brain, cartilage and bone symptoms in rodents. As the approved enzyme replacement therapy cannot stop the progression of CNS involvement and several other symptoms, we develop a rational for personalized treatment to address the unmet clinical need in MPS patients.MethodsFirst, we conducted comprehensive literature reviews on MPS type specific inflammatory immune response and on the safety and efficacy of Adalimumab, Infliximab, Abatacept, Alemtuzumab, Anakinra. Second, by expert consensus top candidates for innovative personalized drug repurposing in MPS patients were identified and ranked.ResultsThe key process is the upregulation of toll-like receptor-4 (TLR4) pathway induced by the accumulation of heparan sulfate (HS) in MPS type I, II and III. This and other relevant mech-anisms indicate TNF-alpha and IL-1 as most promising targets. Systematic analysis of the clinical pharmacology of all relevant candidates and several expert focus group meetings identified Anakinra, Adalimumab, Cladribine and Abatacept as top candidate’s dependent on the individual clinical situation.ConclusionsThese results provide the rational for individual treatment trials (ITTs) with the aim to evaluate immunomodulatory molecules, repurposed in MPS. Furthermore, they will – together with the results of the ITTs – be utilized for the development of a decision tool for the personalized treatment of unmet clinical needs in these patients.

IntroductionMucopolysaccharidoses (MPS), comprise a group of rare chronically debilitating metabolic diseases and associated with reduced life expectancy and a substantial unmet clinical need. Current research directs towards a number of new treatment targets and strategies. Individual treatment trials (ITT) could make these options rapidly available to patients. Based on scientific publication, this is hardly used. We assess the utilization of and relevant barriers to ITT in MPS as well as potential solutions.MethodsPhase 1 was done with 5 international top experts. After this interim analysis, the survey will be rolled out to a broader group of experts.ResultsFive MPS experts from Austria, Brazil, Germany and Italy have been enrolled. In total these clinicians manage about 350 MPS patients. Only three experts ever ran 1–3 numbers of ITT in MPS patients, solely MPS type II (n=2) and VI (n=1), summing up to a total of five ITTs, which is about 1.4% of their patients. The treatments used in ITTs comprise Montelukast, THC, Curcuma and a viral vector with transgene. As barriers for a wider use of ITTs, the im-practicability for implementation (n=1) and the insufficient training in ITT (n=1) have been indicated. All experts consider it highly likely that a decision analysis tool increases the use of ITT in MPS.ConclusionsITT are used in about 1% of MPS patients. This seems extremely low, considering the commonness of off label use in children with severe conditions, the high unmet medical need in MPS and the number of research results, which indicate various promising repurposing strategies. This interim analysis already demonstrates several relevant barriers and high potential of the planned decision framework tool to overcome this.

Pompe disease is a lysosomal multisystem disorder with predominant proximal myopathy. Treatment with enzyme replacement therapy (ERT) is available requiring life-long biweekly infusions of recombinant α-glucosidase. To minimize the burden of ERT patients ask for home infusion therapy.Pompe disease experts from Germany, Austria, and Switzerland discussed in two consensus meetings in 2019 and 2020 requirements for home infusion therapy, adequate execution of treatment, and the legal situation for delegating physicians.Home infusion therapy is principally feasible for patients with Pompe disease if certain preconditions are fulfilled, but the decision to implement has to be made on an individual basis. The treating physician delegates the execution of ERTDer Morbus Pompe ist eine lysosomale Multisystemerkrankung mit prädominanter Myopathie, für die eine Enzymersatztherapie (EET) mit rekombinanter α-Glucosidase verfügbar ist. Diese muss aktuell zweiwöchentlich lebenslang erfolgen. Um die Belastung durch diese Behandlungsform gering zu halten, besteht bei vielen Betroffenen der Wunsch, die EET zu Hause als sog. Heiminfusionstherapie durchzuführen.Im Rahmen zweier Deutsch-Österreichisch-Schweizerischer Konsensus-Expertentreffen in den Jahren 2019 und 2020 wurde diskutiert, welche Voraussetzungen gegeben sein müssen, damit eine Heiminfusionstherapie medizinisch vertretbar erfolgen kann, wie diese sachgemäß durchzuführen ist und wie die Rechtslage für delegierende Ärzte aussieht.Prinzipiell ist bei Patienten mit Morbus Pompe eine Heiminfusionstherapie möglich, wenn bestimmte Voraussetzungen erfüllt sind. Die Entscheidung muss für jeden Patienten individuell getroffen werden. Der behandelnde Arzt delegiert die Durchführung der Heiminfusionstherapie ad

Item does not contain fulltext Aim: Clinical research in pediatrics is progressively initiated by academia. As the reliability of pharmacodynamic measures is closely linked to the quality of bioanalytical data, bioanalytical quality assurance is crucial. However, clear guidance on comprehensive bioanalytical quality monitoring in the academic environment is lacking. Methods & results: By applying regulatory guidelines, international recommendations and scientific discussions, a five-step quality control system for monitoring the bioanalysis of aldosterone by immunoassay was developed. It comprised performance qualification, calibration curve evaluation, analysis of the intra- and inter-run performance via quality control samples, incurred sample reanalysis and external quality assessment by interlaboratory testing. A total of 55 out of 70 runs were qualified for the quantification of aldosterone in the study sample enabling the evaluation of 954 pediatric samples and demonstrating reliability over the 29-month bioanalysis period. Conclusion: The bioanalytical quality control system successfully monitored the aldosterone assay performance and proved its applicability in the academic environment.

Contains fulltext : 220641.pdf (Publisher’s version ) (Closed access) While the role of plasma renin activity (PRA) in heart failure has been widely studied in adults, comprehensive data on pediatric heart failure remain lacking. This drawback is increasingly being addressed by academic research. Nevertheless, such pediatric investigations are commonly conducted only once due to ethical constraints. Therefore, the quality of bioanalytical data must be ensured to acquire meaningful insights into maturing humoral parameters. However, appropriate post-validation assessment of bioanalytical runs is currently underrepresented by regulatory guidance. Thus, for applications in an academic environment, an easy-to-handle six-step bioanalytical quality control system was designed based on regulatory guidelines (e.g. U.S. Food and Drug Administration) combined with international recommendations (e.g. Clinical and Laboratory Standards Institute) and current scientific discussion. Its applicability to an enzyme-linked immunosorbent assay for determination of PRA was investigated within three pediatric trials of the EU-funded "Labeling of Enalapril in Neonates up to Adolescents" project. This quality control system identified 15 % bioanalytical runs as non-compliant to the predefined specifications and ensured the reliable quantification of 940 pharmacodynamic samples. The inter-run assessment of quality controls was able to demonstrate the comparability of the study results. Furthermore, 86 % of incurred sample reanalysis pairs complied with regulatory requirements (>67 %), thus underlining the long-term reproducibility of the utilized ligand-binding assay. Successful participation in interlaboratory testing confirmed the accuracy of the applied method throughout the entire study period. Further investigations showed no notable differences between the five applied lots of the PRA assay. The applicability of this quality control system was proven in an academic environment and ensured reliable results for PRA over the entire 24-month study period.

3-Methylcrotonyl-CoA: carboxylase (EC 6.4.1.4; MCC) deficiency is an inborn error of the leucine degradation pathway (MIM *210200) characterized by increased urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. The clinical phenotypes are highly variable ranging from asymptomatic to profound metabolic acidosis and death in infancy. Sequence similarity with Glycine max and Arabidopsis thaliana genes encoding the two subunits of MCC permitted us to clone the cDNAs encoding the alpha- and beta-subunits of human MCC. The 2580 bp MCCA cDNA encodes the 725 amino acid biotin-containing alpha-subunit. The MCCA gene is located on chromosome 3q26-q28 and consists of 19 exons. The 2304 bp MCCB cDNA encodes the non-biotin-containing beta-subunit of 563 amino acids. The MCCB gene is located on chromosome 5q13 and consists of 17 exons. We have sequenced both genes in four patients with isolated biotin-unresponsive deficiency of MCC. In two of them we found mutations in the MCCA gene. Compound heterozygosity for a missense mutation (S535F) and a nonsense mutation (V694X) were identified in one patient. One heterozygous mutation (S535F) was found in another patient. The remaining two patients had mutations in the MCCB gene. One consanguineous patient was homozygous for a missense mutation (R268T). In the other we identified a missense mutation in one allele (E99Q) and allelic loss of the other. Mutations were correlated with an almost total lack of enzyme activity in fibroblasts. These data provide evidence that human MCC deficiency is caused by mutations in either the MCCA or MCCB gene.