Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Translations
    • Topics A-Z
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Translations
    • Topics A-Z
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Articles
  • Issues

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Genetics
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues

Share

April 2017; 3 (2) Clinical/Scientific NotesOpen Access

Microangiopathy in primary familial brain calcification: Evidence from skin biopsies

Gaël Nicolas, Florent Marguet, Annie Laquerrière, João Ricardo Mendes de Oliveira, Didier Hannequin
First published February 8, 2017, DOI: https://doi.org/10.1212/NXG.0000000000000134
Gaël Nicolas
From the Normandie Univ (G.N., F.L., A.L., D.H.), UNIROUEN, Inserm U1245; Department of Genetics (G.N., D.H.), Department of Pathology (F.M., A.L.), Department of Neurology (D.H.), and CNR-MAJ (G.N., D.H.), Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, Rouen, France; and Keizo Asami Laboratory (LIKA) (J.R.M.d.O.), and Neuropsychiatry Department (J.R.M.d.O.), Universidade Federal de Pernambuco, Recife, Brazil.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Florent Marguet
From the Normandie Univ (G.N., F.L., A.L., D.H.), UNIROUEN, Inserm U1245; Department of Genetics (G.N., D.H.), Department of Pathology (F.M., A.L.), Department of Neurology (D.H.), and CNR-MAJ (G.N., D.H.), Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, Rouen, France; and Keizo Asami Laboratory (LIKA) (J.R.M.d.O.), and Neuropsychiatry Department (J.R.M.d.O.), Universidade Federal de Pernambuco, Recife, Brazil.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Annie Laquerrière
From the Normandie Univ (G.N., F.L., A.L., D.H.), UNIROUEN, Inserm U1245; Department of Genetics (G.N., D.H.), Department of Pathology (F.M., A.L.), Department of Neurology (D.H.), and CNR-MAJ (G.N., D.H.), Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, Rouen, France; and Keizo Asami Laboratory (LIKA) (J.R.M.d.O.), and Neuropsychiatry Department (J.R.M.d.O.), Universidade Federal de Pernambuco, Recife, Brazil.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
João Ricardo Mendes de Oliveira
From the Normandie Univ (G.N., F.L., A.L., D.H.), UNIROUEN, Inserm U1245; Department of Genetics (G.N., D.H.), Department of Pathology (F.M., A.L.), Department of Neurology (D.H.), and CNR-MAJ (G.N., D.H.), Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, Rouen, France; and Keizo Asami Laboratory (LIKA) (J.R.M.d.O.), and Neuropsychiatry Department (J.R.M.d.O.), Universidade Federal de Pernambuco, Recife, Brazil.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Didier Hannequin
From the Normandie Univ (G.N., F.L., A.L., D.H.), UNIROUEN, Inserm U1245; Department of Genetics (G.N., D.H.), Department of Pathology (F.M., A.L.), Department of Neurology (D.H.), and CNR-MAJ (G.N., D.H.), Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, Rouen, France; and Keizo Asami Laboratory (LIKA) (J.R.M.d.O.), and Neuropsychiatry Department (J.R.M.d.O.), Universidade Federal de Pernambuco, Recife, Brazil.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
Microangiopathy in primary familial brain calcification: Evidence from skin biopsies
Gaël Nicolas, Florent Marguet, Annie Laquerrière, João Ricardo Mendes de Oliveira, Didier Hannequin
Neurol Genet Apr 2017, 3 (2) e134; DOI: 10.1212/NXG.0000000000000134

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
400

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

Autosomal dominant primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder defined by the presence of calcifications affecting at least the basal ganglia with no secondary cause. It is associated with diverse symptoms including movement disorders, psychiatric disturbances, and cognitive impairment.1 PFBC is caused by loss-of-function mutations in 2 groups of genes: (1) PDGFB, which encodes the platelet-derived growth factor B2 and PDGFRB, which encodes its main receptor platelet-derived growth factor receptor–beta (PDGFR-β)3 and (2) SLC20A2 and XPR1 encoding inorganic phosphate transporters.4,5 Mice carrying Pdgfb hypomorphic alleles exhibit lower pericyte coverage in cerebral microvessels, blood-brain barrier (BBB) impairment, and cerebral microvascular calcifications.2 Recently, a novel PDGFB mutation was reported in an Italian family with PFBC and white-matter hyperintensities (WMH).6 Although brain calcification is a mandatory criterion for diagnosing PFBC, WMH were also reported as a major neuroimaging feature in the first described families with a PDGFRB or a PDGFB mutation2,3 (table e-1 at Neurology.org/ng). To date, the precise nature of WMH remains unknown but may be regarded as resulting from microangiopathy. This led to the hypothesis that in mice, alterations of the microvessels leading to BBB impairment may be a causal mechanism between microangiopathy and vascular calcifications.2 Transmission electron microscopy analysis of a skin biopsy from a patient belonging to the above-mentioned PDGFB family revealed thickened and fragmented areas in the basal lamina, consistent with microangiopathy.6 We report here the results of skin biopsies performed in 2 patients carrying a PDGFRB and an XPR1 mutation, respectively.

Methods.

This study was approved by our institution's ethics committee. After having obtained written informed consent from the patients, punch biopsy was performed. Ultrastructural studies were conducted according to standardized protocols. Briefly, tissue samples were fixed in a 2% glutaraldehyde fixative solution, postfixed with osmium tetroxide, and embedded in resin epoxy. Semithin sections were stained with toluidine blue. Ultrathin sections were contrasted with uranyl acetate and lead citrate and examined under a Philips CM10 electron microscope.

Results.

In the proband of the family with the p.Leu658Pro PDGFRB mutation,3 biopsy analysis revealed no lesions of endothelial cells, whereas the basal lamina was thickened, and with microcalcifications within and around the pericytes and in the basal lamina (figure, A). These microcalcifications were sometimes included in double- or single-layered membranes in the vicinity of the basal lamina (figure, B). In another patient with a recently described p.Ser136Asn XPR1 mutation,5 microcalcifications were also observed within pericytes of the capillaries (figure, C) but remained located in the cytoplasm of the pericytes, laying under the plasma membrane (figure, D).

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure Ultrastructural hallmarks of small capillary lesions in the 2 patients

p.Leu658Pro PDGFRB mutation carrier (A, B): presence of microcalcifications in a pericyte (A, white arrow) and in the basal lamina (A, black arrow) (OM ×5,200), appearing to be membrane bound at a higher magnification (OM ×28,500) (B). p.Ser136Asn XPR1 mutation carrier (C, D): small calcifications in the pericytes (C, white arrows) (OM ×2,650), sometimes located under the pericyte plasma membrane (OM ×28,500) (D). L = lumen; E = endothelial cell; B = basal lamina; P = pericyte; OM = original magnification.

Discussion.

We herein report hypodermal microvessel calcifications in skin biopsies from patients with PFBC. To our knowledge, only one skin biopsy analysis was previously reported in a patient with PFBC, who carried a PDGFB mutation.6 As for the latter patient, the basal lamina appeared thickened in our patients, particularly in the PDGFRB mutation carrier, although no fragmentation was observed, indicating that PDGFRB and XPR1 mutation carriers also exhibit microangiopathy. WMH on fluid-attenuated inversion recovery or T2-weighted MRI have also been observed in SLC20A2 and XPR1 mutation carriers (table e-1). These lesions are therefore not specific to PDGFB or PDGFRB mutation carriers in which BBB alteration was thought to be a prominent disease mechanism. Furthermore, similar thickening of the microvessel basal lamina on skin biopsies has also been observed in other leukoencephalopathies such as COL4A1-related disorders,7 where different patterns of calcifications might be encountered in some cases. A summary of the literature review of vascular, clinical, imaging, and microvessel examination of skin biopsies found in PFBC and 2 other leukoencephalopathies (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and COL4A1-related disorders) is provided in table e-1. Microangiopathy likely results from different mechanisms in the 2 groups of patients with PFBC and in other cerebral microangiopathies.

Whether BBB alteration is the cause of calcification in PDGFB or PDGFRB mutation carriers or not is currently debated. The original group who linked BBB deficiency in PDGFB-deficient mice and in humans with mutations in the same gene has recently shown that calcification-prone regions in Pdgfbret/ret mice had a more intact BBB and higher pericyte coverage compared with calcification-nonprone brain regions.8 Additional studies in Slc20a2 knockout mice suggest that brain calcifications are found even with normal BBB structure and function, through a 2-hit mechanism whereby increased CSF inorganic phosphate leads to calcification in arteriolar smooth muscle cells due to an enhanced vulnerability caused by Slc20a2 deficiency.9 Although the existence of microangiopathy itself in the context of PDGFB or PDGFRB haploinsufficiency is not challenged by the recent mouse model report,8 a putative direct causal link between microangiopathy and brain calcification is highly questioned. Additional studies on mice models might also evaluate the existence of microangiopathy outside the brain and if these models reproduce properly the phenotype variability found in patients.

Microvascular changes on skin biopsy are not specific to PDGFB mutation carriers. Systematic examination of skin biopsies of other patients with PFBC or differential diagnoses is warranted to replicate and explore these observations in depth. The significance of microangiopathy in both groups of patients and the mechanisms leading to microvascular changes in XPR1 or SLC20A2 mutation carriers remain to be determined, but further encourage to search for the potential pathways connecting the PDGFB/PDGFR-β response to the inorganic phosphate transporters SLC20A2 and XPR1.

Footnotes

  • Supplemental data at Neurology.org/ng

  • Author contributions: Collection and interpretation of data: Gaël Nicolas, Florent Marguet, Annie Laquerrière, and Didier Hannequin. Manuscript draft: Gaël Nicolas, João Ricardo Mendes de Oliveira, Florent Marguet, and Annie Laquerrière. Critical revision: Gaël Nicolas, Florent Marguet, Annie Laquerrière, Didier Hannequin, and João Ricardo Mendes de Oliveira. Study design and supervision: Gaël Nicolas.

  • Study funding: No targeted funding reported.

  • Disclosure: Dr. Nicolas has received research support from Rouen University Hospital and Région Haute Normandie. Dr. Marguet and Dr. Laquerrière report no disclosures. Dr. Mendes de Oliveira has received research support from the Federal Council for Research and Technology and Brazil (CNPq) Foundation for research support in Pernambuco, Brazil (FACEPE). Dr. Hannequin has received research support from the French Ministry of Health. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by Inserm.

  • Received November 19, 2016.
  • Accepted in final form December 29, 2016.
  • Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. Nicolas G,
    2. Charbonnier C,
    3. 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;168:586–594.
    OpenUrl
  2. 2.↵
    1. Keller A,
    2. Westenberger A,
    3. Sobrido MJ, et al
    . Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet 2013;45:1077–1082.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Nicolas G,
    2. Pottier C,
    3. Maltete D, et al
    . Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology 2013;80:181–187.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Wang C,
    2. Li Y,
    3. Shi L, et al
    . Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 2012;44:254–256.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Legati A,
    2. Giovannini D,
    3. Nicolas G, et al
    . Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet 2015;47:579–581.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Biancheri R,
    2. Severino M,
    3. Robbiano A, et al
    . White matter involvement in a family with a novel PDGFB mutation. Neurol Genet 2016;2:e77.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Plaisier E,
    2. Gribouval O,
    3. Alamowitch S, et al
    . COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med 2007;357:2687–2695.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Vanlandewijck M,
    2. Lebouvier T,
    3. Andaloussi Mae M, et al
    . Functional characterization of germline mutations in PDGFB and PDGFRB in primary familial brain calcification. PLoS One 2015;10:e0143407.
    OpenUrlPubMed
  9. 9.↵
    1. Wallingford MC,
    2. Chia J,
    3. Leaf EM, et al
    . SLC20A2 deficiency in mice leads to elevated phosphate levels in cerebrospinal fluid and glymphatic pathway-associated arteriolar calcification, and recapitulates human idiopathic basal ganglia calcification. Brain Pathol 2017;27:64–76.
    OpenUrl

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures
Advertisement

Preferences and User Experiences of Wearable Devices in Epilepsy A Systematic Review and Mixed-Methods Synthesis

Dr. Daniel Friedman and Dr. Sharon Chiang

► Watch

Alert Me

  • Alert me when eletters are published
Neurology Genetics: 9 (2)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Education
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Genetics | Online ISSN: 2376-7839

© 2023 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise