Fahr's Disease Linked to a Novel <b><i>SLC20A2 </i></b>Gene Mutation Manifesting with Dynamic Aphasia

Abstract

Background: Idiopathic basal ganglia calcification (IBGC), also known as Fahr's disease, is a rare disorder characterized by widespread cerebral calcifications, an autosomal dominant pattern of inheritance and clinical and genetic heterogeneity. The recently identified IBGC gene, SLC20A2, encodes for type III sodium-dependent phosphate transporter 2 and its loss-of-function mutations may lead to the regional accumulation of inorganic phosphate in the brain, causing calcium phosphate deposition. Objective: To describe the clinical, neuroimaging and genetic findings in an Italian family with IBGC. Methods: The family members underwent clinical and radiological examination in order to diagnose IBGC according to standard criteria and screening for SLC20A2 gene mutations. The affected subjects also underwent neuropsychological longitudinal assessments and functional neuroimaging investigations. Results: The 2 affected family members harbored a novel missense mutation, G1618A, in the SLC20A2 gene, leading to gly540-to-arg (G540R) substitution in a highly conserved residue. This is the first SLC20A2 gene mutation associated with familial IBGC reported in the Italian population and is damaging according to all prediction programs. In the index case we observed a fair correlation between cortical areas with no calcifications but with significant hypometabolism at [18F]FDG-PET (inferior frontal premotor cortex) and the neuropsychological picture dominated by dynamic aphasia and buccofacial apraxia. Conclusion: These findings expand the catalog of SLC20A2 mutations identified to date and add dynamic aphasia to the spectrum of neuropsychological deficits reported in IBGC, supporting the use of functional neuroimaging studies for better investigation of genotype-phenotype correlations.

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

“…This correlation does not seem absolute. There has been at least one study using [18F] FDG-PET that found areas of cortical hypometabolism, in the areas that did not have calcifications or other morphological changes and this correlated to the patient's neuropsychological symptoms [29]. It is therefore plausible that calcium deposition may not be the only pathophysiological mechanism in patients with the genetic mutations and highlights the importance of future studies investigating asymptomatic patients.…”

Update and Mutational Analysis ofSLC20A2: A Major Cause of Primary Familial Brain Calcification

“…Five novel variations recently identified by collaborators are also reported; it includes a total of 50 pathogenic variants (six of which are recurrent, one of them intronic): 22 missense, 13 frameshift, 2 deletions, 7 nonsense, and 6 splice site; comprising a de novo mutation and a large (563,256 bp) genomic deletion affecting multiple genes besides SLC20A2 [Wang et al, 2012;Schottlaender et al, 2012;Hsu et al, 2013;Lemos et al, 2013;Nicolas et al, 2013aNicolas et al, , 2013bZhang et al, 2013;Chen et al, 2013;Kasuga et al, 2014, Loughran et al, 2013Baker et al, 2014;Zhu et al, 2014., Yamada et al, 2014Ferreira et al, 2014;Carecchio et al, 2014;Rubino et al, 2014;Brighina et al, 2014;Taglia et al, 2014]. These variants are extremely rare or absent in major databases, such as the Exome Sequencing Project, 1000 Genomes, dbSNP, or HapMap.…”

Levodopa‐Responsive Parkinsonism with Prominent Freezing and Abnormal Dopamine Transporter Scan Associated with SANDO Syndrome

“…His mother was a carrier for the latter. He and his mother were also heterozygous for the common POLG c.3428A>G (p. Glul 143Gly) polymorphism …”