Mechanisms of calcification in Fahr disease and exposure of potential therapeutic targets

Abstract

Purpose of reviewThere is growing interest in disorders involved in ectopic mineralization. Fahr disease or idiopathic basal ganglia calcification can serve as a model for ectopic mineralization in the basal ganglia, which is fairly common in the general population. In this review, we will focus on causative gene mutations and corresponding pathophysiologic pathways in Fahr disease.Recent findingsPatients with Fahr disease have a variability of symptoms, such as movement disorders, psychiatric signs, and cognitive impairment, but can also be asymptomatic. Fahr disease is mostly autosomal dominant inherited, and there are mutations found in 4 causative genes. Mutations in SLC20A2 and XPR1 lead to a disrupted phosphate metabolism involving brain-specific inorganic phosphate transporters. Mutations in PDGFB and PDGFRB are associated with disrupted blood-brain barrier integrity and dysfunctional pericyte maintenance. In addition, the MYORG gene has recently been discovered to be involved in the autosomal recessive inheritance of Fahr.SummaryKnowledge about the mutations and corresponding pathways may expose therapeutic opportunities for patients with Fahr disease and vascular calcifications in the brain in general.

A Rare Case of Fahr's Syndrome With Bilateral Vocal Cord Paresis

“…In contrast, our patient presented relatively late in life and had extensive calcifications. A review by Peters et al states that patients who become symptomatic early in life present with cognitive impairment while patients who become symptomatic later in life exhibit mainly motor symptoms [6], which did not comply with our findings considering that psychiatric symptoms were the main complaint in our case.…”

“…Common secondary causes of elevated PTH include medications, hypovitaminosis D, renal insufficiency, malabsorption, and low calcium intake [7]. In turn, Fahr's syndrome is caused by calcium metabolism disorders [6]. Although the most common cause is hypoparathyroidism, hyperparathyroidism is another known cause of Fahr's syndrome [8], as seen in our patient.…”

“…However, our patient had normal calcium, phosphate, and vitamin D levels. Other potential therapies that are still under investigation include bisphosphonates and vitamin D [6].…”

Calcificaciones ganglio basales simétricas bilaterales (Enfermedad de Fahr) en pediatría: Reporte de caso.

“…11 La mutación del gen SLC20A2(transportador de fosfato), representa aproximadamente el 40% de los pacientes con enfermedad de Fahr. 9,12 La mutación de la subunidad del factor de crecimiento derivado de plaquetas (PDGFB) y el receptor del factor de crecimiento derivado de plaquetas subunidad B (PDGFRB) 6,10,12 representan el 11% y el 2% de los pacientes con enfermedad de Fahr, respectivamente. Las mutaciones en el receptor de retrovirus xenotrópico y politrópico (XPR1) 11 se encontraron en aproximadamente el 2% de los pacientes.…”

“…de las mutaciones genéticas, la penetrancia es casi completa para depósitos de calcio, sin embargo, la penetrancia clínica es incompleta y puede estar alrededor del 70%. 12 El mecanismo fisiopatológico reside en el depósito de calcio y otros minerales en el globo pálido, putamen, corona radiada, tálamo, núcleos dentados cerebelosos y sustancia blanca hemisférica y cerebelosa, que se produce primariamente en las paredes de arteriolas y capilares, posteriormente el espacio perivascular y lentamente se extiende hasta que compromete completamente la neurona. 13,14,15,16 Se plantea que los depósitos se deben a un metabolismo anormal de calcio, en el cerebro debido a una alteración de la barrera hematoencefálica.…”