Clinical/Scientific Notes Michael J. Keogh, MRCP Angela Pyle, PhD Daniyal Daud, MBBS Helen Griffin, PhD Konstantinos Douroudis, PhD Gail Eglon, RN James Miller, PhD, MRCP Rita Horvath, MD, PhD Patrick F. Chinnery, PhD, FRCP, FMedSci Supplemental data at Neurology.org CLINICAL HETEROGENEITY OF PRIMARY FAMILIAL BRAIN CALCIFICATION DUE TO A NOVEL MUTATION IN PDGFB Primary familial basal ganglia calcification (PFBC) (previously known as idiopathic basal ganglia calci- fication or Fahr disease) is an autosomal dominant neurodegenerative disorder characterized by bilat- eral cerebral calcification primarily affecting the basal ganglia. Recently, mutations in SLC20A2, 1 PDGFRB, 2 and PDGFB 3,4 have been identified as causing PFBC. However, other than the original study, 3 there has been a paucity of descriptions of families with PFBC. 5 Herein, we describe 4 cases of PFBC within a fam- ily due to a novel mutation in exon 4 of the PDGFB gene (c.C3657T:p.P122L) highlighting significant phenotypic heterogeneity. Cases. Patient III.2. A 31-year-old woman presented with acute psychosis. She was diagnosed in childhood with mild learning difficulties, but reached normal motor milestones. Over the next 6 years, she had recurrent episodes of psychosis and depression requir- ing admission. At age 36, a CT scan of her head revealed basal ganglia calcification precipitating neu- rologic referral (figure, A.b). Examination revealed jerky ocular pursuit, gener- alized chorea, and midline ataxia. Investigations re- vealed a normal full blood count, biochemistry, and autoantibodies. An EEG showed no encephalopathic features. There was no family history of any neurologic dis- order; however, the examining neurologist noted that the patient’s mother, accompanying her to clinic, was ataxic (patient II.4). Patient II.4. A retired shop worker was referred aged 60 years (figure). Both parents died in their 70s with no neurologic symptoms before death. She had 3 siblings, none of whom she remained in contact with. She had episodic psychosis and depression for more than 20 years, and a 2-year history of falls and unsteady gait. Medical history included hypertension and heavy smoking. Examination revealed a severe midline ataxia with jerky ocular pursuit. There were no cognitive abnormalities or extrapyramidal features. Serum biochemistry (including calcium and phos- phate) was normal. A muscle biopsy showed normal histology, normal mitochondrial biochemical studies, and no mitochondrial DNA deletions. An EEG re- vealed transient sharp waves in the temporal regions. MRI showed calcium deposition in the globus pal- lidus and dentate (figure, A.d). Over the next 5 years, her ataxia progressed but cognition remained normal (Mini-Mental State Examination score 28/30 at age 66). Patient III.5. A woman aged 40 years was referred with a 2-year history of gait disturbance. She had no psychiatric history, cognitive symptoms, or evi- dence of abnormal movements. Examination revealed normal cognition, but a midline ataxia. A CT brain scan showed bilateral calcification of the globus pal- lidus (figure, A.c). Three years later, she developed a complex motor tic, and dystonic posturing of both feet. Formal neuropsychometry remained normal. Patient IV.4. A 20-year-old woman was referred with a gait disturbance. She had no other medical or psychiatric history. Neurologic examination was normal. Brain MRI revealed small frontal noncalci- fied white matter changes not in keeping with PFBC, and no evidence of calcium in the basal ganglia even with susceptibility-weighted imaging (figure, A.a). Patients III.1 and III.4. Aged 42 and 46 years, respec- tively, patients III.1 and III.4 were clinically unaf- fected. Patient III.1 died of a traumatic injury with no evidence of basal ganglia calcification at autopsy. Patient III.4 refused imaging studies. Exome sequencing. Whole-exome sequencing was per- formed on patients III.2, II.4, III.5, and IV.4 (appendix e-1 on the Neurology ® Web site at Neurology.org) revealing a shared novel missense mutation in exon 4 of PDGFB (c.C3657T:p.P122L), not seen in the 1000 Genomes or ESP6500 database (figure, C), and pre- dicted to be pathogenic by 4 software programs and conserved across all species (MutationTaster). This mutation was confirmed present in cases and absent in unaffected relatives with Sanger sequencing (III.1 and III.4). The p.P122L mutation is in the same exon as published pathogenic alleles. 3,6 Discussion. These cases highlight the phenotypic heterogeneity of mutations in PDGFB. Two patients exhibited an early psychiatric phenotype followed by Neurology 84 April 28, 2015 1 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Published Ahead of Print on April 1, 2015 as 10.1212/WNL.0000000000001517