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Description Megalencephaly, also called macrencephaly, is a condition in which an infant or child has an abnormally large, heavy, and usually malfunctioning brain. By deﬁnition, the brain weight is greater than average for the age and gender of the child. Head enlargement may be evident at birth or the head may become abnormally large in the early years of life. Megalencephaly is thought to be related to a disturbance in the regulation of cell production in the brain. In normal development, neuron proliferation - the process in which nerve cells divide to form new generations of cells - is regulated so that the correct number of cells is produced in the proper place at the appropriate time. In a megalencephalic brain, too many cells are produced either during development or progressively as part of another disorder, such as one of the neuroﬁbromatoses or leukodystrophies. Symptoms of megalencephaly include delayed development, seizures, and corticospinal (brain cortex and spinal cord) dysfunction. Megalencephaly affects males more often than females. Unilateral megalencephaly or hemimegalencephaly is a rare condition that is characterized by the enlargement of one side of the brain. Children with this disorder may have a large, asymmetrical head accompanied by seizures, partial paralysis, and impaired cognitive development. Megalencephaly is different from macrocephaly (also called megacephaly or megalocephaly), which describes a big head, and which doesn’t necessarily indicate abnormality. Large head size is passed down through the generations in some families. Treatment There is no standard treatment for megalencephaly. Treatment will depend upon the disorder with which the megalencephaly is associated and will address individual symptoms and disabilities. Prognosis The prognosis for infants and children with megalencephaly depends upon the underlying cause and the associated neurological disorders. The prognosis for children with hemimegalencephaly is poor. Research The National Institute of Neurological Disorders and Stroke (NINDS) and other institutes of the National Institutes of Health (NIH) conduct research related to megalencephaly in laboratories at the NIH and also support additional research through grants to major medical institutions across the country. Much of this research explores the complex mechanisms of normal brain development. The knowledge gained from these fundamental studies will provide a foundation for developing ways to prevent megalencephaly and the other cephalic disorders. Information from the National Library of Medicine’s MedlinePlus Brain Malformations BACK TO Disorders List.

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Megalencephaly and Macrocephaly
277 Megalencephaly and Macrocephaly KellenD.Winden,MD,PhD1 Christopher J. Yuskaitis, MD, PhD1 Annapurna Poduri, MD, MPH2 1 Department of Neurology, Boston Children’s Hospital, Boston, Address for correspondence Annapurna Poduri, Epilepsy Genetics Massachusetts Program, Division of Epilepsy and Clinical Electrophysiology, 2 Epilepsy Genetics Program, Division of Epilepsy and Clinical Department of Neurology, Fegan 9, Boston Children’s Hospital, 300 Electrophysiology, Department of Neurology, Boston Children’s Longwood Avenue, Boston, MA 02115 Hospital, Boston, Massachusetts (e-mail: [email protected]). Semin Neurol 2015;35:277–287. Abstract Megalencephaly is a developmental disorder characterized by brain overgrowth secondary to increased size and/or numbers of neurons and glia. These disorders can be divided into metabolic and developmental categories based on their molecular etiologies. Metabolic megalencephalies are mostly caused by genetic defects in cellular metabolism, whereas developmental megalencephalies have recently been shown to be caused by alterations in signaling pathways that regulate neuronal replication, growth, and migration. These disorders often lead to epilepsy, developmental disabilities, and Keywords behavioral problems; speciﬁc disorders have associations with overgrowth or abnor- ► megalencephaly malities in other tissues. The molecular underpinnings of many of these disorders are ► hemimegalencephaly now understood, providing insight into how dysregulation of critical pathways leads to ►
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Polymicrogyria (PMG) ‘Many–Small–Folds’
Polymicrogyria Dr Andrew Fry Clinical Senior Lecturer in Medical Genetics Institute of Medical Genetics, Cardiff [email protected] Polymicrogyria (PMG) ‘Many–small–folds’ • PMG is heterogeneous – in aetiology and phenotype • A disorder of post-migrational cortical organisation. PMG often appears thick on MRI with blurring of the grey-white matter boundary Normal PMG On MRI PMG looks thick but the cortex is actually thin – with folded, fused gyri Courtesy of Dr Jeff Golden, Pen State Unv, Philadelphia PMG is often confused with pachygyria (lissencephaly) Thick cortex (10 – 20mm) Axial MRI 4 cortical layers Lissencephaly Polymicrogyria Cerebrum Classical lissencephaly is due Many small gyri – often to under-migration. fused together. Axial MRI image at 7T showing morphological aspects of PMG. Guerrini & Dobyns Malformations of cortical development: clinical features and genetic causes. Lancet Neurol. 2014 Jul; 13(7): 710–726. PMG - aetiology Pregnancy history • Intrauterine hypoxic/ischemic brain injury (e.g. death of twin) • Intrauterine infection (e.g. CMV, Zika virus) TORCH, CMV PCR, [+deafness & cerebral calcification] CT scan • Metabolic (e.g. Zellweger syndrome, glycine encephalopathy) VLCFA, metabolic Ix • Genetic: Family history Familial recurrence (XL, AD, AR) Chromosomal abnormalities (e.g. 1p36 del, 22q11.2 del) Syndromic (e.g. Aicardi syndrome, Kabuki syndrome) Examin - Monogenic (e.g. TUBB2B, TUBA1A, GPR56) Array ation CGH Gene test/Panel/WES/WGS A cohort of 121 PMG patients Aim: To explore the natural history of PMG and identify new genes. Recruited: • 99 unrelated patients • 22 patients from 10 families 87% White British, 53% male ~92% sporadic cases (NB. ascertainment bias) Sporadic PMG • Array CGH, single gene and gene panel testing - then a subset (n=57) had trio-WES.
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CONGENITAL ABNORMALITIES of the CENTRAL NERVOUS SYSTEM Christopher Verity, Helen Firth, Charles Ffrench-Constant *I3
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.suppl_1.i3 on 1 March 2003. Downloaded from CONGENITAL ABNORMALITIES OF THE CENTRAL NERVOUS SYSTEM Christopher Verity, Helen Firth, Charles ffrench-Constant *i3 J Neurol Neurosurg Psychiatry 2003;74(Suppl I):i3–i8 dvances in genetics and molecular biology have led to a better understanding of the control of central nervous system (CNS) development. It is possible to classify CNS abnormalities Aaccording to the developmental stages at which they occur, as is shown below. The careful assessment of patients with these abnormalities is important in order to provide an accurate prog- nosis and genetic counselling. c NORMAL DEVELOPMENT OF THE CNS Before we review the various abnormalities that can affect the CNS, a brief overview of the normal development of the CNS is appropriate. c Induction—After development of the three cell layers of the early embryo (ectoderm, mesoderm, and endoderm), the underlying mesoderm (the “inducer”) sends signals to a region of the ecto- derm (the “induced tissue”), instructing it to develop into neural tissue. c Neural tube formation—The neural ectoderm folds to form a tube, which runs for most of the length of the embryo. c Regionalisation and specification—Specification of different regions and individual cells within the neural tube occurs in both the rostral/caudal and dorsal/ventral axis. The three basic regions of copyright. the CNS (forebrain, midbrain, and hindbrain) develop at the rostral end of the tube, with the spinal cord more caudally. Within the developing spinal cord specification of the different popu- lations of neural precursors (neural crest, sensory neurones, interneurones, glial cells, and motor neurones) is observed in progressively more ventral locations.
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Classification of Congenital Abnormalities of the CNS
315 Classification of Congenital Abnormalities of the CNS M. S. van der Knaap1 A classification of congenital cerebral, cerebellar, and spinal malformations is pre J . Valk2 sented with a view to its practical application in neuroradiology. The classification is based on the MR appearance of the morphologic abnormalities, arranged according to the embryologic time the derangement occurred. The normal embryology of the brain is briefly reviewed, and comments are made to explain the classification. MR images illustrating each subset of abnormalities are presented. During the last few years, MR imaging has proved to be a diagnostic tool of major importance in children with congenital malformations of the eNS [1]. The excellent gray fwhite-matter differentiation and multi planar imaging capabilities of MR allow a systematic analysis of the condition of the brain in infants and children. This is of interest for estimating prognosis and for genetic counseling. A classification is needed to serve as a guide to the great diversity of morphologic abnormalities and to make the acquired data useful. Such a system facilitates encoding, storage, and computer processing of data. We present a practical classification of congenital cerebral , cerebellar, and spinal malformations. Our classification is based on the morphologic abnormalities shown by MR and on the time at which the derangement of neural development occurred. A classification based on etiology is not as valuable because the various presumed causes rarely lead to a specific pattern of malformations. The abnor malities reflect the time the noxious agent interfered with neural development, rather than the nature of the noxious agent. The vulnerability of the various structures to adverse agents is greatest during the period of most active growth and development.
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Unilateral Megalencephaly. Correlates
523 Unilateral Megalencephaly: Correlation of MR Imaging and Pathologic Characteristics A. James Barkovich 1 Unilateral megalencephaly is a rare and poorly understood malformation resulting in Sylvester H. Chuang2 the enlargement of all or part of a cerebral hemisphere. The clinical and radiologic features of 12 patients with unilateral megalencephaly are presented; pathologic cor relation was available in four. All patients had seizures and developmental delay. Two were in congestive heart failure as a result of arteriovenous shunting through the abnormal hemisphere. The affected hemispheres showed a wide spectrum of involve ment. Anomalies of neuronal migration were present, and there was a roughly inverse correlation between the severity of hemispheric involvement and the magnitude of enlargement. This correlation is explained via a proposed mechanism of a mild hemi spheric insult in the middle-to-late second trimester. One patient had an extremely anomalous hemisphere that did not have characteristics of a neuronal migration anomaly and may have been a hamartomatous malformation. Our correlation of the clinical, radiologic, and pathologic features of unilateral mega lencephaly, together with a theory of pathogenesis, should help elucidate this rare malformation. AJNR 11:523-531, May{June 1990 Unilateral megalencephaly is a rare anomaly of the brain in which all or part of one hemisphere is enlarged in the absence of somatic hemihypertrophy [1- 8). We recently reviewed the imaging studies of 12 patients with this anomaly; histologic material was available in four of these. In this report, we describe the clinical , radiologic, and pathologic features of this anomaly and relate the pathologic anatomy to a proposed theory of pathogenesis.
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Supratentorial Brain Malformations
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MR Imaging of N Euronal Migration Anomaly
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Brain Morphometric Analysis in Neurofibromatosis 1
ORIGINAL CONTRIBUTION Brain Morphometric Analysis in Neurofibromatosis 1 Francis J. DiMario, Jr, MD; Gale R. Ramsby, MD; Joseph A. Burleson, PhD Rationale and Objectives: To investigate the rela- Results: Therewere27patients(20boys,aged1.0-17.7years; tionships between brain and skull base growth in pa- mean age, 8.8 years) and 43 controls (22 boys, aged 0.1-17.7 tients with neurofibromatosis 1 (NF1) compared with years; mean age, 5.9 years). The mean ages between groups healthy control subjects using brain magnetic reso- (boys, girls, and totals) were not statistically different. Sig- nance imaging (MRI) for morphometric analysis. nificant differences were appreciated for 6 of 24 measures. Patients with NF1 had a significantly larger bicaudate width Methods: Evaluated patients included children who (P = .002), biatrial width (P,.001), and biparietal diameter underwent T1- and T2-weighted or dual-echo proton (P = .003), but not hemispheric length. They also had sig- density axial and T1-weighted sagittal brain MRI from nificantly increased iter measures (P = .004), descending sig- January 1, 1988, to December 31, 1995. Study subjects moid sinus (P,.001), and an age-specific increase in brain- (n = 27) received a diagnosis of NF1 by accepted stem height (P = .03) not seen in controls. National Institutes of Health clinical criteria and were compared with an age- and sex-matched control group Conclusions: Patients with NF1 experience dynamic (n = 43). Twenty-four predetermined ventricular and changes in brain morphometry, resulting in a predomi- brain parenchymal dimensions and area calculations nant lateral volume expansion of the supratentorial com- were evaluated. Data were analyzed using 2-tailed t tests, partment and an increasing velocity of brainstem growth x2 analysis, analysis of variance, and analysis of covari- as they age.
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The Identification and Validation of Neural Tube Defects in the General Practice Research Database
THE IDENTIFICATION AND VALIDATION OF NEURAL TUBE DEFECTS IN THE GENERAL PRACTICE RESEARCH DATABASE Scott T. Devine A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Public Health (Epidemiology). Chapel Hill 2007 Approved by Advisor: Suzanne West Reader: Elizabeth Andrews Reader: Patricia Tennis Reader: John Thorp Reader: Andrew Olshan © 2007 Scott T Devine ALL RIGHTS RESERVED - ii- ABSTRACT Scott T. Devine The Identification And Validation Of Neural Tube Defects In The General Practice Research Database (Under the direction of Dr. Suzanne West) Background: Our objectives were to develop an algorithm for the identification of pregnancies in the General Practice Research Database (GPRD) that could be used to study birth outcomes and pregnancy and to determine if the GPRD could be used to identify cases of neural tube defects (NTDs). Methods: We constructed a pregnancy identification algorithm to identify pregnancies in 15 to 45 year old women between January 1, 1987 and September 14, 2004. The algorithm was evaluated for accuracy through a series of alternate analyses and reviews of electronic records. We then created electronic case definitions of anencephaly, encephalocele, meningocele and spina bifida and used them to identify potential NTD cases. We validated cases by querying general practitioners (GPs) via questionnaire. Results: We analyzed 98,922,326 records from 980,474 individuals and identified 255,400 women who had a total of 374,878 pregnancies. There were 271,613 full-term live births, 2,106 pre- or post-term births, 1,191 multi-fetus deliveries, 55,614 spontaneous abortions or miscarriages, 43,264 elective terminations, 7 stillbirths in combination with a live birth, and 1,083 stillbirths or fetal deaths.
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Endosomal Trafficking Defects Alter Neural Progenitor Proliferation And
bioRxiv preprint doi: https://doi.org/10.1101/2020.08.17.254037; this version posted August 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 2 Endosomal trafficking defects alter neural progenitor proliferation 3 and cause microcephaly 4 5 Jacopo A. Carpentieri1, Amandine Di Cicco1, David Andreau1, Laurence Del Maestro2, Fatima 6 El Marjou1, Laure Coquand1, Jean-Baptiste Brault1, Nadia Bahi-Buisson3, Alexandre D. 7 Baffet1,4,# 8 9 1- Institut Curie, PSL Research University, CNRS UMR144, 75005 Paris, France 10 2- Centre Épigénétique et destin cellulaire, Université Paris Diderot, CNRS UMR 7216, 75013 Paris, 11 France 12 3- INSERM U1163, Institut Imagine, Necker Hospital, 75015 Paris, France 13 4- Institut national de la santé et de la recherche médicale (Inserm) 14 # Corresponding author: [email protected] 15 16 Abstract 17 Primary microcephaly and megalencephaly are severe brain malformations defined by reduced 18 and increased brain size, respectively. Whether these two pathologies arise from related alterations at 19 the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, 20 leading to cell death. Here, we investigated the consequences of WDR81 loss of function, which cause 21 severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR, 22 and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial 23 progenitor cells knocked-out for WDR81 display reduced proliferation rates, leading to reduced brain 24 size.
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Chapter III: Case Definition
NBDPN Guidelines for Conducting Birth Defects Surveillance rev. 06/04 Appendix 3.5 Case Inclusion Guidance for Potentially Zika-related Birth Defects Appendix 3.5 A3.5-1 Case Definition NBDPN Guidelines for Conducting Birth Defects Surveillance rev. 06/04 Appendix 3.5 Case Inclusion Guidance for Potentially Zika-related Birth Defects Contents Background ................................................................................................................................................. 1 Brain Abnormalities with and without Microcephaly ............................................................................. 2 Microcephaly ............................................................................................................................................................ 2 Intracranial Calcifications ......................................................................................................................................... 5 Cerebral / Cortical Atrophy ....................................................................................................................................... 7 Abnormal Cortical Gyral Patterns ............................................................................................................................. 9 Corpus Callosum Abnormalities ............................................................................................................................. 11 Cerebellar abnormalities ........................................................................................................................................
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Epidemiology of Congenital Cerebral Anomalies in Europe – a Multi-Centre, Population-Based EUROCAT Study
1 Epidemiology of congenital cerebral anomalies in Europe – a multi-centre, population-based EUROCAT study Joan K Morris1, Diana Wellesley2, Ingeborg Barisic3, Marie-Claude Addor4, Jorieke EH Bergman5 , Paula Braz6, Clara Cavero-Carbonell7, Elizabeth S Draper8, Miriam Gatt9, Martin Haeusler10, Kari Klungsoyr11, Jennifer J Kurinczuk12, Nathalie Lelong13 , Karen Luyt14 , Catherine Lynch15, Mary T O’Mahony16, Olatz Mokoroa17, Vera Nelen18, Amanda J Neville19, Anna Pierini20, Hanitra Randrianaivo21, Judith Rankin22, Anke Rissmann23 , Florence Rouget 24, Bruno Schaub25, David Tucker26, Christine Verellen-Dumoulin27, Awi Wiesel28, Natalia Zymak-Zakutnia29, Monica Lanzoni30, Ester Garne31 Corresponding Author: Professor Joan K Morris, Address: Population Health Research Institute St George’s, University of London, Cranmer Terrace SW17 0RE UK. Email : [email protected] Phone : +44(0)2087251324 1 Population Health Research Institute, St George’s, University of London, London, UK. 2University Hospitals Southampton, Faculty of Medicine and Wessex Clinical Genetics Service, Southampton, UK. 3Children's Hospital Zagreb, Centre of Excellence for Reproductive and Regenerative Medicine, Medical School University of Zagreb, Zagreb, Croatia. 4Department of Woman-Mother-Child, University Hospital Center CHUV, Lausanne, Switzerland. 5Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 6Department of Epidemiology, National Institute of Health Doutor Ricardo Jorge, Lisbon, Portugal. 7Rare Diseases Research Unit, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, Valencia, Spain. 8Department of Health Sciences, University of Leicester, Leicester, UK. 9Directorate for Health Information and Research, Valetta, Malta. 10Medical University of Graz, Graz, Austria. 11Division for mental and physical health, Norwegian Institute of Public Health, Bergen, Norway and Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
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