Mutation information:
NumberExon/IntronNucleotide change Protein changeLocation Mutation typeConsequencesPhenotype InheritanceReference
91617c.3521C>Gp.Thr1174SerDII-DIIIMissenseP/O→P/O (58); G-LOFMyoclonusNAEscayg A.2001
NAGargus JJ.2007
Familial(Maternal,asympt),P=1/2Yordanova I.2011
NARilstone JJ.2012
Familial(Maternal, HM),P=2/2
Benign familial neonatal seizure/JMEFamilial(BFNE Maternal,BFNE,P=2/2; JME Maternal,asympt; P=1/2),,Affected generations:2Lal D.2016

Functional information:
NumberNucleotide changeProtein changeLocationPhenotypeFunctional defect type Details of the major biophysical abnormalities.Reference
27c.3521C>Gp.Thr1174Ser (T1174S)DII-DIII (D-linkers)PEFS+ fG-LOFIncrease of persistent current; positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function.Cest

Inheritance information:
NumberNucleotide changeProtein changeMutation type Proband's phenotype1st transmitter's phenotype Mosaic Affected generationsPenetranceReference
89c.3521C>Gp.Thr1174Ser(DII-DIII)MissenseMAENo symptom(Maternal) 21/2Yordanova I.2011
BOE+FHMNA(Maternal) 35/5Cest
IME and ASDHM(Maternal) 22/2

[c.3521C>G] Clinical description

The three-generation family originated in Calabria (Southern Italy), and contained 13 individuals, 5 of them affected (all women, mean age 32.7 years, range 16–50). The neurologic and psychiatric status and brain magnetic resonance imaging (MRI) of all five affected subjects were normal. None of them had clinical or electroencephalography (EEG) photosensitivity. None of the spouses had a history of seizures or familial epilepsy. The pedigree supports a highly penetrant (>90%) autosomal dominant trait in this family. Patients III-2 and III-3 had simple FS; members III-2, III-3, and IV-2 presented with typical benign occipital epilepsy (BOE) phenotype, with no seizure relapse at long-term follow-up. The proband (IV-2) was a 16-year-old woman with recurrent attacks of migraine without aura since age eight. At age seven, she had an afebrile episode of visual hallucinations, impaired consciousness, head and eye deviation toward the right side, and vomiting, which lasted several minutes. A similar episode relapsed after two months. She also had stereotyped transient episodes of elementary visual hallucinations that were not followed by headache or any other neurologic symptoms. Interictal awake and sleep EEG recordings showed bilateral occipital sharp-wave complexes. She was started on valproate for three years, and no seizure has recurred. Since then, repeat EEG recordings have been normal. The proband’s mother (III-2), a 43-year-old woman, and her 37-year-old sister (III-3) had repeat simple FS from the age of 12-40 months. Both of them had, at age of four and six years, respectively, an afebrile episode of impaired consciousness, head and eye deviation toward one unknown side, and prolonged vomiting, which lasted about 2h. Interictal EEG showed occipital spiking. The proband’s mother was treated with phenobarbital plus phenytoin until the age of eight years, without recurrence of seizures. Her sister had no therapy. At the time of investigation, EEG resulted normal in both members. They also reported migraine with or without visual aura since adolescence. Two additional relatives (II-3, III-6) had clear-cut FHM, without epilepsy or FS. Both the proband’s grand aunt (II-3), a 50-year-old woman, and her 19-year-old daughter began to have typical hemiplegic migraine attacks from the age of 15 years(Cestèle S,et al. Epilepsia. 2013 May;54(5):927-35.[23398611]).