Guidance in social and ethical issues related to clinical, diagnostic care and novel therapies for hereditary neuromuscular rare diseases

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

Herediter neuromusculáris betegségek szűrése molekuláris genetikai módszerekkel hazai roma populációban = Screening of hereditary neuromuscular disorders in the Roma population living in Hungary

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

A spinalis izomatrophiát meghatározó survival motoneuron gének kvantitatív analízise = Quantitative analysis of the genes determining spinal muscular atrophy

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

A veleszületett dongaláb pathogenezisének kutatása

A SE Orthopédiai Klinikán 1998 és 2002 között 29 műtétre került idiopathiás és 15 AMC-s dongalábas gyermekből vettünk biopsziás ideg és izommintákat. Betegenként átlag 3 izommintavétel történt. Összesen 102 izmot és 34 n. suralist elemeztünk komplex kvalitatív és kvantitatív morfológiai módszerek alkalmazásával. A dongalábas izmok neuropathológiai eltéréseit izomfajtánként kiértékeltük és az AMC-s izmokban talált eltérésekkel összehasonlítottuk. Számítógéppel vezérelt idegmorfometriai elemzést adaptáltuk Magyarországra. A dongalábas nervus suralisokat CAMoN szoftverrel analizáltuk. Klinikai és morfológiai összehasonlító vizsgálatot végeztünk. Nem találtunk signifikáns összefüggést az egy vagy több lábizomban észlelt patológiai elváltozás súlyossága és a láb funkciója között. Megállapítottuk, hogy az irodalmi adatok és a mi adataink között nincs jelentős eltérés. A kutatás folyamán azonban olyan morfológiai ismeretekhez jutottunk, melyek alapján a kóreredetére vonatkozóan új elméletet fogalmaztunk meg. Felmérésünk az első teljes igényű morfológiai vizsgálatnak tekinthető Magyarországon. | Sural and nerve biopsies were obtained from 29 children with congenital clubfoot and 15 children with arthrogryposis multiplex congenita operated in period 1998 and 2002 at the Department of Orthopaedics, Semmelweis University. On average 3 muscle biopsies were taken out of every patients. 102 muscles and 34 sural nerves were studied with complex qualitative and quantitative morphological methods. Neuropathological alterations of all muscles types occured in the patients with idiopathic clubfoot were evaluated and compaired with muscle alterations of the arthrogryposis multiplex congenita. Computer assisted morphometric analysis was adapted in Hungary. Sural nerves of the clubfeet were analysed with CAMoN3 software. Clinical and morphological comparative examination was made. We found no significant correlation between seriousness of the pathological lesion observed in one or more muscles of feet and function of the foot. We found no significant difference between data of the other papers and own data. However in the course of the study we found new morphological infomations on base of those we put forward a new pathogenetic theory. Our survay is the first full exact morphological investigation in Hungary

Identification of a novel missense GLRA1 gene mutation in hyperekplexia: a case report

INTRODUCTION: Hereditary hyperekplexia is a neurological disorder characterized by excessive startle responses with violent jerking to noise or touch, stiffening of the trunk and limbs, clenching of the fists and attacks of a high-frequency trembling. Hyperekplexia has a heterogeneous genetic background with several identified causative genes and demonstrates both dominant and recessive inheritance. Mutations in the glycine receptor alpha 1 subunit gene occur in about 30 percent of hyperekplexia cases. CASE PRESENTATION: In this study, we report the case of a Hungarian boy whose abnormal movements, muscle stiffness and convulsions were first noted when he was 4 days old. Neurological and electrophysiological investigation suggested the clinical diagnosis of hyperekplexia. CONCLUSIONS: Direct sequencing of the coding regions and the flanking introns of the glycine receptor alpha 1 subunit gene revealed a novel heterozygous missense mutation (c.211A/T, p.Ile71Phe). Genetic screening of our patient's family revealed that the clinically unaffected parents and sister do not carry the mutation, suggesting that the identified sequence change is a de novo mutation. Since hyperekplexia can have severe consequences, including sudden infant death due to laryngospasm and cardiorespiratory failure, identification of the causative genetic alteration(s) of the disease is high priority. Such knowledge is necessary for prenatal diagnosis, which would allow informed family planning and greater parental sensitivity to hyperekplexia 1-associated risks