Diffuse Brain Calcification, a Novel SLC20A2 Variant, Vertical Supranuclear Gaze Palsy, and Systemic Lupus Erythematosus

Diffuse brain calcification (DBC) is characterized by calcification, especially of the basal ganglia, cerebellar dentate nuclei, and centrum semiovale. Etiology can be genetic (primary familial brain calcification; PFBC), symptomatic of a variety of disorders, including rarely systemic lupus erythematosus (SLE), and idiopathic.1 In PFBC, five genes have been identified to date (four with autosomal‐dominant inheritance: SCL20A2, PDGFB, PDGFRB, and XPR1; and one with autosomal‐recessive inheritance: MYORG). Clinical features in patients with DBC include cognitive impairment and mood and movement disorders, especially parkinsonism, dystonia, chorea, ataxia, and gait dysfunction.1 Vertical supranuclear gaze palsy (VSGP) has been reported as rarely associated with DBC.

We report on a patient with a history of SLE and progressive neurological symptoms, including parkinsonism, gait ataxia, VSGP, and DBC, found to have an unreported variant in the SLC20A2 gene.

Case Report

This 60‐year‐old woman, with a negative neurological family history, had noted slowly progressive speech and walking difficulties since age 30. She was diagnosed with SLE 10 years earlier, limited to the joint and skin, and is currently not on medication. Progression of dysarthria and slowness, notably in the last year, resulted in a fall requiring hospitalization. MRI brain identified extensive symmetrical high‐intensity changes in the basal ganglia, centrum semiovale, dentate nuclei, and generalized cerebral cortical atrophy (Fig. 1).

Figure 1.

CT brain (A–C) with calcification involving the dentate nuclei, basal ganglia, periventricular white matter, and subcortical white matter. MRI brain (D–F) shows similar changes consistent with calcification. There are associated white matter changes and moderate generalized cerebral atrophy, but no midbrain atrophy.

On our examination, Montreal Cognitive Assessment score was 24/30. She had VSGP with slowing of saccades and evidence of right‐side predominant parkinsonism (hypophonia, rigidity, bradykinesia, stooped posture, reduced arm swing and stride length, mild broad based gait, and postural instability).

CT brain showed widespread symmetrical calcification (Fig. 1). Workup for other secondary causes was negative. Genetic testing showed a heterozygous missense mutation in the SLC20A2 gene (c.24G>C p.(Trp8Cys) exon 2). This mutation was reported to be probably damaging (PolyPhen) and disease causing (MutationTaster).

This patient was initially believed to have intracranial calcification secondary to SLE, especially in the absence of relevant family history. There is one previous report of a similar patient with a 13‐year history of SLE (no symptoms of cerebral lupus) with PSP‐like features, including a VSGP and diffuse intracranial calcification, including involvement of the midbrain.2 Genetic testing for pathological variants in the SLC20A2 gene was negative, but other known genetic causes of PFBC were not excluded.

Presence of MRI abnormalities in SLE ranges from 19% to 70%. However, intracranial calcification, especially in isolation, is rare. Nordstrom et al. found 2 of 28 SLE patients with intracranial calcification over a 4‐year period.3 Raymond et al. reported 8 of 27 (30%) consecutive CT brain images of SLE patients with intracranial calcification, three associated with cerebral atrophy, two with atrophy and infarcts, and three in isolation.4 A single case of intracranial calcification was reported in a cohort of 200 patients that were prospectively followed.5 MRI showed evidence of small acute and chronic microinfarction.

Discussion

Distribution of intracerebral calcification in SLE patients consistently involves the basal ganglia and occurs in a similar pattern to that observed in PFBC.3, 4 This includes both symmetrical widespread calcification and focal, punctate calcification. However, these reports preceded the availability of genetic testing for PFBC. Genome‐wide association studies in SLE patients have not identified genes that are known to cause brain calcification.6 It is important to note that these studies have not specifically addressed this question, and so further directed studies will be required to exclude this possibility. The pathophysiology of intracranial calcification in SLE patients is unclear. One suggestion is that repeated episodes of venous inflammation with focal immunological demyelination (antiphospholipid antibodies, antibodies to glial fibrillary acidic protein) lead to repeated leakage of proteins with neurotoxic and procalcification properties.7 Presence of neurological or psychiatric symptoms in the majority of cases with high markers of disease activity suggests an immunological mechanism,3, 4, 5 but does not exclude the possible role of a genetic cause of PBFC.

To our knowledge, VSGP has been reported in only 4 cases with DBC2, 8, 9, 10; 2 secondary to hypoparathyroidism9, 10 and 2 “idiopathic,” including the SLE case described above.2, 8 Both latter patients had additional midbrain calcification. The underlying pathophysiology of gaze impairment is possibly related to calcification of the pathways in, or projecting to, the midbrain. The caudate transiently inhibits the SN through GABAergic pathways that tonically inhibit the superior colliculus.10 The basal ganglia affect these pathways in a task‐specific and learned manner.10 Our patient did not have midbrain atrophy or calcification, although there was caudate involvement. Symmetry and distribution of calcification was similar to that observed in PFBC.

In summary, this experience strongly suggests that some previously reported cases of SLE associated with DBC were examples of unrecognized PFBC. Whether and how underlying SLE could influence clinical or imaging presentation is uncertain; however, the previous report of a similar case of DBC in a patient with SLE without neuropsychiatric symptoms, progressive levodopa‐resistant parkinsonism, and VSGP encourages further consideration of a relationship.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique, C. Final Approval.

D.S.: 1C, 3A

A.L.: 1A, 3B, 3C

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. Informed consent was obtained for the writing of this case, including videotaping, but when approached for publication, she consented for paper publication but declined consent for release of the videotape.

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: The authors declare that there are no disclosures to report.