Publications by authors named "Christine Makowski"

24 Publications

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De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.

Clin Genet 2021 Feb 22. Epub 2021 Feb 22.

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.
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http://dx.doi.org/10.1111/cge.13946DOI Listing
February 2021

Monogenic variants in dystonia: an exome-wide sequencing study.

Authors:
Michael Zech Robert Jech Sylvia Boesch Matej Škorvánek Sandrina Weber Matias Wagner Chen Zhao Angela Jochim Ján Necpál Yasemin Dincer Katharina Vill Felix Distelmaier Malgorzata Stoklosa Martin Krenn Stephan Grunwald Tobias Bock-Bierbaum Anna Fečíková Petra Havránková Jan Roth Iva Příhodová Miriam Adamovičová Olga Ulmanová Karel Bechyně Pavlína Danhofer Branislav Veselý Vladimír Haň Petra Pavelekova Zuzana Gdovinová Tobias Mantel Tobias Meindl Alexandra Sitzberger Sebastian Schröder Astrid Blaschek Timo Roser Michaela V Bonfert Edda Haberlandt Barbara Plecko Birgit Leineweber Steffen Berweck Thomas Herberhold Berthold Langguth Jana Švantnerová Michal Minár Gonzalo Alonso Ramos-Rivera Monica H Wojcik Sander Pajusalu Katrin Õunap Ulrich A Schatz Laura Pölsler Ivan Milenkovic Franco Laccone Veronika Pilshofer Roberto Colombo Steffi Patzer Arcangela Iuso Julia Vera Monica Troncoso Fang Fang Holger Prokisch Friederike Wilbert Matthias Eckenweiler Elisabeth Graf Dominik S Westphal Korbinian M Riedhammer Theresa Brunet Bader Alhaddad Riccardo Berutti Tim M Strom Martin Hecht Matthias Baumann Marc Wolf Aida Telegrafi Richard E Person Francisca Millan Zamora Lindsay B Henderson David Weise Thomas Musacchio Jens Volkmann Anna Szuto Jessica Becker Kirsten Cremer Thomas Sycha Fritz Zimprich Verena Kraus Christine Makowski Pedro Gonzalez-Alegre Tanya M Bardakjian Laurie J Ozelius Annalisa Vetro Renzo Guerrini Esther Maier Ingo Borggraefe Alice Kuster Saskia B Wortmann Annette Hackenberg Robert Steinfeld Birgit Assmann Christian Staufner Thomas Opladen Evžen Růžička Ronald D Cohn David Dyment Wendy K Chung Hartmut Engels Andres Ceballos-Baumann Rafal Ploski Oliver Daumke Bernhard Haslinger Volker Mall Konrad Oexle Juliane Winkelmann

Lancet Neurol 2020 11;19(11):908-918

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany; Lehrstuhl für Neurogenetik, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany. Electronic address:

Background: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

Methods: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.

Findings: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.

Interpretation: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.

Funding: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.
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http://dx.doi.org/10.1016/S1474-4422(20)30312-4DOI Listing
November 2020

Congenital lymphedema as a rare and first symptom of tuberous sclerosis complex.

Gene 2020 Aug 29;753:144815. Epub 2020 May 29.

Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany. Electronic address:

Lymphedema are characterized by interstitial edema leading to swelling of extremities. They can be divided into primary and secondary lymphedema. Developmental abnormalities of the lymphatic system are responsible for the primary form of lymphedema. The secondary form of lymphedema is caused by damage of the lymphatic system due to external factors. Lymphedema can rarely be observed in patients with tuberous sclerosis complex (TSC), which is a neurocutaneous syndrome caused by pathogenic variants in the genes TSC1 or TSC2. Patients with TSC usually present with neurological manifestations and the development of multiple benign tumors of ectodermal origin. Typical onset for several symptoms is during the first year of life and in some cases lesions can be detected prenatally. Epilepsy is one of the most common manifestations, affecting up to 90% of TSC patients, and is associated with developmental delay. Early pharmacotherapy improves long term patient outcome. Trio exome sequencing was performed in a 3 weeks old girl with congenital lymphedema of the right lower extremity. Using a filter for de novo variants, the heterozygous missense variant c.2524C>T, p.(Gln842Ter) in TSC1 (NM_000368.4) could be identified. After the first onset of infantile spams at age 7 months treatment with vigabatrin was started immediately. We propose to include TSC1 and TSC2 analysis in the diagnostic work-up of patients with (isolated) congenital lymphedema as early diagnosis facilitates consequent treatment strategies potentially improving the prognosis of TSC patients.
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http://dx.doi.org/10.1016/j.gene.2020.144815DOI Listing
August 2020

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy.

Genet Med 2019 11 16;21(11):2521-2531. Epub 2019 May 16.

CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada.

Purpose: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established.

Methods: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease.

Results: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration.

Conclusion: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
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http://dx.doi.org/10.1038/s41436-019-0532-zDOI Listing
November 2019

Neurologic phenotypes associated with / mutations: Expanding the spectrum of disease.

Neurology 2018 11 9;91(22):e2078-e2088. Epub 2018 Nov 9.

From the Department of Clinical and Experimental Epilepsy (S.Z., Z.M., L.H.-H., S.K., S. Balestrini, S.M.S.) and Division of Neuropathology (Z.M., M.T.), UCL Institute of Neurology, London, UK; Clinic of Neurology (S.Z.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy; Department of Pediatric Neurology and Neurological Rehabilitation (C.S., T.H., P.W., G.J.K.) and Neurosurgery Clinic and Clinic for Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth; Department of Pediatrics (C.S., M.S.), Children's Hospital Augsburg, Germany; UCL Great Ormond Street Institute of Child Health (J.R.N., K.V., S.M.V., J.H.C.), London, UK; Paediatric Neurology and Neurogenetics Unit and Laboratories (D.M., R.G.), A. Meyer Children's Hospital, University of Florence, Italy; Chalfont Centre for Epilepsy (Z.M., L.H.-H., S.K., S. Balestrini, S.M.S.), Chalfont-St-Peter, Buckinghamshire, UK; CeGaT-Center for Genomics and Transcriptomics (A.P., S. Biskup), Tübingen, Germany; Neurogenetics Unit (M.L.), Department of Medical Genetics, Hospital de São João, Porto, Portugal; Department of Pediatrics and Adolescent Medicine (J.G.), University Medical Center Göttingen; Hospital for Children and Adolescents (A.M.), University Clinic Leipzig, Germany; Freiburg Medical Laboratory (M.J.), Dubai; The Danish Epilepsy Centre (R.S.M., E.G.), Dianalund; Institute for Regional Health Services (R.S.M., E.G.), University of Southern Denmark, Odense; Department of Clinical Genetics (B.S.K.), Odense University Hospital; Hans Christian Andersen Children's Hospital (L.K.H.), Odense, Denmark; Pediatric Neurology and Muscular Diseases Unit (M.S.V., P.S.), Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa "G. Gaslini" Institute, Italy; Division of Neurology (K.L.H.), Children's Hospital of Philadelphia, PA; Department of Neurology (S.D., C.L.S.-H.), Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD; Center for Genomic Medicine (N.H.-F.), Tohoku University; Department of Pediatrics (N.H.-F.), Tohoku University School of Medicine, Sendai, Japan; Department of Pediatrics (T.T., R.L.) and Institute of Clinical Medicine (K.O.), University of Tartu; Children's Clinic (T.T., R.L.), Department of Radiology (P.I.), and Department of Clinical Genetics, United Laboratories (K.O.), Tartu University Hospital, Estonia; Ludwig-Maximilians-University Munich (I.K.); Department of Pediatric Neurology (A.H.), Clinic Traunstein; Children's Hospital (M.K.), Dr. Horst Schmidt Klinik, Wiesbaden; Altona Children's Hospital (J.H.), Hamburg; Department of Pediatrics (C. Makowski), Technische Universität München, Germany; Department of Clinical Genetics (S.G.), Royal North Shore Hospital, St Leonards; John Hunter Children's Hospital (G.M.S.), New Lambton Heights, New South Wales, Australia; Department of Neurology (R.T.), University Hospital of Wales; Institute of Psychological Medicine and Clinical Neurosciences (R.H.T.), Cardiff University; Division of Neuroradiology (C. Micallef), National Hospital for Neurology and Neurosurgery, London; Department of Brain Repair & Rehabilitation (D.J.W.), Stroke Research Centre, UCL Institute of Neurology, London, UK; Paracelsus Medical University (G.J.K.), Salzburg, Austria; and IRCCS Stella Maris Foundation (R.G.), Pisa, Italy.

Objective: To characterize the neurologic phenotypes associated with mutations and to seek genotype-phenotype correlation.

Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with mutations.

Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across and a clear genotype-phenotype correlation did not emerge.

Conclusion: mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.
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http://dx.doi.org/10.1212/WNL.0000000000006567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239PMC
November 2018

Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy.

Am J Hum Genet 2018 11 25;103(5):817-825. Epub 2018 Oct 25.

Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany. Electronic address:

ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose from NAD to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218634PMC
November 2018

PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum.

Neuropediatrics 2018 10 25;49(5):330-338. Epub 2018 Jun 25.

Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.

Background: Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic mutations.

Methods: Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms.

Results: We identified bi-allelic mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the gene and part of the neighboring gene.

Conclusions: deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.
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http://dx.doi.org/10.1055/s-0038-1661396DOI Listing
October 2018

- A Candidate Gene for Epilepsy, Developmental Delay and Behavioral Abnormalities in a Patient With Microdeletion 2q34.

Front Genet 2018 26;9:99. Epub 2018 Mar 26.

Institute of Human Genetics, Technical University of Munich, Munich, Germany.

Microdeletions in the chromosomal region 2q34 and its neighboring regions lead to a phenotypic spectrum including autism, intellectual disability, and epilepsy. Up to now, only few affected patients have been reported. Therefore, the genetic pathogenesis is not completely understood. One of the most discussed candidate genes in this context is , a gene responsible for microtubule polymerization and neurite outgrowth. We present a 4.5-year-old male patient with epilepsy, mild developmental delay, and behavioral abnormalities. SNP-Array analysis was performed to search for pathogenic copy number variations. SNP-Array analysis revealed a 1.5 Mb microdeletion on the long arm of chromosome 2 (2q34). The identified microdeletion included the candidate genes , and most importantly . The reported microdeletion identified in this patient is the smallest one described in the literature so far spanning next to and . In this context is the most important candidate gene concerning neuronal development and its function should be further examined.
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http://dx.doi.org/10.3389/fgene.2018.00099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879085PMC
March 2018

Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency.

Eur J Hum Genet 2018 03 17;26(3):407-419. Epub 2018 Jan 17.

Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.

Variants in the SPATA5 gene were recently described in a cohort of patients with global developmental delay, sensorineural hearing loss, seizures, cortical visual impairment and microcephaly. SPATA5 protein localizes predominantly in the mitochondria and is proposed to be involved in mitochondrial function and brain developmental processes. However no functional studies have been performed. This study describes five patients with psychomotor developmental delay, microcephaly, epilepsy and hearing impairment, who were thought clinically to have a mitochondrial disease with subsequent whole-exome sequencing analysis detecting compound heterozygous variants in the SPATA5 gene. A summary of clinical data of all the SPATA5 patients reported in the literature confirms the characteristic phenotype. To assess SPATA5's role in mitochondrial dynamics, functional studies were performed on rat cortical neurons. SPATA5-deficient neurons had a significant imbalance in the mitochondrial fusion-fission rate, impaired energy production and short axons. In conclusion, SPATA5 protein has an important role in mitochondrial dynamics and axonal growth. Biallelic variants in the SPATA5 gene can affect mitochondria in cortical neurons and should be considered in patients with a neurodegenerative disorder and/or with clinical presentation resembling a mitochondrial disorder.
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http://dx.doi.org/10.1038/s41431-017-0001-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838984PMC
March 2018

A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy.

Brain 2017 12;140(12):3105-3111

Department of Child Neurology, VU University Medical Center, and Amsterdam Neuroscience, Amsterdam, The Netherlands.

Hypomyelinating leukodystrophies are a heterogeneous group of disorders with a clinical presentation that often includes early-onset nystagmus, ataxia and spasticity and a wide range of severity. Using next-generation sequencing techniques and GeneMatcher, we identified four unrelated patients with brain hypomyelination, all with the same recurrent dominant mutation, c.754G>A p.(Asp252Asn), in TMEM106B. The mutation was confirmed as de novo in three of the cases, and the mildly affected father of the fourth affected individual was confirmed as mosaic for this variant. The protein encoded by TMEM106B is poorly characterized but is reported to have a role in regulation of lysosomal trafficking. Polymorphisms in TMEM106B are thought to modify disease onset in frontotemporal dementia, but its relation to myelination is not understood. Clinical presentation in three of the four patients is remarkably benign compared to other hypomyelinating disorders, with congenital nystagmus and mild motor delay. These findings add TMEM106B to the growing list of genes causing hypomyelinating disorders and emphasize the essential role lysosomes play in myelination.
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http://dx.doi.org/10.1093/brain/awx314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841038PMC
December 2017

Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults.

JAMA Neurol 2018 01;75(1):105-113

MitoLab Team, Unités Mixtes de Recherche Centre National de la Recherche Scientifique 6015-INSERM U1083, Institut MitoVasc, Angers University and Hospital, Angers, France.

Importance: Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies.

Objective: To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase.

Design, Setting, And Participants: This study involved 12 individuals from 11 families with severe central nervous system diseases and optic atrophy. Targeted and whole-exome sequencing were performed-at Hospital Angers (France), Institute of Neurology Milan (Italy), Imagine Institute Paris (France), Helmoltz Zentrum of Munich (Germany), and Beijing Genomics Institute (China)-to clarify the molecular diagnosis of patients. Each patient's neurologic, ophthalmologic, magnetic resonance imaging, and biochemical features were investigated. This study was conducted from May 1, 2014, to June 30, 2016.

Main Outcomes And Measures: Recessive mutations in RTN4IP1 were identified. Clinical presentations ranged from isolated optic atrophy to severe encephalopathies.

Results: Of the 12 individuals in the study, 6 (50%) were male and 6 (50%) were female. They ranged in age from 5 months to 32 years. Of the 11 families, 6 (5 of whom were consanguineous) had a member or members who presented isolated optic atrophy with the already reported p.Arg103His or the novel p.Ile362Phe, p.Met43Ile, and p.Tyr51Cys amino acid changes. The 5 other families had a member or members who presented severe neurologic syndromes with a common core of symptoms, including optic atrophy, seizure, intellectual disability, growth retardation, and elevated lactate levels. Additional clinical features of those affected were deafness, abnormalities on magnetic resonance images of the brain, stridor, and abnormal electroencephalographic patterns, all of which eventually led to death before age 3 years. In these patients, novel and very rare homozygous and compound heterozygous mutations were identified that led to the absence of the protein and complex I disassembly as well as mild mitochondrial network fragmentation.

Conclusions And Relevance: A broad clinical spectrum of neurologic features, ranging from isolated optic atrophy to severe early-onset encephalopathies, is associated with RTN4IP1 biallelic mutations and should prompt RTN4IP1 screening in both syndromic neurologic presentations and nonsyndromic recessive optic neuropathies.
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http://dx.doi.org/10.1001/jamaneurol.2017.2065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833489PMC
January 2018

Biallelic Mutations in SLC1A2; an Additional Mode of Inheritance for SLC1A2-Related Epilepsy.

Neuropediatrics 2018 02 15;49(1):59-62. Epub 2017 Sep 15.

Institute of Human Genetics, Technische Universität München, Munich, Germany.

Recently, heterozygous de novo mutations in have been reported to underlie severe early-onset epileptic encephalopathy. In one male presenting with epileptic seizures and visual impairment, we identified a novel homozygous splicing variant in (c.1421 + 1G > C) by using exome sequencing. Functional studies on cDNA level confirmed a consecutive loss of function. Our findings suggest that not only de novo mutations but also biallelic variants in can cause epilepsy and that there is an additional autosomal recessive mode of inheritance. These findings also contribute to the understanding of the genetic mechanism of autosomal dominant -related epileptic encephalopathy as they exclude haploinsufficiency as exclusive genetic mechanism.
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http://dx.doi.org/10.1055/s-0037-1606370DOI Listing
February 2018

Combined Respiratory Chain Deficiency and Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies.

Oxid Med Cell Longev 2017 19;2017:7202589. Epub 2017 Jul 19.

Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria.

Vertebrate respiratory chain complex III consists of eleven subunits. Mutations in five subunits either mitochondrial (MT-CYB) or nuclear (CYC1, UQCRC2, UQCRB, and UQCRQ) encoded have been reported. Defects in five further factors for assembly (TTC19, UQCC2, and UQCC3) or iron-sulphur cluster loading (BCS1L and LYRM7) cause complex III deficiency. Here, we report a second patient with UQCC2 deficiency. This girl was born prematurely; pregnancy was complicated by intrauterine growth retardation and oligohydramnios. She presented with respiratory distress syndrome, developed epileptic seizures progressing to status epilepticus, and died at day 33. She had profound lactic acidosis and elevated urinary pyruvate. Exome sequencing revealed two homozygous missense variants in , leading to a severe reduction of UQCC2 protein. Deficiency of complexes I and III was found enzymatically and on the protein level. A review of the literature on genetically distinct complex III defects revealed that, except TTC19 deficiency, the biochemical pattern was very often a combined respiratory chain deficiency. Besides complex III, typically, complex I was decreased, in some cases complex IV. In accordance with previous observations, the presence of assembled complex III is required for the stability or assembly of complexes I and IV, which might be related to respirasome/supercomplex formation.
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http://dx.doi.org/10.1155/2017/7202589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540226PMC
May 2018

Identification of a de novo microdeletion 1q44 in a patient with hypogenesis of the corpus callosum, seizures and microcephaly - A case report.

Gene 2017 Jun 21;616:41-44. Epub 2017 Mar 21.

Institute of Human Genetics, Technical University Munich, Munich, Germany.

Microdeletion 1q44 on the long arm of chromosome 1 leads to a phenotype that includes microcephaly, seizure, agenesis or hypogenesis of the corpus callosum, polydactyly, congenital heart defects and severe developmental delay along with characteristic facial dysmorphic signs. Until today, the distinct genetic causes for the different symptoms remain unclear. We here report a 1.2Mb de novo microdeletion 1q44 identified by performing a SNP array analysis. The female patient presented with microcephaly, seizure, hypogenesis of corpus callosum, postaxial hexadactyly, an atrial septal defect, a ventricular septal defect, hypertelorism, a long and smooth philtrum, thin vermilion borders, and micrognathia, all common features of microdeletion 1q44. An additionally performed chromosome analysis excluded any chromosomal rearrangements. The deleted region included the genes ZBTB18 as well as HNRNPU amongst others. Both are possibly candidate genes for the dysgenesis of the corpus callosum. AKT3, another candidate gene, was not affected by the deletion in this patient. Thus, the genetic findings in this case report spotlight ZBTB18 and HNRNPU in the genesis of the typical microdeletion 1q44 symptoms, especially concerning the dysgenesis of the corpus callosum, and therefore could help to unveil more of the genetic background of this syndrome.
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http://dx.doi.org/10.1016/j.gene.2017.03.025DOI Listing
June 2017

Effectiveness of antiepileptic therapy in patients with PCDH19 mutations.

Seizure 2016 Feb 6;35:106-10. Epub 2016 Jan 6.

Neuropädiatrie, Schön Klinik Vogtareuth, Germany; Paracelsus Medical University, Salzburg, Austria.

Purpose: PCDH19 mutations cause epilepsy and mental retardation limited to females (EFMR) or Dravet-like syndromes. Especially in the first years of life, epilepsy is known to be highly pharmacoresistant. The aim of our study was to evaluate the effectiveness of antiepileptic therapy in patients with PCDH19 mutations.

Methods: We report a retrospective multicenter study of antiepileptic therapy in 58 female patients with PCDH19 mutations and epilepsy aged 2-27 years (mean age 10.6 years).

Results: The most effective drugs after 3 months were clobazam and bromide, with a responder rate of 68% and 67%, respectively, where response was defined as seizure reduction of at least 50%. Defining long-term response as the proportion of responders after 12 months of treatment with a given drug in relation to the number of patients treated for at least 3 months, the most effective drugs after 12 months were again bromide and clobazam, with a long-term response of 50% and 43%, respectively. Seventy-four percent of the patients became seizure-free for at least 3 months, 47% for at least one year.

Significance: The most effective drugs in patients with PCDH19 mutations were bromide and clobazam. Although epilepsy in PCDH19 mutations is often pharmacoresistant, three quarters of the patients became seizure-free for at least for 3 months and half of them for at least one year. However, assessing the effectiveness of the drugs is difficult because a possible age-dependent spontaneous seizure remission must be considered.
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http://dx.doi.org/10.1016/j.seizure.2016.01.006DOI Listing
February 2016

High resolution transbulbar sonography in children with suspicion of increased intracranial pressure.

Childs Nerv Syst 2016 Apr 13;32(4):655-60. Epub 2016 Jan 13.

Department for Paediatric and Adolescent Medicine, Schwabing Hospital, Munich, Germany.

Purpose: To evaluate the accuracy of high resolution transbulbar sonography for the estimation of intracranial pressure (ICP) in children.

Methods: In children and adolescents with acute neurologic symptoms of various origin, transbulbar sonography was performed. Besides measurement of the optic nerve sheath diameter (ONSD), the ultrastructure of the subarachnoid space of the optic nerve sheath was evaluated. The results of transbulbar sonography were correlated with clinical data based on cross-sectional imaging, ICP measurement, and ophthalmologic examination.

Results: Eighty-one patients (age 3-17.8 years, mean 11.7 years) were included. In 25 children, cross-sectional imaging and ICP measurement revealed increased intracranial pressure. The mean ONSD was 6.85 ± 0.81 mm. Twenty patients (20/25, 80 %) had a microcystic appearance of the subarachnoid space of the optic nerve. In 56 children without evidence of increased intracranial pressure, the mean ONSD was 5.77 ± 0.48 mm. Forty-nine patients (49/56, 87.5 %) had a normal homogenous appearance of the subarachnoid space. The ONSD in children with increased intracranial pressure was significantly higher than in patients without (p < 0.001).

Conclusion: High resolution transbulbar sonography of the optic nerve is a useful technique for the rapid and non-invasive estimation of intracranial pressure in children. Besides measurement of the optic nerve sheath diameter, evaluation of the ultrastructure of the subarachnoid space of the optic nerve is a helpful parameter.
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http://dx.doi.org/10.1007/s00381-015-3001-2DOI Listing
April 2016

Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency.

Front Genet 2015 13;6:123. Epub 2015 Apr 13.

Institute of Human Genetics, Technische Universität München Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München Neuherberg, Germany.

Disorders of the mitochondrial energy metabolism are clinically and genetically heterogeneous. An increasingly recognized subgroup is caused by defective mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, with defects in 13 genes being linked to human disease to date. Mutations in three of them, NFU1, BOLA3, and IBA57, affect the assembly of mitochondrial [4Fe-4S] proteins leading to an impairment of diverse mitochondrial metabolic pathways and ATP production. Patients with defects in these three genes present with lactic acidosis, hyperglycinemia, and reduced activities of respiratory chain complexes I and II, the four lipoic acid-dependent 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). To date, five different NFU1 pathogenic variants have been reported in 15 patients from 12 families. We report on seven new patients from five families carrying compound heterozygous or homozygous pathogenic NFU1 mutations identified by candidate gene screening and exome sequencing. Six out of eight different disease alleles were novel and functional studies were performed to support the pathogenicity of five of them. Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients. Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration (seven out of seven). Our study contributes to a better definition of the phenotypic spectrum associated with NFU1 mutations and to the diagnostic workup of future patients.
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http://dx.doi.org/10.3389/fgene.2015.00123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394698PMC
April 2015

Spectrum of combined respiratory chain defects.

J Inherit Metab Dis 2015 Jul 17;38(4):629-40. Epub 2015 Mar 17.

Department of Paediatrics, Paracelsus Medical University, SALK Salzburg, Salzburg, 5020, Austria,

Inherited disorders of mitochondrial energy metabolism form a large and heterogeneous group of metabolic diseases. More than 250 gene defects have been reported to date and this number continues to grow. Mitochondrial diseases can be grouped into (1) disorders of oxidative phosphorylation (OXPHOS) subunits and their assembly factors, (2) defects of mitochondrial DNA, RNA and protein synthesis, (3) defects in the substrate-generating upstream reactions of OXPHOS, (4) defects in relevant cofactors and (5) defects in mitochondrial homeostasis. Deficiency of more than one respiratory chain enzyme is a common finding. Combined defects are found in 49 % of the known disease-causing genes of mitochondrial energy metabolism and in 57 % of patients with OXPHOS defects identified in our diagnostic centre. Combined defects of complexes I, III, IV and V are typically due to deficiency of mitochondrial DNA replication, RNA metabolism or translation. Defects in cofactors can result in combined defects of various combinations, and defects of mitochondrial homeostasis can result in a generalised decrease of all OXPHOS enzymes. Noteworthy, identification of combined defects can be complicated by different degrees of severity of each affected enzyme. Furthermore, even defects of single respiratory chain enzymes can result in combined defects due to aberrant formation of respiratory chain supercomplexes. Combined OXPHOS defects have a great variety of clinical manifestations in terms of onset, course severity and tissue involvement. They can present as classical encephalomyopathy but also with hepatopathy, nephropathy, haematologic findings and Perrault syndrome in a subset of disorders.
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http://dx.doi.org/10.1007/s10545-015-9831-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493854PMC
July 2015

Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations.

Mol Genet Metab 2014 Dec 5;113(4):301-6. Epub 2014 Oct 5.

Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria.

Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate, a cofactor for a number of enzymes, including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. Episodic encephalopathy type thiamine metabolism dysfunction (OMIM 614458) due to TPK1 mutations is a recently described rare disorder. The mechanism of the disease, its phenotype and treatment are not entirely clear. We present two patients with novel homozygous TPK1 mutations (Patient 1 with p.Ser160Leu and Patient 2 with p.Asp222His). Unlike the previously described phenotype, Patient 2 presented with a Leigh syndrome like non-episodic early-onset global developmental delay, thus extending the phenotypic spectrum of the disorder. We, therefore, propose that TPK deficiency may be a better name for the condition. The two cases help to further refine the neuroradiological features of TPK deficiency and show that MRI changes can be either fleeting or progressive and can affect either white or gray matter. We also show that in some cases lactic acidosis can be absent and 2-ketoglutaric aciduria may be the only biochemical marker. Furthermore, we have established the assays for TPK enzyme activity measurement and thiamine pyrophosphate quantification in frozen muscle and blood. These tests will help to diagnose or confirm the diagnosis of TPK deficiency in a clinical setting. Early thiamine supplementation prevented encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. We present evidence suggesting that thiamine supplementation may rescue TPK enzyme activity. Lastly, in silico protein structural analysis shows that the p.Ser160Leu mutation is predicted to interfere with TPK dimerization, which may be a novel mechanism for the disease.
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http://dx.doi.org/10.1016/j.ymgme.2014.09.010DOI Listing
December 2014

Visual loss without headache in children with pseudotumor cerebri and growth hormone treatment.

Neuropediatrics 2013 Aug 28;44(4):203-7. Epub 2012 Dec 28.

Department of Ophthalmology, Centre for Ophthalmology, University Eye Hospital, Tuebingen, Germany.

We report on two prepubescent girls with visual loss due to idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, both treated with recombinant human growth hormone for growth failure. The interval from starting hormone therapy to diagnosis of IIH was 3 and 18 months, respectively. Both girls did not complain of headache and nausea. They were neither obese nor did they suffer from renal insufficiency. In both patients, we observed bilateral optic disc edema with visual loss and elevated cerebrospinal fluid (CSF) pressures. Other causes of IIH were excluded with neuroimaging and CSF examination. Cessation of drug administration is often sufficient for symptom resolution in cases of hormone therapy-associated IIH. However, visual field defects in one girl remained unchanged during follow-up of 8 months. In children with IIH, the spectrum of neurologic and visual manifestations might be variable and unspecific. Diagnosis and management of IIH can be difficult in the absence of headache. Blurred or double vision due to cranial nerve palsy might be the only symptom rather than complaints about reduced visual acuity. Therefore, regular clinical monitoring of visual function and fundus appearance is essential for early diagnosis, efficient management, and improvement of visual outcome in children receiving recombinant human growth hormone.
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http://dx.doi.org/10.1055/s-0032-1330855DOI Listing
August 2013

Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome.

J Inherit Metab Dis 2012 Nov 3;35(6):943-8. Epub 2012 Aug 3.

Institute of Human Genetics, Technische Universität München, Trogerstrasse 22, München, 81675, Germany.

Brown-Vialetto-Van Laere syndrome (BVVLS [MIM 211530]) is a rare neurological disorder characterized by infancy onset sensorineural deafness and ponto-bulbar palsy. Mutations in SLC52A3 (formerly C20orf54), coding for riboflavin transporter 2 (hRFT2), have been identified as the molecular genetic correlate in several individuals with BVVLS. Exome sequencing of just one single case revealed that compound heterozygosity for two pathogenic mutations in the SLC52A2 gene coding for riboflavin transporter 3 (hRFT3), another member of the riboflavin transporter family, is also associated with BVVLS. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities. While mutations in SLC52A3 cause decreased plasma riboflavin levels, concordant with a role of SLC52A3 in riboflavin uptake from food, the SLC52A2-mutant individual had normal plasma riboflavin concentrations, a finding in line with a postulated function of SLC52A2 in riboflavin uptake from blood into target cells. Our results contribute to the understanding of human riboflavin metabolism and underscore its role in the pathogenesis of BVVLS, thereby providing a rational basis for a high-dose riboflavin treatment.
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http://dx.doi.org/10.1007/s10545-012-9513-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470687PMC
November 2012

Cryptic del/dup aberration of 60.6 Mb at 5q15-5q23.3 predicting adult-onset leukodystrophy.

Eur J Med Genet 2012 Oct 7;55(10):568-72. Epub 2012 Jul 7.

Institut für Humangenetik, Klinikum rechts der Isar, TU München, Trogerstr. 32, 81675 München, Germany.

We report on a de novo interstitial del/dup aberration consisting of a 13.3 Mb deletion of 5q15-5q21.3 (92.1-105.4 Mb, hg19) and a 23.6 Mb tandem direct duplication of 5q21.3-5q23.3 (106.1-129.7 Mb, hg19). Although the aberration covered a total of 60.6 Mb, it was cryptic, i.e., not detectable by karyotyping at a resolution of 430 bands. Array-CGH indicated a diploid region of 0.6 Mb between the duplicated and the deleted segment. The aberration affected a 14-month-old boy conceived after intracytoplasmic sperm injection who presented with developmental delay, muscular hypotonia, partial agenesis of the corpus callosum, prominent forehead, low set ears, hypertelorism, hyperopia, wide-bridged nose, retrognathia, high palate, and cryptorchidism. The duplicated segment comprised the LMNB1 gene, thus predicting adult-onset autosomal-dominant leukodystrophy and revealing a temporal dimension of the phenotype. Counseling problems implicated by this prediction include "the right not to know" that the patient might want to exercise when coming of age.
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http://dx.doi.org/10.1016/j.ejmg.2012.06.010DOI Listing
October 2012

First European long-term experience with the orphan drug rufinamide in childhood-onset refractory epilepsy.

Epilepsy Behav 2010 Apr 24;17(4):546-8. Epub 2010 Feb 24.

Neuropediatric Department, BHZ Vogtareuth, Vogtareuth, Germany.

Objective: Recently, we published the first postmarketing European experience with rufinamide (RUF) in a retrospective 12-week observational study. This follow-up report summarizes the long-term effectiveness and tolerability of RUF after 18 months for the same patient sample.

Methods: In total, 52 of 60 initially included patients from eight centers in Germany and Austria (45 children and 15 adults aged 1-50 years) with various severe and inadequately controlled epilepsy syndromes continued treatment with RUF after the initial 3-month observation period (mean final dose: 38.2+/-17.3mg/kg/day). Efficacy was assessed by seizure frequency evaluated by comparison with baseline frequency. Tolerability was evaluated by analysis of parental report of adverse events and laboratory tests. Responders were defined as patients who achieved a 50% or greater decrease in countable seizures within 18 months of initiating RUF therapy.

Results: Mean overall duration of RUF treatment was 14.5 months (range: 3-18 months). Retention rate, defined as the percentage of patients still taking RUF after 18 months, was 41.7% (n=25/60). The overall response rate after 18 months was 26.7% (16/60 patients). The highest response rates were found in the subgroup of patients with Lennox-Gastaut syndrome (LGS, 35.5%) and in patients with other generalized epilepsy syndromes. Complete seizure control was maintained in one patient (1.6%). A total of 73 adverse events were reported in 37 of 60 patients. The most frequently occurring adverse events were fatigue (18.3%), vomiting (15.0%), and loss of appetite (10.0%). Only 4 new adverse events were reported after week 12. No serious adverse events were observed.

Conclusions: The present data suggest that RUF is efficacious and well tolerated in the long-term treatment of children and adults with various epilepsy syndromes and difficult-to-control seizures.
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http://dx.doi.org/10.1016/j.yebeh.2010.01.005DOI Listing
April 2010

Effectiveness and tolerability of rufinamide in children and adults with refractory epilepsy: first European experience.

Epilepsy Behav 2009 Mar 20;14(3):491-5. Epub 2009 Jan 20.

Neuropediatric Department, BHZ Vogtareuth, Vogtareuth, Germany.

Objective: The aim of the study was to explore the effectiveness and tolerability of rufinamide in a heterogeneous group of patients with refractory epilepsies in Europe, immediately after the drug became available as an orphan drug for the adjunctive treatment of Lennox-Gastaut syndrome (LGS).

Methods: This observational study was conducted as a collection of retrospective data from multiple centers in Germany and Austria. Clinical course in patients treated with rufinamide was documented. Initial dosage and titration schedule of rufinamide were at the discretion of the treating physician according to medical need. The observation period was 12 weeks. Effectiveness was evaluated by comparing the frequency of seizures with limitations to the countability between baseline and the last 4-week period of observation.

Results: The study population consisted of 45 children and 15 adults (mean age: 14.5+/-11.6 years, range: 1-50) with various severe and inadequately controlled epilepsy syndromes, that is, LGS (n=31), idiopathic generalized epilepsy syndromes (n=5), cryptogenic unclassified generalized epilepsy (n=7), and partial epilepsy (n=17). The response rate (50% reduction in countable seizures) was 46.7% (28 of 60 patients) in total; 25.0% experienced a 75% reduction in seizure frequency and 21.7% experienced a 50-75% reduction. Complete seizure control was achieved by 8.3%. The highest response rate was observed in patients with LGS (17/31, 54.8%), and the lowest in patients with partial epilepsy (4/17, 23.5%). Response rate in patients with unclassified generalized epilepsy was 42.8% (3/7 patients). A total of 67 adverse events were reported by 35 of 60 patients. The most frequently occurring adverse events were fatigue (18.3%), vomiting (13.3%), and loss of appetite (10.0%). No serious adverse events were observed.

Conclusions: These preliminary data suggest that rufinamide may be effective and well tolerated in the treatment of children and adults with various epilepsy syndromes and difficult-to-control seizures. The results of our study suggest that the efficacy of rufinamide in patients with generalized epilepsy might be comparable to that in patients with LGS, whereas rufinamide was less effective in patients with partial epilepsy.
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http://dx.doi.org/10.1016/j.yebeh.2008.12.013DOI Listing
March 2009