title: 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.
authors.affiliation: Department of Genetics, Rouen University Hospital, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Inserm U1079, IRIB, Normandy University, Rouen, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Nicolas
authors.affiliation: CNR-MAJ, Rouen University Hospital, Rouen, France.|Inserm U1079, IRIB, Normandy University, Rouen, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Charbonnier
authors.affiliation: Keizo Asami Laboratory (LIKA), Universidade Federal de Pernambuco (UFPE), Recife, Brazil.
authors.forename: Roberta Rodrigues
authors.initials: RR
authors.lastname: de Lemos
authors.affiliation: CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Richard
authors.affiliation: Inserm U1079, IRIB, Normandy University, Rouen, France.|University Department, Rouvray Psychiatric Hospital and Rouen University Hospital, Sotteville-lès-Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Guillin
authors.affiliation: CNR-MAJ, Rouen University Hospital, Rouen, France.|Inserm U1079, IRIB, Normandy University, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors.forename: David
authors.initials: D
authors.lastname: Wallon
authors.affiliation: Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Legati
authors.affiliation: Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.|Deparment of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Geschwind
authors.affiliation: Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.|Deparment of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Genetics, Rouen University Hospital, Rouen, France.|Inserm U1079, IRIB, Normandy University, Rouen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: CNR-MAJ, Rouen University Hospital, Rouen, France.|Inserm U1079, IRIB, Normandy University, Rouen, France.|Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.affiliation: Keizo Asami Laboratory (LIKA), Universidade Federal de Pernambuco (UFPE), Recife, Brazil.|Neuropsychiatry Department, Universidade Federal de Pernambuco, Recife, Brazil.
authors.forename: João Ricardo Mendes
authors.initials: JR
authors.lastname: de Oliveira
authors.affiliation: Department of Genetics, Rouen University Hospital, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Inserm U1079, IRIB, Normandy University, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
mesh_terms: D000328:Adult; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002113:Calcification, Physiologic / Q000235:genetics; D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics* / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000235:genetics* / Q000378:metabolism
chemical_list: D020574:Proto-Oncogene Proteins c-sis; C493589:SLC20A2 protein, human; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; C000605860:PDGFRB protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: Fahr disease; PDGFB; PDGFRB; SLC20A2; idiopathic basal ganglia calcification; primary familial brain calcification