Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification.
Idiopathic basal ganglia calcification is characterized by mineral deposits in the brain, an autosomal dominant pattern of inheritance in most cases and genetic heterogeneity. The first causal genes, SLC20A2 and PDGFRB, have recently been reported. Diagnosing idiopathic basal ganglia calcification necessitates the exclusion of other causes, including calcification related to normal ageing, for which no normative data exist. Our objectives were to diagnose accurately and then describe the clinical and radiological characteristics of idiopathic basal ganglia calcification. First, calcifications were evaluated using a visual rating scale on the computerized tomography scans of 600 consecutively hospitalized unselected controls. We determined an age-specific threshold in these control computerized tomography scans as the value of the 99th percentile of the total calcification score within three age categories: <40, 40-60, and >60 years. To study the phenotype of the disease, patients with basal ganglia calcification were recruited from several medical centres. Calcifications that rated below the age-specific threshold using the same scale were excluded, as were patients with differential diagnoses of idiopathic basal ganglia calcification, after an extensive aetiological assessment. Sanger sequencing of SLC20A2 and PDGFRB was performed. In total, 72 patients were diagnosed with idiopathic basal ganglia calcification, 25 of whom bore a mutation in either SLC20A2 (two families, four sporadic cases) or PDGFRB (one family, two sporadic cases). Five mutations were novel. Seventy-one per cent of the patients with idiopathic basal ganglia calcification were symptomatic (mean age of clinical onset: 39 ± 20 years; mean age at last evaluation: 55 ± 19 years). Among them, the most frequent signs were: cognitive impairment (58.8%), psychiatric symptoms (56.9%) and movement disorders (54.9%). Few clinical differences appeared between SLC20A2 and PDGFRB mutation carriers. Radiological analysis revealed that the total calcification scores correlated positively with age in controls and patients, but increased more rapidly with age in patients. The expected total calcification score was greater in SLC20A2 than PDGFRB mutation carriers, beyond the effect of the age alone. No patient with a PDGFRB mutation exhibited a cortical or a vermis calcification. The total calcification score was more severe in symptomatic versus asymptomatic individuals. We provide the first phenotypical description of a case series of patients with idiopathic basal ganglia calcification since the identification of the first causative genes. Clinical and radiological diversity is confirmed, whatever the genetic status. Quantification of calcification is correlated with the symptomatic status, but the location and the severity of the calcifications don't reflect the whole clinical diversity. Other biomarkers may be helpful in better predicting clinical expression.
1 Inserm U1079, Rouen, France.
Gaël
G
Nicolas
Cyril
C
Pottier
Camille
C
Charbonnier
Lucie
L
Guyant-Maréchal
Isabelle
I
Le Ber
Jérémie
J
Pariente
Pierre
P
Labauge
Xavier
X
Ayrignac
Luc
L
Defebvre
David
D
Maltête
Olivier
O
Martinaud
Romain
R
Lefaucheur
Olivier
O
Guillin
David
D
Wallon
Boris
B
Chaumette
Philippe
P
Rondepierre
Nathalie
N
Derache
Guillaume
G
Fromager
Stéphane
S
Schaeffer
Pierre
P
Krystkowiak
Christophe
C
Verny
Snejana
S
Jurici
Mathilde
M
Sauvée
Marc
M
Vérin
Thibaud
T
Lebouvier
Olivier
O
Rouaud
Christel
C
Thauvin-Robinet
Stéphane
S
Rousseau
Anne
A
Rovelet-Lecrux
Thierry
T
Frebourg
Dominique
D
Campion
Didier
D
Hannequin
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001480:Basal Ganglia Diseases / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D002114:Calcinosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*; D016037:Single-Blind Method; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000235:genetics*; D014057:Tomography, X-Ray Computed / Q000379:methods; D055815:Young Adult
C493589:SLC20A2 protein, human; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D020797:Receptor, Platelet-Derived Growth Factor beta
Fahr’s disease; PDGFRB; SLC20A2; ageing; calcification