Vol 58, No 1 (2024)
Research Paper
Published online: 2023-12-29

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Small vessel disease in primary familial brain calcification with novel truncating PDGFB variants

Maha Yektay Farahmand12, Johan Wasselius3, Elisabet Englund4, Irwin Braverman5, Andreas Puschmann126, Andreea Ilinca12
Pubmed: 38156729
Neurol Neurochir Pol 2024;58(1):94-105.


Introduction. Primary familial brain calcification (PFBC) is a neurodegenerative disease characterised by bilateral calcification in the brain, especially in the basal ganglia, leading to neurological and neuropsychiatric manifestations. White matter hyperintensities (WMH) have been described in patients with PFBC and pathogenic variants in the gene for platelet-derived growth factor beta polypeptide (PDGFB), suggesting a manifest cerebrovascular process. We present below the cases of two PFBC families with PDGFB variants and stroke or transient ischaemic attack (TIA) episodes. We examine the possible correlation between PFBC and vascular events as stroke/TIA, and evaluate whether signs for vascular disease in this condition are systemic or limited to the cerebral vessels.

Material and methods. Two Swedish families with novel truncating PDGFB variants, p.Gln140* and p.Arg191*, are described clinically and radiologically. Subcutaneous capillary vessels in affected and unaffected family members were examined by light and electron microscopy.

Results. All mutation carriers showed WMH and bilateral brain calcifications. The clinical presentations differed, with movement disorder symptoms dominating in family A, and psychiatric symptoms in family B. However, affected members of both families had stroke, TIA, and/or asymptomatic intracerebral ischaemic lesions. Only one of the patients had classical vascular risk factors. Skin microvasculature was normal.

Conclusions. Patients with these PDGFB variants develop microvascular changes in the brain, but not the skin. PDGFB-related small vessel disease can manifest radiologically as cerebral haemorrhage or ischaemia, and may explain TIA or stroke in patients without other vascular risk factors.

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  1. Duckett S, Galle P, Escourolle R, et al. Presence of zinc, aluminum, magnesium in striopalledodentate (SPD) calcifications (Fahr's disease): electron probe study. Acta Neuropathol. 1977; 38(1): 7–10.
  2. Kobayashi S, Yamadori I, Miki H, et al. Idiopathic nonarteriosclerotic cerebral calcification (Fahr's disease): an electron microscopic study. Acta Neuropathol. 1987; 73(1): 62–66.
  3. Manyam BV. What is and what is not 'Fahr's disease'. Parkinsonism Relat Disord. 2005; 11(2): 73–80.
  4. Shen Y, Shu S, Ren Y, et al. Case report: two novel frameshift mutations in SLC20A2 and one novel splice donor mutation in PDGFB associated with primary familial brain calcification. Front Genet. 2021; 12: 643452.
  5. Chen SY, Ho CJ, Lu YT, et al. The genetics of primary familial brain calcification: a literature review. Int J Mol Sci. 2023; 24(13).
  6. Bu W, Hou L, Zhu M, et al. SLC20A2-related primary familial brain calcification with purely acute psychiatric symptoms: a case report. BMC Neurol. 2022; 22(1): 265.
  7. Lenglez S, Sablon A, Fénelon G, et al. Distinct functional classes of PDGFRB pathogenic variants in primary familial brain calcification. Hum Mol Genet. 2022; 31(3): 399–409.
  8. Biancheri R, Severino M, Robbiano A, et al. White matter involvement in a family with a novel PDGFB mutation. Neurol Genet. 2016; 2(3): e77.
  9. Nicolas G, Rovelet-Lecrux A, Pottier C, et al. PDGFB partial deletion: a new, rare mechanism causing brain calcification with leukoencephalopathy. J Mol Neurosci. 2014; 53(2): 171–175.
  10. Shen J, Shillington A, Espay AJ, et al. Familial brain calcifications with leukoencephalopathy: a novel PDGFB variant. Neurol Genet. 2022; 8(4): e200001.
  11. Lindblom P, Gerhardt H, Liebner S, et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 2003; 17(15): 1835–1840.
  12. Sgulò FG, di Nuzzo G, de Notaris M, et al. Cerebrovascular disorders and fahr's disease: report of two cases and literature review. J Clin Neurosci. 2018; 50: 163–164.
  13. Eroglu U, Kahilogullari G, Demirel A, et al. Fahr's syndrome associated with multiple intracranial aneurysms: a case report. Turk Neurosurg. 2016; 26(4): 643–645.
  14. Asensio Moreno C, Arias Jiménez JL, Aramburu Bodas O, et al. [Transient ischemic attack associated with a calcinosis cerebri syndrome]. An Med Interna. 2008; 25(1): 33–35.
  15. Al-Jehani H, Ajlan A, Sinclair D. Fahr's disease presenting with aneurysmal subarachnoid hemorrhage. J Clin Imaging Sci. 2012; 2: 27.
  16. Bartecki BF, Kamienowski J. [Transient focal ischemia in Fahr's disease]. Neurol Neurochir Pol. 1979; 13(4): 443–447.
  17. Iwase T, Yoshida M, Hashizume Y, et al. Intracranial vascular calcification with extensive white matter changes in an autopsy case of pseudopseudohypoparathyroidism. Neuropathology. 2019; 39(1): 39–46.
  18. Iwase T, Yoshida M, Iwasaki Y, et al. Selective extension of cerebral vascular calcification in an autopsy case of Fahr's syndrome associated with asymptomatic hypoparathyroidism. Neuropathology. 2021; 41(5): 387–395.
  19. Batla A, Tai XY, Schottlaender L, et al. Deconstructing Fahr's disease/syndrome of brain calcification in the era of new genes. Parkinsonism Relat Disord. 2017; 37: 1–10.
  20. Mulroy E, Ilinca A, Gonzalez-Robles C, et al. Throat-clearing vocalizations in primary brain calcification syndromes. Mov Disord Clin Pract. 2021; 8(4): 627–630.
  21. Duan RN, Zhao DD, Liu YM, et al. A heterozygous deletion of PDGFB gene causes paroxysmal kinesigenic dyskinesia with primary familial brain calcification. Parkinsonism Relat Disord. 2021; 92: 83–87.
  22. Hayashi T, Legati A, Nishikawa T, et al. First Japanese family with primary familial brain calcification due to a mutation in the PDGFB gene: an exome analysis study. Psychiatry Clin Neurosci. 2015; 69(2): 77–83.
  23. Keller A, Westenberger A, Sobrido MJ, et al. Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet. 2013; 45(9): 1077–1082.
  24. Sekine SI, Kaneko M, Tanaka M, et al. Functional evaluation of PDGFB-variants in idiopathic basal ganglia calcification, using patient-derived iPS cells. Sci Rep. 2019; 9(1): 5698.
  25. Ramos EM, Carecchio M, Lemos R, et al. Primary brain calcification: an international study reporting novel variants and associated phenotypes. Eur J Hum Genet. 2018; 26(10): 1462–1477.
  26. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5): 405–424.
  27. Ilinca A, Samuelsson S, Piccinelli P, et al. A stroke gene panel for whole-exome sequencing. Eur J Hum Genet. 2019; 27(2): 317–324.
  28. Ilinca A, Puschmann A, Putaala J, et al. Updated stroke gene panels: rapid evolution of knowledge on monogenic causes of stroke. Eur J Hum Genet. 2023; 31(2): 239–242.
  29. Nicolas G, Pottier C, Charbonnier C, et al. Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification. Brain. 2013; 136(Pt 11): 3395–3407.
  30. Charidimou A, Boulouis G, Frosch MP, et al. The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study. Lancet Neurol. 2022; 21(8): 714–725.
  31. Keogh MJ, Pyle A, Daud D, et al. Clinical heterogeneity of primary familial brain calcification due to a novel mutation in PDGFB. Neurology. 2015; 84(17): 1818–1820.
  32. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013; 12(8): 822–838.
  33. Avrahami E, Cohn DF, Feibel M, et al. MRI demonstration and CT correlation of the brain in patients with idiopathic intracerebral calcification. J Neurol. 1994; 241(6): 381–384.
  34. Nicolas G, Charbonnier C, de Lemos RR, et al. Brain calcification process and phenotypes according to age and sex: lessons from SLC20A2, PDGFB, and PDGFRB mutation carriers. Am J Med Genet B Neuropsychiatr Genet. 2015; 168(7): 586–594.
  35. Nicolas G, Pottier C, Maltête D, et al. Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology. 2013; 80(2): 181–187.
  36. Tadic V, Westenberger A, Domingo A, et al. Primary familial brain calcification with known gene mutations: a systematic review and challenges of phenotypic characterization. JAMA Neurol. 2015; 72(4): 460–467.
  37. Miklossy J, Mackenzie IR, Dorovini-Zis K, et al. Severe vascular disturbance in a case of familial brain calcinosis. Acta Neuropathol. 2005; 109(6): 643–653.
  38. Unkrig S, Gullotta F, Madea B. Morbus Fahr--considerations on a case of sudden death. Forensic Sci Int. 2011; 204(1-3): e12–e15.
  39. Ebke M, Dichgans M, Bergmann M, et al. CADASIL: skin biopsy allows diagnosis in early stages. Acta Neurol Scand. 1997; 95(6): 351–357.
  40. Plaisier E, Gribouval O, Alamowitch S, et al. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med. 2007; 357(26): 2687–2695.
  41. Yao XP, Wang C, Su HZ, et al. Mutation screening of PDGFB gene in Chinese population with primary familial brain calcification. Gene. 2016.
  42. Wang C, Ma X, Xu X, et al. A PDGFB mutation causes paroxysmal nonkinesigenic dyskinesia with brain calcification. Mov Disord. 2017; 32(7): 1104–1106.
  43. Zhan FX, Tian WT, Zhang C, et al. Primary familial brain calcification presenting as paroxysmal kinesigenic dyskinesia: genetic and functional analyses. Neurosci Lett. 2020; 714: 134543.
  44. Koyama S, Sato H, Kobayashi R, et al. Clinical and radiological diversity in genetically confirmed primary familial brain calcification. Sci Rep. 2017; 7(1): 12046.

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