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A new gene for Fahr's syndrome—PDGF‐B

Familial idiopathic basal ganglia calcification (IBGC), or Fahr’s disease, is characterized by symmetric and bilateral calcification in the basal ganglia and other brain regions. Originally recognized by Delacour in 1850, brain calcification mainly affecting the basal ganglia was described on brain pathology by Fahr in 1930. Some cases may be asymptomatic, but the usual presentation is a variable combination of dystonia, parkinsonism, ataxia, cognitive impairment, behavioral changes, and autosomal-dominant transmission. The inherited nature of the disorder became recognized when Boller et al described 9 members of a family with this condition. A number of other familial cases were reported. It also became clear that the disorder was genetically heterogeneous, and 4 genetic loci were described based on linkage and haplotype analyses: 14q11.221.3 (IBGC1), 2q37 (IBGC2), 8p21.1-q11.13 (IBGC3), and 5q32 (IBGC4). SLC20A2 was the first gene identified (IBGC3 region), and so far 218 patients from 29 IBGC families have been found to have mutations in SLC20A2. The fourth locus (IBGC4), identified most recently, was linked to mutations in the PDGFRB gene encoding platelet-derived growth factor receptor b using exome sequencing in 2 affected family members. In the August issue of Nature Genetics, Keller et al reported genetic analysis in 6 families with nonsense and missense mutations in the gene encoding beta (PDGF-B) the main ligand for PDGF RB in familial IBGC. This is a new gene identified as a cause for IBGC (located at 22q13.1) in patients that had been tested negative for SLC20A2 and PDGFRB genes. The important aspect is that the authors also showed that experimental mice expressing 50% less endothelial PDGF-B developed substantial brain calcification at 1 year of age. PDGFRB and PDGFB are two new genes identified after the description of SLC20A2. Hsu et al reported that 41% of their cohort of familial IBGC had the SLC20A2 mutations. However, at the moment it is not clear which of these two will be the more prevalent, and further studies are needed. The identification of PDGF-B leads a clinician to question if there is a clear genotypic–phenotypic association that can help to guide the genetic diagnosis toward PDGF-B or SLC20A2. The diagnostic feature in all the reported cases is bilateral basal ganglia calcification with the additional involvement of the cerebellum (subcortical or dentate nucleus), thalamus, and white matter (subcortical) and rarely the cortex. However, at the moment there does not seem to be a particular pattern of calcification that can help to identify the genotype. Clinically, cases with either of these 2 genotypes are heterogeneous and can have a combination of parkinsonism, psychiatric features, dystonia, tremor, epilepsy, and dementia. Interestingly, some gene carriers are asymptomatic, and others have had migraines/ headaches with or without movement disorders. The PDGF-B and SLC20A2 mutations, however, clearly have different underlying pathophysiological mechanisms. Loss of endothelial PDGF-B is the proposed mechanism, with the first leading to a pericyte and blood-brain barrier deficiency. SLC20A2, however, is a member of the type III sodiumdependent phosphate transporter family, and loss-of-function mutations may lead to the regional accumulation of inorganic phosphate in the brain, causing calcium phosphate deposition. It is likely that additional genes related to IBGC at IBGC1 loci and perhaps some others will be found in the near future. Fahr’s disease has long been labeled as idiopathic, but in light of these findings, it seems likely that there would be at least 2 clearly defined genetic diseases under this broad syndrome. The precise elucidation of the pathophysiology using the mouse model by Kellar et al gives hope for possible new therapies both for pre-symptomatic carriers and IBGC patients due to PDGFB mutations.