NEUROLOGY 2004;63:51-56
© 2004 American Academy of Neurology
Germline and mosaic mutations of FLN1 in men with periventricular heterotopia
R. Guerrini, MD,
D. Mei, BS,
S. Sisodiya, MD,
F. Sicca, MD,
B. Harding, MD,
Y. Takahashi, MD,
T. Dorn, MD,
A. Yoshida, MD,
J. Campistol, MD,
G. Krämer, MD,
F. Moro, PhD,
W. B. Dobyns, MD and
E. Parrini, PhD
From the Division of Child Neurology and Psychiatry (Dr. Guerrini), University of Pisa, Italy; IRCCS Stella Maris Foundation (Drs. Guerrini, Sicca, Moro, and Parrini, D. Mei), Scientific Institute for Child and Adolescence Neurology and Psychiatry, Pisa, Italy; Institute of Neurology (Dr. Sisodiya), University College London, UK; Department of Histopathology (Dr. Harding), Great Ormond Street Hospital for Children, London, UK; National Epilepsy Center (Drs. Takahashi and Yoshida), Shizuoka Medical Institute of Neurological Disorders, Japan; Swiss Epilepsy Center (Drs. Dorn and Krämer), Zurich, Switzerland; Department of Human Genetics (Dr. Dobyns), University of Chicago, IL; and Servicio de Neurología (Dr. Campistol), Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain.
Address correspondence and reprint requests to Dr. Renzo Guerrini, Division of Child Neurology and Psychiatry, University of Pisa and IRCCS Fondazione Stella Maris, via dei Giacinti 2, 56018 Calambrone Pisa, Italy; e-mail: renzo.guerrini{at}inpe.unipi.it
Objective: To describe the phenotypic spectrum and genetics of periventricular nodular heterotopia (PNH) caused by FLN1 mutations in four men.
Background: X-linked PNH caused by FLN1 mutations (MIM #300049) implies prenatal or early postnatal lethality in boys and 50% recurrence risk in daughters of affected women.
Methods: Clinical examination, cognitive testing, MRI, and mutation analysis (denaturing high-performance liquid chromatography and direct sequencing) on blood lymphocytes and single hair roots were performed for nine affected individuals, including three men. Neuropathologic study of the brain was performed for an affected boy.
Results: In two families, missense mutations were transmitted from mother to son (Met102Val) and from father to daughter (Ser149Phe), causing mild phenotypes in both genders, including unilateral PNH. In a third family, a man was mosaic for an A>G substitution (intron 11 acceptor splice site) on leukocyte DNA and hair roots (mutant = 42% and 69%). Single hair root analysis confirmed that the mutation was not present in all ectodermal derivative cells. A healthy daughter had inherited the X chromosome from her father’s wild-type germinal cell population. In the fourth family, an eight-base deletion (AGGAGGTG, intron 25 donor splice site) led to early deaths of boys. Postmortem study in a newborn boy revealed PNH and cardiovascular, genitourinary, and gut malformations.
Conclusions: Periventricular nodular heterotopia caused by FLN1 mutations in men has a wide clinical spectrum and is caused by different genetic mechanisms, including somatic mosaicism. Mutation analysis of FLN1 should support genetic counseling in men with periventricular nodular heterotopia.
Received January 23, 2004.
Accepted in final form March 8, 2004.
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80(4):
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|
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|
|
|
|
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72(9):
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|
|
|
|
|
|
|
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18(3):
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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67(4):
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|
|
|
|
|
|
|
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Cardiac malformations and midline skeletal defects in mice lacking filamin A
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15(16):
2457 - 2467.
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|
|
|
|
|
|
|
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129(7):
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|
|
|
|
|
|
|
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43(6):
541 - 544.
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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65(12):
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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3(4):
229 - 233.
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|
|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
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|
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