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Cortical Brain Malformations: Effect of Clinical, Neuroradiological, and Modern Genetic Classification

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Cortical Brain Malformations: Effect of Clinical, Neuroradiological, and Modern Genetic Classification ORIGINAL CONTRIBUTION Cortical Brain Malformations Effect of Clinical, Neuroradiological, and Modern Genetic Classification Marie Claire Yvette de Wit, MD; Maarten H. Lequin, MD, PhD; Ireneaus F. M. de Coo, MD, PhD; Esther Brusse, MD; Dicky J. J. Halley, PhD; Raoul van de Graaf, BSc; Rachel Schot, BSc; Frans W. Verheijen, PhD; Grazia M. S. Mancini, MD, PhD Background: Malformations of cortical development Results: We established an etiological diagnosis in 45 of (MCDs) are a major source of handicap. Much progress 113 cases (40%). For 21 patients (19%), this included mo- in understanding the genetic causes has been made re- lecular and/or genetic confirmation (Miller-Dieker syn- cently. The number of affected children in whom a mo- drome; LIS1, DCX, FLNA, EIF2AK3, or KIAA1279 muta- lecularly confirmed diagnosis can be made is unclear. tions; or an inborn error of metabolism). In 17 (15%), a syndrome with an unknown genetic defect was diag- Objective: To evaluate the etiology of MCDs in chil- nosed. In 7 patients (6%), we found evidence of a gesta- dren and the effect of a combined radiological, clinical, tional insult. Of the remaining 68 patients, 34 probably and syndrome classification. have a yet-unknown genetic disorder based on the pres- ence of multiple congenital anomalies (15 patients), a fam- Design: A case series of 113 children with a radiologi- ily history with multiple affected persons (12 patients), or cal diagnosis of MCD from January 1, 1992, to Janu- consanguineous parents (7 patients). ary 1, 2006. Conclusions: In our cohort, combining diagnostic mo- Setting: The Erasmus Medical Center–Sophia Chil- lecular testing with clinical, radiological, and genetic clas- dren’s Hospital, a secondary and tertiary referral center. sification; syndrome identification; and family study pro- vided a diagnosis in 40% of the cases of MCD. This Patients: Patients with MCD underwent a complete ra- contributes to the possibility of prenatal diagnosis and diological, clinical, and neurological assessment and test- improved patient treatment and disease management. ing for known genes involved in the pathogenesis of MCD as appropriate for their phenotype. Arch Neurol. 2008;65(3):358-366 ALFORMATIONS OF COR- Accurate classification is important for tical development patient care and for improving insight into (MCDs) are a major different phenotypes and causes. The 2005 source of mental retar- classification system for MCD distin- dation, motor dysfunc- guishes disorders of cell proliferation, mi- tion,M and epilepsy in children. Up to 10% gration, and cortical organization and is of children with epilepsy are estimated to useful for guiding the diagnostic ap- have an MCD, and the percentage is greater proach in individual patients.7 in those with intractable epilepsy.1 Not all This approach starts with a detailed patients with MCD develop epilepsy, how- brain magnetic resonance imaging (MRI) ever, and the level of motor and mental study, combined with medical and fam- handicap varies. In recent years, much ily history and a pediatric and neurologi- Author Affiliations: progress has been made in understanding cal examination. Affected relatives, paren- Departments of Pediatric the genetic and molecular basis of cortical tal consanguinity, dysmorphic features, Neurology (Drs de Wit, de Coo, development. Several essential genes have and typical MCD patterns can suggest ge- and Brusse), Pediatric been identified (Table 1). Also, MCDs netic causes. Complications during preg- Neuroradiology (Dr Lequin), have been described in patients with known nancy or congenital infections can be com- and Clinical Genetics syndromes such as the Adams-Oliver, Del- patible with a fetal insult. Internal organ (Drs Halley, Verheijen, and leman, MICRO, and Kabuki make-up syn- dysfunction and a progressive course may Mancini; Mr van de Graaf; and 2-6 8 Ms Schot), Erasmus Medical dromes. Illustratively, the London Medi- suggest a metabolic disease. Center–Sophia Children’s cal Dysmorphology Database includes 46 Apart from monogenetic mutations, Hospital, Rotterdam, syndromes with MCD as a requirement and chromosomal anomalies should be looked the Netherlands. 232 with MCD as a possible feature. for. Some microdeletions can cause dis- (REPRINTED) ARCH NEUROL / VOL 65 (NO. 3), MAR 2008 WWW.ARCHNEUROL.COM 358 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Table 1. Genes Known to Be Involved in MCD Gene Chromosome OMIM No.a Protein Inheritance Description MCPH1 8p 607117 Microcephalin AR MCPH phenotype of a simplified gyral pattern, microcephaly, and relatively good clinical function ASPM 1q 608716 Abnormal spindle-like, microcephaly- AR MCPH phenotype associated protein CDK5RAP2 9q34 608201 CDK5 regulatory subunit–associated protein 2 AR MCPH phenotype CENPJ 13q12.2 609279 Centromeric protein J AR MCPH phenotype SLC25A19 17q25.3 607196 Mitochondrial deoxynucleotide carrier AR Simplified gyration, early death, 2-ketoglutaric aciduria EIF2AK3 2p12 226980 eIF2␣ kinase 3 AR Simplified gyral pattern in Wolcott-Rallison syndrome LIS1 17p13.3 607432 Platelet-activating factor acetylhydrolase, AD Pachygyria with a posterior-to-anterior gradient isoform 1b, ␣ subunit DCX Xq22-23 300121 Doublecortin XL In boys, lissencephaly; in girls, subcortical band heterotopia RELN 7q22 600514 Reelin AR Lissencephaly with cerebellar and brainstem hypoplasia VLDLR 9p24 192977 Very low-density lipoprotein receptor AR Pachygyria with cerebellar hypoplasia ARX Xp22.13 300382 Aristaless-related homeobox protein XL Diverse phenotypes from lissencephaly, abnormal genitalia, and corpus callosum agenesis to XL mental retardation TUBA3 12q12 602529 Tubulin AD Pachygyria, hypoplastic splenium, vermis, and medulla FLNA Xq28 300017 Filamin A XL Loss-of-function mutations, periventricular nodular heterotopia; sometimes with Ehlers-Danlos syndrome, other skeletal disorder, or cardiac malformation ARFGEF2 20q13.13 605371 Brefeldin A–inhibited guanine nucleotide AR Periventricular nodular heterotopia, congenital exchange protein 2 microcephaly, severe developmental delay GPR56 16q13 604110 G protein–coupled receptor 56 AR Bilateral frontoparietal PMG, white matter abnormalities KIAA1279 10q22.1 609367 Unknown AR Diffuse PMG, Hirschsprung disease, dysmorphic features FKRP 19q13.3 606596 Fukutin-related protein AR Cobblestone-type lissencephaly, muscular dystrophy, eye abnormalities FCMD 9q31 607440 Fukutin AR Walker-Warburg syndrome POMT1 9q34.1 607423 O-mannosyltransferase-1 AR Walker-Warburg syndrome POMGnT1 14q24.3 607439 O-mannosyltransferase-2 AR Walker-Warburg syndrome LARGE 22q12.3-13.1 603590 Acetylglucosaminyl transferase–like protein AR Muscular dystrophy, eye abnormalities, structural brain abnormalities RAB3GAP1 2q21.3 602536 RAB3 glutamyl transpeptidase–activating AR Warburg MICRO syndrome with pachygyria, protein microcephaly, microphthalmia, congenital cataract, hypogonadism Abbreviations: AD, autosomal dominant; AR, autosomal recessive; MCD, malformations of cortical development; PMG, polymicrogyria; XL, X-linked. aAvailable at http://www.ncbi.nlm.nih.gov/omim. tinctive MCD, particularly interstitial deletions of chro- cal Genetics at the Erasmus Medical Center were retrospec- mosome 17p in lissencephaly, duplications of 5p in nodu- tively collected from January 1, 1992, through December 31, lar heterotopia, and microdeletions of 22q11 in 2001, and prospectively from January 1, 2002, to January 1, polymicrogyria (PMG).9-11 2006. We stopped inclusion when we started to recruit referrals The aims of the present study were to evaluate the effect actively. Information on the retrospective group was collected of clinical, radiological, and genetic test results on etio- using the radiology reports as documented in the medical cor- logical diagnosis in a series of consecutive cases of MCD respondence database of the Erasmus Medical Center–Sophia in a university children’s hospital; to describe the rela- Children’s Hospital using the terms simplified gyral pattern, lis- tionship between diagnosis and clinical features; and to sencephaly, pachygyria, polymicrogyria, heterotopia, cortical dys- plasia, and migration disorder. All patients with available neu- evaluate the consequences of an etiological diagnosis for roimaging studies were included. All neuroimaging findings disease management and genetic counseling. (MRI and computed tomography) were reevaluated by a pedi- atric neurologist (I.F.M.d.C.), a clinical geneticist (G.M.S.M.), METHODS and a pediatric neuroradiologist (M.H.L.). From 1992 to 2005, we included the most recent MRI study if a diagnosis of MCD PATIENT POPULATION was made when the patient was younger than 16 years. Con- sensus was required and patients were classified into 4 groups The medical records of children with MCD referred to the De- on the basis of MRI criteria.7,12 None of the patients had a mo- partment of Pediatric Neurology or the Department of Clini- lecularly confirmed diagnosis. (REPRINTED) ARCH NEUROL / VOL 65 (NO. 3), MAR 2008 WWW.ARCHNEUROL.COM 359 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 We excluded patients with neoplasms, tuberous sclerosis, and RESULTS neurofibromatosis 1. We excluded those with hydranen- cephaly and holoprosencephaly, unless associated with obvi- ous MCD such as periventricular nodular heterotopia. We ex- PATIENT CLASSIFICATION cluded patients with infratentorial abnormalities only and patients
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