Endosomal Trafficking Defects Alter Neural Progenitor Proliferation And
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Description Treatment
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. -
1Q21.1 Duplication Syndrome and Epilepsy Case Report and Review
CLINICAL/SCIENTIFIC NOTES OPEN ACCESS 1q21.1 Duplication syndrome and epilepsy Case report and review Ioulia Gourari, MD, Romaine Schubert, MD, and Aparna Prasad, PhD Correspondence Dr. Gourari Neurol Genet 2018;4:e219. doi:10.1212/NXG.0000000000000219 [email protected] Copy number variants (CNVs) of 1q21.1 are increasingly being recognized due to the wide- spread use of genetic screening tests for the investigation of developmental disorders and epilepsy. These include microdeletion and microduplication syndromes, associated with a wide variety of pathology including autism spectrum disorders, attention-deficit disorder, learning disabilities, hypotonia, facial dysmorphisms, and schizophrenia. The 1q21.1 region is consid- ered to be genetically unstable because it contains one of the largest areas of identical dupli- cation sequences in the human genome. Epilepsy has been reported in the literature, particularly in microdeletion syndromes, but rarely in association with microduplication syn- dromes. We report a patient with epilepsy and autism spectrum disorder due to a distal 1q21.1 microduplication and review the available literature and genetic information. Case report We present a 10-year-old girl with a low-functioning autism spectrum disorder and focal motor epilepsy. On examination, she has hypertelorism, minimal communicative language skills, and severe macrocephaly (HC = 57 cm, 3.6 SD > 99%). Seizures started at 7 years of age and consisted of head deviation to the left, generalized stiffening, clonic activity of the mouth, and fluttering of the eyelids, lasting for 1–2 minutes. Multiple video EEG recordings showed a right temporal focus with a less active, independent left temporal focus. 3T MRI scan of the brain was normal. -
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 ► -
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. -
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. -
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. -
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. -
Supratentorial Brain Malformations
Supratentorial Brain Malformations Edward Yang, MD PhD Department of Radiology Boston Children’s Hospital 1 May 2015/ SPR 2015 Disclosures: Consultant, Corticometrics LLC Objectives 1) Review major steps in the morphogenesis of the supratentorial brain. 2) Categorize patterns of malformation that result from failure in these steps. 3) Discuss particular imaging features that assist in recognition of these malformations. 4) Reference some of the genetic bases for these malformations to be discussed in greater detail later in the session. Overview I. Schematic overview of brain development II. Abnormalities of hemispheric cleavage III. Commissural (Callosal) abnormalities IV. Migrational abnormalities - Gray matter heterotopia - Pachygyria/Lissencephaly - Focal cortical dysplasia - Transpial migration - Polymicrogyria V. Global abnormalities in size (proliferation) VI. Fetal Life and Myelination Considerations I. Schematic Overview of Brain Development Embryology Top Mid-sagittal Top Mid-sagittal Closed Neural Tube (4 weeks) Corpus Callosum Callosum Formation Genu ! Splenium Cerebral Hemisphere (11-20 weeks) Hemispheric Cleavage (4-6 weeks) Neuronal Migration Ventricular/Subventricular Zones Ventricle ! Cortex (8-24 weeks) Neuronal Precursor Generation (Proliferation) (6-16 weeks) Embryology From ten Donkelaar Clinical Neuroembryology 2010 4mo 6mo 8mo term II. Abnormalities of Hemispheric Cleavage Holoprosencephaly (HPE) Top Mid-sagittal Imaging features: Incomplete hemispheric separation + 1)1) No septum pellucidum in any HPEs Closed Neural -
MR Imaging of N Euronal Migration Anomaly
대 한 방 사 선 의 학 회 지 1991; 27(3) : 323~328 Journal of Korean Radiological Society. May. 1991 MR Imaging of N euronal Migration Anomaly Hyun Sook Hong, M.D., Eun Wan Choi, M.D., Dae Ho Kim, M.D., Moo Chan Chung, M.D., Kuy Hyang Kwon, M.D., Ki Jung Kim, M.D. Department o[ RadíoJogy. Col1ege o[ Medícine. Soonchunhyang University patients ranged in age from 5 months to 42 years with Introduction a mean of 16 years. The mean age was skewed by 2 patients with schizencephaly who were 35 and 42 Abnormalities of neuronal migration Sl re years old. characterized by anectopic location of neurons in the MR was performed with a 0:2T permanent type cerebral cortex (1-9). This broad group of anomalies (Hidachi PRP 20). Slice thickness was 5mm with a includes agyria. pachygyria. schizencephaly. 2.5mm interslice gap or 7.5mm thickness. Spin echo unilateral megalencephaly. and gray matter axial images were obtained. including Tl weighted hcterotopia. Patients with this anomaly present images (TIWI) with a repetition time (TR) of clinically with a variety of symptoms which are pro 400-500ms and echo time (TE) of 25-40ms. in portional to the extent of the brain involved. These termediate images of TR/TE 2000/38. and T2 abnormalities have been characterized pathologically weighted images (T2Wl) with a TR/TE of 2000/110. in vivo by sonography and CT scan (2. 3. 10-14. Occasionally. sagittal and coronal images were ob 15-21). tained. Gd-DTPA enhanced Tl WI were 려 so obtain MR appears to be an imaging technique of choice ed in 6 patients. -
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. -
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. -
South Carolina Birth Defects Program Resource Guide
South Carolina Birth Defects Program Resource Guide A South Carolina where healthy births are promoted, every birth defect matters, and families impacted by birth defects are supported. Table Of Contents Introduction Introduction 1 Thousands of families in South Carolina have been impacted by a birth defect. Birth defects are structural changes which are already there when a baby is born that can affect any part of the body (e.g., heart, brain, South Carolina Birth Defects Program Mission and Vision 2 foot). They may affect how the body looks, works, or both. Birth defects can vary from mild to severe. The well-being of each child affected with a birth defect depends mostly on which organ or body part is involved, General Information on Birth Defects in South Carolina 4 how much it is affected, early detection, and timely entry into Early Intervention services. Cardiovascular (Heart) Birth Defects in South Carolina 5 Learning that a child has a birth defect can be difficult for a family. Families often feel alone when they find out about a birth defect. They are not alone. According to the Centers for Disease Control and Prevention, birth Interview with a Parent of a Child with a Critical Congenital Heart Birth Defect 7 defects affect 1 in 33 babies born every year and cause 1 in 5 infant deaths. In 2004, South Carolina government officials created a way to track these important conditions through a law called “The South Carolina Birth Orofacial Birth Defects 11 Defects Act.” The South Carolina Birth Defects Program (SCBDP) was created through this law.