Mutation in filamin A causes periventricular heterotopia, developmental regression, and West syndrome in males.
OBJECTIVE
Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray-matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant pattern. Heterozygotic female patients usually remain asymptomatic until the second or third decade of life, when they may have predominantly focal seizures, whereas hemizygotic male fetuses typically die in utero. Recent studies have also reported mutations in FLNA in male patients with PH who are cognitively normal. We describe PH in three male siblings with PH due to FLNA, severe developmental regression, and West syndrome.


METHODS
The study includes the three affected brothers and their parents. Video-EEG recordings and magnetic resonance image (MRI) scanning were performed on all individuals. Mutations for FLNA were detected by using polymerase chain reaction (PCR) on genomic DNA followed by single-stranded conformational polymorphism (SSCP) analysis or sequencing.


RESULTS
Two of the siblings are monozygotic twins, and all had West syndrome with hypsarrhythmia on EEG. MRI of the brain revealed periventricular nodules of cerebral gray-matter intensity, typical for PH. Mutational analyses demonstrated a cytosine-to-thymidine missense mutation (c. C1286T), resulting in a threonine-to-methionine amino acid substitution in exon 9 of the FLNA gene.


CONCLUSIONS
The association between PH and West syndrome, to our knowledge, has not been previously reported. Males with PH have been known to harbor FLNA mutations, although uniformly, they either show early lethality or survive and have a normal intellect. The current studies show that FLNA mutations can cause periventricular heterotopia, developmental regression, and West syndrome in male patients, suggesting that this type of FLNA mutation may contribute to severe neurologic deficits.
Masruha
Marcelo R
MR
Department of Neurology, Federal University of Sao Paulo, Sao Paulo, Brazil. mmasruha@ig.com.br
Caboclo
Luis O S F
LO
Carrete
Henrique
H
Cendes
Iscia L
IL
Rodrigues
Murilo G
MG
Garzon
Eliana
E
Yacubian
Elza M T
EM
Sakamoto
Américo C
AC
Sheen
Volney
V
Harney
Megan
M
Neal
Jason
J
Hill
R Sean
RS
Bodell
Adria
A
Walsh
Christopher
C
Vilanova
Luiz C P
LC
D001927:Brain Diseases / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D002552:Cerebral Ventricles / Q000473:pathology; D002828:Choristoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D003285:Contractile Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D004569:Electroencephalography / Q000706:statistics & numerical data; D005260:Female; D064448:Filamins; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000473:pathology; D005838:Genotype; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012737:Sex Factors; D013036:Spasms, Infantile / Q000453:epidemiology / Q000235:genetics*; D014743:Videotape Recording
D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins