Mutations at the SLC20A2 gene and brain resilience in families with idiopathic basal ganglia calcification (“Fahr's disease”)

Wang et al. (2012) recently identified seven novel mutations at the SLC20A2 gene in families from China, Spain and Brazil, suggesting that Familial Idiopathic Basal Ganglia Calcification (IBGC) might be a phosphate imbalance disorder. Expressing wild-type human SLC20A2 and the mutated variants, using transport assays in Xenopus oocytes, resulted in significant impaired Pi transport. On the other hand, mutants did not have an obvious effect on the Pi transport activity when co-expressed with the wild-type PiT2 protein, encoded by SLC20A2. This suggests that such mutations have an effect through haploinsufficiency (Wang et al., 2012). Additional analysis showed that this gene is responsible for ∼50% of the familial cases (Hsu et al., 2013; Lemos et al., 2013). More recently, two French families with IBGC were reported with mutations at the platelet derived growth factor receptor B (PDGFRB) gene, opening now a new venue for the comprehension of this phenotype as being caused by different molecular failures in mechanisms of vascular homeostasis (Nicolas et al., 2013). Familial or sporadic IBGC, often called by the misnomer “Fahr’s Disease,” is a neuropsychiatric disorder with variable clinical outcome, including parkinsonism, psychosis, dementia and headaches. The diagnosis criteria include bilateral calcifications, often documented with computerized tomography, in the absence of hormonal and metabolic imbalances. Such subjects are often misdiagnosed as patients with schizophrenia, Parkinson’s disease, bipolar Disorder, and Alzheimer’s disease (Manyam, 2005; Lemos et al., 2011). Calcifications might also be detected in cerebellum, thalamus and cortex. The mode of inheritance of IBGC is mainly reported in literature as autosomal dominant, sometimes displaying anticipation, a phenomenon widely described in diseases with similar pattern of inheritance and first reported in familial IBGC by Geschwind et al. (1999). Families affected with IBGC also show a variable clinical manifestation and a lack of full penetrance. Recent functional studies aiming to access the expression profiles of SLC20A2 at the kidney, have reported that the expression of this gene is tightly linked to inorganic phosphate (Pi) concentration into the organism. Moreover, together with SLC20A1, these genes act at the Pi uptake under different conditions of pH and dietary Pi (Villa-Bellosta et al., 2009). Calcification is an unspecific biochemical process occurring normally even under physiological conditions, through phosphate deposition and hydroxyapatite crystals formation, similar to the mineral fraction of the bones. However, disturbances in this process, which are often related to phosphate transport alterations at epithelial cells of blood vessels, lead to calcification around these tissues, jeopardizing the vessels’ elasticity and leading to arteriosclerosis as well (Villa-Bellosta and Sorribas, 2011). Curiously, Wang et al. (2012) and other authors also reported subjects with calcifications but no symptoms. Brain resilience for such lesions is still the most compelling challenge for the complete understanding of the pathological mechanisms of IBGC and others autosomal dominant neuropsychiatric conditions. Argylean et al. (2009) used neuroimaging techniques to assess the cerebellumthalamocortical connectivity (CbTC) in individuals with dystonia and compared these data with that was yielded by the analysis of this same circuit in control individuals and asymptomatic carriers of mutations for dystonia. Their analysis showed reduced integrity of cerebellothalamocortical fiber tracts, in both clinically manifesting and nonmanifesting mutation carriers. In these subjects, reductions in cerebellothalamic connectivity were associated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Nonmanifesting mutation carriers displayed an additional area of fiber tract disruption, distally situated along the thalamocortical segment, in tandem with a proximal cerebellar outflow abnormality. In individual gene carriers, clinical penetrance was determined by the difference in connectivity measured at these two sites. Other approaches to investigate the lack of full penetrance in genetic traits have been based on functional studies using the one-thousand-cells nematode Caenorhabditis elegans. These analyses state that this phenomenon may occur due to mitigating mechanisms involving