ABCC6 Involvement in Cerebral Small Vessel Disease: Potential Mechanisms and Associations

Abstract

ABCC6, a key regulator in ectopic calcification, plays a crucial role in mineralization through the modulation of extracellular purinergic pathways and production of inorganic pyrophosphate (PPi), which inhibits calcification. Inherited deficiencies in ABCC6 lead to pseudoxanthoma elasticum (PXE) and related conditions, characterized by calcification in various tissues, particularly affecting the skin, eyes, and cardiovascular system. Although PXE does not directly impact the nervous system, secondary neurological issues arise from cerebrovascular complications, increasing the risk of strokes linked to arterial blockages resembling atherosclerosis. This review investigates the connection between ABCC6 mutations and cerebral small vessel disease (SVD), expanding the understanding of PXE and related phenotypes. Mutations in ABCC6, identified as causing PXE, contribute to systemic metabolic dysfunction, with significant implications for cerebrovascular health. An association between ABCC6 mutations and cerebral SVD has been suggested in various studies, particularly in populations with distinct genetic backgrounds. Emerging evidence indicates that pathogenic mutations increase the risk of ischemic strokes, with both homozygous and heterozygous carriers showing susceptibility. Mechanistically, ABCC6 deficiency is implicated in dyslipidemia and atherosclerosis, further exacerbating cerebrovascular risks. Increased arterial pulsatility, linked to carotid siphon calcification, may also contribute to microvascular damage and subsequent brain injury. Understanding these mechanisms is vital for developing targeted diagnostic and therapeutic strategies for managing cerebrovascular risks in PXE patients. This review emphasizes the need for comprehensive genetic screening and the consideration of traditional vascular risk factors in patient management, highlighting the complex interplay between genetic mutations and environmental influences affecting cerebrovascular health. Future research should focus on longitudinal studies to elucidate the causal pathways linking arterial calcification, pulsatility, and brain damage in PXE.

Keywords: ABCC6; SVD; calcifications; lacunar; small vessel disease; stroke.

Figure 1

Brain Magnetic Resonance Imaging (MRI) of a 72-year-old man with a mutation ABCC6(NM_001351800.1):c.3840delG:(p.Lys1280AsnfsTer9) in heterozygosis. The patient has a very mild arterial hypertension and was sent to the neurological attention because of the occurrence of transient neurological deficit. In panel (a), some examples of axial Fluid Attenuated Inversion Recovery (FLAIR) images are provided at basal ganglia level (left image) and at centrum semiovale level (right image), showing symmetric, extensive, confluent white matter hyperintensities that are prevalent in the centrum semiovale. In panel (b), coronal T2W images show the enlarged perivasculae spaces in the basal ganglia on both sides. In panel (c), Gradient Recalled Echo (GRE) images show isolated pontine and deep, supratentorial, hypointense rounded signals similar to those observed for microbleeds.

Figure 2

Brain MRI of a 56-year-old woman with a mutation ABCC6 (NM_001351800.1):c.3071G>A:p.(Arg1024Gln) in heterozygosis. The patient had no relevant vascular risk factors and no systemic signs of PXE. In panel (a), axial FLAIR images are provided, showing symmetric, extensive, confluent white matter hyperintensities involving the anterior temporal pole, the external and extrema capsula, the thalamus and the centrum semiovale on both sides (the other known genes responsible for SVD were tested and no mutations were identified). In panel (b), axial FLAIR, axial Diffusion Weighted Imaging and axial Apparent Diffusion Coefficient map images show an acute subcortical ischemia in the corona radiata close to the occipital pole of the right lateral ventricle. In panel (c), coronal T2W images show the enlarged perivascular spaces in the basal ganglia on both sides.