Anticipation in familial intracranial aneurysms in consecutive generations

Abstract

Intracranial aneurysms (IA) are the major cause of subarachnoid haemorrhages (SAH). A positive family history for SAH is reported in 5-10% of the patients. The mode of inheritance is not unambiguously established; both autosomal dominant and recessive modes have been reported. In sporadic as well as in familial SAH, approximately 60% of the SAH patients are female. Recently, anticipation has been described in familial SAH. Since up to 15% of the SAHs are not caused by an IA, we have analysed anticipation, sex ratio and mode of inheritance only in families with patients with a proven IA in two consecutive generations. A total of 10 families were studied in which at least two persons in consecutive generations were affected by SAH, a symptomatic IA (SIA) or a presymptomatic IA (PIA). We also analysed published data from families with a proven IA in two consecutive generations on age of SIA onset and sex ratios among affected family members (both SIA and PIA). The age of SIA onset in the parental generation (mean 55.5 years) differed significantly from the age of onset in their children (mean 32.4 years). In the parental generation 11 men and 37 women were affected (both SIA and PIA), in the consecutive generation these numbers were 28 men and 32 women. There is a significant difference in sex ratio of affected family members when the generations are compared (Po0.02). No family could be found in which three consecutive generations were affected by an IA (SIA or PIA).

Genome-Wide Linkage in a Large Dutch Consanguineous Family Maps a Locus for Intracranial Aneurysms to Chromosome 2p13

“…Several studies described familial occurrence of intracranial aneurysms and 1 study described a very high concordance (87.5%) of IAs in monozygotic twins. [7][8][9] The risk of rupture appears to be associated with, besides genetic factors, several environmental risk factors like smoking and alcohol consumption. 10 -12 The risk of rupture in first-degree relatives of patients with aneurysmal SAH is 4-times higher, and in siblings 6-times higher, than in the general population.…”

Age at intracranial aneurysm rupture among generations

“…Those investigators reported that patients with SAH and a family history of IA were 6.8 years younger than sporadic SAH patients 4. A separate report showed a 23.1-year difference between subsequent generations for proven IA 5. This study included asymptomatic IA, which may have been sought due to parental history, which may lead to an artificial “anticipation.” An additional report examined 20 families with ruptured IA in subsequent generations and identified a 19.8-year difference between generations 6.…”

Molecular Genetics of Human Intracranial Aneurysms

“…Given the very high, early mortality of ruptured IA and the common multifactorial nature of this disease, successful, adequately powered genetic linkage study of IA is challenging. More intriguingly, genetic anticipation, a common neuro-degenerative disease phenomenon, was also observed in familial IA (15,60). Efforts to elucidate IA susceptibility loci are also hindered by the issues faced in studying other complex genetic disorders, such as low penetrance, late onset, and uncertain modes of inheritance.…”

“…Among IA patients, 5–10% reports an aneurysm in a first-degree relative. Both genetic and environmental factors have been implicated to explain the clustering of IAs in these families (15, 60). In a twin study, intraclass correlations among monozygotic and dizygotic twin pairs are calculated and compared under one assumption that each twin pair (monozygotic or dizygotic) shares the same environment.…”

“…Like most common medical conditions that are multifactorial diseases (4,5), IA is associated with many factors that can be classified into two major groups: first, a strong but complex genetic component, second, modifiable environmental risk factors (6,7), or possibly interactions of both. Environmental factors include cigarette smoking (8)(9)(10)(11), heavy alcohol consumption (12), advancing age (13), female gender (2,14,15), hypertension (16), drug abuse (17)(18)(19), and certain medications known to generate arteriosclerosis and elevate blood pressure (20)(21)(22). Among them, hypertension, cigarette smoking, and female gender are the three most important risk factors for IA formation and growth (9,(23)(24)(25)(26).…”