Objective: Our main aim was to define the clinical presentation and genotypes of a cohort with primary familial brain calcifications (PFBC) at a tertiary center in Sweden.

Background: PFBC constitute a group of rare disorders with variable presentation and reduced penetrance. Mutations in five genes are associated with PFBC, three of them (SLC20A2, PDGFB, PDGFB, and XPR1) follow an autosomal dominant pattern of inheritance whereas mutations in MYORG are autosomal recessive.

Method: Clinical characterization, radiology and next-generation sequencing were applied in a total of 19 patients. These patients belong to eight different families, two cases were sporadic. Acquired causes of brain calcifications were ruled out first and patients examined with standard protocols for movement disorders. Total calcification score (TCS) was used to assess the radiological abnormalities.

Results: Two families have pathogenic variants in PDGFB and SLC20A2 as previously reported by our group. Three additional families have mutations in SLC20A2, two were new and a third one reported by another group. Fourteen patients display different types of movement disorders: tremor and parkinsonism were the most common presentation, followed by chorea, ataxia, and dystonia. Psychiatric symptoms, migraine and cognitive impairment were less common. Five patients were asymptomatic. The index case of one family had late onset and slowly progressive parkinsonism, with dementia, hallucinations and orthostatism. In his case a VUS in STUB1 was found but segregation was not possible to perform. A sporadic case had Apert’s syndrome and an aggressive parkinsonian syndrome but no candidate variants were found. This condition made him wheel-chair bound and shortened his life. No mutations were found in family with MYORG, XPR1 or PDGFRB. Patients with SLC20A2 mutations have a more severe degree of brain calcifications when compared with the remaining cohort.

Conclusion: Our studies demonstrate again that pathogenic variants in SLC20A2 are the most common cause of PFBC. Also in keeping with previous descriptions, expressivity is very variable with a clinical penetrance around 74% despite full radiological penetrance.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/primary-familial-brain-calcifications-in-sweden/