Systemic large vessel arterial calcification in Fahr's disease patients harboring truncating mutations in SLC20A2
Fahr’s disease is a neurodegenerative disorder characterized by bilateral basal ganglia calcifications. Typically diagnosed during adulthood, symptoms of Fahr’s disease are variable but include progressive neuropsychiatric symptoms headaches and various movement disorders. Familial Fahr’s disease is inherited in an autosomal dominant pattern. Mutations in four known genes have been associated with this phenotype: PDGFRB, PDGFB, XPR1, and SLC20A2, the latter of which encodes the sodium-inorganic phosphate co-transporter PiT-2. To date, Fahr’s disease has not been associated with systemic vascular calcifications.
We evaluated >15 patients with evidence of brain calcification in the NIH Undiagnosed Diseases Program (UDP). We performed high resolution full body CT scans to evaluate for abnormal calcification outside the brain. We performed whole exome sequencing (WES) to identify any pathogenic mutations in the four known Fahr’s disease genes.
Amongst our cohort of Fahr’s disease patients, we discovered four individuals with evidence of abnormal large vessel calcification (Table 1) who were also found to carry truncating mutations in SLC20A2 (Table 2).
Inorganic phosphate (Pi) is fundamental to many metabolic processes and is a component of many biological structures. Loss-of-function mutations in the SLC20A2 gene likely induce changes in phosphate transport at the blood brain barrier that promote regional brain accumulation of inorganic phosphate, which subsequently causes calcium phosphate deposition. Pathology studies in brains of Fahr’s disease patients show the calcification occurs in vessel walls rather than the neuronal tissue itself. Given that SLC20A2 is ubiquitously expressed, the truncating mutations observed in this study may lead to accelerated and more widespread calcification.