Consensus statement on enzyme replacement therapy for mucopolysaccharidosis IVA in Central and South-Eastern European countries.

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA), or Morquio A syndrome, is a rare inherited metabolic disorder caused by deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. A progressive systemic skeletal chondrodysplasia, leading to significant morbidity and reduced life expectancy is the main clinical feature of this multisystemic disease. Although enzyme replacement therapy with elosulfase alfa is established in Europe, the rarity of disease and other factors still set hurdles in having patients treated in some countries. Aim of this statement is to provide evidence-based guidance for the enzyme replacement treatment of Morquio A patients, harmonizing recommendations from published guidelines with the real-life clinical practice in the Central and South-Eastern European region. PARTICIPANTS: The Consensus Group, convened by 8 Steering Committee (SC) members from 7 Central and South-Eastern European countries, consisted of a multidisciplinary group of 17 experts in the management of MPS in Central and South-Eastern Europe. CONSENSUS PROCESS: The SC met in a first virtual meeting with an external scientific coordinator, to discuss on clinical issues to be analyzed in guidance statements. Statements were developed by the scientific coordinator, evaluated by the SC members in a first modified-Delphi voting and adapted accordingly, to be submitted to the widest audience in the Consensus Conference. Following discussion and further modifications, all participants contributed to a second round of modified-Delphi voting. RESULTS: Nine of ten statements, concerning general guidelines for management of MPS IVA patients and specific recommendations for treatment, received final consensus. CONCLUSIONS: European guidelines and evidence-based recommendations for Morquio A patients should be considered in the real life of Central and South-Eastern European countries and adapted to unique clinical practice approaches and criteria for patients' access to treatment and reimbursement in the region.

The landscape of Mucopolysaccharidosis in Southern and Eastern European countries: a survey from 19 specialistic centers.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defects in genes coding for different lysosomal enzymes which degrade glycosaminoglycans. Impaired lysosomal degradation causes cell dysfunction leading to progressive multiorgan involvement, disabling consequences and poor life expectancy. Enzyme replacement therapy (ERT) is now available for most MPS types, offering beneficial effects on disease progression and improving quality of life of patients. The landscape of MPS in Europe is not completely described and studies on availability of treatment show that ERT is not adequately implemented, particularly in Southern and Eastern Europe. In this study we performed a survey analysis in main specialist centers in Southern and Eastern European countries, to outline the picture of disease management in the region and understand ERT implementation. Since the considerable number of MPS IVA patients in the region, particularly adults, the study mainly focused on MPS IVA management and treatment. RESULTS: 19 experts from 14 Southern and Eastern European countries in total responded to the survey. Results outlined a picture of MPS management in the region, with a high number of MPS patients managed in the centers and a high level of care. MPS II was the most prevalent followed by MPS IVA, with a particular high number of adult patients. The study particularly focused on management and treatment of MPS IVA patients. Adherence to current European Guidelines for follow-up of MPS IVA patients is generally adequate, although some important assessments are reported as difficult due to the lack of MPS skilled specialists. Availability of ERT in Southern and Eastern European countries is generally in line with other European regions, even though regulatory, organizational and reimbursement constrains are demanding. CONCLUSIONS: The landscape of MPS in Southern and Eastern European countries is generally comparable to that of other European regions, regarding epidemiology, treatment accessibility and follow up difficulties. However, issues limiting ERT availability and reimbursement should be simplified, to start treatment as early as possible and make it available for more patients. Besides, educational programs dedicated to specialists should be implemented, particularly for pediatricians, clinical geneticists, surgeons, anesthesiologists and neurologists.

Correlation of GAA Genotype and Acid-α-Glucosidase Enzyme Activity in Hungarian Patients with Pompe Disease.

Pompe disease is caused by the accumulation of glycogen in the lysosomes due to a deficiency of the lysosomal acid-α-glucosidase (GAA) enzyme. Depending on residual enzyme activity, the disease manifests two distinct phenotypes. In this study, we assess an enzymatic and genetic analysis of Hungarian patients with Pompe disease. Twenty-four patients diagnosed with Pompe disease were included. Enzyme activity of acid-α-glucosidase was measured by mass spectrometry. Sanger sequencing and an MLPA of the GAA gene were performed in all patients. Twenty (83.33%) patients were classified as having late-onset Pompe disease and four (16.66%) had infantile-onset Pompe disease. Fifteen different pathogenic GAA variants were detected. The most common finding was the c.-32-13 T > G splice site alteration. Comparing the α-glucosidase enzyme activity of homozygous cases to the compound heterozygous cases of the c.-32-13 T > G disease-causing variant, the mean GAA activity in homozygous cases was significantly higher. The lowest enzyme activity was found in cases where the c.-32-13 T > G variant was not present. The localization of the identified sequence variations in regions encoding the crucial protein domains of GAA correlates with severe effects on enzyme activity. A better understanding of the impact of pathogenic gene variations may help earlier initiation of enzyme replacement therapy (ERT) if subtle symptoms occur. Further information on the effect of GAA gene variation on the efficacy of treatment and the extent of immune response to ERT would be of importance for optimal disease management and designing effective treatment plans.

[The long-term follow-up of enzyme replacement treatment in late onset Pompe disease]. / A késoi kezdetu Pompe-kórban szenvedok enzimpótló kezelésének hosszú távú követése.

Pompe disease (PD) is a rare lysosomal disease caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme due to mutations in the GAA gene. The enzymatic deficiency leads to the accumulation of glycogen within the lysosomes. Clinically, the disease has been classically classified in infantile and childhood/adult forms. Presently cc. close to 600 mutations distributed throughout the whole gene have been reported. The c.-32-13T>G splice mutation that is very common in patients of Caucasian origin affected by the childhood/adult form of the disease, with an allelic frequency close to 70%. Enzyme replacement treatment (ERT) is available for the patients with Pompe disease (Myozyme). In this paper, we are presenting the long term follow up of 13 adult onset cases treated more than 5 years. The longest follow up was 15 years. To evaluate the treatment efficacy, the 6 minutes walking test (6MWT) and the respiratory functions were monitored annually. The analysis revealed that at the beginning of ERT for 3-4 years the 6MWT had been generally increasing, then it declined, and after 10 years it was lower in 77% of the cases than it had been at the start of the treatment. In 23% of the cases the 6MWT increased during the follow up time. Only one of the patients become wheelchair dependent during the follow-up period. The respiratory function showed similar results especially in supine position. A high degree of variability was observed among patients in their responses to the treatment, which only partially associated with the antibody titer against the therapeutic protein. The efficacy of the ERT was associated with the type of the disease causing mutation, the baseline status of the disease, the lifestyle and the diet of the patient. The long-term follow up of the patients with innovative orphan drugs is necessary to really understand the value of the treatment and the need of the patients.

The Psychometric Properties of the Hungarian Version of the Proactive Coping Inventory: Reliability, Construct Validity and Factor Structure

The purpose of the study was to adapt the Proactive Coping Inventory to a Hungarian language context, and to evaluate its psychometric properties. The psychometric characteristics of the Hungarian version of the Proactive Coping Inventory (PCI-H) were examined, based on the data of 452 individuals (mean age= 25.84). Self-report questionnaires were filled out: Proactive Coping Inventory and the short version of the Beck Depression Inventory. In this paper we will present results referring to the reliability of the PCI-H subscales (Cronbach’s alpha= .71 to .86), the construct validity of the inventory and the item analysis. We will also present the results of the Confirmatory Factor Analysis (CFA), which was conducted to test the fit of the original theoretically derived seven-factor structure of the PCI-H. The result of the factor analysis identified seven scales of the inventory (χ2/df= 1.870; CFI= .855; TLI=.845 RMSEA=.045; SRMR=.0678). Overall, the results of this validation study are highly promising. The subscales of the PCI have good reliability and construct validity, moreover the results of the CFA verify that the seven-factor model represents the original factor structure of PCI in an appropriate way (AU)

No disponible

Applicability results of a nonlinear model-based robust blood glucose control algorithm.

INTRODUCTION: Generating optimal control algorithms for an artificial pancreas is an intensively researched problem. The available models are all nonlinear and rather complex. Model predictive control or run-to-run-based methodologies have proven to be efficient solutions for individualized treatment of type 1 diabetes mellitus (T1DM). However, the controller has to ensure safety and stability under all circumstances. Robust control methods seek to provide this safety and guarantee to handle even the worst-case situations and, hence, to generalize and complement results obtained by individualized control algorithms. METHODS: Modern robust (e.g., Hinf) control is a linear model-based methodology that we have combined with the nonlinear model-based linear parameter varying technique. The control algorithm was designed on the high-complexity modified nonlinear glucose-insulin model of Sorensen, and it was compared step-by-step with linear model-based Hinf control results published in the literature. The applicability of the developed algorithm was tested first on a control cohort of 10 healthy persons' oral glucose tolerance test results and then on a large meal absorption profile adapted from the literature. In the latter case, two preliminary virtual patients were generated based on 1-1 week real continuous glucose monitor measurements. RESULTS: We have found that the algorithm avoids hypoglycemia (not caused by physical activity or stress) independently from the considered absorption profiles. CONCLUSION: Use of hard constraints proved their efficiency in fitting blood glucose level within a defined interval. However, in the future, more data of different T1DM patients will be collected and tested, including dynamic absorption model and in silico tests on validated simulators.

Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease.

UNLABELLED: Mucopolysaccharidosis type II (MPS II) is a rare, life-limiting, X-linked recessive disease characterised by deficiency of the lysosomal enzyme iduronate-2-sulfatase. Consequent accumulation of glycosaminoglycans leads to pathological changes in multiple body systems. Age at onset, signs and symptoms, and disease progression are heterogeneous, and patients may present with many different manifestations to a wide range of specialists. Expertise in diagnosing and managing MPS II varies widely between countries, and substantial delays between disease onset and diagnosis can occur. In recent years, disease-specific treatments such as enzyme replacement therapy and stem cell transplantation have helped to address the underlying enzyme deficiency in patients with MPS II. However, the multisystem nature of this disorder and the irreversibility of some manifestations mean that most patients require substantial medical support from many different specialists, even if they are receiving treatment. This article presents an overview of how to recognise, diagnose, and care for patients with MPS II. Particular focus is given to the multidisciplinary nature of patient management, which requires input from paediatricians, specialist nurses, otorhinolaryngologists, orthopaedic surgeons, ophthalmologists, cardiologists, pneumologists, anaesthesiologists, neurologists, physiotherapists, occupational therapists, speech therapists, psychologists, social workers, homecare companies and patient societies. TAKE-HOME MESSAGE: Expertise in recognising and treating patients with MPS II varies widely between countries. This article presents pan-European recommendations for the diagnosis and management of this life-limiting disease.

[Clinical manifestations, course and outcome of enzyme replacement therapy in Hungarian patients with Pompe's disease]. / Pompe-kór fenotípusvariációi, kórlefolyása és az enzimpótló kezelés eredményei: hazai tapasztalatok.

UNLABELLED: Pompe's disease is an autosomal recessive disease caused by deficiency of acid-alpha-glucosidase. AIMS AND METHODS: Authors analyzed the phenotype of 11 Hungarian patients with Pompe's disease and evaluated clinical parameters and response to enzyme replacement therapy during a long-term follow-up in 8 patients. RESULTS: One patient with atypical infantile form presented with cardiomyopathy and a very slow progression of motor deficits; after 2 years of enzyme replacement therapy no disability was present at the age 6 years. Another patient was asymptomatic at the age of 2.5 years. The adult onset form was characterized by slight to prominent limb-girdle myopathy with an age of onset between 20 and 50 years. In 3 of such cases respiratory insufficiency was also present. CONCLUSIONS: Hungarian patients with Pompe's disease presented with a wide phenotypic variability ranging from atypical early childhood form with slowly progressive course to late-onset limb-girdle myopathy with variable courses. Enzyme replacement therapy resulted in significant improvement in motor and respiratory functions in most of the patients.

Differences in the laboratory parameters of obese and healthy Hungarian children and their use in automatic classification.

Obesity is a rapidly spreading endemic in almost every country of the developed world, of which Hungary is no exception. By a joint research project we aim to deepen our understanding of obesity-associated, and especially obesity-predicting changes of clinical markers (anthropometric indices, body composition, laboratory results etc.) in children, especially in teenage population. This paper presents the preliminary results of our investigations which pertain to obesity-related alterations in routine blood test parameters. For that end, we examined 340 healthy and obese children. Results show that there are differences between the routine laboratory parameters of obese and healthy subjects that are both statistically significant and medically interesting. We point out these differences in a statistically precise way, and show a method which can be efficiently used to classify children based on their laboratory parameters. This result can be used later to develop a more realistic model to predict the risk of obesity.

[Cartilage-hair hypoplasia]. / Porc-haj hypoplasia.

Cartilage-hair hypoplasia is a rare, autosomal recessive primary immunodeficiency disorder characterized by predominantly T-cell deficiency and metaphyseal chondrodysplasia. The authors summarize current knowledge on molecular genetics, diagnostic characteristics and therapeutic options of this inherited immunodeficiency.