37 research outputs found
3-Methylcrotonyl-CoA: Carboxylase Mangel
Der isolierte 3-Methylcrotonyl-CoA: Carboxylase (MCC) Mangel ist eine angeborene
Störung im Abbau der AminosÀure Leucin. Es sind sowohl bis ins Erwachsenenalter
asymptomatische als auch frĂŒhe letale VerlĂ€ufe beschrieben. Die Ursachen des variablen
PhĂ€notyps sind nicht verstanden. Das Enzym ist zusammengesetzt aus α- und ÎČ -
Untereinheiten. Die kodierenden humanen Gene MCCA und MCCB wurden kĂŒrzlich in
unserer Arbeitsgruppe kloniert. Die Erweiterung des Neugeborenen-Screenings mittels
Tandem-Massenspektrometrie in Bayern erbrachte die ĂŒberraschende Erkenntnis, daĂ der
MCC Mangel wahrscheinlich die hÀufigste organische AzidÀmie (etwa 1 : 40 000) darstellt
und asymptomatische MutationstrĂ€ger existieren. Ăber Risiko und Prognose dieser
metabolischen Störung ist derzeit noch keine Aussage möglich. In dieser Arbeit sollte daher
eine Methode zur molekulargenetischen Charakterisierung von Patienten mit MCC Mangel
etabliert werden, um den prognostischen Wert des Genotyps studieren und damit die Beratung
und Betreuung der betroffenen Familien verbessern zu können. Es wurden 3 asymptomatische
Patienten aus dem Neugeborenenscreening sowie ein Patient, der mit cerebralen
KrampfanfÀllen aufgefallen war, untersucht. Die Diagnose war bei allen Patienten durch
Bestimmung der typischen Metabolite in Urin (3-HydroxyisovaleriansÀure und 3-
Methylcrotonylglycin) und Blut (3-Hydroxyisovaleryl-Carnitin) gestellt worden.
FĂŒr die molekulargenetische Diagnostik des MCC Mangels wurde die Mutationsanalyse auf
genomischer und cDNA Ebene fĂŒr MCCA und MCCB etabliert. Es wurden zwei Patienten mit
verÀnderten Allelen im MCCA- und zwei Patienten mit Mutationen im MCCB-Gen
identifiziert. Ein Patient war compound-heterozygot fĂŒr die Missense-Mutation S535F
(1604C>T) und die Nonsense-Mutation V694X (2079delA) im MCCA Gen. Bei einem
zweiten Patienten wurde S535F (1604C>T) heterozygot nachgewiesen. Ein Patient mit
konsanguinen Eltern war homozygot fĂŒr die Missense-Mutation S535F (1604C>T). Ein
weiterer wies die Missense-Mutation E99Q (295G>C, cDNA: homozygot; gDNA:
heterozygot) mit einen Allelverlust auf. In zwei FÀllen werden zusÀtzliche Mutationen in der
Promotorregion bzw. in einem Intron angenommen. FĂŒr alle gefundenen Mutationen kann
von phÀnotypischer Relevanz ausgegangen werden. Drei davon waren bisher unbekannt und
wurden von uns erstbeschrieben. Unsere Ergebnisse bestÀtigen die Rolle von MCCA und
MCCB azielfĂŒhrende Methode zur molekulargenetischen Charkterisierung von Patienten mit MCC
Mangel dar und bildet damit die Grundlage fĂŒr Expressionsstudien und Studien zur
Untersuchung der Genotyp-PhÀnotypkorrelation.ls humane Krankheitsgene. Die hier etablierte Mutationsanalyse stellt ein
The inflammation in the cytopathology of patients with mucopolysaccharidoses : immunomodulatory drugs as an approach to therapy
Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSDs), characterized by the accumulation of glycosaminoglycans (GAGs). GAG storageinduced inflammatory processes are a driver of cytopathology in MPS and pharmacological immunomodulation can bring improvements in brain, cartilage and bone pathology in rodent models. This manuscript reviews current knowledge with regard to inflammation in MPS patients and provides hypotheses for the therapeutic use of immunomodulators in MPS. Thus, we aim to set the foundation for a rational repurposing of the discussed molecules to minimize the clinical unmet needs still remaining despite enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT)
The PompeQoL questionnaire: Development and validation of a new measure for children and adolescents with Pompe disease
Genetic disorders pose great challenges for affected individuals and their families, as they must cope with the irreversible nature of the disease and a lifeâlong dependence on medical assistance and treatment. Children and adolescents dealing with Pompe disease (PD) often struggle to keep up with their peers in physical activities. To gain valuable insights into their subjective experiences and better understand their perception and coping related to daily challenges linked to their condition and treatment, the use of standardized questionnaires is crucial. This study introduces the novel PompeQoL 1.0 questionnaire for children and adolescents with PD, designed for comprehensive assessment of both diseaseâspecific FDH and HRQoL through selfâ and proxy reports. Content validity was ensured through patients' and parents' involvement at the initial stages of development and in subsequent cognitive debriefing process. Participants found the questionnaire easy to understand, answerable, relevant, and comprehensive. Adjustments based on feedback from patients and their parents improved its utility as a patientâ and observerâreported outcome measure. After careful item examination, 52 items were selected, demonstrating moderate to excellent testâretest reliability for most scales and initial evidence for satisfactory construct validity. The PompeQoL questionnaire stands as a valuable screening instrument for both clinical and research purposes. Future research should prioritize additional revisions and larger validation studies, focusing on testing the questionnaire in clinical practice and trials. Nevertheless, the PompeQoL 1.0 stands out as the first standardized measure providing insights into diseaseâspecific FDH and HRQoL among children and adolescents with various forms of PD
Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients
Phenylketonuria (PKU, MIM 261600) is an autosomal recessive disorder caused by mutations of the phenylalanine hydroxylase gene (PAH, GenBank U49897.1, RefSeq NM_000277). To date more than 560 variants of the PAH gene have been identified. In Europe there is regional distribution of specific mutations. Due to recent progress in chaperone therapy, the prevalence of BH4-responsive alleles gained therapeutic importance. Here we report the mutational spectrum of PAH deficiency in 147 unrelated Austrian families. Overall mutation detection rate was 98.6%. There was a total of 62 disease-causing mutations, including five novel mutations IVS4â+â6T>A, p.H290Y, IVS8-2A>G, p.A322V and p.I421S. The five most prevalent mutations found in patients were p.R408W, IVS12â+â1G>A, p.R261Q, p.R158Q and IVS2â+â5G>C. Neonatal phenylalanine levels before treatment were available in 114/147 patients. Prediction of BH4-responsiveness in patients with full genotypes was exclusively made according to published data. Among the 133 patients needing dietary treatment, 28.4% are expected to be BH4 "non-responsive", 4.5% are highly likely BH4-responsive, 35.8% are probably BH4-responsive while no interpretation was possible for 31.3%. The mutation data reflect the population history of Austria and provide information on the likely proportion of Austrian PKU patients that may benefit from BH4-therap
Pharmacology of enalapril in children: a review
Enalapril is an angiotensin-converting enzyme (ACE) inhibitor that is used for the treatment of (paediatric) hypertension, heart failure and chronic kidney diseases. Because its disposition, efficacy and safety differs across the paediatric continuum, data from adults cannot be automatically extrapolated to children. This review highlights paediatric enalapril pharmacokinetic data and demonstrates that these are inadequate to support with certainty an age-related effect on enalapril/enalaprilat pharmacokinetics. In addition, our review shows that evidence to support effective and safe prescribing of enalapril in children is limited, especially in young children and heart failure patients; studies in these groups are either absent or show conflicting results. We provide explanations for observed differences between age groups and indications, and describe areas for future research
Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo
The recent approval of sapropterin dihydrochloride, the synthetic form of 6[R]-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4), for the treatment of phenylketonuria (PKU) as the first pharmacological chaperone drug initiated a paradigm change in the treatment of monogenetic diseases. Symptomatic treatment is now replaced by a causal pharmacological therapy correcting misfolding of the defective phenylalanine hydroxylase (PAH) in numerous patients. Here, we disclose BH4 responsiveness in Pahenu1, a mouse model for PAH deficiency. Loss of function resulted from loss of PAH, a consequence of misfolding, aggregation, and accelerated degradation of the enzyme. BH4 attenuated this triad by conformational stabilization augmenting the effective PAH concentration. This led to the rescue of the biochemical phenotype and enzyme function in vivo. Combined in vitro and in vivo analyses revealed a selective pharmaceutical action of BH4 confined to the pathological metabolic state. Our data provide new molecular-level insights into the mechanisms underlying protein misfolding with loss of function and support a general model of pharmacological chaperone-induced stabilization of protein conformation to correct this intracellular phenotype. Pahenu1 will be essential for pharmaceutical drug optimization and to design individually tailored therapie
Simulation Training to Improve Informed Consent and Pharmacokinetic/Pharmacodynamic Sampling in Pediatric Trials
Background: Pediatric trials to add missing data for evidence-based pharmacotherapy are still scarce. A tailored training concept appears to be a promising tool to cope with critical and complex situations before enrolling the very first patient and subsequently to ensure high-quality study conduct. The aim was to facilitate study success by optimizing the preparedness of the study staff shift. Method: An interdisciplinary faculty developed a simulation training focusing on the communication within the informed consent procedure and the conduct of the complex pharmacokinetic/pharmacodynamic (PK/PD) sampling within a simulation facility. Scenarios were video-debriefed by an audio-video system and manikins with artificial blood simulating patients were used. The training was evaluated by participants' self-assessment before and during trial recruitment. Results: The simulation training identified different optimization potentials for improved informed consent process and study conduct. It facilitated the reduction of avoidable errors, especially in the early phase of a clinical study. The knowledge gained through the intervention was used to train the study teams, improve the team composition and optimize the on-ward setting for the FP-7 funded âLENAâ project (grant agreement no. 602295). Self-perceived ability to communicate core elements of the trial as well as its correct performance of sample preparation increased significantly (mean, 95% CI, p †0.0001) from 3 (2.5â3.5) to four points (4.0â4.5), and from 2 (1.5â2.5) to five points (4.0â5.0). Conclusion: An innovative training concept to optimize the informed consent process and study conduct was successfully developed and enabled high-quality conduct of the pediatric trials as of the very first patient visit
Simulation Training to Improve Informed Consent and Pharmacokinetic/Pharmacodynamic Sampling in Pediatric Trials
Background: Pediatric trials to add missing data for evidence-based pharmacotherapy are still scarce. A tailored training concept appears to be a promising tool to cope with critical and complex situations before enrolling the very first patient and subsequently to ensure high-quality study conduct. The aim was to facilitate study success by optimizing the preparedness of the study staff shift. Method: An interdisciplinary faculty developed a simulation training focusing on the communication within the informed consent procedure and the conduct of the complex pharmacokinetic/pharmacodynamic (PK/PD) sampling within a simulation facility. Scenarios were video-debriefed by an audio-video system and manikins with artificial blood simulating patients were used. The training was evaluated by participants' self-assessment before and during trial recruitment. Results: The simulation training identified different optimization potentials for improved informed consent process and study conduct. It facilitated the reduction of avoidable errors, especially in the early phase of a clinical study. The knowledge gained through the intervention was used to train the study teams, improve the team composition and optimize the on-ward setting for the FP-7 funded âLENAâ project (grant agreement no. 602295). Self-perceived ability to communicate core elements of the trial as well as its correct performance of sample preparation increased significantly (mean, 95% CI, p †0.0001) from 3 (2.5â3.5) to four points (4.0â4.5), and from 2 (1.5â2.5) to five points (4.0â5.0). Conclusion: An innovative training concept to optimize the informed consent process and study conduct was successfully developed and enabled high-quality conduct of the pediatric trials as of the very first patient visit
Extent, impact, and predictors of diagnostic delay in Pompe disease: A combined survey approach to unveil the diagnostic odyssey
Background
Early diagnosis is of substantial benefit for patients with Pompe disease. Yet underdiagnosing and substantial diagnostic delay are still frequent and the determinants of this are unknown. This study is the first to systematically investigate the diagnostic odyssey in Pompe disease from patients', parents', and physicians' perspectives.
Methods
Patients with infantile or late onset Pompe disease, their parents as well as their metabolic experts were invited to fill in respective surveys. The survey addressed perceived disease symptoms at onset and during the course of the disease, specialties of involved physicians, activities of patient-initiated search for diagnosis and the perceived impact of time to diagnosis on outcome. Results of experts' and patients'/parents' surveys were compared and expressed by descriptive statistics.
Results and Discussion
We collected data on 15 males and 17 females including 9 infantile and 23 late onset Pompe patients. All received the correct diagnosis at a metabolic or musculoskeletal expert center. Patients with direct referral to the expert center had the lowest diagnostic delay, while patients who were seen by several physicians, received the correct diagnosis after 44%-200% longer delay. The proportion of direct referral varied strongly between pediatricians (57%) and other disciplines (18%-36%).
Conclusion
Our study highlights a substantially larger diagnostic delay in Pompe patients that are not directly referred to expert centers for diagnostic work. Our findings may be used to develop more successful strategies for early diagnosis.
Synopsis
Diagnostic delay in Pompe disease is substantial particularly in patients that are not directly referred to expert centers for diagnostic workup, so facilitating direct referral may be a new strategy for early diagnosis