Abstract TP260: Familial Brain Calcification and Truncating PDGFB Mutation: A Small Vessel Disease

Abstract

Background: Mutations in platelet-derived growth factor-B (PDGFB) have been associated with primary familial brain calcification, presenting with variable neurological and neuropsychiatric symptoms, and progressive peri-capillary calcifications. PDGFB mutations have also been linked to venous thromboembolism. Methods: We have examined a Swedish family with a novel mutation in PDGFB c.418C>T, p.Gln140* (Q140*). Clinical, hematological, radiological brain examinations and 123I-FP-CIT SPECT were performed. Systemic small vessel changes were analyzed by light and electron microscopy from skin biopsies. The effect of levodopa as symptomatic treatment was assessed. Results: Three family members in three successive generations carried the mutation and had significant brain calcifications (Fig. A). The index patient developed gait abnormalities in his 40s that improved on 200mg/d levodopa. Subsequently he developed throat-clearing tics and mild cognitive impairment. His mother, in her late 50s, had transitory ischemic attacks and, on MRI, bilateral confluent periventricular white matter hyperintensities of otherwise undetermined cause (Fig. C). She subsequently developed cognitive dysfunction. The index patient’s son has normal white matter on MRI and remains clinically unaffected in his early 40s. Skin biopsies showed generalised small vessel disease with progressive thickening of the arteriolar wall and hypertrophic endothelial cells that seem to almost entirely obliterate the lumen (Fig. B). Extensive characterisation of leucocyte markers showed no pronounced differences between 2 mutation carriers and 2 wild type relatives, but the index patient had had episodes of unexplained pulmonary embolism. Conclusion: The PDGFB Q140* mutation causes basal ganglia calcification, not directly correlated with clinical symptoms, and systemic vasculopathy with age-related cerebral white matter disease, associated with the clinical symptoms.