Familial periventricular heterotopia: missense and distal truncating mutations of the FLN1 gene.
OBJECTIVE
To examine the clinical and MRI associations in bilateral periventricular nodular heterotopia (BPNH) (MIM # 300049) in two families segregating a missense mutation and a C-terminal deletion of the filamin 1(FLN1) gene.


BACKGROUND
Classical familial BPNH, an X-linked dominant disorder, has been associated with protein truncations or splicing mutations, which tend to cluster at the N-terminal of the FLN1 protein, causing severe predicted loss of the protein function. The clinical syndrome includes symmetrical contiguous nodular heterotopia lining the lateral ventricles, epilepsy, mild retardation to normal cognitive level in affected females, and prenatal lethality in hemizygous boys.


METHODS
Clinical examination, cognitive testing, MRI, mutation analysis (direct sequencing, single-strand conformation polymorphism) in seven patients from two families with BPNH.


RESULTS
In Family 1, harboring an A > T change in exon 2 (E82V), heterotopic nodules were few, asymmetric, and noncontiguous. Five boys born from affected females had died unexpectedly early in life. In Family 2, harboring an 8 base pair deletion in exon 47 (7627_7634del TGTGCCCC), heterotopic nodules were thick and contiguous. Affected females in both families showed normal to borderline IQ and epilepsy.


CONCLUSIONS
Missense mutations and distal truncations consistent with partial loss of FLN1 function cause familial BPNH with the classical clinical phenotype including epilepsy and mild mental retardation, if any. However, missense mutations have milder anatomic consequences in affected females and are possibly compatible with live birth but short survival of boys.
Moro
F
F
Neurogenetics Laboratory, Division of Child Neurology and Psychiatry, University of Pisa, Italy.
Carrozzo
R
R
Veggiotti
P
P
Tortorella
G
G
Toniolo
D
D
Volzone
A
A
Guerrini
R
R
D000022:Abortion, Spontaneous / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002540:Cerebral Cortex; D002828:Choristoma / Q000235:genetics* / Q000473:pathology*; D003285:Contractile Proteins / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics / Q000473:pathology; D005260:Female; D064448:Filamins; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020547:Lateral Ventricles / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree
D003285:Contractile Proteins; C578663:FLNA protein, human; D064448:Filamins; D008840:Microfilament Proteins