Linkage analysis and disease models in benign familial infantile seizures: a study of 16 families.
OBJECTIVE
Benign familial infantile seizures (BFIS) is a genetically heterogeneous condition characterized by partial seizures, onset age from 3 to 9 months, and favorable outcome. BFIS loci were identified on chromosomes 19q12-13.1 and 16p12-q12, allelic to infantile convulsions and choreathetosis. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS may show overlapping clinical features. Infantile seizures also were in a family with familial hemiplegic migraine and mutations in the ATP1A2 gene. We have examined the heterogeneous genetics of BFIS by means of linkage analysis.


METHODS
Sixteen families were examined. Probands underwent neurologic examination, at least one EEG recording, and, when possible, brain CT and MRI. Clinical information about relatives was collected. Families with SCN2A or ATP1A2 mutations were excluded from the study. Chromosome 16p and 19q loci were examined by linkage analysis using two models that differed in penetrance rate. Genetic heterogeneity was evaluated with both models.


RESULTS
Clinical information was available for 124 members of affected families. BFIS was diagnosed in 69 subjects. One patient without BFIS had a single febrile seizure, and another had rare episodes of paroxysmal dystonia. Evidence of linkage was obtained only for chromosome 16. Moreover, the high penetrance allowed the identification of genetic heterogeneity.


CONCLUSIONS
Our data confirm the relevance of the chromosome 16 locus in BFIS and suggest the presence of an additional locus. This study shows that the genetic model used affects the outcome of linkage analysis.
Striano
Pasquale
P
Laboratory of Neurogenetics, Unit of Muscular and Neurodegenerative Disease, Istituto G. Gaslini, University of Genova, Genova, and Division of Neurology, Ospedale Pediatrico Bambino Gesù, Roma, Italy.
Lispi
Maria Luisa
ML
Gennaro
Elena
E
Madia
Francesca
F
Traverso
Monica
M
Bordo
Laura
L
Aridon
Paolo
P
Martinelli Boneschi
Filippo
F
Barone
Baldassare
B
dalla Bernardina
Bernardo
B
Bianchi
Amedeo
A
Capovilla
Giuseppe
G
De Marco
Pasquale
P
Dulac
Olivier
O
Gaggero
Roberto
R
Gambardella
Antonio
A
Nabbout
Rima
R
Prud'homme
Jean-François
JF
Day
Ruth
R
Vanadia
Francesca
F
Vecchi
Marilena
M
Veggiotti
Pierangelo
P
Vigevano
Federico
F
Viri
Maurizio
M
Minetti
Carlo
C
Zara
Federico
F
D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D004569:Electroencephalography / Q000706:statistics & numerical data; D020936:Epilepsy, Benign Neonatal / Q000175:diagnosis / Q000235:genetics*; D005190:Family; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D009460:Neurologic Examination; D010375:Pedigree; D019683:Penetrance; D014057:Tomography, X-Ray Computed