Genetic Causes of Cerebrovascular Disorders in Childhood

Genetic Causes of Cerebrovascular Disorders in Childhood Marije Meuwissen Genetic Causes of Cerebrovascular Disorders in Childhood Cover photo: Robert Ludlow, UCL Institute of Neurology, Wellcome Images (used with permission) Cover design and layout: R. Grefhorst Printing: Druk. Tan Heck, Delft © 2014, M.E.C. Meuwissen All rights reserved. No part of this publication may be reproduced in any form or by any means, electronic, mechanical, photocopy, recording or otherwise, without the written permission of the author. ISBN: 978-90-6824-047-4 The work presented in this thesis was performed at the Department of Clinical Genetics at the Erasmus University Medical Center, Rot- terdam This work was financially supported by Fonds NutsOhra Genetic Causes of Cerebrovascular Disorders in Childhood Genetische oorzaken van cerebrovasculaire aandoeningen op de kinderleeftijd Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.A.P. Pols en volgens besluit van het College voor Promoties De openbare verdediging zal plaatsvinden op Woensdag 2 april om 15:30 uur door Marije Ellen Carolien Meuwissen geboren te Leidschendam PROMOTIECOMMISSIE Promotor Prof. dr. R.M.W. Hofstra Co-promotor Dr. G.M.S. Mancini Overige leden Prof. dr. I.K.M. Reiss Prof. dr. R.C.M. Hennekam Prof. dr. K. Braun Het verschijnen van dit proefschrift werd mede mogelijk gemaakt door de steun van de Nederlandse Hartstichting. CONTENTS GENERAL INTRODUCTION Chapter 1 General introduction and outline of the thesis 11 PART I GENETIC CAUSES OF ISCHEMIC STROKE Chapter 2.1 ACTA2 mutation with childhood cardiovascular, autonomic 45 and brain anomalies and severe outcome Chapter 2.2 Neurological findings in Incontinentia Pigmenti; a review 57 PART II GENETIC CAUSES OF HEMORRHAGIC STROKE Chapter 3 The expanding phenotype of COL4A1 and COL4A2 mutations; 81 clinical data on 13 newly identified families and review of literature Chapter 4.1 Sporadic COL4A1 mutations with extensive prenatal 107 porencephaly resembling hydranencephaly Chapter 4.2 Novel COL4A1 mutation in familial anterior segment dysgenesis 117 Chapter 4.3 Is autosomal recessive inheritance possible in hereditary 125 porencephaly due to COL4A1 mutations? Chapter 5 COL4A2 mutation associated with familial porencephaly 133 and small-vessel disease Chapter 6 Interferon type 1 response regulator USP18 is 163 mutated in severe pseudo-TORCH syndrome DISCUSSION AND SUMMARY Chapter 7 General discussion 193 Summary 213 Samenvatting 219 Curriculum Vitae 225 PhD Portfolio 227 List of publications 231 Dankwoord 235 Colour figures 241 INTRODUCTION Chapter 1 GENERAL INTRODUCTION AND OUTLINE OF THE THESIS GENERAL INTRODUCTION Cerebrovascular disorders are defined as focal cerebral injury with an underlying vascular basis and can be divided in stroke resulting from arterial ischemic event, cerebral sinove- nous thrombosis and hemorrhage1. Stroke at young age (< age 18) is not common, but is an important cause of lifelong morbidity and is among the top ten causes of death in child- hood2-4. It has an incidence of approximately 1.3-13 per 100.000 per year in the developed countries. Causes, risk factors and pathogenic mechanisms of pediatric stroke differ in the perinatal period or in childhood. Pediatric arterial ischemic stroke Arterial ischemic stroke (AIS) in childhood is usually non-atherosclerotic, which is differ- ent from the adult population. In half of the children with AIS, a pre-existing condition can be identified, such as congenital heart disease or sickle cell disease; in the other part it remains uncertain and may be due to an interplay of both genetic and environmental factors. AIS can occur for example in the presence of genetic prothrombotic disorders, but also in the context of a metabolic disease (Fabry disease, congenital disorders of glycosylation) or other underlying genetic cerebral arteriopathies. In the perinatal period, most relevant risk factors are linked to maternal risk factors, such as autoimmune disease, preeclamp- sia, traumas, and neonatal, such as infection, systemic illness (including inborn errors of metabolism) and complex congenital heart disease. Very few genetic causes are known. In the first part of this thesis, two examples of genetic disorders leading to ischemic cerebral arteriopathy, Incontinentia pigmenti and ACTA2 mutations, are described in more detail. Pediatric Hemorrhagic stroke In the main part of this thesis, we will focus on processes underlying cerebral hemorrhage occurring at young age, mostly in the perinatal and infantile period. In the childhood population, the proportion of hemorrhagic stroke is approximately 50%, versus only 15% in the adult population1,2,4. Hemorrhagic stroke (bleeding) is the result of a weakened vessel that ruptures and bleeds into the surrounding brain. Overall mortality of hemorrhagic stroke in children is approximately 25% and of those who survive, 42% shows signifi- cant disability5. Hemorrhagic stroke comprises spontaneous intracerebral (parenchymal and intraventricular) hemorrhage (ICH) and non-traumatic subarachnoid hemorrhage (SAH)2. A parenchymal hemorrhage is located within the brain parenchyma, whereas an General introduction and outline of the thesis 13 intraventricular hemorrhage is located inside the brain’s ventricular system. Subarachnoi- dal hemorrhages are located in the subarachnoidal space, the area between the arachnoid membrane and the pia mater, that surrounds the brain and are most often due to intracra- nial aneurysms6. Common risk factors for hemorrhagic stroke at young age are listed in Table 17. Most of them undely occurrence in childhood. Besides common risk factors, rare genetic causes of cerebral hemorrhage have been identified at any age, from pregnancy to adulthood and are summarized in Table 2, together with the known genetic causes of arterial ischemic stroke and our newly identified genes, which will be discussed in detail in this thesis. Neonatal/ infantile cerebral hemorrhage is a subset of the childhood intracerebral (parenchymal or intraventricular) hemorrhage and among all types pediatric strokes is the least well characterized. It is often regarded as non-genetic, and risk factors include low birth weight and prematurity8-11. It usually presents as a germinal matrix hemorrhage or intraventricular hemorrhage. The germinal matrix a highly vascularized, transient layer near the ventricles that is present between 8 and 36 weeks of gestation. It has a role in the production of neurons and glial cells. The structure of the germinal matrix is selectively vulnerable to hemorrhage, which can be explained by limited astrocyte end-feet coverage of microvessels, reduced expression of fibronectin, an extracellular matrix component, and immature tight junctions12. In approximately 15% of infants these hemorrhages lead to venous infarction Table 1. Risk factors for pediatric hemorrhagic stroke Arteriovenous malformations 14-50% Cerebral aneurysms 10-13% Cavernous malformations 15-25% Hematological abnormalities 10-30% Thrombocytopenia Idiopathic thrombocytopenia purpura (ITP) Hemophilia Coagulopathies Liver failure Disseminated intravascular coagulation Iatrogenic Sickle cell anemia Brain tumors 13% 14 Chapter 1 due to occlusion of the periventricular collector veins, subsequent tissue destruction and the development of porencephaly, defined as a cavity in the brain parenchyma communicating with the lateral ventricle13. This process is depicted in Figure 1. The hemorrhage usually occurs at late pregnancy or around birth14. In case of early extensive hemorrhage, the destruction can extend to the cortex and can lead to major destructive lesions such as hydranencephaly15. Affected neonates have a high chance of developing long term com- plications, such as hydrocephaly, motor impairment such as cerebral palsy, intellectual disability or epilepsy, depending on the extension of the lesions. Already since the 1980s, familial occurrence of cerebral hemorrhage has been documented, for instance familial cases of porencephaly16-21. The discovery of an underlying genetic cause of childhood cerebral hemorrhage is of importance for appropriate genetic counselling. Expanding the knowledge on underlying mechanisms will hopefully result in the development of specific treatment and preventive options in the future. To achieve this, it is crucial to elucidate the pathogenic mechanisms underlying these disorders. By investigating the childhood population, we expect to find a greater influence of genetic factors compared to Figure 1. Schematic overview of pathogenic mechanism leading to porencephaly119,120. The lateral ventricles with surrounding deep veins are depicted in A. Porencephaly originates from a germinal matrix hemorrhage, often followed by intraventricular hemorrhage. This leads to deep venous infarctions and destruction of white matter in that area, eventually leading to a cyst communicating with the ventricle (B) General introduction and outline of the thesis 15 the adult population, since the role of additional environmental factors contributing to the hemorrhage is smaller. However, a common genetic factor may underly both neonatal and adult onset cerebral hemorrhage, due to variable expression, which is, for example, documented for COL4A1 and COL4A2 mutations. Pathophysiological processes underlying the disorders described in this thesis The identification of genetic causes of cerebrovascular disease has led to the identification of

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