Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a developmental brain disorder characterized by an enlarged brain size with bilateral perisylvian polymicrogyria and a variable degree of ventriculomegaly. MPPH syndrome is associated with oromotor dysfunction, epilepsy, intellectual disability and postaxial hexadactyly. The molecular diagnosis of this disorder is established by the identification of a pathogenic variant in either AKT3, CCND2 or PIK3R2. Previously reported AKT3 variants are associated with various brain abnormalities and may lead to megalencephaly. MPPH syndrome is usually due to germline pathogenic AKT3 variants. Somatic mosaic pathogenic variants associated with hemimegalencephaly, which is similar to MPPH, have also been observed. A Hungarian Roma family with two half-siblings, which present with intellectual disability, dysmorphic features, epilepsy, brain malformations, and megalencephaly was studied. Whole exome sequencing (WES) analysis was performed. WES analysis revealed a heterozygous c.1393C > T p.(Arg465Trp) pathogenic missense AKT3 variant in both affected half-siblings. The variant was verified via Sanger sequencing and was not present in the DNA sample from the healthy mother, which was derived from peripheral blood, suggesting maternal germline mosaicism. In conclusion, this is the first report in which maternal germline mosaicism of a rare pathogenic AKT3 variant leads to autosomal dominantly inherited MPPH syndrome.

[DISEASE BURDEN OP DUCHENNE MUSCULAR DYSTROPHY PATIENTS AND THEIR CAREGIVERS]. / DUCHENNE-FÉLE IZOMDISZTRÓFIÁVAL ÉLO BETEGEK ÉS GONDOZÓIK BETEGSÉGTERHEI.

BACKGROUND AND PURPOSE: Data on the disease burden of Duchenne Muscular Dystrophy are scarce in Hungary. The aim of this study was to assess patients' and their caregivers' health related quality of life and healthcare utilisations. METHODS: A cross sectional survey was performed as part of the European BURQOL-RD project. The EQ-5D-5L and Barthel Index questionnaires were applied, health care utilisations and patients' informal carers were surveyed. RESULTS: One symptomatic female carer, 50 children (boys 94%) and six adult patients (five males) participated in the study, the latter two subgroups were included in the analysis. The average age was 9.7 (SD = 4.6) and 24.3 (SD = 9.8) years, respectively. Median age at time of diagnosis was three years. The average EQ-5D score among children and adults was 0.198 (SD = 0.417) and 0.244 (SD = 0.322), respectively, the Barthel Index was 57.6 (SD = 29.9) and 53.0 (SD = 36.5). Score of satisfaction with healthcare (10-point Likert-scale) was mean 5.3 (SD = 2.1) and 5.3 (SD = 2.9). 15 children were hospitalised in the past 12 months for mean 12.9 (SD = 24.5) days. Two patients received help from professional carer. 25 children (mean age 11.1, SD = 4.4 years) were helped/supervisied by principal informal carer (parent) for mean 90.1 (SD = 44.4) hours/week and further family members helped in 21 cases. Correlation between EQ-5D and Barthel Index was strong and significant (0.731; p < 0.01) as well as with informal care time (-0.770; p < 0.01), but correlation with satisfaction with health care was not significant (EQ-5D: 0.241; Barthel Index: 0.219; informal care: -0.142). CONCLUSION: Duchenne muscular dystrophy leads to a significant deterioration in the quality of life of patients. Parents play outstanding role in the care of affected children. This study is the first in the Central and Eastern European region that provides quality of life data in this rare disease for further health economic studies.

[FINANCING OF MEDICINES FOR TREATMENT OF RARE DISEASES OF THE NERVOUS SYSTEM. ORPHAN DRUGS IN RARE NEUROLOGICAL DISEASES]. / RITKA IDEGRENDSZERI BETEGSÉGEK KEZELÉSÉRE SZOLGALÓ GYÓGYSZEREK TÁMOGATÁSA. ÁRVA GYÓGYSZEREK RITKA NEUROLÓGIAI KÓRKEPÉKBEN.

OBJECTIVES: Nervous system involvement is expected up to 60-70% in case of rare diseases. This article aims to present the financial methods and expenditures of rare neurological diseases' orphan medicinal products being financed in the frame of Hungarian social insurance system in 2012. METHODS: The subsidized orphan medicines were selected on the Orphanet portal 2012 while orphans financed by compessionate use were provided by the Hungarian National Insurance Fund Administration (OEP) database. Three products exist without orphan designation, however those are intended for the treatment of rare neurological ailments. The medicines were categorized by financial methods and determined by costs. RESULTS: Numerically, out of 36 pieces of subsidized orphan or orphan criteria fulfilled medicines 17 were authorized for the treatments of rare neurological diseases in the year of 2012. Most of the drugs (14 pieces) were to be financed in the frame of compassionate use by the reimbursement system. The cost amount of social insurance for 387 rare neurological disease patients reached more than 4.5 billion HUF (1.4% of the total pharmaceutical budget in outpatient care). CONCLUSIONS: In Hungary half of the subsidized orphans are intended for the treatments of rare neurological ailments. 30% of the total amount of social insurance for rare diseases' medicinal treatments were used to subsidizing rare neurological disease patients in 2012. Most of the orphan medicines were to be financed in the frame of compassionate use by the reimbursement system for outpatient care. Consequently, a great deal of crucial problems occurred in relation with the unconventional subsidizing method. At the end of 2012 new financial methods have been elaborated and introduced in a pilot phase from 1 January 2013. In spite of the high cost commitment, nearly the entire diagnosed rare disease subpopulation has been provided with subsidized treatments in Hungary. In order to facilitate the access to orphan drugs, collaboration is needed between the financing agencies and the professional representatives for identifying the optimal form of financial subsidy.

Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype.

BACKGROUND: Kleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features - brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia. Some additional symptoms are observed in different percentage of the patients. Epilepsy is common symptom as well. The underlying cause of the syndrome is a submicroscopic deletion in the chromosomal region 9q34.3 or disruption of the euchromatin histone methyl transferase 1. CASE PRESENTATION: We describe two Hungarian Kleefstra syndrome patients, one with the classic phenotype of the syndrome, the diagnosis was confirmed by subtelomeric FISH. Meanwhile in our second patient beside the classic phenotype a new symptom - abnormal antiepileptic drug metabolic response - could be observed. Subtelomere FISH confirmed the 9q34.3 terminal deletion. Because of the abnormal drug metabolism in our second patient, we performed array CGH analysis as well searching for other rearrangements. Array CGH analysis indicated a large - 1.211 Mb -, deletion only in the 9q subtelomeric region with breakpoints ch9:139,641,471-140,852,911. CONCLUSIONS: This is the first report on Kleefstra syndrome in patients describing a classical and a complex phenotype involving altered drug metabolism.

Phenotypic variability in a Hungarian patient with the 4q21 microdeletion syndrome.

BACKGROUND: Interstitial deletions of 4q21 (MIM 613509) have already been reported in more than a dozen patients with deletions ranging from 2 to 15.1 Mb delineating a common phenotype including marked growth restriction, hypotonia, severe developmental delay with absent or delayed speech and distinctive facial features. A minimal critical region of 1.37 Mb accounting for the common features with 5 known genes (PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1) has been described so far. RESULTS: Here we report on a 5 year-old Hungarian girl presenting with severe developmental delay, good receptive language but absent spoken speech, short stature, dystrophy, hypotonia, distinctive facies including broad forehead, frontal bossing, downward slanting palpebral fissures, hypertelorism, hypoplastic ear-lobes, anteverted nostrils, short philtrum, small mouth, higharched palate, short, small hands and feet, distally narrowing fingers and clinodactyly. Cerebral MRI showed ventricular dilation and an increase in periventricular signal intensity. After extensive metabolic tests and exclusion of subtelomeric deletions array CGH analysis was performed using the Agilent Human Genome G3 SurePrint 8x60K Microarray (Agilent Technologies, USA), which detected a 4,85 Mb de novo interstitial deletion of 4q21.21-4q21.23. The clinical symptoms only partly overlap with reported 4q21 microdeletion cases. Among multiple annotated genes our patient is also haploinsufficient for the following genes: RASGEF1B being a strong candidate for the neurodevelopmental features and PRKG2 for severe growth delay. CONCLUSION: The first Hungarian case of 4q21 deletion adds to the phenotypic spectrum of this novel microdeletion syndrome and underlines the importance of array CGH to uncover the heterogeneous causes of intellectual disability.

It is time to take timing seriously in clinical genetics.

Observations made by molecular techniques on the genome along the individuals' lifetime indicate that the genome in somatic cells displays changes at molecular, cellular, and organismal levels. Timing of genetic events leading to somatic mosaicism and gene expression dynamism results in a highly important variable for comprehending the role of genetics in health and disease. Consideration of time in clinical genetics should be enthusiastically invested into research strategy, interpretation of the results, diagnostic routine, and particularly in ethical discussions.

Partial trisomy of the pericentromeric region of chromosome 5 in a girl with binder phenotype.

The patient reported here displayed most characteristic features of Binder syndrome (OMIM: 155050), a rare maxillonasal malformation with unknown etiology. She was sent for genetic evaluation at the age of 10 years because of facial dysmorphism and borderline intellectual disability. Cytogenetic analyses showed a de novo supernumerary small ring chromosome with a pericentromeric region of chromosome 5 in all lymphocytes. Array painting revealed that the marker contains a 20,950-kb genomic region comprising cytogenetic band 5p14.1q11.1. Additionally, 7 reports have been published in the literature with partial trisomy of chromosome 5 overlapping with our case. These 8 cases were analyzed for phenotype/genotype correlation which suggested that the maxillonasal anomalies of Binder phenotype and trisomy of the pericentromeric region of chromosome 5 may be in causal relationship. Future functional annotation studies of genes localized in this genomic region should take this into consideration. To the best of our knowledge, this is the first report on a patient with association of a chromosome abnormality and clinical characteristics of Binder phenotype.

[Cystic fibrosis -- disease burden and health-related quality of life of patients and their caregivers: results of the European BURQOL-RD survey in Hungary]. / Cystás fibrosissal élo betegek és gondozóik életminosége és betegségterhei: a BURQOL-RD európai felmérés magyarországi eredményei.

INTRODUCTION: Data on disease burden of cystic fibrosis in Hungary are scarce. AIM: To assess quality of life and resource utilisations of patients with cystic fibrosis. METHOD: In a cross-sectional survey (BURQOL-RD project), the EQ-5D-5L questionnaire was applied and healthcare utilisations were retrospectively surveyed. RESULTS: 110 patients participated in the study (age-groups, year: 0-13, N = 48; 14-17, N = 12; ≥18, N = 50), median age at the diagnosis was 1 year. EQ-5D-5L score in age-groups 18-24 and 25-34 was significantly lower than in the general population (p<0.05). 75 patients (68%) attended pulmonology care, 55 patients (50%) were hospitalised in the past 6 and 12 months, respectively, and 57 patients (52%) were taking dornase alpha. Five adult patients (10%) received help from non-professional caregiver. CONCLUSIONS: Cystic fibrosis leads to significant deterioration of quality of life. This study is the first from the Central Eastern European region that provides basic inputs for further health economic evaluations of cystic fibrosis care.

[Shift of focus in the financing of Hungarian drugs. Reimbursement for orphan drugs for treating rare diseases: financing of enzyme replacement therapy in Hungary]. / Hangsúlyeltolódások a hazai gyógyszerek finanszírozásában. A ritka betegségek kezelésére szolgáló árva gyógyszerek támogatása. Enzimpótló kezelések finanszírozása hazánkban.

Focusing on the benefits of patients with rare disease the authors analysed the aspects of orphan medicines financed in the frame of the Hungarian social insurance system in 2012 in order to make the consumption more rational, transparent and predictable. Most of the orphan drugs were financed in the frame of compassionate use by the reimbursement system. Consequently, a great deal of crucial problems occurred in relation to the unconventional subsidized method, especially in the case of the highest cost enzyme replacement therapies. On the base of the findings, proposals of the authors are presented for access to orphan drugs, fitting to the specific professional, economical and ethical aspects of this unique field of the health care system. The primary goal is to provide a suitable subsidized method for the treatment of rare disease patients with unmet medical needs. The financial modification of orphans became indispensible in Hungary. Professionals from numerous fields dealing with rare disease patients' care expressed agreement on the issue. Transforming the orphan medicines' financial structure has been initiated according to internationally shared principles.

Deletion of 4q28.3-31.23 in the background of multiple malformations with pulmonary hypertension.

The 4q deletion syndrome shows a broad spectrum of clinical manifestations consisting of key features comprising growth failure, developmental delay, craniofacial dysmorphism, digital anomalies, and cardiac and skeletal defects. We have identified a de novo interstitial distal deletion in a 9 month-old girl with growth failure, developmental delay, ventricular septum defect in the subaortic region, patent foramen ovale and patent ductus arteriosus, vascular malformation of the lung, dysgenesis of the corpus callosum and craniofacial dysmorphism using array-comparative genomic hybridization. This de novo deletion is located at 4q28.3-31.23 (136,127,048 - 150,690,325), its size is 14.56 Mb, and contains 8 relevant genes (PCDH18, SETD7, ELMOD2, IL15, GAB1, HHIP, SMAD1, NR3C2) with possible contributions to the phenotype. Among other functions, a role in lung morphogenesis and tubulogenesis can be attributed to the deleted genes in our patient, which may explain the unique feature of vascular malformation of the lung leading to pulmonary hypertension. With the detailed molecular characterization of our case with 4q- syndrome we hope to contribute to the elucidation of the genetic spectrum of this disorder.

[Hungarian national plan and strategy for rare diseases]. / Ritka Betegségek Nemzeti Terve.

The rarity of low prevalence diseases and the lack of information, research, diagnosis, treatment and expert availability may mean that the people affected do not benefit from the health resources and services they need. Rare diseases are considered to have little impact on society as a whole, yet they pose serious difficulties for sufferers and their families. By the end of the last century, two robust achievements in science and technology, i.e. the biotechnological and informatics revolutions, have created a real base for global approach to rare diseases by coordinating the capacities for health care, biomedical research and drug development and pooling the very limited resources available both nationally and transnationally. The European Commission has taken a number of actions which help patients and professionals to share expertise and information across borders with the objective of reducing the number of people suffering from these types of diseases. These actions together form the legal basis of the European Union policy on rare diseases. Orphan or rare diseases are now one of the priorities in the public health programmes in European Union. In 2009, the document "European Union Council Recommendation on an action in the field of rare diseases" was released with the main goal to provide national health authorities with supporting tools for the development and implementation of national plans and strategies for rare diseases by the end of 2013. This recommendation adopted by European Union Member States, allows common policy guidelines to be shared everywhere in Europe. By September 2013 the Hungarian National Plan for Rare Diseases, a health policy strategy until 2020 was finalized. The present report gives a short view on the document.

[Identifying rare genomic disorders with array comparative genomic hybridization in Hungary]. / Ritka genomikai betegségek azonosítása array komparatív genomhibridizációs módszerrel - elsoként Magyarországon.

INTRODUCTION: In the past decade the study of genomic disorders has received more interest. Array comparative genome hybridization is a widely spread diagnostic method in the research of genomic disorders. This method was implemented in the laboratory of the authors in 2012. AIM: This molecular cytogenetic method was first used to examine patients with complex developmental disorders in whom no genetic background was identified by traditional methods. METHOD: The authors complemented traditional diagnostic methods with array comparative genome hybridization, which has not been used in routine diagnostics in Hungary so far. RESULTS: Using this novel method the authors were able to identify genomic alterations in 7 out of 18 patients with complex developmental disorders. They found de novo alterations in 6 out of 7 patients, which were most likely causative in the development of the phenotype, while in one case they detected a familial genomic alteration. This method helped the authors to determine the breakpoint of genomic variation in their patients and delineate the affected genes contributing to the phenotype. CONCLUSIONS: These results call attention to the usefulness of next generation diagnostic methods available in the laboratory of the authors.

[Diagnostic delay of rare diseases in Europe and in Hungary]. / A ritka betegségek diagnosztikájának késedelme Európában és Magyarországon.

UNLABELLED: The long diagnostic delay is a characteristic problem of rare disease patients. AIMS: Diagnostic delay was studied in 14 countries by EurordisCare2 involving patient organizations. METHODS: 252 Hungarian patients (cystic fibrosis; Duchenne muscular dystrophy; tuberous sclerosis, retinitis pigmentosa, and Williams' syndrome) completed the questionnaires. RESULTS: The median delay was longer in Hungary than in Europe (cystic fibrosis: 227 vs. 45 days; Duchenne muscular dystrophy: 467 vs. 360 days; tuberous sclerosis: 155 vs. 120 days). Patients' experience was similar in Hungary and in Europe. The proportion of misdiagnosis was 30.8% in Hungary (Europe: 41%), 34.8% of patients got diagnosis outside of living place region (EU: 26%) and 19.9% of them found the personal expenses too high (EU: 10%). Delivery of the diagnosis was unnecessary according to 27.4% of Hungarian patients (EU: 35%). CONCLUSIONS: The qualitative survey demonstrated that the problems with the diagnosis of rare diseases are widespread, the identified areas require interventions, and it confirmed the importance of centralized care.

Jumping translocation of 15q24-qter resulting in partial trisomy: a case report.

We report on a jumping translocation with five different cell lines detected in four tissues in a 2-year-old patient. This rare type of chromosomal abnormality (not more than 30 cases published so far) proved to be a series of non-reciprocal translocations of the 15q24-qter donor chromosome segment to the telomeric region of chromosomes 5q, 10q, 16q and 19p, respectively. The process, in addition to a few cells without translocation, resulted in partial trisomy of 15q24-qter which was associated with somatic overdevelopment in the patient, with hemihypertrophy and minor anomalies. The phenotype of our patient was different from that of the other two patients found in the literature having the same donor chromosome segment involved in a similar rearrangement. Possibly, the difference in the phenotype lies in the various ratios of somatic mosaicism with five cell lines, in particular the presence of normal one which is extremely rare in patients with jumping translocation. Here we discuss the various ways on how the rearrangement could arise.

Hypothesis: epigenetic effects will require a review of the genetics of child development.

The worldwide prevalence of developmental disorders in children including birth defects, mental dysfunctions, as well as early-life abnormalities leading to the predisposition for adult diseases is one of the major unsolved problems in medicine and societies. Child development is influenced by both genes and the environment; however, the role of the environment is more emphatic, since the genome is most vulnerable to environmental factors during early development due to the high cellular differentiation rate. This inherent characteristic of child development lays the stress on a probabilistic rather than a deterministic view with regard to the manifestation of developmental disorders. Therefore, the analysis of gene-environment interactions in child development, beyond providing information about the developmental disorders of children, has an additional value that contributes to the knowledge on epigenetics in general and the interface between the genome and the environment playing a significant part in causing a wide range of diseases, in particular. The present study, rather than attempting to give a complete overview on epigenetics, is intended to illustrate that the issue of child development is an attractive target to extend the scope of genetics both in health and disease. Since the results might be extrapolated to the understanding of the pathomechanism of many age-dependent multifactorial diseases, the importance of studying gene-environment interaction in child development also lies in identifying new and potentially modifiable risk factors for diseases that are, therefore, of public health significance.

Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations.

Rett syndrome (RTT) is characterized by a relatively specific clinical phenotype. We screened 152 individuals with RTT phenotype. A total of 22 different known MECP2 mutations were identified in 42 subjects (27.6%). Of the 22 mutations, we identified 7 (31.8%) frameshift-causing deletions, 4 (18.2%) nonsense, 10 (45.5%) missense mutations and one insertion (4.5%). The most frequent pathologic changes were: p.Thr158Met (14.2%) and p.Arg133Cys (11.9%) missense, and p.Arg255Stop (9.5%) and p.Arg294Stop (9.5%) nonsense mutations. We also detected the c.925C >T (p.Arg309Trp) mutation in an affected patient, whose role in RTT pathogenesis is still unknown. Patients without detectable MECP2 defects were screened for mutations of cyclin-dependent kinase-like 5 (CDKL5) gene, responsible for the early-onset variant of RTT. We discovered two novel mutations: c.607G >T resulting in a termination codon at aa203, disrupting the catalytic domain, and c.1708G >T leading to a stop at aa570 of the C terminus. Both patients with CDKL5 mutation presented therapy-resistant epilepsy and a phenotype fitting with the diagnosis of early-onset variant of RTT. No FOXG1 mutation was detected in any of the remaining patients. A total of 110 (72.5%) patients remained without molecular genetic diagnosis that necessitates further search for novel gene mutations in this phenotype. Our results also suggest the need of screening for CDKL5 mutations in patients with Rett phenotype tested negative for MECP2 mutations.

[First decade of post-genomic era. Hopes, disappointments, new answers]. / Az elso posztgenom évtized az orvostudományban.

The first decade after the announcement of the draft sequence of human genome has brought spectacular advances in basic science, however, the fact that human health did not benefit that much caused disappointment, as well. In order to explore the causes of the absence of revolution in medicine, beside the extension of research strategy new conception about the role of genetics in health and disease should also be considered. In order to resolve the disappointments, the author recommends a new perspective to view the role of genetics in health and diseases. When the contribution of recent research results is evaluated not only in the original transgenerational aspect but also in developmental aspect of genetics, some questions about the genomic medicine might be clearer. This review discusses the advantage of this concept in (1) clinical interpretation of the findings of molecular technologies, (2) understanding the novel concept of gene-environment relationship, and (3) organizing the health service delivery through reasonable professional competences. The developmental aspect of genetics is suggested to consider in future research strategy, interpretation of the results, understanding the role of genes and environment in health and disease, and construction of health service delivery system in genomic medicine.

The medical geneticist as expert in the transgenerational and developmental aspects of diseases.

The increased knowledge of genetics has raised new questions, and confusion has been growing about the evaluation of the results of recent research and the role of geneticists in the genomic medicine. If we focus on transgenerational and developmental aspects of diseases, the answers might be more evident.

The genetics and clinical characteristics of constitutional ring chromosomes.

Constitutional ring chromosomes are generally believed to be the result of de novo breakage of both end-segments of a chromosome during meiosis or early postzygotic mitosis, with the ends joining to give a continuous ring. This mechanism presumes the loss of some genetic material during ring formation. Ring chromosomes thus represent deletions of genetic material. But an accurate delineation of identifiable syndromes is not possible in the majority of cases even when the patients have apparently identical ring chromosomes and phenotypic charactristics. In many patients with a ring, independent of the chromosome involved, there is a similar clinical phenotype characterized by the presence of extreme growth failure without major malformation, with only a few or no minor anomalies and mild to moderate mental retardation. This phenotype is generally referred to as "ring syndrome." The description of the features of this chromosome anomaly has to-date been based on standard cytogenetic banding techniques. However, recent observations made with novel molecular techniques have brought new insights into the nature of ring chromosomes, contributing to the understanding of the genetic and clinical consequences. This review examines constitutional rings and is based on the generally accepted "classical" knowledge but also takes into consideration new molecular findings.