Abstract Details

PFBC is a rare, inherited syndrome characterized by bilateral basal ganglia calcifications presenting with neuropsychiatric symptoms, seizures, headaches, and movement disorders. Mutations in PDGFB are known to cause autosomal dominant PFBC. Leukoencephalopathy has been rarely reported.

To describe a family with primary familial brain calcification (PFBC) and leukoencephalopathy associated with a novel variant in PDGFB.

We present three consecutive generations of a family with PFBC associated with a previously gnomAD-unreported variant in PDGFB. Publicly available computational (in silico) programs predicted protein dysfunction. We reviewed PubMed for cases of PFBC with leukoencephalopathy using search terms Fahr, primary familial brain calcifications, leukoencephalopathy, white matter changes, PDGFB, PDGFRB, SLC20A2, XPR1, JAM2, and MYORG.

A 24-year-old woman with episodic migraine, depression, and anxiety was found to have bilateral calcifications of the basal ganglia on head CT as well as frontally-predominant white matter hyperintensities on brain MRI.  Her father had mild cognitive impairment, bilateral action-induced hand tremor, and calcifications of the basal ganglia and cerebellum on head CT.  Her paternal grandmother had dementia, severe parkinsonism, calcifications of the basal ganglia and cerebellum on head CT, and confluent periventricular white matter hyperintensity on brain MRI. Genetic testing in the proband and her father revealed a novel PDGFB variant (NM_002608.3:c.298C>T p.(Arg100Cys)), unavailable in publicly available databases. Multiple in silico analysis tools predicted it to be pathogenic. Our literature review found three reports of PDGFB-associated PFBC with leukoencephalopathy.

Our report expands the list of PDGFB variants in PFBC and adds to the growing collection of genetic leukoencephalopathies. Clinicians should consider PDGFB disease in individuals with neurologic symptoms, familial leukoencephalopathy, and brain calcifications.