Parental Influence on Intracerebral Hemorrhage Onset in Hereditary Dutch-Type Cerebral Amyloid Angiopathy

Ingeborg Rasing; Lisa Jellema; Sabine Voigt; Kanishk Kaushik; Emma A Koemans; Erik W van Zwet; Ellis S van Etten; Steven M Greenberg; Marianne A A van Walderveen; Gisela M Terwindt; Marieke J H Wermer

doi:10.1159/000540040

Parental Influence on Intracerebral Hemorrhage Onset in Hereditary Dutch-Type Cerebral Amyloid Angiopathy

Cerebrovasc Dis. 2024 Jul 17:1-6. doi: 10.1159/000540040. Online ahead of print.

Authors

Affiliations

¹ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
² Department of Biostatistics, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁴ Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands.

PMID: 38952109
DOI: 10.1159/000540040

Abstract

Introduction: Dutch-type cerebral amyloid angiopathy (D-CAA) is an autosomal dominant hereditary form of CAA causing intracerebral hemorrhage (ICH) and cognitive decline. The age of onset of ICH in D-CAA mutation carriers is strikingly variable and ranges from late thirties up to 70 years. We investigated the presence of genetic anticipation and assessed the influence of parental age at onset and sex on age of ICH onset in offspring.

Methods: We included (potential) D-CAA mutation carriers from our prospective D-CAA family database. Participants were sent a questionnaire by mail and asked for the onset age of symptomatic ICH and the onset age of symptomatic ICH of their affected first-degree relative(s), their siblings and affected parent. We used a Cox regression model with the age of onset of the parent as the covariate and the sex of the offspring as the factor. Next, we replaced the sex of the offspring with a factor with four levels: mother/daughter, mother/son, father/daughter, and father/son. We used a random effect per household.

Results: A total of 66 respondents completed the questionnaire. Reported mean age of first symptomatic ICH was similar (both 52 years, p = 0.87) for D-CAA parents (n = 60) and their offspring (n = 100). Offspring with a mother with D-CAA seemed to have an earlier ICH onset (50 years, standard deviation [SD] ± 7) than offspring with a paternal inheritance (54 years, SD ± 6, p = 0.03). There was no association between onset of first ICH of the parent and offspring after adding sex of the offspring to the Cox regression model: hazard ratio 0.99, 95% CI: 0.94-1.03, p = 0.51. The interaction between parent's sex and child's sex was not significant (p = 0.70). The results with and without random effect were essentially identical.

Conclusion: We found no indication for genetic anticipation in D-CAA in general, although maternal inheritance seemed to be associated with an earlier ICH onset.

Keywords: Cerebral amyloid angiopathy; Dutch type; Hereditary disease; Intracerebral hemorrhage.