Agnes Herczegfalvi

The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, ENG, United Kingdom

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Publications (27)63.11 Total impact

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    ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene on chromosome 5. SMA shows a wide range of clinical severity, with SMA type I patients often dying before 2 years of age, whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here, we describe the design, setup and utilisation of the TREAT-NMD national SMA patient registries characterised by a small, but fully standardised set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care. Our study included 5,068 SMA patients in 25 countries. A total of 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high-income countries with comparable wealth and health care systems. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning.
    Journal of Neurology 10/2013; · 3.58 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. While many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence < 5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately, global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardised patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organisations and industry. This article is protected by copyright. All rights reserved.
    Human Mutation 08/2013; · 5.21 Impact Factor
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    ABSTRACT: Drug trials in children engage with many ethical issues, from drug-related safety concerns to communication with patients and parents, and recruitment and informed consent procedures. This paper addresses the field of neuromuscular disorders where the possibility of genetic, mutation-specific treatments, has added new complexity. Not only must trial design address issues of equity of access, but researchers must also think through the implications of adopting a personalised medicine approach, which requires a precise molecular diagnosis, in addition to other implications of developing orphan drugs. It is against this background of change and complexity that the Project Ethics Council (PEC) was established within the TREAT-NMD EU Network of Excellence. The PEC is a high level advisory group that draws upon the expertise of its interdisciplinary membership which includes clinicians, lawyers, scientists, parents, representatives of patient organisations, social scientists and ethicists. In this paper we describe the establishment and terms of reference of the PEC, give an indication of the range and depth of its work and provide some analysis of the kinds of complex questions encountered. The paper describes how the PEC has responded to substantive ethical issues raised within the TREAT-NMD consortium and how it has provided a wider resource for any concerned parent, patient, or clinician to ask a question of ethical concern. Issues raised range from science related ethical issues, issues related to hereditary neuromuscular diseases and the new therapeutic approaches and questions concerning patients rights in the context of patient registries and bio-banks. We conclude by recommending the PEC as a model for similar research contexts in rare diseases.
    PLoS currents. 01/2013; 5.
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    ABSTRACT: Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of the D4Z4 repeat region on 4q35. In addition, epigenetic modifying factors play a role in the complex pathomechanism of the disease. Aims: Introduction of a new diagnostic panel in Hungary for the extended molecular analysis of the disease which also provides new insights into the pathomechanism. Methods: In total, DNA samples of 185 clinically diagnosed FSHD patients and 71 asymptomatic relatives were analyzed by EcoRI and BlnI restriction digestion and Southern blot technique with probe p13-E11. Further investigations of the 4q35 alleles associated with the FSHD phenotype utilized qA and qB probes and a restriction analysis of the proximal D4Z4 unit by detecting a G/C SNP and the methylation status. Results: From the patients analyzed 115 had the D4Z4 repeat contraction, whereas from 71 asymptomatic family members five harbored the pathogenic fragment size. In eight families, prenatal testing had to be offered with an outcome of four affected fetuses. Methylation test was performed in 31 genetically confirmed FSHD patients and hypomethylation status was detected in all cases. All the 115 confirmed patients had 4qA alleles with the G polymorphism. Translocation events between 4q35 and the homologous 10q26 regions were also detected. Conclusion: Molecular diagnosis of FSHD became a routine approach in Hungary thus supporting the work of the clinicians, improving quality of life and genetic counseling of the affected families. The provided results from this research suggest that FSHD is associated with complex epigenetic disease mechanisms.
    Orvosi Hetilap 09/2011; 152(39):1576-85.
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    ABSTRACT: 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.
    Orvosi Hetilap 09/2011; 152(39):1569-75.
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    ABSTRACT: Mutations in the nebulin gene are the main cause of autosomal recessive nemaline myopathy, with clinical presentations ranging from mild to severe disease. We have previously reported a nonspecific distal myopathy caused by homozygous missense mutations in the nebulin gene in six Finnish patients from four different families. Here we describe three non-Finnish patients in two unrelated families with distal nemaline myopathy caused by four different compound heterozygous nebulin mutations, only one of which is a missense mutation. One of the mutations has previously been identified in one family with the severe form of nemaline myopathy. We conclude that nemaline myopathy and distal myopathy caused by nebulin mutations form a clinical and histological continuum. Nemaline myopathy should be considered as a differential diagnosis in patients presenting with an early-onset predominantly distal myopathy.
    Neuromuscular Disorders 07/2011; 21(8):556-62. · 3.46 Impact Factor
  • European Journal of Paediatric Neurology - EUR J PAEDIATR NEUROL. 01/2011; 15.
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    ABSTRACT: Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting approximately one in 10,000 live births and with a carrier frequency of approximately one in 35. The disease is caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN1 and SMN2 genes. Due to a single nucleotide polymorphism in exon 7, SMN2 produces less full-length transcript than SMN1 and cannot prevent neuronal cell death at physiologic gene dosages. On the other hand, the copy number of SMN2 affects the amount of SMN protein produced and the severity of the SMA phenotype. SMN gene dosage analysis can determine the copy number of SMN1 to detect carriers and patients heterozygous for the absence of SMN1 exon 7. This study provides copy number estimation of SMN1 gene by real-time PCR technique in 56 SMA type I., II., III. patients, 159 parents and healthy relatives and in 152 undefined SMA patients. Among the family members, 91 carriers have been detected and in 56 patients homozygous deletion of SMN1 exon 7 has been confirmed. Moreover, in 12 patients compound heterozygosity of SMN1 exon 7 mutation has been detected, thus providing the possible diagnosis of SMA. In 94 patients, copy number of SMN2 has also been evaluated and a good correlation has been found with the phenotype of the disease. Due to the genetic complexity and the high carrier frequency, accurate risk assessment and genetic counselling are particularly important for the families. These new results provide improvement of the diagnostic service in SMA in Hungary with focus on proper genetic counselling and possible enrolment of the patients in future therapeutic interventions.
    Ideggyógyászati szemle 11/2009; 62(11-12):390-7. · 0.35 Impact Factor
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    ABSTRACT: A comprehensive study of the Hungarian Duchenne/Becker muscular dystrophy (DMD/BMD) families is presented. Deletions in the hot spots regions were identified by multiplex PCR, whereas rare mutations were detected by Southern blot and multiplex ligation-dependent probe amplification (MLPA) techniques. DMD/BMD disease was confirmed and exact deletion borders were determined in 19 out of 135 affected males using multiplex PCR. Additional exons involved as well as rare exon deletions were identified by MLPA in 71 male patients, whereas duplications were observed in seven patients. In two DMD patients, the entire dystrophin gene and adjacent genes were deleted. Out of the 95 female relatives, 41 proved to be carriers, including three manifesting carrier females. Using MLPA method, a large portion of the Hungarian DMD/BMD patients and their female relatives were exactly genotyped. For the first time, the incidence and prevalence of asymptomatic and symptomatic female carriers in Hungary was estimated.
    Neuromuscular Disorders 01/2009; 19(2):108-12. · 3.46 Impact Factor
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    ABSTRACT: Muscular dystrophies are a genetically heterogeneous group of degenerative muscle disorders. This article focuses on two severe forms of muscular dystrophies and provides genetic data for a large cohort of Hungarian patients diagnosed within the last few years by the authors. The Duchenne/Becker muscular dystrophy (DMD/BMD) is caused by mutations in the dystrophin gene, which is located on chromosome Xp21. The genetic analysis of dystrophin is usually performed by multiplex polymerase chain reaction (PCR), which detects approximately 95% of all deletions but does not distinguish between one and two copies of the exons investigated. The present work, therefore, concentrates on the improvement of the diagnostic panel for the analysis of DMD/BMD in Hungary. Radioactively labelled cDNA probes, encompassing the whole dystrophin gene detect all the deletions and the analysis is quantitative. In addition, the new multiple ligation-dependent probe amplification (MLPA) technique was recently introduced that enabled more reliable and faster quantitative detection of the entire dystrophin gene. The genomic basis of facioscapulohumeral muscular dystrophy (FSHD) is associated with contraction of the D4Z4 repeat region in the subtelomere of chromosome 4q. In case of FSHD, molecular genetic criteria still have to be improved because of the complexity of the disorder.
    Acta Physiologica Hungarica 01/2009; 95(4):405-18. · 0.88 Impact Factor
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    ABSTRACT: Severe myoclonic epilepsy in infancy (SMEI; Dravet's syndrome) is a malignant epilepsy syndrome characterized by prolonged febrile hemiconvulsions or generalized seizures starting in the first year of life. Later on myoclonic, atypical absence, and complex partial seizures appear. When one of these seizure forms is lacking the syndrome of borderline SMEI (SMEB) is defined. Psychomotor delay resulting in mental retardation is observed during the second year of life. In most patients a de novo sodium channel alpha-1 subunit (SCN1A) mutation can be identified. By reviewing the clinical, laboratory, and neuroimaging data of our SMEI patients diagnosed between 2000 and 2008, we would like to share our experiences in this rare but challenging syndrome. Our results will facilitate the earlier and better diagnosis of Hungarian children with SMEI. Clinical, EEG, MRI and DNA mutation data of 20 SMEI patients treated in the Bethesda Children's Hospital (Budapest) were reviewed. The first seizure appeared at age 6.3+/-3.0 months. At least one of the first two seizures were complex febrile seizures in 19/20 and unilateral seizures in 12/20 children. All children except for one showed hemiconvulsions at least once; all children had seizures lasting longer than 15 minutes. Eight of twenty patients had SMEB. DNA diagnostics identified an SCN1A mutation in 17 patients (6 missense, 4 nonsense, 4 frameshift, 2 splice site, 1 deletion) while 3 children had no mutation. Early diagnosis of SMEI is important for the avoiding unnecessary examinations and false therapies as well as for genetic counselling. Typical symptoms of SMEI are early and prolonged febrile hemiconvulsions with neurological symptoms, mental retardation and secondary seizure types later on. The presence of an SCN1A mutation supports the diagnosis. We propose the availability of molecular diagnostics and stiripentol therapy for SMEI children in Hungary
    Ideggyógyászati szemle 12/2008; 61(11-12):402-8. · 0.35 Impact Factor
  • Agnes Herczegfalvi, Henriett Pikó, Veronika Karcagi
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    ABSTRACT: Recent medical genetic research has identified a number of novel, or previously known, but rare conditions, caused by private founder mutations. The Finnish and Ashkenazi Jew populations provide the best examples for identifying genes in unique genetic disorders. In these populations, research efforts and high-level medical services resulted in intense improvements of medical care and in organization of population-based screening programs. Hereditary disorders of the Roma populations are known for a long time. The genetic background of these diseases has been established by extensive molecular genetic studies. The Romas represent 6% of the Hungarian population and live under extremely bad health conditions. Therefore, our aim was to map the incidence of the hereditary neuromuscular disorders among the Hungarian Roma population. Moreover, we intended to provide proper information, genetic counseling and possible prevention strategies for the families at risk, which should represent a primer task in public health. Because of our experience in neuromuscular disorders, we choose six, frequent, autosomal recessive disorders for these clinical and genetic studies: hereditary motor and sensory neuropathy type Lom (HMSNL), hereditary motor and sensory neuropathy type Russe (HMSNR), congenital cataracts facial dysmorphism syndrome (CCFDN), limb-girdle muscular dystrophy 2C (LGMD2C), congenital myasthenic syndrome (CMS) and spinal muscular atrophy (SMA). Following identification of the founder mutations, the possibility of prenatal diagnosis and carrier screening for family members will contribute to the decrease of the recurrence risk for these severe, mostly untreatable disorders.
    Ideggyógyászati szemle 12/2008; 61(11-12):426-30. · 0.35 Impact Factor
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    ABSTRACT: Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COLQ) cause synaptic basal-lamina associated CMS with end-plate AChE deficiency. Here we present the clinical and molecular genetic findings of 22 COLQ-mutant CMS patients, carrying a total of 20 different COLQ mutations, 11 of them had not previously been reported. Typically, patients with esterase deficiency suffer from a severe, progressive weakness with onset at birth or in early infancy. In addition, patients with a late onset showing a mild course of disease are described. AChE inhibitor therapy, beneficial for other forms of CMS, is of no effect in cases of esterase deficiency. The large cohort of COLQ patients studied here enabled us to define additional clinical presentations associated with COLQ mutations that differ from the 'classical' phenotypes: several patients with disease onset at birth or in early infancy presented an unexpected, mild disease course without significant progression of weakness. Moreover, many patients had clinical features reminiscent of limb-girdle CMS with mutations in the recently discovered DOK7 gene, including sparing of eye movements and a predominantly proximal muscle weakness. There was no long-term objective benefit from esterase inhibitors treatment in COLQ patients. Surprisingly, a short-term beneficial effect was observed in four patients and a Tensilon test was positive in two. Treatment with ephedrine was efficient in all five cases where it was administered. The variability of phenotypes caused by COLQ mutations, the divergence from the previously published classical clinical features and an initial positive response to esterase inhibitors in some patients may obscure AChE deficiency as the molecular cause of the disease and delay the start of appropriate therapy. Moreover, overlap with other CMS subtypes and potentially absence of a repetitive compound muscle action potential should be considered in the diagnosis of COLQ-mutated patients.
    Brain 04/2008; 131(Pt 3):747-59. · 10.23 Impact Factor
  • V. Karcagi, A. Herczegfalvi, L. Timar
    Neuromuscular Disorders - NEUROMUSCULAR DISORD. 01/2008; 18(9):762-762.
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    ABSTRACT: Duchenne/Becker muscular dystrophy is a severe, recessive, X-linked neuromuscular disease with an incidence of 1/3500 (Duchenne type) and 1/30,000 (Becker type) in newborn boys. The gene responsible for the Duchenne/Becker muscular dystrophy phenotype is located at Xp21 and its 427 kD protein product is called dystrophin. Deletions, point mutations and rarely duplications can occur almost anywhere in the DMD gene, which makes the molecular diagnosis difficult. Multiple polymerase chain reactions detect 95% of deletions in affected males [2, 4], but are not suitable for carrier detection in female relatives. Southern-blot analysis with six different cDNA probes covers the whole 14 kb dystrophin transcript and allows the detection of female carriers by comparing the intensity of the signals corresponding to the different exons. This method is time consuming compared to the newly introduced multiple ligation-dependent probe amplification method. Multiple ligation-dependent probe amplification is a method suitable for relative quantification of several DNA sequences in one reaction. The authors report results on 93 cases where the carrier status was analysed simultaneously by cDNA hybridisation and multiple ligation-dependent probe amplification technique. In 42 cases the carrier state was confirmed and in this carrier population the authors additionally detected two cases with duplication, two cases with one copy of the whole dystrophin gene and three manifest carrier females. On the basis of these results the MLPA technique, which has been newly introduced in Hungary, proved to be a sensitive and quick method for the detection of carrier state in the DMD/BMD disease. Moreover, the exact deletion or duplication border can be detected and as a result, prediction on the phenotype can be given. This will provide the right therapeutic intervention for the affected patients in the future.
    Orvosi Hetilap 01/2008; 148(51):2403-9.
  • V. Karcagi, H. Piko, J. Balog, B. Nagy, A. Herczegfalvi
    European Journal of Paediatric Neurology 09/2007; 11:76-76. · 1.98 Impact Factor
  • European Journal of Paediatric Neurology 09/2007; 11:113-113. · 1.98 Impact Factor
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    ABSTRACT: Dok ('downstream-of-kinase') family of cytoplasmic proteins play a role in signalling downstream of receptor and non-receptor phosphotyrosine kinases. Recently, a skeletal muscle receptor tyrosine kinase (MuSK)-interacting cytoplasmic protein termed Dok-7 has been identified. Subsequently, we and others identified mutations in DOK7 as a cause of congenital myasthenic syndromes (CMS), providing evidence for a crucial role of Dok-7 in maintaining synaptic structure. Here we present clinical and molecular genetic data of 14 patients from 12 independent kinships with 13 different mutations in the DOK7 gene. The clinical picture of CMS with DOK7 mutations is highly variable. The age of onset may vary between birth and the third decade. However, most of the patients display a characteristic 'limb-girdle' pattern of weakness with a waddling gait and ptosis, but without ophthalmoparesis. Respiratory problems were frequent. Patients did not benefit from long-term therapy with esterase inhibitors; some of the patients even worsened. DOK7 mutations have emerged as one of the major genetic defects in CMS. The clinical picture differs significantly from CMS caused by mutations in other genes, such as the acetylcholine receptor (AChR) subunit genes. None of the patients with DOK7 mutations had tubular aggregates in the muscle biopsy, implying that 'limb-girdle myasthenia (LGM) with tubular aggregates' previously described in literature may be a pathogenic entity distinct from CMS caused by DOK7 mutations.
    Brain 07/2007; 130(Pt 6):1497-506. · 10.23 Impact Factor
  • Neuromuscular Disorders - NEUROMUSCULAR DISORD. 01/2007; 17(9):856-856.

Publication Stats

214 Citations
63.11 Total Impact Points

Institutions

  • 2013
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      • Institute of Genetic Medicine
      Newcastle upon Tyne, ENG, United Kingdom
  • 2011
    • Heim Pal Children'S Hospital
      Budapeŝto, Budapest, Hungary
  • 2008–2009
    • National Institute of Environmental Health, Hungary
      Budapeŝto, Budapest, Hungary
  • 2004–2009
    • Bethesda Children Hospital Budapest
      Budapeŝto, Budapest, Hungary
  • 2007–2008
    • Ludwig-Maximilian-University of Munich
      • Department of Neurology
      München, Bavaria, Germany