The clinical and genetic spectrum of primary familial brain calcification

Abstract

Primary familial brain calcification (PFBC), formerly known as Fahr’s disease, is a rare neurodegenerative disease characterized by bilateral progressive calcification of the microvessels of the basal ganglia and other cerebral and cerebellar structures. PFBC is thought to be due to an altered function of the Neurovascular Unit (NVU), where abnormal calcium-phosphorus metabolism, functional and microanatomical alterations of pericytes and mitochondrial alterations cause a dysfunction of the blood–brain barrier (BBB) and the generation of an osteogenic environment with surrounding astrocyte activation and progressive neurodegeneration. Seven causative genes have been discovered so far, of which four with dominant (SLC20A2, PDGFB, PDGFRB, XPR1) and three with recessive inheritance (MYORG, JAM2, CMPK2). Clinical presentation ranges from asymptomatic subjects to movement disorders, cognitive decline and psychiatric disturbances alone or in various combinations. Radiological patterns of calcium deposition are similar in all known genetic forms, but central pontine calcification and cerebellar atrophy are highly suggestive of MYORG mutations and extensive cortical calcification has been associated with JAM2 mutations. Currently, no disease-modifying drugs or calcium-chelating agents are available and only symptomatic treatments can be offered.

Fahr’s disease with neuropsychiatric symptoms and intermittent course: a case report

“…Currently, four causative genes have been identi ed: SCL20A2, PDGFB, PDGFRB, and XPR1 (13). Genetic testing can aid in con rming the diagnosis and identifying potential risks for family members (3).…”

Basal Ganglia Calcification: A Case Report of Two Siblings With Fahr's Disease

“…Motor manifestations were reported in approximately one-third of patients [ 3 ]. About 42% of cases display anxiety, psychosis, cognitive decline, and headache [ 3 ]. Parkinsonism represents the primary motor phenotype in FD [ 12 ].…”

“…According to recent data, it has an estimated prevalence of 4.5 per 10,000 persons [ 2 ]. It commonly exhibits an autosomal dominant inheritance, and seven genes have been implicated in its genetic aetiology, of which four with dominant inheritance (SLC20A2, PDGFB, PDGFRB, XPR1) and three with recessive inheritance (MYORG, JAM2, CMPK2) [ 1 , 3 ]. The mean age of clinical onset is around 40-50 years, but symptoms can manifest at any age [ 4 ].…”

“…Calcified areas are identified as hyperdense lesions on unenhanced brain computed tomography (CT), which is the most reliable exam for the diagnosis. These calcifications are commonly symmetrical, most frequently found in the basal ganglia, but they may also involve the cerebellar dentate nuclei, thalamus, cerebral cortex, subcortical white matter, and hippocampus [ 3 , 5 ].…”

Regulation of Phosphate Transporters and Novel Regulator of Phosphate Metabolism

“…Defects in SLC34A3 cause hypophosphatemic rickets with hereditary hypercalciuria [28][29][30][31]. Defects in SLC20A2 are involved in idiopathic basal ganglia calcification [32,33], and XPR1 is associated with primary familial brain calcification [34].…”