Brain calcification process and phenotypes according to age and sex: Lessons from SLC20A2, PDGFB, and PDGFRB mutation carriers

Abstract

Primary Familial Brain Calcification (PFBC) is a dominantly inherited cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Three causative genes have been identified: SLC20A2, PDGFRB and, recently, PDGFB, whose associated phenotype has not yet been extensively studied. We included in the largest published case series of genetically confirmed PFBC, 19 PDGFB (including three new mutations), 24 SLC20A2 (including 4 new mutations), and 14 PDGFRB mutation carriers, from two countries (France and Brazil). We studied clinical features and applied our visual rating scale on all 49 available CT scans. Among the symptomatic mutation carriers (33/57, 58%), the three most frequently observed categories of clinical features were psychiatric signs (72.7%, 76.5%, and 80% for PDGFB, SLC20A2, and PDGFRB, respectively), movement disorders (45.5%, 76.5%, and 40%), and cognitive impairment (54.6%, 64.7%, and 40%). The median age of clinical onset was 31 years, 25% had an early onset (before 18) and 25% a later onset (after 53). Patients with an early clinical onset exhibited mostly isolated psychiatric or cognitive signs, while patients with a later onset exhibited mostly movement disorders, especially in association with other clinical features. CT scans rating allowed identifying four patterns of calcification. The total calcification score was best predicted by the combined effects of gene (SLC20A2 > PDGFB > PDGFRB mutations), sex (male), and (increasing) age, defining three risk classes, which correlated with the four patterns of calcification. These calcification patterns could reflect the natural history of the calcifying process, with distinct risk classes characterized by different age at onset or rate of progression.

Deconstructing Fahr's disease/syndrome of brain calcification in the era of new genes

“…The reason for including this group in our study and analysis is supported by the overall similarity in neurological presentation of these cases to genetically determined PFBC as there was no statistically significant difference in movement disorders and cognitive changes between PFBC and pseudohypoparathyroidism. There was a trend of higher frequency of hyperkinetic movement disorders in comparison to parkinsonism but that was not statistically significant features of these cases were quite like the cases with genetically confirmed mutations in SLC20A2 or PDGFRB [62].…”

“…It has been suggested that clinical features among the commonly reported mutations were psychiatric signs (72.7%, 76.5%, and 80% for PDGFB, SLC20A2, and PDGFRB, respectively), movement disorders (45.5%, 76.5%, and 40%), and cognitive impairment (54.6%, 64.7%, and 40%) [62].…”

Identification of partial SLC20A2 deletions in primary brain calcification using whole-exome sequencing

“…Among them, the most frequent three categories are: psychiatric disturbances (mainly mood, psychotic or personality disorders), cognitive impairment (involving mainly memory and executive functions), and movement disorders (mainly extrapyramidal signs). 1 Patients may present other symptoms such as gait disorder, cerebellar syndrome, dysarthria, and rarely seizures. Cephalalgia and especially migraine are frequent circumstances allowing the identification of brain calcification.…”

“…Cephalalgia and especially migraine are frequent circumstances allowing the identification of brain calcification. 1 PBC is inherited as an autosomal dominant trait. In this context, causative variants have been identified in 4 genes: SLC20A2 (OMIM 158378), 2 PDGFRB (OMIM 173410), 3 PDGFB (OMIM 190040), 4 and XPR1 (OMIM 605237).…”

“…All were symptomatic, which seems different from the 58% of symptomatic mutation carriers in our previous report. 1 Of note, in family ROU-1129, the grandmother developed cognitive decline only after the age of 86 (of unknown cause), and 2 affected relatives were asymptomatic by family interview. This suggests that the apparent high proportion of symptomatic patients in the present report could be an inclusion bias.…”