Novel mutation of SLC20A2 in an Italian patient presenting with migraine

Abstract

We report the case of an Italian patient with IBGC associated with a novel mutation in the SLC20A2 gene, who presented with episodic migraine. In September 2013, a 48-year-old woman presented to our outpatient clinic with a 29-years history of headache. The recurrent attacks were characterized by pulsating pain of moderate intensity in frontotemporal location, associated with severe nausea and photo/phonophobia, lasting up to 72 hours, with six-eight episodes a month. The reported symptoms fulfilled ICHD-III beta version criteria for episodic migraine without aura (code 1.1) [2]. The medical history of the patient was unremarkable. A positive family history for migraine (mother and maternal aunt) and psychosis (another maternal aunt) was reported. Neurological examination showed hyperreflexia and slightly neck rigidity, while no cerebellar signs were identified. A computed tomography scan showed severe calcifications at the bilateral globus pallidus, caudate nuclei, putamen, and dentate nuclei ( Figure 1A). Laboratory tests were normal (including serum 25-hydroxyvitamin D and calcium concentrations) and excluded any parathyroid dysfunction. Neuropsychological screening showed a mild impairment in verbal fluency and mild attention deficit. The remaining neuropsycological tests had normal scores, also in those for visuospatial functions. STAIx-1 and STAIx-2 tests showed high level of anxiety.The patient received genetic counselling and on the basis of the neuroradiological findings with calcifications both in basal ganglia and cerebellum, SLC20A2 was sequenced. We analyzed the 3 candidate gene by direct genomic sequencing of the coding exons, performed on an ABI Prism 3130 XL platform. We identified a novel frameshift mutation p.Val507Glufs*2 in the isoform 1 (c.1520_1521delTG, exon 8, NM_006749) ( Figure 1B,C). This genetic change was predicted to change an aminoacid and insert a stop codon, likely leading to a degradation of the mutated messanger RNA due to nonsense mediated decay [3]. No other relative was available for segregation analysis.SCL20A2 encodes the type III sodium dependent phosphate transporter 2, broadly expressed and with high levels in brain. SLC20A2 gene mutations have been reported in China, Brazil, Japan, and Spain

Slc20a2 is critical for maintaining a physiologic inorganic phosphate level in cerebrospinal fluid

“…It is now well-established that deleterious mutations in the gene SLC20A2 are linked to PFBC [ 1 – 17 ], which is characterized by cerebrovascular-associated calcifications [ 18 , 19 ]. A similar calcification phenotype is present in Slc20a2 -KO mice [ 20 ].…”

“…At least 40 % of the cases of PFBC are linked to deleterious mutations in the gene SLC20A2 , which encodes the type III Na + -dependent inorganic phosphate (NaPi) symporter PiT2 [ 1 – 3 ], and recently, also a de novo mutation in SLC20A2 was identified in a patient presenting with brain calcifications [ 4 ]. The mutations are predicted to result in lack of PiT2 protein or in PiT2 proteins, which are shown or predicted to be unable to transport Pi [ 1 – 17 ]. Both types of mutations have been suggested to result in haplo-insufficiency of Pi transport in affected cells [ 1 ].…”

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.…”

Cortical myoclonus and epilepsy in a family with a new SLC20A2 mutation

“…Migraine seems also to be common, Antonietta Coppola and Laura Hernandez-Hernandez equally contributed to this manuscript. but the specific prevalence is difficult to ascertain given the high prevalence in the general population [20]. Epilepsy has been reported more rarely (7.8%) [17,19].…”