Novel SLC20A2 variant in a Japanese patient with idiopathic basal ganglia calcification-1 (IBGC1) associated with dopa-responsive parkinsonism

Idiopathic basal ganglia calcification-1 (IBGC1) is an autosomal dominant disorder characterized by calcification in the basal ganglia, which can manifest a range of neuropsychiatric symptoms, including parkinsonism. We herein describe a 64-year-old Japanese IBGC1 patient with bilateral basal ganglia calcification carrying a novel SLC20A2 variant (p.Val322Glufs*92). The patient also presented with dopa-responsive parkinsonism with decreased dopamine transporter (DAT) density in the bilateral striatum and decreased cardiac 123I-meta-iodobenzylguanidine uptake.

The patient was a 63-year-old Japanese woman who presented to our hospital with a one-month history of lumbago and unsteady gait. Neurological examination revealed gait disturbance with stooped posture and short steps, but rigidity, tremor, weakness, and cerebellar symptoms were not observed. Computed tomography (CT) images of her brain revealed marked calcifications in the bilateral basal ganglia, thalami, and dentate nuclei (Fig. 1a). Laboratory tests showed that serum calcium, phosphate, and intact parathyroid hormone levels were all within the normal ranges. There was no family history of IBGC or parkinsonism. After written informed consent was obtained, we analyzed all the coding regions of the IBGC causative genes, SLC20A2, PDGFRB, and PDGFB, by Sanger sequencing as previously reported 10 . We diagnosed her as IBGC1 based on the identification of a novel heterozygous frameshift variant, p.Val322Glufs*92 (NM_006749.4:c.965_966delTG, exon 8), in SLC20A2 (Fig. 1b). The variant was absent in the following genome databases: dbSNP 151 (https://www.ncbi. nlm.nih.gov/projects/SNP/), Integrative Japanese Genome Variation Database (http://ijgvd.megabank.tohoku.ac.jp/), Exome Aggregation Consortium database version 0.3.1 (http://exac.broadinstitute.org/), and Human Gene Mutation Database (HGMD® Professional 2019.1).
Ten months after her first visit, she was hospitalized because of difficulties in standing up without assistance at the age of 64. She showed severe bradykinesia, postural instability, and mild symmetric rigidity without tremor. Her Unified Parkinson Disease Rating Scale part III (UPDRS-III) score was 43 of 108 on the ninth hospital day. Her Mini-Mental State Examination score was 24 of 30, and her Hasegawa dementia scale revised was 22 of 30. Dopamine transporter (DAT) single photon emission CT using I-ioflupane showed diffusely decreased DAT density in the bilateral striatum (Fig. 1c). The specific binding ratios (SBRs) of both striatum were 0.51 (right) and 0.14 (left). Her 123 I-meta-iodobenzylguanidine ( 123 I-MIBG) myocardial scintigraphy revealed reduced cardiac 123 I-MIBG uptake with early and delayed heart to mediastinum (H/M) rates of 1.995 and 1.585, respectively (Fig. 1d). Levodopa therapy (200 mg/day) was started on the 14th hospital day and was effective against bradykinesia and postural instability. She was able to walk without assistance in her room. On the 122nd hospital day, she received 600 mg/day of levodopa, and her UPDRS-III score markedly improved from 43 to 11.
The variants associated with IBGC are located widely in SLC20A2 among the patients with IBGC, and the correlation of genotype and phenotype remains unclear 1,9,11 .
Parkinsonism is one of the common clinical symptoms of IBGC. Tadic et al. showed that 13% of patients with SLC20A2 or PDGFRB variants presented with parkinsonism 1 . Another review reported motor improvement with dopatherapy in five patients with genetically confirmed IBGC 12 . Genetically confirmed Japanese IBGC1 patients presenting with parkinsonism have also been reported (Table 1) 10,13,14 . Among the five variants summarized in Table 1, two variants (c.516+1G>A and c.965_966delTG) are frameshift variants, presumably resulting in loss of function of SLC20A2. In addition, a decreased level of SLC20A2 protein was described in the case with the missense variant (c.1909A>C, S637R), raising the possibility of unstable mutant protein 13 . Although the functional investigations were not reported for the two missense variants (R71H and G90V), loss-of-function variants are considered for the three variants shown in Table 1. Consistent with previous reports, the majority of variants associated with IBGC are loss-of-function variants 8,9 , and the present study also suggests that loss-offunction mechanisms are likely involved in at least of the  (Fig. 1c, d). The decreased DAT density in the bilateral striatum suggested presynaptic dopaminergic dysfunction, which was reported in patients with IBGC 14-17 . Saito et al. also showed that postsynaptic dopaminergic dysfunction in the bilateral striatum matched calcified regions 16 . These findings suggested that basal ganglia calcification might result in dopaminergic dysfunction in IBGC patients. The three cases with reduced DAT density in the striatum (cases 2, 5, and 7. Table 1) also presented with decreased cardiac 123 I-MIBG uptake, which was indistinguishable from that observed in patients with Lewy body diseases, including idiopathic Parkinson disease (PD) 18 . Since PD is a relatively common disease in Japan (prevalence of~150 per 100,000 persons in Japan) 19 , the coincidental presence of idiopathic PD and IBGC remains a possibility concerning doparesponsive parkinsonism of patients with IBGC1. However, it is important to pay attention to patients with IBGC who show dopa-responsive parkinsonism to provide appropriate treatment. To clarify the etiologies of dopa-responsive parkinsonism occasionally observed in patients with IBGC, further functional analyses including DAT SPECT and 123 I-MIBG myocardial scintigraphy will be required in a larger number of patients with genetically confirmed IBGC.

HGV Database
The relevant data from this Data Report are hosted at the Human Genome Variation Database at https://doi.org/10.6084/m9.figshare.hgv.2603