ABSTRACT
Ischemic stroke causes a high mortality and morbidity worldwide. It results from a complex interplay of incompletely known environmental and genetic risk factors. We investigated the ABCC6 gene as a candidate risk factor for ischemic stroke because of the increased ischemic stroke incidence in the autosomal recessive disorder pseudoxanthoma elasticum, caused by biallelic pathogenic ABCC6 variants, the higher cardiovascular risk in heterozygous carriers and the established role of ABCC6 dysfunction in myocardial ischemia. We established segregation of a known pathogenic ABCC6 variant (p.[Arg1314Gln]) in 11/19 family members of an ischemic stroke patient in a large multigenerational family suffering from ischemic stroke and/or cardiovascular disease at a relatively young age. In an independent case-control study in 424 ischemic stroke patients and 250 healthy controls, pathogenic ABCC6 variants were 4.9 times more frequent (P = 0.036; 95% CI 1.11-21.33) in the ischemic stroke patient cohort. To study cellular consequences of ABCC6 deficiency in the brain, immunostaining of brain sections in Abcc6-deficient mice and wild-type controls were performed. An upregulation of Bmp4 and Eng and a downregulation of Alk2 was identified in Abcc6-/- mice, suggesting an increase in apoptosis and angiogenesis. As both of these processes are induced in ischemia, we propose that a pro-ischemic state may explain the higher risk to suffer from ischemic stroke in patients carrying a pathogenic ABCC6 variant, as this may lower the threshold to develop acute ischemic events in these patients. In conclusion, this study identified heterozygous ABCC6 variants as a risk factor for ischemic stroke. Further, dysregulation of Bmp (Bmp4, Alk2) and Tgfß (Eng) signaling in the brain of Abcc6-/- mice could lead to a pro-ischemic state, lowering the threshold to develop acute ischemic events. These data demonstrate the importance of a molecular analysis of the ABCC6 gene in patients diagnosed with cryptogenic ischemic stroke.
Subject(s)
Multidrug Resistance-Associated Proteins/genetics , Stroke/epidemiology , Stroke/genetics , Activin Receptors, Type I/genetics , Adult , Aged , Aged, 80 and over , Animals , Apoptosis/physiology , Bone Morphogenetic Protein 4/metabolism , Case-Control Studies , Cohort Studies , Endoglin/metabolism , Female , Humans , Male , Mice , Mice, Knockout , Middle Aged , Multidrug Resistance-Associated Proteins/blood , Neovascularization, Physiologic , Pseudoxanthoma Elasticum/complications , Pseudoxanthoma Elasticum/genetics , Risk Factors , Vascular Endothelial Growth Factor A/metabolismABSTRACT
"Pusher syndrome" is classically described as a disorder of body orientation in the coronal plane. Although it mainly occurs in stroke patients, non-stroke causes have been described. Pusher behaviour is characterized by a tilt towards the contralesional paretic side and a resistance to external attempts to rectify. It may occur with or without hemispatial neglect, which in itself may be the cause of a usually ipsilesional shift of attention and body orientation in the axial plane. In this report we describe two patients with a marked disturbance of body orientation in the sagittal plane with imbalance, posterior tilt and an active resistance to forward pulling or pushing. By analogy we propose the term "posterior pusher" syndrome for the clinical picture.
