Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.
OBJECTIVE
To define the clinical, radiologic, and genetic features of periventricular heterotopia (PH) with Ehlers-Danlos syndrome (EDS).


METHODS
Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region.


RESULTS
The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected.


CONCLUSIONS
These results suggest that the Ehlers-Danlos variant of periventricular heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.
Sheen
V L
VL
Division of Neurogenetics, Department of Neurology, Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Jansen
A
A
Chen
M H
MH
Parrini
E
E
Morgan
T
T
Ravenscroft
R
R
Ganesh
V
V
Underwood
T
T
Wiley
J
J
Leventer
R
R
Vaid
R R
RR
Ruiz
D E
DE
Hutchins
G M
GM
Menasha
J
J
Willner
J
J
Geng
Y
Y
Gripp
K W
KW
Nicholson
L
L
Berry-Kravis
E
E
Bodell
A
A
Apse
K
K
Hill
R S
RS
Dubeau
F
F
Andermann
F
F
Barkovich
J
J
Andermann
E
E
Shugart
Y Y
YY
Thomas
P
P
Viri
M
M
Veggiotti
P
P
Robertson
S
S
Guerrini
R
R
Walsh
C A
CA
D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D001921:Brain / Q000002:abnormalities*; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics; D003285:Contractile Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004252:DNA Mutational Analysis; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000473:pathology; D004827:Epilepsy / Q000209:etiology; D005091:Exons / Q000235:genetics; D005260:Female; D064448:Filamins; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008840:Microfilament Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D018895:Microsatellite Repeats; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D017384:Sequence Deletion
D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins