Familial Intracranial Aneurysms An Analysis of 346 Multiplex Finnish Families Shannon Wills, BA; Antti Ronkainen, MD, PhD; Monique van der Voet, Ing; Helena Kuivaniemi, MD, PhD; Katariina Helin, RN; Eira Leinonen, RN; Juhana Frösen, MB; Mika Niemelä, MD, PhD; Juha Jääskeläinen, MD, PhD; Juha Hernesniemi, MD, PhD; Gerard Tromp, PhD Background and Purpose—Genetic risk factors are considered important in the development, growth, and rupture of intracranial aneurysms; however, few have been identified. We analyzed intracranial aneurysm families with at least 2 affected persons and determined relationships between affected persons and assessed the inheritance patterns of aneurysms. Methods—Families with 2 members with verified diagnoses of intracranial aneurysms were recruited from Kuopio and Helsinki, Finland. Families with a diagnosis of other heritable disorders that have associated intracranial aneurysms, such as autosomal dominant polycystic kidney disease, were excluded. Results—We identified 346 Finnish multiplex families with 160 (46.2%) male and 186 (53.8%) female index cases. There were a total of 937 aneurysm cases, with an average of 2.7 cases per family. The majority of the families had only 2 affected relatives (n=206; 59.5%), although there were families with up to 6 (n=10), 7 (n=1), 8 (n=1), or 10 (n=2) affected persons. The affected relatives of the index cases included 108 sisters, 116 brothers, 105 parents, 30 children, 15 grandparents, 102 aunts or uncles, and 64 cousins. Of the 937 affected persons, 569 (60.7%) were alive and available for genetic analysis. Inheritance patterns consistent with autosomal recessiveness were observed in 198 (57.2%), autosomal dominance in 126 (36.4%), and autosomal dominance with incomplete penetrance in 19 (5.5%) of the families. Conclusions—The collection is the most extensive published to date and extends previous observations of familial aggregation that are consistent with a major gene effect. (Stroke. 2003;34:1370-1374.) Key Words: genetics  pedigree  risk factors  stroke  subarachnoid hemorrhage I ntracranial aneurysms (IAs) are moderately common in industrialized countries and have a substantial impact on society. 1 Lifetime prevalence estimates from autopsy and angiography studies range from 0.2% to 9.9% (mean, 5.5%). 2–8 Rupture of IA is the cause of 75% of all subarachnoid hemorrhage (SAH) cases. In some reports, 90% of SAH cases are due to ruptured IA, and most ruptured IAs present with SAH. 1,2,7,9 –11 SAH has high mor- bidity and mortality; approximately half of those who suffer from a ruptured IA will die within 30 days from the onset of SAH. Only one fifth to one third of SAH survivors will have a moderately good to good recovery. 2,9,12,13 Since half the survivors remain permanently disabled as a result of cogni- tive dysfunction, economic and social ramifications are ex- tensive. 14 It has been estimated that 10 to 15 million persons in the United States already have or will develop an IA. 15 The mean age at onset of rupture of IA in the Finnish population (49.3 years; SD 13 years) 11 is similar to that in other industrialized countries 1,7,15 and is approximately nor- mally distributed. 11 IA and SAH have been extensively studied in Finland, 2,6,11,16 –20 and the incidence is higher than in most other countries. 6 – 8,11 A variety of factors may influence the development, growth, and rupture of IA and include factors that have behavioral components such as smoking, 1,9,12,17,21–26 alcohol consumption, 12,25,27,28 and use of contraceptives, 26,29,30 as well as hypertension 1,12,18,22,23,31–33 and stochastic factors. Reports of IA in some patients with rare mendelian disorders such as autosomal dominant poly- cystic kidney disease (ADPKD), 1,10,34 –37 Ehlers-Danlos syn- drome type IV (EDS-IV), 10 Marfan syndrome, 13 and fibro- muscular dysplasia 38 suggested that it was more common in subjects with these diseases than in the general population. Recent careful and systematic studies on larger groups of patients with Marfan syndrome 39,40 and fibromuscular dys- plasia 41 have, however, demonstrated that IAs are only infrequently part of the clinical manifestations in these rare Received October 4, 2002; final revision received December 17, 2002; accepted January 8, 2003. From the Center for Molecular Medicine and Genetics (S.W., M. van der V., H.K., G.T.) and Department of Surgery (H.K.), Wayne State University School of Medicine, Detroit, Mich; Department of Neurosurgery, University of Kuopio, Kuopio, Finland (A.R., K.H.); and Department of Neurosurgery, University of Helsinki, Helsinki, Finland (E.L., J.F., M.N., J.J., J.H.). Reprint requests to Gerard Tromp, PhD, 3116 Gordon H. Scott Hall of Basic Medical Sciences, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 540 E Canfield Ave, Detroit, MI 48201. E-mail tromp@sanger.med.wayne.edu © 2003 American Heart Association, Inc. Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000072822.35605.8B 1370 by guest on May 14, 2016 http://stroke.ahajournals.org/ Downloaded from