Publications by authors named "Angela Kaindl"

98 Publications

Lumbar Puncture Opening Pressure in Patients with Spinal Muscular Atrophy.

Neuropediatrics 2021 Feb 12. Epub 2021 Feb 12.

Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

The announcement of a hydrocephalus as a possible side effect in patients with spinal muscular atrophy (SMA) receiving the drug nusinersen, promoted major concern and warrants further evaluation. In this retrospective monocentric study, we analyzed clinical data, lumbar puncture opening pressure (LOP) measurement, and ophthalmologic and neuroimaging results in 34 patients with SMA types 1 to 3 undergoing treatment with nusinersen. None of the patients reported symptoms indicative of increased intracranial pressure. In our cohort, the LOP was >20 cm HO in 25 patients (70.5%), and within this group ≥28 cm HO in 12 patients (35.3%), in two patients, it was increased prior to treatment initiation. Signs of increased intracranial pressure in ophthalmological assessments or brain imaging were only seen in one patient. We did not identify a correlation between increased LOP and SMA type, scoliosis, or age of the patients; however, it was slightly higher in patients receiving sedation. Our results raise the question whether the LOP is generally increased in SMA as part of the underlying disease, if so, what the etiology is, and whether the increased LOP needs to be treated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1722687DOI Listing
February 2021

Systematic Classification of Spina Bifida.

J Neuropathol Exp Neurol 2021 Feb 12. Epub 2021 Feb 12.

From the Charité - Universitätsmedizin Berlin, Institute of Cellbiology and Neurobiology, Berlin, Germany (KHS, FP, GS-D, AMK); Charité - Universitätsmedizin Berlin, Institute of Pathology, Berlin, Germany (AS); Charité - Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, Germany (AMK); and Charité - Universitätsmedizin Berlin, Center for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Berlin, Germany (AMK).

Spina bifida (SB) is an umbrella term for multiple conditions characterized by misclosure of vertebral arches. Neuropathologic findings in SB cases are often reported with imprecise and overlapping terminology. In view of the increasing identification of SB-associated genes and pathomechanisms, the precise description of SB subtypes is highly important. In particular, the term "myelomeningocele" is applied to various and divergent SB subtypes. We reevaluated 90 cases with SB (58 prenatal; 32 postnatal). The most frequent SB phenotype in our cohort was myeloschisis, which is characterized by an open neural plate with exposed ependyma (n = 28; 31.1%). An open neural plate was initially described in only in two-thirds of the myeloschisis cases. An additional 21 cases (23.3%) had myelomeningocele; 2 cases (2.2%) had a meningocele; and 21 cases (23.3%) had an unspecified SB aperta (SBA) subtype. Overall, the SB phenotype was corrected in about one-third of the cases. Our findings highlight that "myelomeningocele" and "SB aperta" cannot be used as synonymous terms and that myeloschisis is an underreported SB phenotype. Based on our findings and a review of literature we propose a classification of SB subtypes in SB occulta and the 3 SBA subtypes, meningocele, myelomeningocele, and myeloschisis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nlab007DOI Listing
February 2021

Immunofluorescence Staining of Paraffin Sections Step by Step.

Front Neuroanat 2020 9;14:582218. Epub 2020 Nov 9.

Charité - Universitätsmedizin Berlin, Institute of Cell and Neurobiology, Berlin, Germany.

Immunofluorescence staining is the most frequently applied technique to detect and visualize various molecules in biological samples. Many protocols can be found in the literature and the websites of commercial antibody producers. This can result in a time-consuming and costly methodical work to establish "simple" antibody staining. We here summarize in a stepwise manner an easy-to-follow immunofluorescence staining protocol with an improved specific fluorescent signal and a reduced background and non-specific binding signal. This will help scientists to save time, effort, and antibody costs during the application of such a valuable technique.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnana.2020.582218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680859PMC
November 2020

Brain malformations and cognitive performance in spina bifida.

Dev Med Child Neurol 2021 Mar 2;63(3):295-302. Epub 2020 Nov 2.

Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Aim: To systematically characterize radiological features of patients with spina bifida, their relationship to cognitive function, and differences between spina bifida aperta (SBA) and spina bifida occulta (SBO).

Method: In a retrospective study of 265 patients (117 females, 148 males; median age at imaging 11y, range 1-47y; SBA n=206, SBO n=59), the radiological phenotype was assessed through magnetic resonance imaging (MRI) (SBA n=171, SBO n=59). In 126 patients (SBA n=116, SBO n=10) Kaufman Assessment Battery for Children (KABC) or Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) and Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) were performed.

Results: Patients with spina bifida show numerous brain malformations, always present for SBA but rarely for SBO. The most frequent brain malformations in SBA included abnormal corpus callosum (69%), hypoplastic pons (50%), and hypoplastic mesencephalon (20%). Cognitive total IQ scores were below average in 44% (KABC) to 49% (WISC-IV) of children with SBA, while almost all children with SBO scored at least average. Stenogyria (p=0.006), pons (p=0.003), and mesencephalon hypoplasia (p=0.01) correlated with lower total IQ score and verbal comprehension. Various brain malformations correlate significantly with several cognitive domains, while lesion level only correlates with processing speed.

Interpretation: IQ scores were significantly lower in patients with SBA than in patients with SBO. Verbal competence, perceptual reasoning, and working memory were significantly impaired for SBA and correlated with stenogyria and abnormalities of the midbrain and corpus callosum.

What This Paper Adds: Brain malformations occur more frequently in spina bifida aperta (SBA) than in spina bifida occulta (SBO). Cognitive impairment is less frequent in SBO. Hydrocephalus, stenogyria, midbrain, and corpus callosum abnormalities are associated with lower cognitive function. Difference in prognosis in SBO versus SBA can alter prenatal counselling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.14717DOI Listing
March 2021

SIGLEC1 (CD169) as a potential diagnostical screening marker for monogenic interferonopathies.

Pediatr Allergy Immunol 2020 Oct 25. Epub 2020 Oct 25.

Pediatric Pneumology, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pai.13400DOI Listing
October 2020

Abnormal brain structure and behavior in MyD88-deficient mice.

Brain Behav Immun 2021 Jan 28;91:181-193. Epub 2020 Sep 28.

Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address:

While the original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis, the role of its ortholog Toll-like receptors (TLRs), the interleukin 1 receptor (IL-1R) family, and the associated signaling pathways in mammalian brain development and structure is poorly understood. Because the adaptor protein myeloid differentiation primary response protein 88 (MyD88) is essential for downstream signaling of most TLRs and IL-1R, we systematically investigated the effect of MyD88 deficiency on murine brain structure during development and on behavior. In neonatal Myd88 mice, neocortical thickness was reduced, while density of cortical neurons was increased. In contrast, microglia, astrocyte, oligodendrocyte, and proliferating cell numbers were unchanged in these mice compared to wild-type mice. In adult Myd88 mice, neocortical thickness was unaltered, but neuronal density in neocortex and hippocampus was increased. Neuron arborization was less pronounced in adult Myd88 mice compared to wild-type animals. In addition, numbers of microglia and proliferating cells were increased in the neocortex and subventricular zone, respectively, with unaltered astrocyte and oligodendrocyte numbers, and myelinization was enhanced in the adult Myd88 neocortex. These morphologic changes in the brain of adult Myd88 mice were accompanied by specific behavioral traits, such as decreased locomotor activity, increased anxiety-like behavior, but normal day/light activity, satisfactory learning, short- and long-term spatial memory, potential cognitive inflexibility, and increased hanging and locomotor behavior within their home cage. Taken together, MyD88 deficiency results in morphologic and cellular changes in the mouse brain, as well as in altered natural and specific behaviors. Our data indicate a pathophysiological significance of MyD88 for mammalian CNS development, structure, and function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2020.09.024DOI Listing
January 2021

Intravenous Nimodipine Treatment for Severe Episode of ATP1A2 Hemiplegic Migraine.

Pediatr Neurol 2020 11 22;112:71-72. Epub 2020 Jul 22.

Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin, Berlin, Germany; Institute for Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2020.07.009DOI Listing
November 2020

Clinical Outcome of Children With Corpus Callosum Agenesis.

Pediatr Neurol 2020 11 11;112:47-52. Epub 2020 Aug 11.

Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin, Berlin, Germany; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Agenesis of the corpus callosum is a rare congenital brain malformation that can be associated with other cerebral malformations and/or underlying genetic causes. Prenatal counseling is hampered due to the lack of reliable long-term data on neurodevelopmental outcome.

Methods: Since 2010, a total of 23 children with agenesis of the corpus callosum (mean age 3.8 years, range 0.7 to 9.7 years) were registered in our ACC outpatient clinic and diagnosed in a standardized manner; the data were analyzed retrospectively. Prenatal and postnatal imaging, associated malformations, genetic and clinical findings, and psychological testing (Bayley Scales, Kaufman Assessment Battery for Children II, Snijders-Oomen Non-verbal Test, Wechsler Preschool and Primary Scale I-III) were included. The clinical outcome was classified as "normal" (intelligence quotient 85 to 115, unremarkable motor skills), "moderate developmental delay" (intelligence quotient 70 to 85, mild motor abnormalities), and "severe developmental delay" (intelligence quotient less than 70, severe movement disorder).

Results: Isolated corpus callosum malformation was diagnosed in 15 of 23 (65%), associated cerebral malformations in four of 23 (17%), and associated cerebral malformations plus intracranial cyst in four of 23 (17%) children. Prenatal diagnosis changed in nine of 23 (39%) cases. Overall, a normal outcome or moderate or severe developmental delay was present in 15 of 23 (65%) or five of 23 (22%) or three of 23 (13%) children, respectively. Also six of eight children with associated cerebral malformations showed normal outcome.

Conclusion: Our findings support the notion that developmental outcome is favorable in about two-thirds of children with prenatally diagnosed agenesis of corpus callosum. However, the individual outcome in children with agenesis of corpus callosum is difficult to predict. Even children with correctly characterized phenotypes show a variety of outcomes, making prenatal counseling challenging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2020.07.013DOI Listing
November 2020

Presence of anti-neuronal antibodies in children with neurological disorders beyond encephalitis.

Eur J Paediatr Neurol 2020 Sep 30;28:159-166. Epub 2020 Jul 30.

Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität, Humboldt-Universität, Berlin Institute of Health, Berlin, Germany; Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität, Humboldt-Universität, Berlin Institute of Health, Berlin, Germany; NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität, Humboldt-Universität, Berlin Institute of Health, Berlin, Germany. Electronic address:

Background: Anti-neuronal autoantibodies have been reported as the cause of several neurologic disorders other than encephalitis. Unfortunately, data are mostly based on serum analysis. Predictions about pathogenicity are thus limited. To determine the presence of so far unidentified autoantibody-derived neuroreactivity we analyzed cerebrospinal fluid (CSF) of children with neurological disorders other than encephalitis.

Patients And Methods: We did a retrospective analysis of CSF from 254 children with various neurologic diseases other than encephalitis and searched for reactivity against neuronal surface antigens by immunofluorescence on unfixed murine brain sections (tissue-based assay, TBA) and by commercial cell-based assays (CBA). A semi-quantitative fluorescence score classified our results and we described the clinical course of all positive patients with strong neuroreactivity.

Results: Strong anti-neuronal IgG immunoreactivity of unknown antigen specificity was detected in CSF samples of 10 pediatric patients (4%, n = 10/254) with unsolved neurological disorders. CSF inflammatory markers were elevated. Most patients did not or only partly recover. Five screening-positive patients presented with a combination of headache and visual impairment due to optic nerve atrophy. Our data suggest to consider inflammatory, autoantibody-related etiologies, especially in cases without definite diagnoses.

Conclusions: We present an overview of CSF neuroreactivity in children with neurological disorders other than encephalitis, indicating the presence of unidentified anti-neuronal autoantibodies. As TBA enables screening for unknown autoantibodies, we suggest this method as a second step if commercial CBAs do not yield a result. Further studies are necessary to characterize such antibodies, evaluate pathogenicity, and answer the question whether positive CSF neuroreactivity should prompt an immunotherapeutic approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2020.07.004DOI Listing
September 2020

The clinical, histologic, and genotypic spectrum of -related myopathy: A case series.

Neurology 2020 09 13;95(11):e1512-e1527. Epub 2020 Aug 13.

From the Basic and Translational Myology Lab (R.N.V.-Q., V.G., A.F.), UMR8251, Université de Paris/CNRS; Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France (R.N.V.-Q., B. Eymard, N.B.R., A.F.) and Neuromuscular Morphology Unit (N.B.R., M.F.), Institut de Myologie, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Department of Paediatric Neurology (M.v.d.H.), Medinzinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany; AP-HP (C.M., P.R.), Centre de Génétique Moléculaire et Chromosomique, UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire, GH Pitié-Salpêtrière, Paris; Department of Neurology (V.G.), University Hospital of Montpellier, France; Neuromuscular and Neurogenetic Disorders of Childhood Section (S.D.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Unit of Neuromuscular and Neurodegenerative Disorders (E.B.), Bambino Gesu' Children's Research Hospital, Rome, Italy; Departamento de Neurología Pediátrica (C.C.), Clínica Las Condes, Santiago, Chile; Paediatrics Department (D.C.), Hôpital de Hautepierre, Strasbourg, France; Neuromuscular Unit (J.C.), Neuropaediatrics Department, Institut de Recerca Hospital Universitari Sant Joan de Deu, Barcelona; Center for the Biomedical Research on Rare Diseases (CIBERER) (J.C.), ISCIII; Department of Neurology (M.L.C.), Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos; Department of Medicine (M.L.C.), Universidad Complutense de Madrid, Spain; Department of Neurology (M.d.V.), Amsterdam University Medical Centre, Amsterdam Neuroscience, the Netherlands; Department of Pediatric Neurology (I.D.), Necker Enfants Malades Hospital, Paris Descartes University, France; Department of Child Neurology (N.G.), University Hospitals Leuven, Belgium; Department of Pediatric Neurology (A.K.), Center for Chronically Sick Children, Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Germany; Department of Neuropediatrics (E.L.), CHRU de Tours, Université François Rabelais de Tours, UMR INSERM U1253, Tours, France; Department of Neuropediatrics (J.L.), University Children's Hospital of Basel (UKBB), Switzerland; Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France (E.M.), Neurology Department, Raymond-Poincaré Hospital, AP-HP, Garches; Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France (M.M.), Service de Neuropédiatrie, Hôpital Trousseau, Paris, France; Department of Biomedical and Neuromotor Sciences (L.M.), University of Bologna, Italy; Réanimation Médicale, Physiologie-Explorations Fonctionnelles et Centre d'Investigation Clinique, UMR 1429 (D.O.), INSERM-UMR, 1179, UVSQ (D.O.), and Neuromuscular Unit, Department of Pediatric Neurology, Intensive Care and Rehabilitation, AP-HP, UVSQ Paris Saclay (B. Estournet, S.Q.-R.), Hôpital Raymond Poincaré, Garches, France; Department of Neurology (U.R.), Medizinische Fakultät Carl Gustav Carus Technische Universität Dresden, German; Division of Pediatric Neurology, Department of Pediatrics (M.A.S.), College of Medicine, King Saud University, Riyadh, Saudi Arabia; Friedrich-Baur-Institut (B.S.-W.), Department of Neurology, Ludwig-Maximilians-University of Munich; Department of Pediatric Neurology (M.S.), University of Tübingen, Germany; The John Walton Muscular Dystrophy Research Centre (V.S.), Institute of Genetic Medicine, Newcastle University, Newcastle Hospitals NHS Foundation Trust, UK; Department of Child Neurology (H.T.), Hacettepe University, School of Medicine, Ankara, Turkey; Centre de Compétence Neuromusculaire (J.A.U.), Hôpital Marin, Hendaye, France; Department of Neurology (A.v.d.K.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, the Netherlands; Pediatrics and Adolescent Medicine, Division of Pediatric Neurology (E.W.), University Medical Center Göttingen, Georg-August University Göttingen, Germany; Neuromuscular and Neurogenetic Disorders of Childhood Section (C.G.B.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; and Department of Pediatric Neurology (U.S.), Developmental Neurology and Social Pediatrics, University of Essen, Germany.

Objective: To clarify the prevalence, long-term natural history, and severity determinants of -related myopathy (SEPN1-RM), we analyzed a large international case series.

Methods: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades.

Results: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity ( = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for age stratification.

Conclusion: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000010327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713742PMC
September 2020

The clinical-phenotype continuum in DYNC1H1-related disorders-genomic profiling and proposal for a novel classification.

J Hum Genet 2020 Nov 12;65(11):1003-1017. Epub 2020 Aug 12.

Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne (CMMC), Center for Rare Diseases, University of Cologne, Cologne, Germany.

Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13). Phenotypes and genotypes of ten pediatric patients with pathogenic DYNC1H1 variants were analyzed in a multi-center study. Data mining of large-scale genomic variant databases was used to investigate domain-specific vulnerability and conservation of DYNC1H1. We identified ten patients with nine novel mutations in the DYNC1H1 gene. These patients exhibit a broad spectrum of clinical findings, suggesting an overlapping disease manifestation with intermixed phenotypes ranging from neuropathy (peripheral nervous system, PNS) to severe intellectual disability (central nervous system, CNS). Genomic profiling of healthy and patient variant datasets underlines the domain-specific effects of genetic variation in DYNC1H1, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype-phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength in DYNC1H1-NMD and motor domain with cerebral malformations in DYNC1H1-NDD. We highlight that the current classification into distinct disease entities does not sufficiently reflect the clinical disease manifestation that clinicians face in the diagnostic work-up of DYNC1H1-related disorders. We propose a novel clinical classification for DYNC1H1-related disorders encompassing a spectrum from DYNC1H1-NMD with an exclusive PNS phenotype to DYNC1H1-NDD with concomitant CNS involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-020-0803-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719554PMC
November 2020

Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

Ann Neurol 2020 07 29;88(1):148-159. Epub 2020 May 29.

Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Objective: To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients.

Methods: We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity.

Results: Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome.

Interpretation: Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25754DOI Listing
July 2020

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

J Clin Endocrinol Metab 2020 05;105(5)

Clinical Research Branch, National Institute of Environmental Health Sciences, Durham, North Carolina.

Context: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.

Objective: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.

Methods: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.

Results: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient.

Conclusions: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108682PMC
May 2020

Age-specific occurrence of pathological fractures in patients with spina bifida.

Eur J Pediatr 2020 May 6;179(5):773-779. Epub 2020 Jan 6.

Charité-Universitätsmedizin Berlin, Center for Chronically Sick Children, Berlin, Germany.

Pathological fractures (PFs) are common in patients with spina bifida. However, most previous studies refer to the overall fracture rate and largely neglecting putative age-dependent aspects. The aim of this retrospective study was to characterize patterns of fracture occurrence in childhood. In a retrospective study, we identified PF, all in the lower limbs, in 13% of 210 patients with spina bifida aperta. We further identified a bimodal frequency distribution of pathological fractures, with peaks at 1-5 and 10-12 years. We could thereby distinguish two groups of patients: (i) Children with a first fracture before an age of 6 years developed frequently multiple fractures within the following years, but fracture series typically stopped by 6 years-of-age. (ii) Children with a first fracture after the age of 6 years had fewer fractures, but these occurred also in adolescence. PF occurred rarely after the age of 13 years. The age at fracture correlated with the fracture site with 85% of the fractures occurring in the femur in the first five years of life and an increased frequency of tibia and foot fractures later in life. While, overall high lesion levels and preceding immobilizing events were risk factors for PF, femur fractures in children under 6 years-of-age occurred independent of their lesion level, and the age at verticalization did not correlate with PF rates.Conclusion: Based on these findings, standardized and effective preventive physiotherapeutic and/or pharmacological interventions to tackle PF in spina bifida need to consider age-specific differences in occurrence and reoccurrence of fractures.What is Known:• Pathological fractures are common in patients with spina bifida aperta, and associated risk factors include high lesion level, immobilization and low bone density.What is New:• We first report a bimodal frequency distribution of pathological fractures in childhood (first peak 1-5 years, second peak 10-12 years) and link early-onset fracture occurrence with the risk of multiple fractures arise in a short time period but a the chance of self-limitation of fracture series within a few years.• We show that femur fractures in children under 6 years-of-age occurred independent of their lesion level, and the age at verticalization did not correlate with PF rates.• We further link the age-dependent occurrence pattern with the risk of further fractures and with the chance of self-limitation of fracture series. The earlier a first fracture occurs, the more probable multiple fractures arise in a short time period. Nevertheless, early fracture series are often self-limiting within a few years.• Femur fractures in children under 6 years-of-age occurred independent of their lesion level, and the age at verticalization did not correlate with PF rates.• Based on these findings, physiotherapeutic and/or pharmaceutical concepts need to be developed in an age-adapted manner and in consideration of the potential self-limiting nature of fracture series.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00431-019-03537-yDOI Listing
May 2020

MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.

Brain 2020 01;143(1):55-68

Laboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz379DOI Listing
January 2020

Early Onset, Long Illness Duration, Epilepsy Type, and Polypharmacy Have an Adverse Effect on Psychosocial Outcome in Children with Epilepsy.

Neuropediatrics 2020 04 21;51(2):164-169. Epub 2019 Nov 21.

Charité - Universitätsmedizin Berlin, Center for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Berlin, Germany.

Epilepsy is often associated with psychosocial comorbidity and this can be more disabling than the seizure activity. Still, these associated conditions are often underdiagnosed and therefore not sufficiently treated. We studied a large pediatric cohort of 371 patients with epilepsy to identify factors associated with negative outcome. We found that patients with early-onset epilepsy, epilepsy of known etiology, and polypharmacy were the most likely to display cognitive impairment. Behavioral problems were particularly prevalent in patients with an epilepsy duration ≥ 5 years. Similarly, early-onset epilepsy, long illness duration, epilepsy of known etiology, and polypharmacy had an adverse effect on school placement and/or social contact. With polypharmacy being the only potentially modifiable factor, it is important to balance between benefits and adverse effects of antiepileptic drugs and consider alternative therapy options in selected patients such as epilepsy surgery, vagal nerve stimulation, and ketogenic diet early-on.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-3399529DOI Listing
April 2020

A missense mutation in SNRPE linked to non-syndromal microcephaly interferes with U snRNP assembly and pre-mRNA splicing.

PLoS Genet 2019 10 31;15(10):e1008460. Epub 2019 Oct 31.

Department of Biology, Southern University of Science and Technology (SUSTech), Shenzhen, China.

Malfunction of pre-mRNA processing factors are linked to several human diseases including cancer and neurodegeneration. Here we report the identification of a de novo heterozygous missense mutation in the SNRPE gene (c.65T>C (p.Phe22Ser)) in a patient with non-syndromal primary (congenital) microcephaly and intellectual disability. SNRPE encodes SmE, a basal component of pre-mRNA processing U snRNPs. We show that the microcephaly-linked SmE variant is unable to interact with the SMN complex and as a consequence fails to assemble into U snRNPs. This results in widespread mRNA splicing alterations in fibroblast cells derived from this patient. Similar alterations were observed in HEK293 cells upon SmE depletion that could be rescued by the expression of wild type but not mutant SmE. Importantly, the depletion of SmE in zebrafish causes aberrant mRNA splicing alterations and reduced brain size, reminiscent of the patient microcephaly phenotype. We identify the EMX2 mRNA, which encodes a protein required for proper brain development, as a major mis-spliced down stream target. Together, our study links defects in the SNRPE gene to microcephaly and suggests that alterations of cellular splicing of specific mRNAs such as EMX2 results in the neurological phenotype of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1008460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850558PMC
October 2019

Just Expect It: Compound Heterozygous Variants of POMT1 in a Consanguineous Family-The Role of Next Generation Sequencing in Neuromuscular Disorders.

Neuropediatrics 2020 02 18;51(1):72-75. Epub 2019 Oct 18.

Charité-Universitätsmedizin Berlin, Klinik für Pädiatrie mit Schwerpunkt Neurologie, Augustenburger Platz 1, Berlin, Germany.

Muscular dystrophy-dystroglycanopathies (MDDG) are a group of genetically heterogeneous autosomal recessive disorders characterized by hypoglycosylation of α-dystroglycan. Here, we report on two female patients from a consanguineous Lebanese family that presented in early infancy with generalized muscle hypotonia and primary microcephaly. Brain magnetic resonance imaging (MRI) showed different degrees of hypoplasia of the cerebellar vermis and hypoplasia of corpus callosum. Muscle biopsy analyses revealed a muscular dystrophy with reduced expression of α-dystroglycan and merosin in immunoblot analyses. Homozygosity mapping failed to elucidate the causal mutation due to the accepted notion that, in consanguineous families, homozygote mutations cause disease. However, by applying whole exome sequencing, we identified a novel compound heterozygous mutation that segregates with the phenotype and is in line with the clinical presentation. This underscores that a less expected compound heterozygous instead of homozygous mutation in a consanguineous marriage results in a recessive disorder and highlights the growing role of next generation sequencing in neuromuscular disorder diagnostics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-1695787DOI Listing
February 2020

Congenital microcephaly-linked CDK5RAP2 affects eye development.

Ann Hum Genet 2020 01 29;84(1):87-91. Epub 2019 Jul 29.

Institute of Cell and Neurobiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Biallelic mutations in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause autosomal recessive primary microcephaly type 3 (MCPH3). MCPH is characterized by intellectual disability and microcephaly at birth, classically without further organ involvement. Only recently, congenital cataracts were reported in four patients of one pedigree with MCPH3. Given the lack of a further pedigree with this phenotype, it remained unclear whether this was a true causal relationship. Here we support the link between CDK5RAP2 and eye development by showing that most Cdk5rap2 mutant mice (an/an) exhibit eye malformations ranging from reduced size of one or both eyes (microphthalmia) to total absence of both eyes (anophthalmia). We also detected increased apoptosis in the an/an retinal progenitor cells associated with more mitotic cells. This indicates an important role of Cdk5rap2 in physiologic eye development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ahg.12343DOI Listing
January 2020

Fulminant cerebral venous thrombosis associated with the m.3243A>G MELAS mutation: A new guise for an old disease.

Brain Dev 2019 Nov 22;41(10):901-904. Epub 2019 Jul 22.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Neuropediatrics, Berlin, Germany; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Sozialpädiatrisches Zentrum, Berlin, Germany; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), NeuroCure Clinical Research Center, Berlin, Germany. Electronic address:

MELAS-syndrome (mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with various presentations. Common clinical manifestations include stroke-like episodes, encephalopathy with seizures, muscle weakness, recurrent headaches and vomiting, hearing impairment, and short stature. Uncommon clinical presentations like cerebral venous thrombosis, which is almost unprecedented for MELAS-syndrome, impede correct diagnosis. We describe a novel presentation of MELAS-syndrome with severe cerebral venous thrombosis (CVT) and inflammation with a vasculopathy that affects the venous system as well. This case does not only extend the clinical spectrum of a multifaceted disease, but offers new clues for the pathomechanism of MELAS-syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2019.07.002DOI Listing
November 2019

PEDIA: prioritization of exome data by image analysis.

Genet Med 2019 12 5;21(12):2807-2814. Epub 2019 Jun 5.

Institute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany.

Purpose: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists.

Methods: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds.

Results: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene.

Conclusion: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0566-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892739PMC
December 2019

Altered inhibition and excitation in neocortical circuits in congenital microcephaly.

Neurobiol Dis 2019 09 15;129:130-143. Epub 2019 May 15.

Charité - Universitätsmedizin Berlin, Institute of Cell- and Neurobiology, Charitéplatz 1, 10117 Berlin, Germany; Charité - Universitätsmedizin Berlin, Center for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Augustenburger Platz 1, 13353 Berlin, Germany; Charité - Universitätsmedizin Berlin, Department of Pediatric Neurology, Augustenburger Platz 1, 13353 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10178 Berlin, Germany. Electronic address:

Congenital microcephaly is highly associated with intellectual disability. Features of autosomal recessive primary microcephaly subtype 3 (MCPH3) also include hyperactivity and seizures. The disease is caused by biallelic mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2. In the mouse, Cdk5rap2 mutations similar to the human condition result in reduced brain size and a strikingly thin neocortex already at early stages of neurogenesis that persists through adulthood. The microcephaly phenotype in MCPH arises from a neural stem cell proliferation defect. Here, we report a novel role for Cdk5rap2 in the regulation of dendritic development and synaptogenesis of neocortical layer 2/3 pyramidal neurons. Cdk5rap2-deficient murine neurons show poorly branched dendritic arbors and an increased density of immature thin spines and glutamatergic synapses in vivo. Moreover, the excitatory drive is enhanced in ex vivo brain slice preparations of Cdk5rap2 mutant mice. Concurrently, we show that pyramidal neurons receive fewer inhibitory inputs. Together, these findings point towards a shift in the excitation - inhibition balance towards excitation in Cdk5rap2 mutant mice. Thus, MCPH3 is associated not only with a neural progenitor proliferation defect but also with altered function of postmitotic neurons and hence with altered connectivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2019.05.008DOI Listing
September 2019

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.

Ann Clin Transl Neurol 2019 Apr 3;6(4):655-668. Epub 2019 Mar 3.

Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders University Medical Center Göttingen Göttingen Germany.

Objective: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations.

Methods: We compiled 34 patients with a heterozygous (likely) pathogenic variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult +/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies.

Results: Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix.

Interpretation: Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469254PMC
April 2019

Subtelomeric methylation distinguishes between subtypes of Immunodeficiency, Centromeric instability and Facial anomalies syndrome.

Hum Mol Genet 2018 10;27(20):3568-3581

Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa, Israel.

Human telomeres and adjacent subtelomeres are packaged as heterochromatin. Subtelomeric DNA undergoes methylation during development by DNA methyltransferase 3B (DNMT3B), including the CpG-rich promoters of the long non-coding RNA (TERRA) embedded in these regions. The factors that direct DNMT3B methylation to human subtelomeres and maintain this methylation throughout lifetime are yet unknown. The importance of subtelomeric methylation is manifested through the abnormal telomeric phenotype in Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome type 1 patients carrying mutations in DNMT3B. Patient cells demonstrate subtelomeric hypomethylation, accompanied by elevated TERRA transcription, accelerated telomere shortening and premature senescence of fibroblasts. ICF syndrome can arise due to mutations in at least three additional genes, ZBTB24 (ICF2), CDCA7 (ICF3) and HELLS (ICF4). While pericentromeric repeat hypomethylation is evident in all ICF syndrome subtypes, the status of subtelomeric DNA methylation had not been described for patients of subtypes 2-4. Here we explored the telomeric phenotype in cells derived from ICF2-4 patients with the aim to determine whether ZBTB24, CDCA7 and HELLS also play a role in establishing and/or maintaining human subtelomeric methylation. We found normal subtelomeric methylation in ICF2-4 and accordingly low TERRA levels and unperturbed telomere length. Moreover, depleting the ICF2-4-related proteins in normal fibroblasts did not influence subtelomeric methylation. Thus, these gene products are not involved in establishing or maintaining subtelomeric methylation. Our findings indicate that human subtelomeric heterochromatin has specialized methylation regulation and highlight the telomeric phenotype as a characteristic that distinguishes ICF1 from ICF2-4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddy265DOI Listing
October 2018

Identification of a novel homozygous TRAPPC9 gene mutation causing non-syndromic intellectual disability, speech disorder, and secondary microcephaly.

Am J Med Genet B Neuropsychiatr Genet 2017 Dec 14;174(8):839-845. Epub 2017 Oct 14.

Charité - Universitätsmedizin Berlin, Institute of Neuroanatomy and Cell Biology, Berlin, Germany.

TRAPPC9 gene mutations have been linked recently to autosomal recessive mental retardation 13 (MRT13; MIM#613192) with only eight families reported world-wide. We assessed patients from two consanguineous pedigrees of Pakistani descent with non-syndromic intellectual disability and postnatal microcephaly through whole exome sequencing (WES) and cosegregation analysis. Here we report six further patients from two pedigrees with homozygous TRAPPC9 gene mutations, the novel nonsense mutation c.2065G>T (p.E689*) and the previously identified nonsense mutation c.1423C>T (p.R475*). We provide an overview of previously reported clinical features and highlight common symptoms and variability of MRT13. Common findings are intellectual disability and absent speech, and frequently microcephaly, motor delay and pathological findings on MRI including diminished cerebral white matter volume are present. Mutations in TRAPPC9 should be considered in non-syndromic autosomal recessive intellectual disability with severe speech disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.32602DOI Listing
December 2017

Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia.

Mitochondrion 2017 11 4;37:46-54. Epub 2017 Jul 4.

NeuroCure Clinical Research Center (NCRC), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Department of Neuropediatrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany. Electronic address:

Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitochondrial complex I and pyruvate dehydrogenase complex (PDHc) deficiency. Whole exome sequencing uncovered a known EXOSC3 mutation p.(D132A) as the underlying cause. In patient fibroblasts, a large portion of the EXOSC3 protein was trapped in the cytosol. MtDNA copy numbers in muscle were reduced to 35%, but mutations in the mtDNA and in nuclear mitochondrial genes were ruled out. RNA-Seq of patient muscle showed highly increased mRNA copy numbers, especially for genes encoding structural subunits of OXPHOS complexes I, III, and IV, possibly due to reduced degradation by a dysfunctional exosome complex. This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of PCH1B. We discuss the links between exosome and mitochondrial dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mito.2017.06.007DOI Listing
November 2017

Corrigendum: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Nat Genet 2017 05;49(6):969

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng0617-969cDOI Listing
May 2017

Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation.

PLoS Genet 2017 04 28;13(4):e1006746. Epub 2017 Apr 28.

Institute of Cell Biology and Neurobiology, Charité University Medicine Berlin, Berlin, Germany.

Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF) family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain-hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1006746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428974PMC
April 2017