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Germline mosaicism in X-linked periventricular nodular heterotopia

BACKGROUND: X-linked periventricular nodular heterotopia is a disorder of neuronal migration resulting from mutations in the filamin A gene. This is an X-linked dominant condition where most affected patients are female and present with seizures. Extra–cerebral features such as cardiac abnormalities...

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Autores principales: LaPointe, Monique M, Spriggs, Elizabeth L, Mhanni, Aizeddin A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057563/
https://www.ncbi.nlm.nih.gov/pubmed/24906659
http://dx.doi.org/10.1186/1471-2377-14-125
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author LaPointe, Monique M
Spriggs, Elizabeth L
Mhanni, Aizeddin A
author_facet LaPointe, Monique M
Spriggs, Elizabeth L
Mhanni, Aizeddin A
author_sort LaPointe, Monique M
collection PubMed
description BACKGROUND: X-linked periventricular nodular heterotopia is a disorder of neuronal migration resulting from mutations in the filamin A gene. This is an X-linked dominant condition where most affected patients are female and present with seizures. Extra–cerebral features such as cardiac abnormalities and thrombocytopenia have also been documented. Loss of function mutations in filamin A are predicted to result in prenatal lethality in males. Somatic mosaicism and mutations that lead to partial loss of function of the protein are hypothesized to explain viability of males reported in the literature. We report the first case of germline mosaicism involving a loss of function mutation in filamin A in a family where brain MRI, clinical exam, and mutation analysis is normal in both biological parents. CASE PRESENTATION: The index patient, a 39 year old female with normal development, had her first seizure at 24 years with no evidence of any precipitating factors. Brain MRI shows bilateral periventricular nodular heterotopia. She has thrombocytopenia and an echocardiogram at age 32 years revealed a mildly dilated aortic root and ascending aorta with mild aortic regurgitation. The second patient, the 36 year old younger sister of the index case, is currently healthy with no evidence of seizures or cardiac abnormalities. Her brain MRI is consistent with bilateral periventricular nodular heterotopia. The mother is healthy at 57 years of age with a normal brain MRI. The father is healthy at 59 years of age with a normal brain MRI. DNA sequencing of lymphocyte extracted DNA from the two sisters shows a c.2002C > T transition in exon 13 of filamin A resulting in a p.Gln668Ter mutation. This nonsense mutation was not detected in peripheral blood lymphocytes from the unaffected parents. CONCLUSION: This report provides evidence for germline mosaicism in filamin A-associated periventricular nodular heterotopia. This case must now be considered when providing genetic counseling to families where a proband presents as an isolated case and parental investigations are unremarkable.
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spelling pubmed-40575632014-06-15 Germline mosaicism in X-linked periventricular nodular heterotopia LaPointe, Monique M Spriggs, Elizabeth L Mhanni, Aizeddin A BMC Neurol Case Report BACKGROUND: X-linked periventricular nodular heterotopia is a disorder of neuronal migration resulting from mutations in the filamin A gene. This is an X-linked dominant condition where most affected patients are female and present with seizures. Extra–cerebral features such as cardiac abnormalities and thrombocytopenia have also been documented. Loss of function mutations in filamin A are predicted to result in prenatal lethality in males. Somatic mosaicism and mutations that lead to partial loss of function of the protein are hypothesized to explain viability of males reported in the literature. We report the first case of germline mosaicism involving a loss of function mutation in filamin A in a family where brain MRI, clinical exam, and mutation analysis is normal in both biological parents. CASE PRESENTATION: The index patient, a 39 year old female with normal development, had her first seizure at 24 years with no evidence of any precipitating factors. Brain MRI shows bilateral periventricular nodular heterotopia. She has thrombocytopenia and an echocardiogram at age 32 years revealed a mildly dilated aortic root and ascending aorta with mild aortic regurgitation. The second patient, the 36 year old younger sister of the index case, is currently healthy with no evidence of seizures or cardiac abnormalities. Her brain MRI is consistent with bilateral periventricular nodular heterotopia. The mother is healthy at 57 years of age with a normal brain MRI. The father is healthy at 59 years of age with a normal brain MRI. DNA sequencing of lymphocyte extracted DNA from the two sisters shows a c.2002C > T transition in exon 13 of filamin A resulting in a p.Gln668Ter mutation. This nonsense mutation was not detected in peripheral blood lymphocytes from the unaffected parents. CONCLUSION: This report provides evidence for germline mosaicism in filamin A-associated periventricular nodular heterotopia. This case must now be considered when providing genetic counseling to families where a proband presents as an isolated case and parental investigations are unremarkable. BioMed Central 2014-06-07 /pmc/articles/PMC4057563/ /pubmed/24906659 http://dx.doi.org/10.1186/1471-2377-14-125 Text en Copyright © 2014 LaPointe et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Case Report
LaPointe, Monique M
Spriggs, Elizabeth L
Mhanni, Aizeddin A
Germline mosaicism in X-linked periventricular nodular heterotopia
title Germline mosaicism in X-linked periventricular nodular heterotopia
title_full Germline mosaicism in X-linked periventricular nodular heterotopia
title_fullStr Germline mosaicism in X-linked periventricular nodular heterotopia
title_full_unstemmed Germline mosaicism in X-linked periventricular nodular heterotopia
title_short Germline mosaicism in X-linked periventricular nodular heterotopia
title_sort germline mosaicism in x-linked periventricular nodular heterotopia
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057563/
https://www.ncbi.nlm.nih.gov/pubmed/24906659
http://dx.doi.org/10.1186/1471-2377-14-125
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