ABSTRACT 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. SIMILAR CONTENT BEING VIEWED BY OTHERS BIALLELIC _NAA60_ VARIANTS WITH IMPAIRED N-TERMINAL ACETYLATION CAPACITY CAUSE AUTOSOMAL RECESSIVE PRIMARY

(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). 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. HGV DATABASE The relevant data from this

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[Nanbyo]-Ippan-080) from the Ministry of Health, Labour and Welfare, Japan (S.T.). AUTHOR INFORMATION AUTHORS 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

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CORRESPONDING AUTHOR Correspondence to Yaeko Ichikawa. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ADDITIONAL INFORMATION PUBLISHER’S

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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 Download citation * Received: 01 June 2019 * Revised: 18 July 2019 * Accepted: 25 July 2019 * Published: 04 September 2019 * DOI:

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