Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification

Abstract

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.

Enfermedad de Fahr

“…El tamaño de la calcificación se relaciona con la gravedad de la sintomatología pero la localización y severidad de la misma no reflejan toda la diversidad clínica. Su fenotipo es variable reconociéndose formas esporádicas y familiares (el patrón de herencia es autosómico dominante en la mayoría de los casos) 3 . Recientemente se han descubierto genes implicados en dicha entidad como son SLC20A2 y PDGFRB con pocas diferencias clínicas entre ellos; si bien es cierto que los portadores de la mutación PDGFRB no han presentado calcificaciones en la cortical ni en vérmix.…”

Occurrence of Fahr's syndrome in patient suffering from systemic lupus erythematosus: A case report

“…Kalcifikacija bazalnih ganglija vidljiva je kod oko 1% slučajeva radioloških pregleda mozga (8)(9)(10). Prevalenca bolesti verovatno je niža od 0,5% i kreće se od 0,3% do 1,2% prilikom rutinskih radioloških pretraga u ranijim izveštajima, dok raste do 20,6% u skorijim studijama (11)(12)(13) ganglija, idiopatska striopalidodentalna kalcifikacija, cerebrovaskularna ferokalcinoza i nuklearna kalcinoza (7). Razlikujemo dva entiteta: primarni oblik, Fahrovu bolest, sporadičnu bolest naslednog karaktera i nepoznatog uzroka, koju karakteriše idiopatska kalcifikacija moždanog tkiva, i Fahrov sindrom, koji srećemo kao sekundarnu formu kod drugih endokrinoloških, metaboličkih, infektivnih i degenerativnih bolesti (3,14,15).…”

“…Kalcifikacija bazalnih ganglija vidljiva je kod oko 1% slučajeva radioloških pregleda mozga (8-10). Prevalenca bolesti verovatno je niža od 0,5% i kreće se od 0,3% do 1,2% prilikom rutinskih radioloških pretraga u ranijim izveštajima, dok raste do 20,6% u skorijim studijama (11)(12)(13) …”

Novel mutation of SLC20A2 in an Italian patient presenting with migraine

“…Because migraine is a common disorder in general population (mainly in women), the coexistence of IBGC and migraine may be coincidental in our patient. On the other way, migraine has frequently been reported as symptom in a large series of IBGC patients with SLC20A2 mutations [13].…”

“…We suggest that migraine should be considered when evaluating patients with IBGC and their first- Mutations nomenclature was revised accordingly to Human Genome Variation society (HGV) (http://www.hgvs.org/mutnomen/; version September 13, 2013), and in [7,8,13,14,18,26] is different from those reported in the original paper.…”