Microangiopathy in primary familial brain calcification: Evidence from skin biopsies

Autosomal dominant primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder defined by the presence of calcifications affecting at least the basal ganglia with no secondary cause. It is associated with diverse symptoms including movement disorders, psychiatric disturbances, and cognitive impairment. PFBC is caused by lossof-function mutations in 2 groups of genes: (1) PDGFB, which encodes the platelet-derived growth factor B and PDGFRB, which encodes its main receptor platelet-derived growth factor receptor–beta (PDGFR-b) and (2) SLC20A2 and XPR1 encoding inorganic phosphate transporters. Mice carrying Pdgfb hypomorphic alleles exhibit lower pericyte coverage in cerebral microvessels, blood-brain barrier (BBB) impairment, and cerebral microvascular calcifications. Recently, a novel PDGFB mutation was reported in an Italian family with PFBC and white-matter hyperintensities (WMH). Although brain calcification is a mandatory criterion for diagnosing PFBC, WMH were also reported as a major neuroimaging feature in the first described families with a PDGFRB or a PDGFB mutation (table e-1 at Neurology.org/ng). To date, the precise nature of WMH remains unknown but may be regarded as resulting from microangiopathy. This led to the hypothesis that in mice, alterations of the microvessels leading to BBB impairment may be a causal mechanism between microangiopathy and vascular calcifications. Transmission electron microscopy analysis of a skin biopsy from a patient belonging to the above-mentioned PDGFB family revealed thickened and fragmented areas in the basal lamina, consistent with microangiopathy. We report here the results of skin biopsies performed in 2 patients carrying a PDGFRB and an XPR1 mutation, respectively.