Mutation Screening Of SLC20A2, PDGFRB And PDGFB Genes In Southern Han Chinese Patients With Idiopathic Basal Ganglia Calcification And Analysis Of Their Clinical Characteristics

Part IMutation analysis for SLC20A2, PDGFRB, PDGFB in SouthernHan Chinese patients with idiopathic basal ganglia calcificationObjective Idiopathic basal ganglia calcification （IBGC） was a rare neuropsychiatric disordercharacterized by bilateral basal ganglia calcifications on CT, also called Fahr disease. Themainly clinical manifestations were movement disorders, cognitive and psychiatric symptoms,with highly clinical heterogeneity. The progression of its etiology and pathogenesis was veryslow; until2012, Liu et al successfully cloned the first causative gene, SLC20A2, whichlargely promoted the clarification of IBGC’s molecular mechanism. In the following year,studies have also shown that PDGFRB and PDGFB were another two causative genes forIBGC. In the present study, we aimed to detect the pathogenic mutations of SLC20A2,PDGFRB and PDGFB genes in Southern Han Chinese patients with IBGC.Method Four IBGC families and37sporadic cases,49patients in all, were recruited from theHan ethnic group in southern China. PCR and Sanger sequencing were employed to screenthe mutations within exons, intron-exon boundaries of SLC20A2, PDGFRB and PDGFBgenes.Result1Four novel SLC20A2mutations （c.82G>A, c.185T>C,c.1470₁478delGCAGGTCCT and c.935-1G>A） were identified in two families and twosporadic cases, respectively. None were detected in200unrelated controls. Among them, themutation c.935-1G>A was located in the intron area and we further confirmed that themutation could lead to abnormal splicing on RNA level.2No pathogenic mutation of PDGFRB and PDGFB were detected in the remaining2familiesand35sporadic cases without SLC20A2mutations. Only1PDGFB gene polymorphism andsix PDGFRB gene polymorphisms were found. Among them, the MAF of polymorphismc.1108c> T was less than0.01. We further analyzed in179healthy controls and did not findan association of the T allele with IBGC （p>0.05）.Conclusion1Our data supported the hypothesis that SLC20A2was a causative gene of IBGC in Southern Han Chinese population and expanded the mutation spectrum of SLC20A2.2PDGFRB and PDGFB were not the common causative genes in our cohort of IBGCpatients. Part IIClinical analysis in Southern Han Chinese patients with idiopathicbasal ganglia calcificationObjective The clinical manifestations of IBGC patients are highly heterogeneous and mainlyinclude movement disorders, cognitive and psychiatric symptoms, which, unfortunately, givesrise to an increasing missed diagnosis or misdiagnosis. Baseing on the data of mutationscreening above, we further analysis their phenotype spectrum, aiming to improve therecognition of IBGC.Method The research objects were49patients, including10patients with SLC20A2genediagnosed. We mainly summarized the age of onset, clinical symptoms, biochemical data andimaging characteristics of IBGC patients in our cohort. Meanwhile, we further made acomparison of IBGC clinical features between our cohort and the Western patients havingbeen reported. Finally, we also made a genotype-phenotype analysis among those patientscarrying SLC20A2gene mutations. Chi-square and Fisher’s exact probability method wereadopted for statistical analysis.Result1Among the49patients, a variety of clinical symptoms we found, mainly includedmovement disorders（13/49,33.3%）, cognitive（5/49,12.8%） and psychiatric（3/49,7.7%）symptoms, epilepsy（7/49,17.9%）, chronic headache（12/49,30.8%） and dizziness（6/49,15.4%）.There was a little link between the amount of calcification and age of onset （p>0.05）, andexistence of symptoms （p>0.05）, which was consistent with the previous studies.2The most common clinical symptom was movement disorder both in the Western and Southern Han Chinese patients. However, in the Western patients, the second and thirdcommon clinical symptoms were cognitive impairment （47.8%） and mental disorder （42.4%）,which account for small proportions relatively, and were substituted by headache （30.8%） anddizziness （15.4%） in Southern Han China.3In the2IBGC families with SLC20A2gene mutations, we found that those patients withc.185T>C mutation all showed speech difficulties and calcification on the bilateral putamen,while with c.935-1G>A mutation all manifested with paroxysmal dystonia and extensivecerebral calcifications.Conclusion1The main clinical symptoms of Fahr patients in Southern Han China weremovement disorders, headache, dizziness and epilepsy. There was little link between theamount of calcification and existence of symptoms, and onset of age.2Compared with the Western patients, our cohort patients prominently manifested withheadache and dizziness.3The Fahr’s disease patients carrying the same SLC20A2mutations likely showed a similarclinical manifestation.