Download PDF Data Report Open access Published: 04 September 2019 Novel SLC20A2 variant in a Japanese patient with idiopathic basal ganglia calcification-1 (IBGC1) associated with

dopa-responsive parkinsonism Yaeko Ichikawa1, Masaki Tanaka2,3, Eriko Kurita1, Masanori Nakajima1, Masaki Tanaka1, Chizuko Oishi1, Jun Goto4, Shoji Tsuji  ORCID:

orcid.org/0000-0001-5602-56862,3,5 & …Atsuro Chiba1 Show authors Human Genome Variation volume 6, Article number: 44 (2019) Cite this article

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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.

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Idiopathic basal ganglia calcification (IBGC), also known as Fahr disease or primary familial brain calcification (PFBC), is a disorder characterized by bilateral calcifications in the basal

ganglia and other brain regions. Clinical manifestations of IBGC range from asymptomatic to neuropsychiatric symptoms, including dystonia, parkinsonism, ataxia, and cognitive impairment1.

Typically, the inheritance mode of familial IBGC is an autosomal dominant one and to date, four dominant causal genes of familial IBGC have been identified, including SLC20A2 (IBGC1, MIM:

#213600), PDGFRB (IBGC4, MIM: #615007), PDGFB (IBGC5, MIM: #615483), and XPR1 (IBGC6, MIM: #616413)2,3,4,5. Recently, MYORG was reported as an autosomal recessive causal gene for IBGC

(IBGC7, MIM: #618317)6,7. Variants in SLC20A2, encoding the type III sodium-dependent phosphate transporter 2 (PiT-2), are a major cause of IBGC8,9. Herein, we report an IBGC1 patient with a

novel variant in SLC20A2 associated with dopa-responsive parkinsonism.

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 reported10. 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).

a Computed tomographic (CT) images of the patient show calcifications in the bilateral basal ganglia, thalami, and dentate nuclei. b Electropherogram and sequence of SLC20A2 (NM_006749.4)

from the patient’s DNA shows the c.965_966delTG variant. DNA and corresponding amino acid sequences of wild-type and mutant SLC20A2 alleles are also shown. The c.965_966delTG variant causes

a frameshift variant (p.Val322Glufs*92). c Dopamine transporter (DAT) single photon emission CT shows diffusely decreased DAT density in the bilateral striatum. The specific binding ratios

(SBRs) of both striatum were 0.51 (right) and 0.14 (left). d 123I-meta-iodobenzylguanidine (123I-MIBG) myocardial scintigraphy shows decreased cardiac 123I-MIBG uptake with early and delayed

heart to mediastinum (H/M) rates of 1.995 and 1.585, respectively

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 123I-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 123I-meta-iodobenzylguanidine (123I-MIBG) myocardial scintigraphy

revealed reduced cardiac 123I-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 unclear1,9,11.

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 parkinsonism1. Another review reported

motor improvement with dopatherapy in five patients with genetically confirmed IBGC12. 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 protein13. 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 variants8,9, and the present study also suggests that loss-of-function mechanisms are likely involved in

at least of the three variants. The present case demonstrated decreased DAT density in the bilateral striatum and decreased cardiac 123I-MIBG uptake (Fig. 1c, d). The decreased DAT density

in the bilateral striatum suggested presynaptic dopaminergic dysfunction, which was reported in patients with IBGC14,15,16,17. Saito et al. also showed that postsynaptic dopaminergic

dysfunction in the bilateral striatum matched calcified regions16. 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 123I-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 dopa-responsive 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 123I-MIBG myocardial scintigraphy will be required in a larger number of patients with genetically confirmed IBGC.

SLC20A2 and clinical features of genetically confirmed IBGC1 Japanese patients with parkinsonismFull size table 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

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This work was supported by Grant-in-Aid (No. H26-Jitsuyoka [Nanbyo]-Ippan-080) from the Ministry of Health, Labour and Welfare, Japan (S.T.).

Author informationAuthors and Affiliations Department of Neurology, Kyorin University School of Medicine, Tokyo, Japan

Yaeko Ichikawa, Eriko Kurita, Masanori Nakajima, Masaki Tanaka, Chizuko Oishi & Atsuro Chiba

Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan

Masaki Tanaka & Shoji Tsuji

Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan

Masaki Tanaka & Shoji Tsuji

Department of Neurology, International University of Health and Welfare Mita Hospital, Tokyo, Japan

Jun Goto

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Shoji Tsuji

AuthorsYaeko IchikawaView author publications You can also search for this author inPubMed Google Scholar

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About this articleCite this article Ichikawa, Y., Tanaka, M., Kurita, E. et al. Novel SLC20A2 variant in a Japanese patient with idiopathic basal ganglia calcification-1 (IBGC1) associated

with dopa-responsive parkinsonism. Hum Genome Var 6, 44 (2019). https://doi.org/10.1038/s41439-019-0073-7

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Received: 01 June 2019

Revised: 18 July 2019

Accepted: 25 July 2019

Published: 04 September 2019

DOI: https://doi.org/10.1038/s41439-019-0073-7

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