J Neurol DOI 10.1007/s00415-016-8033-3
LETTER TO THE EDITORS
Primary familial brain calcification in a Norwegian family, caused by a novel SLC20A2 gene mutation Oddveig Røsby1 • Andrea Legati2 • Giovanni Coppola2,3
Received: 29 October 2015 / Revised: 12 January 2016 / Accepted: 13 January 2016 Ó Springer-Verlag Berlin Heidelberg 2016
Dear Sirs, Primary familial brain calcification (PFBC) is a rare autosomal dominant neurodegenerative disease. Brain calcifications (of the basal ganglia and/or cerebellar structures, subcortical white matter, thalamus and brain stem) are the main features together with cognitive, psychiatric and neurologic symptoms [1]. Mutations in SLC20A2 [2], PDGFRB [3], PDGFB [4] and XPR1 [5] have been reported as causing PFBC [PMID: 25686319], with SLC20A2 being the most frequent in large series [6]. We here report a novel SLC20A2 mutation in a Norwegian PFBC family. The proband, referred to Department of Medical Genetics, Oslo University Hospital, as well as other family members (her brother and six cousins, generation III, Fig. 1a) have underwent neurological/clinical examinations, brain CT scan and/or MRI and biochemical investigations. Medical records including brain CT scan or X-ray were obtained for individuals in generation II (Fig. 1a). SLC20A2 is the gene with the highest rate of mutations discovered so far to cause PFBC, therefore was screened first. Exonic and flanking regions of SLC20A2 gene were
& Oddveig Røsby [email protected] 1
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
2
Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
3
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
amplified by PCR and subsequently sequenced in both forward and reverse directions by Sanger sequencing. Chromatogram traces were analyzed using the Sequencher software (Gene Codes Corporation). Novelty of the variants was investigated using public online Databases of human genetic variation: dbSNP (http://www.ncbi.nlm.nih. gov), 1000 Genomes Project (http://www.1000genomes. org), Exome Variant Server (6500 exomes) (http://evs.gs. washington.edu/EVS), and the Exome Aggregation Consortium (*61,000 exomes) (http://exac.broadinstitute.org/ ). The potential effect of the variants at protein level was predicted using SIFT (http://sift.jcvi.org) and Mutation Taster (http://www.mutationtaster.org). One heterozygous variant was found in the SLC20A2 gene compared to the reference genome sequence (GRCh37/hg19), the insertion c.219_220insA, p.I74fs (chr8:42329689insT). This variant correctly segregates with the disease in the five affected members of the family and it is absent in the three healthy members (Fig. 1a). The presence of the insertion (the first to be reported in SLC20A2) was investigated in dbSNP, 1000 Genomes Project, Exome Variant Server (6500) and Exome Aggregation Consortium (*61,000 exomes), and it resulted to be absent in all the databases of human variation previously mentioned. The variant is predicted to cause the synthesis of a truncated protein of 75 amino acids, with a disease causing effect predicted by Mutation Taster and a non sense-mediated decay predicted by SIFT. We observed almost complete penetrance of the SLC20A2 insertion in this family regarding brain calcifications, supporting previous observations of a high penetrance. Calcification in the basal ganglia and/or cerebellum and thalamus were shown by CT scan and/or MRI in the five affected of generation III and in 3 (II:1, II:3 and II:5) of their probably affected parents. II:4 with a serious
123
J Neurol
a
b I:1
II:1
+ + III:1
III:2
II:2
I:2
II:3
II:4
+
+ -
III:3
III:4
III:5
II:5
II:6
- + III:6
II:7
-
III:7
III:8
Fig. 1 a Pedigree of the Norwegian family, generation I, II and III. Late onset 70–80 years, All affected have brain calcifications. dementia and/or polyneuropathy. Onset 40–50 years, depression, Onset 30–40 years, severe impaired memory and/or fatigue. phenotype with psychiatric symptoms, movement disorder/ataxia.
No signs of PFBC. Presence of SLC20A2 insertion. Absence of SLC20A2 insertion. b Trace view in Codon Code of the SLC20A2 variant identified in the affected members of the family (top trace) and the same genomic position in unaffected members of the same family (bottom trace)
phenotype had calcifications in the back part of the left hemisphere on X-ray of brain. The diversity in age of onset and clinical symptoms is remarkable in this Norwegian family, in accordance with the reported heterogenous picture of PFBC. Age at onset varied between 30 and 70–80 years. Neuropsychiatric symptoms ranged from fatigue and impaired memory (III:1, III:4), serious depression (III:7, II:3) to dementia in the previous generation (II:1, II:5). Cases II:4 and III:3 have a complex phenotype. II:4 was diagnosed with encephalopathy, spasticity and ataxia in addition to psychiatric symptoms, and he died at 44. III:3 had serious depression after birth of second child at 30. Epilepsy was diagnosed at 40 and Parkinsonism at 45 years of age. Her movement disorder has progressed and includes dysarthria, mask-like face, limb rigidity and dystonia-like spasms of feet. She is now wheelchair-bound. At the other end of the clinical spectrum is III:2, presenting at 75 with loss of consciousness and polyneuropathy. The reasons for the variable expression are yet to be described. Interaction between genes in molecular networks exemplified by brain resilience mechanisms for calcification lesions in PFBC [7], environmental risk factors and epigenetic mechanisms might contribute to this phenomenon of variable expression. We have identified a novel SLC20A2 gene variant, c.219_220insA, p.I74fs, causing PFBC in a Norwegian family, with variable age at onset and clinical symptoms. This is the first frameshift insertion mutation to be found in the SLC20A2 gene. The variant adds to the catalog of known mutations causing PFBC (https://coppolalab.ucla. edu/lovd/genes/SLC20A2).
Compliance with ethical standards
123
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standards This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Written consent was obtained from the family members.
References 1. Nicolas G, Pottier C, Charbonnier C, Guyant-Mare´chal L, Le Ber I, Pariente J, Labauge P, Ayrignac X, Defebvre L, Malteˆte D, Martinaud O, Lefaucheur R, Guillin O, Wallon D, Chaumette B, Rondepierre P, Derache N, Fromager G, Schaeffer S, Krystkowiak P, Verny C, Jurici S, Sauve´e M, Ve´rin M, Lebouvier T, Rouaud O, Thauvin-Robinet C, Rousseau S, Rovelet-Lecrux A, Frebourg T, Campion D, Hannequin D, French IBGC Study Group (2013) Phenotypic spectrum of probable and genetically confirmed idiopathic basal ganglia calcification. Brain 136:3395–3407 2. Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, de Oliveira JR, Sobrido MJ, Quinta´ns B, Baquero M, Cui X, Zhang XY, Wang L, Xu H, Wang J, Yao J, Dai X, Liu J, Zhang L, Ma H, Gao Y, Ma X, Feng S, Liu M, Wang QK, Forster IC, Zhang X, Liu JY (2012) Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 44:254–256 3. Nicolas G, Pottier C, Malteˆte D, Coutant S, Rovelet-Lecrux A, Legallic S, Rousseau S, Vaschalde Y, Guyant-Mare´chal L, Augustin J, Martinaud O, Defebvre L, Krystkowiak P, Pariente J, Clanet M, Labauge P, Ayrignac X, Lefaucheur R, Le Ber I, Fre´bourg T, Hannequin D, Campion D (2013) Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology 80:181–187 4. Keller A, Westenberger A, Sobrido MJ, Garcı´a-Murias M, Domingo A, Sears RL, Lemos RR, Ordon˜ez-Ugalde A, Nicolas G, da Cunha JE, Rushing EJ, Hugelshofer M, Wurnig MC, Kaech A, Reimann R, Lohmann K, Dobricˇic´ V, Carracedo A, Petrovic´ I, Miyasaki JM, Abakumova I, Ma¨e MA, Raschperger E, Zatz M,
J Neurol Zschiedrich K, Klepper J, Spiteri E, Prieto JM, Navas I, Preuss M, Dering C, Jankovic´ M, Paucar M, Svenningsson P, Saliminejad K, Khorshid HR, Novakovic´ I, Aguzzi A, Boss A, Le Ber I, Defer G, Hannequin D, Kostic´ VS, Campion D, Geschwind DH, Coppola G, Betsholtz C, Klein C, Oliveira JR (2013) Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet 45:1077–1082 5. Legati A, Giovannini D, Nicolas G, Lo´pez-Sa´nchez U, Quinta´ns B, Oliveira JRM, Sears RL, Ramos EM, Spiteri E, Sobrido M-J, ´ , Castro-Ferna´ndez C, Cubizolle S, Fogel BL, Goizet Carracedo A C, Jen JC, Kirdlarp S, Lang AE, Miedzybrodzka Z, Mitarnum W, Paucar M, Paulson H, Pariente J, Richard A-C, Salins N S, Simpson SA, Striano P, Svenningsson P, Tison F, Unni VK, Vanakker O, Wessels MW, Wetchaphanphesat S, Yang M, Boller
F, Campion D, Hannequin D, Sitbon M, Geschwind DH, Battini J-L, Coppola G (2015) Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet 47(6):579–581. doi:10.1038/ng.3289 [Epub 2015 May 4] 6. Nicolas G, Richard A-C, Pottier C, Verny C, Durif F, Roze E, Favrole P, Rudolf G, Anheim M, Tranchant C, Frebourg T, Campion D, Hannequin D (2014) Overall mutational spectrum of SLC20A2, PDGFB and PDGFRB in idiopathic basal ganglia calcification. Neurogenetics 15:215–216 7. Oliveira DF, Lemos RR, Oliveira JRM (2013) Mutations at the SLC20A2 gene and brain resilience in families with idiopathic basal ganglia calcification (‘‘Fahr’s disease’’). Front Hum Neurosci 7:420
123
LETTER TO THE EDITORS
Primary familial brain calcification in a Norwegian family, caused by a novel SLC20A2 gene mutation Oddveig Røsby1 • Andrea Legati2 • Giovanni Coppola2,3
Received: 29 October 2015 / Revised: 12 January 2016 / Accepted: 13 January 2016 Ó Springer-Verlag Berlin Heidelberg 2016
Dear Sirs, Primary familial brain calcification (PFBC) is a rare autosomal dominant neurodegenerative disease. Brain calcifications (of the basal ganglia and/or cerebellar structures, subcortical white matter, thalamus and brain stem) are the main features together with cognitive, psychiatric and neurologic symptoms [1]. Mutations in SLC20A2 [2], PDGFRB [3], PDGFB [4] and XPR1 [5] have been reported as causing PFBC [PMID: 25686319], with SLC20A2 being the most frequent in large series [6]. We here report a novel SLC20A2 mutation in a Norwegian PFBC family. The proband, referred to Department of Medical Genetics, Oslo University Hospital, as well as other family members (her brother and six cousins, generation III, Fig. 1a) have underwent neurological/clinical examinations, brain CT scan and/or MRI and biochemical investigations. Medical records including brain CT scan or X-ray were obtained for individuals in generation II (Fig. 1a). SLC20A2 is the gene with the highest rate of mutations discovered so far to cause PFBC, therefore was screened first. Exonic and flanking regions of SLC20A2 gene were
& Oddveig Røsby [email protected] 1
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
2
Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
3
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
amplified by PCR and subsequently sequenced in both forward and reverse directions by Sanger sequencing. Chromatogram traces were analyzed using the Sequencher software (Gene Codes Corporation). Novelty of the variants was investigated using public online Databases of human genetic variation: dbSNP (http://www.ncbi.nlm.nih. gov), 1000 Genomes Project (http://www.1000genomes. org), Exome Variant Server (6500 exomes) (http://evs.gs. washington.edu/EVS), and the Exome Aggregation Consortium (*61,000 exomes) (http://exac.broadinstitute.org/ ). The potential effect of the variants at protein level was predicted using SIFT (http://sift.jcvi.org) and Mutation Taster (http://www.mutationtaster.org). One heterozygous variant was found in the SLC20A2 gene compared to the reference genome sequence (GRCh37/hg19), the insertion c.219_220insA, p.I74fs (chr8:42329689insT). This variant correctly segregates with the disease in the five affected members of the family and it is absent in the three healthy members (Fig. 1a). The presence of the insertion (the first to be reported in SLC20A2) was investigated in dbSNP, 1000 Genomes Project, Exome Variant Server (6500) and Exome Aggregation Consortium (*61,000 exomes), and it resulted to be absent in all the databases of human variation previously mentioned. The variant is predicted to cause the synthesis of a truncated protein of 75 amino acids, with a disease causing effect predicted by Mutation Taster and a non sense-mediated decay predicted by SIFT. We observed almost complete penetrance of the SLC20A2 insertion in this family regarding brain calcifications, supporting previous observations of a high penetrance. Calcification in the basal ganglia and/or cerebellum and thalamus were shown by CT scan and/or MRI in the five affected of generation III and in 3 (II:1, II:3 and II:5) of their probably affected parents. II:4 with a serious
123
J Neurol
a
b I:1
II:1
+ + III:1
III:2
II:2
I:2
II:3
II:4
+
+ -
III:3
III:4
III:5
II:5
II:6
- + III:6
II:7
-
III:7
III:8
Fig. 1 a Pedigree of the Norwegian family, generation I, II and III. Late onset 70–80 years, All affected have brain calcifications. dementia and/or polyneuropathy. Onset 40–50 years, depression, Onset 30–40 years, severe impaired memory and/or fatigue. phenotype with psychiatric symptoms, movement disorder/ataxia.
No signs of PFBC. Presence of SLC20A2 insertion. Absence of SLC20A2 insertion. b Trace view in Codon Code of the SLC20A2 variant identified in the affected members of the family (top trace) and the same genomic position in unaffected members of the same family (bottom trace)
phenotype had calcifications in the back part of the left hemisphere on X-ray of brain. The diversity in age of onset and clinical symptoms is remarkable in this Norwegian family, in accordance with the reported heterogenous picture of PFBC. Age at onset varied between 30 and 70–80 years. Neuropsychiatric symptoms ranged from fatigue and impaired memory (III:1, III:4), serious depression (III:7, II:3) to dementia in the previous generation (II:1, II:5). Cases II:4 and III:3 have a complex phenotype. II:4 was diagnosed with encephalopathy, spasticity and ataxia in addition to psychiatric symptoms, and he died at 44. III:3 had serious depression after birth of second child at 30. Epilepsy was diagnosed at 40 and Parkinsonism at 45 years of age. Her movement disorder has progressed and includes dysarthria, mask-like face, limb rigidity and dystonia-like spasms of feet. She is now wheelchair-bound. At the other end of the clinical spectrum is III:2, presenting at 75 with loss of consciousness and polyneuropathy. The reasons for the variable expression are yet to be described. Interaction between genes in molecular networks exemplified by brain resilience mechanisms for calcification lesions in PFBC [7], environmental risk factors and epigenetic mechanisms might contribute to this phenomenon of variable expression. We have identified a novel SLC20A2 gene variant, c.219_220insA, p.I74fs, causing PFBC in a Norwegian family, with variable age at onset and clinical symptoms. This is the first frameshift insertion mutation to be found in the SLC20A2 gene. The variant adds to the catalog of known mutations causing PFBC (https://coppolalab.ucla. edu/lovd/genes/SLC20A2).
Compliance with ethical standards
123
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standards This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Written consent was obtained from the family members.
References 1. Nicolas G, Pottier C, Charbonnier C, Guyant-Mare´chal L, Le Ber I, Pariente J, Labauge P, Ayrignac X, Defebvre L, Malteˆte D, Martinaud O, Lefaucheur R, Guillin O, Wallon D, Chaumette B, Rondepierre P, Derache N, Fromager G, Schaeffer S, Krystkowiak P, Verny C, Jurici S, Sauve´e M, Ve´rin M, Lebouvier T, Rouaud O, Thauvin-Robinet C, Rousseau S, Rovelet-Lecrux A, Frebourg T, Campion D, Hannequin D, French IBGC Study Group (2013) Phenotypic spectrum of probable and genetically confirmed idiopathic basal ganglia calcification. Brain 136:3395–3407 2. Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, de Oliveira JR, Sobrido MJ, Quinta´ns B, Baquero M, Cui X, Zhang XY, Wang L, Xu H, Wang J, Yao J, Dai X, Liu J, Zhang L, Ma H, Gao Y, Ma X, Feng S, Liu M, Wang QK, Forster IC, Zhang X, Liu JY (2012) Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 44:254–256 3. Nicolas G, Pottier C, Malteˆte D, Coutant S, Rovelet-Lecrux A, Legallic S, Rousseau S, Vaschalde Y, Guyant-Mare´chal L, Augustin J, Martinaud O, Defebvre L, Krystkowiak P, Pariente J, Clanet M, Labauge P, Ayrignac X, Lefaucheur R, Le Ber I, Fre´bourg T, Hannequin D, Campion D (2013) Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology 80:181–187 4. Keller A, Westenberger A, Sobrido MJ, Garcı´a-Murias M, Domingo A, Sears RL, Lemos RR, Ordon˜ez-Ugalde A, Nicolas G, da Cunha JE, Rushing EJ, Hugelshofer M, Wurnig MC, Kaech A, Reimann R, Lohmann K, Dobricˇic´ V, Carracedo A, Petrovic´ I, Miyasaki JM, Abakumova I, Ma¨e MA, Raschperger E, Zatz M,
J Neurol Zschiedrich K, Klepper J, Spiteri E, Prieto JM, Navas I, Preuss M, Dering C, Jankovic´ M, Paucar M, Svenningsson P, Saliminejad K, Khorshid HR, Novakovic´ I, Aguzzi A, Boss A, Le Ber I, Defer G, Hannequin D, Kostic´ VS, Campion D, Geschwind DH, Coppola G, Betsholtz C, Klein C, Oliveira JR (2013) Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet 45:1077–1082 5. Legati A, Giovannini D, Nicolas G, Lo´pez-Sa´nchez U, Quinta´ns B, Oliveira JRM, Sears RL, Ramos EM, Spiteri E, Sobrido M-J, ´ , Castro-Ferna´ndez C, Cubizolle S, Fogel BL, Goizet Carracedo A C, Jen JC, Kirdlarp S, Lang AE, Miedzybrodzka Z, Mitarnum W, Paucar M, Paulson H, Pariente J, Richard A-C, Salins N S, Simpson SA, Striano P, Svenningsson P, Tison F, Unni VK, Vanakker O, Wessels MW, Wetchaphanphesat S, Yang M, Boller
F, Campion D, Hannequin D, Sitbon M, Geschwind DH, Battini J-L, Coppola G (2015) Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet 47(6):579–581. doi:10.1038/ng.3289 [Epub 2015 May 4] 6. Nicolas G, Richard A-C, Pottier C, Verny C, Durif F, Roze E, Favrole P, Rudolf G, Anheim M, Tranchant C, Frebourg T, Campion D, Hannequin D (2014) Overall mutational spectrum of SLC20A2, PDGFB and PDGFRB in idiopathic basal ganglia calcification. Neurogenetics 15:215–216 7. Oliveira DF, Lemos RR, Oliveira JRM (2013) Mutations at the SLC20A2 gene and brain resilience in families with idiopathic basal ganglia calcification (‘‘Fahr’s disease’’). Front Hum Neurosci 7:420
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