Peter Balicza

MSTO1 is a cytoplasmic pro-mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans.

The protein MSTO1 has been localized to mitochondria and linked to mitochondrial morphology, but its specific role has remained unclear. We identified a c.22G > A (p.Val8Met) mutation of MSTO1 in patients with minor physical abnormalities, myopathy, ataxia, and neurodevelopmental impairments. Lactate stress test and myopathological results suggest mitochondrial dysfunction. In patient fibroblasts, MSTO1 mRNA and protein abundance are decreased, mitochondria display fragmentation, aggregation, and decreased network continuity and fusion activity. These characteristics can be reversed by genetic rescue. Short‐term silencing of MSTO1 in HeLa cells reproduced the impairment of mitochondrial morphology and dynamics observed in the fibroblasts without damaging bioenergetics. At variance with a previous report, we find MSTO1 to be localized in the cytoplasmic area with limited colocalization with mitochondria. MSTO1 interacts with the fusion machinery as a soluble factor at the cytoplasm‐mitochondrial outer membrane interface. After plasma membrane permeabilization, MSTO1 is released from the cells. Thus, an MSTO1 loss‐of‐function mutation is associated with a human disorder showing mitochondrial involvement. MSTO1 likely has a physiologically relevant role in mitochondrial morphogenesis by supporting mitochondrial fusion.

Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with unknown genetic and environmental causation in most of the affected individuals. On the other hand, there are a growing number of ASD-associated syndromes, where the exact genetic origin can be revealed. Here we report a method, which included the targeted next generation sequencing (NGS) and filtering of 101 ASD associated genes, followed by database search. Next, RNA sequencing was used to study the region of interest at the transcriptional level. Using this workflow, we identified a de novo mutation in the euchromatic histone-lysine N-methyltransferase 1 gene (EHMT1) of an autistic patient with dysmorphisms. Sequencing of EHMT1 transcripts showed that the premature termination codon (Trp1138Ter) created by a single nucleotide change elicited nonsense-mediated mRNA decay, which led to haploinsufficiency already at the transcriptional level. Database and literature search provided evidence that this mutation caused Kleefstra syndrome (KS), which was confirmed by the presence of the disorder-specific phenotype in the patient. We provide a proof of principle that the implemented method is capable to elucidate the genetic etiology of individuals with syndromic autism. The novel mutation detected in the EHMT1 gene is responsible for KSs symptoms. In addition, further genetic factors might be involved in the ASD pathogenesis of the patient including a missense DPP6 mutation (Arg322Cys), which segregated with the autistic phenotype within the family.

The European Association of Young Neurologists and Trainees in 2014: the dream of a united European neurology enters the limelight

The European Association of Young Neurologists and Trainees (EAYNT) was founded in the year 2000 by enthusiastic junior colleagues realizing that their voice was not present and their interests insufficiently advocated within major European bodies. The association continues to be independent and remains unrivalled in lobbying for the interests of European junior neurologists [1]. We have established an excellent reputation for stringent work since the foundation [2]. Indeed, the success story and sturdiness of the organization may be traced back to its independence, from both pharmaceutical companies and bodies led by senior colleagues. On the other hand, the EAYNT has been able to attract highly motivated and dynamic officers over the years who pursued their non-profit work without compromise. The EAYNT office team for 2014 was elected at the General Assembly during the European Federation of Neurological Sciences (EFNS) World Federation of Neurology (WCN) congress 2013 in Vienna. Details of the officers who were elected are listed in Table 1. Additional support is provided by office members at large, who were assigned for specific tasks (Table 2). This article aims to highlight recent developments in the interests of European junior neurologists and standpoints of the EAYNT. Moreover, key events organized by the EAYNT in 2014 are described for the purpose of inviting junior colleagues to participate and get actively involved in future activities of the EAYNT. Regular updates and deadlines for applications can be found on the homepage of the organization (www.eaynt.org) and the Facebook blog (European Young Neurologists). Activities and priorities in 2014

Genetic background of the hereditary spastic paraplegia phenotypes in Hungary - An analysis of 58 probands

BACKGROUND Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases with progressive lower limb spasticity and weakness. The aim of this study is to determine the frequency of different SPG mutations in Hungarian patients, and to provide further genotype-phenotype correlations for the known HSP causing genes. METHODS We carried out genetic testing for 58 probands with clinical characteristics of HSP. For historical reasons, three different approaches were followed in different patients: 1) Sanger sequencing of ATL1 and SPAST genes, 2) whole exome, and 3) targeted panel sequencing by next generation sequencing. RESULTS Genetic diagnosis was established for 20 probands (34.5%). We detected nine previously unreported mutations with high confidence for pathogenicity. The most frequently affected gene was SPAST with pathogenic or likely pathogenic mutations in 10 probands. The most frequently detected variant in our cohort was the SPG7 p.Leu78*, observed in four probands. Altogether five probands were diagnosed with SPG7. Additional mutations were detected in SPG11, ATL1, NIPA1, and ABCD1. CONCLUSION This is the first comprehensive genetic epidemiological study of patients with HSP in Hungary. Next generation sequencing improved the yield of genetic diagnostics in this disease group even when the phenotype was atypical. However, considering the frequency of the HSP-causing gene defects, SPG4, the most common form of the disease, should be tested first to be cost effective in this economic region.

European Association of Young Neurologists and Trainees in 2016: the year of changes and the introduction of the Residents and Research Fellows section of the European Academy of Neurology

V. Papp, P. Balicza, A. Sauerbier, L. Klingelh€ ofer, P. Zis, O. Gyorfi and A. Macerollo Department of Neurology, Aarhus University Hospital, Aarhus, Denmark, Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary, King’s College London and King’s College Hospital, Neurology, London, UK, Department of Neurology, Technical University Dresden, Dresden, Germany, Department of Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK, Department of Neurology, Nyiro Gyula Hospital National Institute of Psychiatry and Addiction, Budapest, Hungary and Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK

Insufficient global health education in European neurological post-graduate training: a European Association of Young Neurologists and Trainees survey.

The awareness of and demand for neurological expertise in global health (GH) have emerged over recent years and have become more relevant due to the increasing numbers of refugees from developing countries arriving in Europe. This study aimed to assess the provision of GH education and opportunities for international exchange during neurology post‐graduate training with a focus on Europe.

European junior neurologists perceive various shortcomings in current residency curricula

Whether residency programs in Europe and neighboring countries appropriately prepare one for clinical practice is a matter of discussion.

Mitochondrial dysfunction and autism: comprehensive genetic analyses of children with autism and mtDNA deletion

BackgroundThe etiology of autism spectrum disorders (ASD) is very heterogeneous. Mitochondrial dysfunction has been described in ASD; however, primary mitochondrial disease has been genetically proven in a small subset of patients. The main goal of the present study was to investigate correlations between mitochondrial DNA (mtDNA) changes and alterations of genes associated with mtDNA maintenance or ASD.MethodsSixty patients with ASD and sixty healthy individuals were screened for common mtDNA mutations. Next generation sequencing was performed on patients with major mtDNA deletions (mtdel-ASD) using two gene panels to investigate nuclear genes that are associated with ASD or are responsible for mtDNA maintenance. Cohorts of healthy controls, ASD patients without mtDNA alterations, and patients with mitochondrial disorders (non-ASD) harbouring mtDNA deletions served as comparison groups.ResultsMtDNA deletions were confirmed in 16.6% (10/60) of patients with ASD (mtdel-ASD). In 90% of this mtdel-ASD children we found rare SNVs in ASD-associated genes (one of those was pathogenic). In the intergenomic panel of this cohort one likely pathogenic variant was present. In patients with mitochondrial disease in genes responsible for mtDNA maintenance pathogenic mutations and variants of uncertain significance (VUS) were detected more frequently than those found in patients from the mtdel-ASD or other comparison groups. In healthy controls and in patients without a mtDNA deletion, only VUS were detected in both panel.ConclusionsMtDNA alterations are more common in patients with ASD than in control individuals. MtDNA deletions are not isolated genetic alterations found in ASD; they coexist either with other ASD-associated genetic risk factors or with alterations in genes responsible for intergenomic communication. These findings indicate that mitochondrial dysfunction is not rare in ASD. The occurring mtDNA deletions in ASD may be mostly a consequence of the alterations of the causative culprit genes for autism or genes responsible for mtDNA maintenance, or because of the harmful effect of environmental factors.

The European Association of Young Neurologists and Trainees in 2015: strengthening collaboration with the European Academy of Neurology

The European Association of Young Neurologists and Trainees (EAYNT) was founded in the year 1999 with the purpose of independently representing the interests of neurologists at the beginning of their career. This has been maintained by manifold clinical and scientific activities throughout Europe. Interested readers are referred to previous publications [1–6]. In 2014, the European Academy of Neurology (EAN) was founded during the Joint Congress of European Neurology in Istanbul [7]. In answer to the invitation of EAN, the previous office (2014) and the newly elected EAYNT office for 2015 (Tables 1 and 2) came to the consensus that EAYNT must also move forward and build a closer relationship with the EAN. Further details about this new cooperation will be made at the general assembly during the first congress of the EAN. The exact date will be announced on our webpage www.eaynt.org. Here, we aim to introduce EAYNT activities and draw attention to relevant events and opportunities in 2015. Activities in 2015

Implementation of personalized medicine in Central-Eastern Europe: pitfalls and potentials based on citizen’s attitude

ObjectiveNext-generation sequencing is increasingly utilized worldwide as a research and diagnostic tool and is anticipated to be implemented into everyday clinical practice. Since Central-Eastern European attitude toward genetic testing, especially broad genetic testing, is not well known, we performed a survey on this issue among Hungarian participants.MethodsA self-administered questionnaire was distributed among patients and patient relatives at our neurogenetic outpatient clinic. Members of the general population were also recruited via public media. We used chi-square testing and binary logistic regression to examine factors influencing attitude.ResultsWe identified a mixed attitude toward genetic testing. Access to physician consultation positively influenced attitude. A higher self-determined genetic familiarity score associated with higher perceived genetic influence score, which in turn associated with greater willingness to participate in genetic testing. Medical professionals constituted a skeptical group.ConclusionsWe think that given the controversies and complexities of the next-generation sequencing field, the optimal clinical translation of NGS data should be performed in institutions which have the unique capability to provide interprofessional health education, transformative biomedical research, and crucial patient care. With optimization of the clinical translational process, improvement of genetic literacy may increase patient engagement and empowerment.Relevance of the article for predictive, preventive, and personalized medicineThe paper highlights that in countries with relatively low-genetic literacy, a special strategy is needed to enhance the implementation of personalized medicine.