Chinnery PF

Daud D

Douroudis K

Eglon G

Griffin H

Horvath R

Keogh MJ

Miller J

Pyle A

Primary familial basal ganglia calcification (PFBC) (previously known as idiopathic basal ganglia calcification or Fahr disease) is an autosomal dominant neurodegenerative disorder characterized by bilateral 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.(

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              This work is licensed under a Creative Commons Attribution 4.0 International License   Newcastle University ePrints - eprint.ncl.ac.uk  Keogh MJ, Pyle A, Daud D, Griffin H, Douroudis K, Eglon G, Miller J, Horvath R, Chinnery PF. Clinical heterogeneity of primary familial brain calcification due to a novel mutation in PDGFB. Neurology 2015, 84(17), 1818-1820.   Copyright: © 2015 American Academy of Neurology This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI link to article: http://dx.doi.org/10.1212/WNL.0000000000001517  Date deposited:   30/06/2015   publication of the Oxford Specialist Handbook Parkinson’s Diseaseand Other Movement Disorders (Oxford University Press, 2008)and ofMarsden’s Book of Movement Disorders (Oxford UniversityPress, 2012). He received funding for travel from GlaxoSmithKline,Orion Corporation, Ipsen, and Merz Pharmaceuticals. Go toNeurology.org for full disclosures.Received July 29, 2014. Accepted in final form December 10, 2014.Correspondence to Prof. Bhatia: k.bhatia@ion.ucl.ac.uk© 2015 American Academy of Neurology1. Schneider SA, Hardy J, Bhatia KP. Syndromes of neurodegen-eration with brain iron accumulation (NBIA): an update onclinical presentations, histological and genetic underpinnings,and treatment considerations. Mov Disord 2012;27:42–53.2. Kruer MC, Boddaert N, Schneider SA, et al. Neuroimagingfeatures of neurodegeneration with brain iron accumulation.AJNR Am J Neuroradiol 2012;33:407–414.3. Schipper HM. Neurodegeneration with brain iron accumu-lation: clinical syndromes and neuroimaging. Biochim Bio-phys Acta 2012;1822:350–360.4. McNeill A, Birchall D, Hayflick SJ, et al. T2* and FSEMRI distinguishes four subtypes of neurodegeneration withbrain iron accumulation. Neurology 2008;70:1614–1619.5. Lehn A, Mellick G, Boyle R. Teaching NeuroImages: neu-roferritinopathy. Neurology 2011;77:e107.6. Vidal R, Ghetti B, Takao M, et al. Intracellular ferritinaccumulation in neural and extraneural tissue characterizesa neurodegenerative disease associated with a mutation inthe ferritin light polypeptide gene. J Neuropathol Exp Neu-rol 2004;63:363–380.7. Li W, Wu B, Batrachenko A, et al. Differential develop-mental trajectories of magnetic susceptibility in humanbrain gray and white matter over the lifespan. Hum BrainMapp 2014;35:2698–2713.CLINICAL HETEROGENEITY OF PRIMARYFAMILIAL BRAIN CALCIFICATION DUE TO ANOVEL MUTATION IN PDGFBPrimary familial basal ganglia calcification (PFBC)(previously known as idiopathic basal ganglia calci-fication or Fahr disease) is an autosomal dominantneurodegenerative disorder characterized by bilat-eral cerebral calcification primarily affecting thebasal ganglia. Recently, mutations in SLC20A2,1PDGFRB,2 and PDGFB3,4 have been identified ascausing PFBC. However, other than the originalstudy,3 there has been a paucity of descriptions offamilies with PFBC.5Herein, we describe 4 cases of PFBC within a fam-ily due to a novel mutation in exon 4 of the PDGFBgene (c.C3657T:p.P122L) highlighting significantphenotypic heterogeneity.Cases. Patient III.2. A 31-year-old woman presentedwith acute psychosis. She was diagnosed in childhoodwith mild learning difficulties, but reached normalmotor milestones. Over the next 6 years, she hadrecurrent episodes of psychosis and depression requir-ing admission. At age 36, a CT scan of her headrevealed 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, andautoantibodies. An EEG showed no encephalopathicfeatures.There was no family history of any neurologic dis-order; however, the examining neurologist noted thatthe patient’s mother, accompanying her to clinic, wasataxic (patient II.4).Patient II.4.A retired shop worker was referred aged60 years (figure). Both parents died in their 70s withno neurologic symptoms before death. She had 3siblings, none of whom she remained in contact with.She had episodic psychosis and depression formore than 20 years, and a 2-year history of falls andunsteady gait. Medical history included hypertensionand heavy smoking. Examination revealed a severemidline ataxia with jerky ocular pursuit. There wereno cognitive abnormalities or extrapyramidal features.Serum biochemistry (including calcium and phos-phate) was normal. A muscle biopsy showed normalhistology, 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 butcognition remained normal (Mini-Mental StateExamination score 28/30 at age 66).Patient III.5. A woman aged 40 years was referredwith a 2-year history of gait disturbance. She hadno psychiatric history, cognitive symptoms, or evi-dence of abnormal movements. Examination revealednormal cognition, but a midline ataxia. A CT brainscan showed bilateral calcification of the globus pal-lidus (figure, A.c). Three years later, she developeda complex motor tic, and dystonic posturing of bothfeet. Formal neuropsychometry remained normal.Patient IV.4. A 20-year-old woman was referredwith a gait disturbance. She had no other medicalor psychiatric history. Neurologic examination wasnormal. Brain MRI revealed small frontal noncalci-fied white matter changes not in keeping with PFBC,and no evidence of calcium in the basal ganglia evenwith susceptibility-weighted imaging (figure, A.a).Michael J. Keogh, MRCPAngela Pyle, PhDDaniyal Daud, MBBSHelen Griffin, PhDKonstantinos Douroudis,PhDGail Eglon, RNJames Miller, PhD, MRCPRita Horvath, MD, PhDPatrick F. Chinnery, PhD,FRCP, FMedSciSupplemental dataat Neurology.org1818 Neurology 84 April 28, 2015ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.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 withno 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 (appendixe-1 on the Neurology® Web site at Neurology.org)revealing a shared novel missense mutation in exon 4of PDGFB (c.C3657T:p.P122L), not seen in the 1000Genomes or ESP6500 database (figure, C), and pre-dicted to be pathogenic by 4 software programs andconserved across all species (MutationTaster). Thismutation was confirmed present in cases and absentin unaffected relatives with Sanger sequencing(III.1 and III.4). The p.P122L mutation is in thesame exon as published pathogenic alleles.3,6Discussion. These cases highlight the phenotypicheterogeneity of mutations in PDGFB. Two patientsexhibited an early psychiatric phenotype followed byFigure Neuroimaging features and genotype details of affected individuals(A) CT andMRI scans of cases. (A.a) Case IV.4 (age 20 years): T2MRI scan with no evidence of calcium deposition within the basal ganglia. (A.b) Case III.2 (age36 years): CT scan showing calcium deposition in the caudate, lentiform nuclei, and thalamus. (A.c) Case III.5 (age 40 years): CT scan showing isolated subtlecalcium deposition in the globus pallidus. (A.d) Case II.4 (age 66 years): T1 MRI showing calcification in the globus pallidus together with periventricular andpontine vascular white matter changes. (B) Pedigree of the family with the PDGFB p.P122L mutation. Black 5 affected individuals; clear 5 unaffected. (C)Details of the mutation found in affected individuals. MAF 5 minor allele frequency.Neurology 84 April 28, 2015 1819ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.late-onset ataxia or chorea; an isolated movementdisorder was identified in a third. All 3 had ataxia,which has been described in isolated cases,5 but notconsistently in PDGFB families.3 In addition, theataxia in our cases occurred without obviouscerebellar calcification. This suggests that (1) themechanism may not be primarily mediated bycalcium deposition (although we cannot exclude thepresence of microcalcification), and (2) there issignificant clinical overlap with common neurologicand psychiatric disorders.5 Our data also show aheterogeneous radiologic phenotype that may bemuch milder than previously described,3 and similarto PDGFRB families.7 In keeping with this, case IV.4showed no basal ganglia calcification and a normalneurologic examination at age 20 years, providingthe first evidence of potential incomplete radiologicpenetrance for a pathogenic PDGFB mutation,highlighting that normal imaging does not excludethe diagnosis of PFBC.From the Wellcome Centre for Mitochondrial Research (M.J.K.,A.P., D.D., H.G., K.D., G.E., R.H., P.F.C.), Institute of GeneticMedicine, Centre for Life, Newcastle University; and Royal VictoriaInfirmary (M.J.K., J.M., R.H., P.F.C.), Newcastle Upon Tyne, UK.Author contributions: M.J. Keogh: study concept and design, analysisand interpretation of data, acquisition of data, statistical analysis, draft-ing/revising the manuscript. A. Pyle: analysis and interpretation of data,statistical analysis. D. Daud: analysis or interpretation of data, acqui-sition of data, drafting manuscript for content. H. Griffin: statisticalanalysis. K. Douroudis: statistical analysis. G. Eglon: acquisition of data.J. Miller: acquisition of data, drafting the manuscript. R. Horvath:study concept and design. P.F. Chinnery: study concept and design,analysis and interpretation of data, study supervision, drafting themanuscript.Study funding: Dr. Michael Keogh is a Wellcome Trust ClinicalResearch Training Fellow. Prof. Horvath is supported by the MedicalResearch Council (UK) (G1000848) and the European ResearchCouncil (309548). Prof. Chinnery is a Wellcome Trust Senior Fel-low in Clinical Science and National Institute for Health ResearchSenior Investigator. He receives funding from the Medical ResearchCouncil and the National Institute for Health Research BiomedicalResearch Centre for Ageing and Age-Related Disease award to theNewcastle Upon Tyne Foundation Hospitals National Health Ser-vice Trust.Disclosure: The authors report no disclosures relevant to the manu-script. Go to Neurology.org for full disclosures. The Article ProcessingCharge was paid by Wellcome Trust.This is an open access article distributed under the Creative Com-mons Attribution License, which permits unrestricted use, distribu-tion, and reproduction in any medium, provided the original workis properly cited.Received August 19, 2014. Accepted in final form December 15, 2014.Correspondence to Prof. Chinnery: p.f.chinnery@newcastle.ac.uk© 2015 American Academy of Neurology1. Wang C, Li Y, Shi L, et al. Mutations in SLC20A2 linkfamilial idiopathic basal ganglia calcification with phosphatehomeostasis. Nat Genet 2012;44:254–256.2. Nicolas G, Pottier C, Maltete D, et al. Mutation of thePDGFRB gene as a cause of idiopathic basal ganglia calci-fication. Neurology 2013;80:181–187.3. Keller A, Westenberger A, Sobrido MJ, et al. Mutations inthe gene encoding PDGF-B cause brain calcifications inhumans and mice. Nat Genet 2013;45:1077–1082.4. Nicolas G, Rovelet-Lecrux A, Pottier C, et al. PDGFB par-tial deletion: a new, rare mechanism causing brain calcifica-tion with leukoencephalopathy. J Mol Neurosci 2014;53:171–175.5. Hayashi T, Legati A, Nishikawa T, Coppola G. First Jap-anese family with primary familial brain calcification due toa mutation in the PDGFB gene: an exome analysis study.Psychiatry Clin Neurosci 2015;69:77–83.6. Nicolas G, Jacquin A, Thauvin-Robinet C, et al. A de novononsense PDGFB mutation causing idiopathic basal gangliacalcification with laryngeal dystonia. Eur J Hum Genet2014;22:1236–1238.7. Nicolas G, Pottier C, Charbonnier C, et al. Phenotypicspectrum of probable and genetically-confirmed idiopathicbasal ganglia calcification. Brain 2013;136:3395–3407.Share Your Artistic Expressions in Neurology ‘Visions’AAN members are urged to submit medically or scientifically related artistic images, such as photo-graphs, photomicrographs, and paintings, to the “Visions” section of Neurology®. These images arecreative in nature, rather than the medically instructive images published in the NeuroImages sec-tion. The image or series of up to six images may be black and white or color and must fit into onepublished journal page. Accompanying description should be 100 words or less; the title should be amaximum of 96 characters including spaces and punctuation.Learn more at www.aan.com/view/Visions, or upload a Visions submission at submit.neurology.org.1820 Neurology 84 April 28, 2015ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.DOI 10.1212/WNL.00000000000015172015;84;1818-1820 Published Online before print April 1, 2015Neurology Michael J. Keogh, Angela Pyle, Daniyal Daud, et al. PDGFBClinical heterogeneity of primary familial brain calcification due to a novel mutation in This information is current as of April 1, 2015ServicesUpdated Information & http://www.neurology.org/content/84/17/1818.full.htmlincluding high resolution figures, can be found at:Supplementary Material 001517.DC1.htmlhttp://www.neurology.org/content/suppl/2015/04/01/WNL.0000000000Supplementary material can be found at: References http://www.neurology.org/content/84/17/1818.full.html##ref-list-1This article cites 7 articles, 2 of which you can access for free at: Subspecialty Collections http://www.neurology.org//cgi/collection/gait_disorders_ataxiaGait disorders/ataxia http://www.neurology.org//cgi/collection/dystoniaDystonia http://www.neurology.org//cgi/collection/cerebellumCerebellum http://www.neurology.org//cgi/collection/basal_gangliaBasal ganglia http://www.neurology.org//cgi/collection/all_movement_disordersAll Movement Disordersfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://www.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://www.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:rights reserved. 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Clinical heterogeneity of primary familial brain calcification due to a novel mutation in PDGFB

Clinical heterogeneity of primary familial brain calcification due to a novel mutation in PDGFB

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