PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine.
OBJECTIVE
Whole genome sequencing and the screening of 103 families recently led us to identify PRRT2 (proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKD/IC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKD/IC or PKD/IC with migraine.


METHODS
We performed Sanger sequencing of all PRRT2 coding exons and of exon-intron boundaries in the probands and in their relatives whenever appropriate.


RESULTS
Two known and 2 novel PRRT2 mutations were detected in 18 families. The p.R217Pfs*8 recurrent mutation was found in ≈50% of typical PKD/IC, and the unreported p.R145Gfs*31 in one more typical family. PRRT2 mutations were also found in PKD/IC with migraine: p.R217Pfs*8 cosegregated with PKD associated with HM in one family, and was also detected in one IC patient having migraine with aura, in related PKD/IC familial patients having migraine without aura, and in one sporadic migraineur with abnormal MRI. Previously reported p.R240X was found in one patient with PKD with migraine without aura. The novel frameshift p.S248Afs*65 was identified in a PKD/IC family member with IC and migraine with aura.


CONCLUSIONS
We extend the spectrum of PRRT2 mutations and phenotypes to HM and to other types of migraine in the context of PKD/IC, and emphasize the phenotypic pleiotropy seen in patients with PRRT2 mutations.
Institut de Neurobiologie de la Méditerranée, Marseille, France.
Robin
R
Cloarec
Nadine
N
Bruneau
Gabrielle
G
Rudolf
Annick
A
Massacrier
Manal
M
Salmi
Marc
M
Bataillard
Clotilde
C
Boulay
Roberto
R
Caraballo
Natalio
N
Fejerman
Pierre
P
Genton
Edouard
E
Hirsch
Alasdair
A
Hunter
Gaetan
G
Lesca
Jacques
J
Motte
Agathe
A
Roubertie
Damien
D
Sanlaville
Sau-Wei
SW
Wong
Ying-Hui
YH
Fu
Jacques
J
Rochette
Louis J
LJ
Ptácek
Pierre
P
Szepetowski
D001483:Base Sequence; D002819:Chorea / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D020820:Dyskinesias / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D020936:Epilepsy, Benign Neonatal / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008881:Migraine Disorders / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D012640:Seizures / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C569370:PRRT2 protein, human