Table 1.
Summary of molecular, clinical, EEG, and neuroimaging features of all published and unpublished patients with FHF1 developmental and epileptic encephalopathies.
| PATIENT ID | A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Reference | Siekierska et al. 2016 | Siekierska et al. 2016 | Al-mehmadi et al. 2016 | Al-mehmadi et al. 2016 | Al-mehmadi et al. 2016 | Guella et al. 2016 | Guella I. et al. 2016 | Villeneuve et al. 2017 | Shi RM. et al. 2017 | Takeguchi R. et al. 2018 | Takeguchi R. et al. 2018 | Epilepsy Genetics Initiative, 2019* phenotype unpublished | unpublished | unpublished | unpublished | unpublished | Paprocka et al. 2019 |
|
Gender/
Age at last observation/death (cause) |
F/died age 7y (SE) | M/died age 3y6m (unknow cause) | M/3y | F/16y | F/8y | F/3y3m | F/15y | M/9y | M/15y1m | M/33y3m | M/2y6m | M/5y8m | F/1 m | F/13y | M/2y10m | M/4y2m | M/4y6m |
| FHF1 variant, inheritance | c.341G>A* presumed gonadal mosaicism |
c.341G>A* presumed gonadal mosaicism |
c.341G>A de novo | c.341G>A de novo | c.341G>A de novo | c.341G>A de novo | c.341G>A de novo | c.341G>A de novo | arr[hg19] 3q28q29 ×1, 0.58-Mb gain, including FHF1 gene, de novo | c.341G>A^ inherited, see legend |
c.341G>A de novo | c.341G>A de novo | c.341G>A de novo | c.341G>A de novo | c.341G>A$
inherited, see legend |
c.334G>A#
inherited, see legend |
c.334G>A de novo |
| EPILEPSY | |||||||||||||||||
| Epilepsy onset | 14d | 28d | 2d | 42d | 2d | 2d | 2d | 1d | 3y5m | 7d | 1d | 31d | 2d | 3d | 8d | 4m | 4m |
| Seizure type | TS | TS | FTS, FBTCS | FTS, MS, FBTCS | FTS, FS | FTS | FS, FBTCS | AS, FS | GTCS, FS, FTS | TS, ES | FTS, FS, FBTCS | TS | FS FTS |
A, FTS, FBTCS | FS, TS, FBTCS | TS, FBTCS | TS, MS, ES, FTS,FBTCS |
| Epilepsy Type | Combined generalized and focal epilepsy | Combined generalized and focal epilepsy | Focal epilepsy | Combined generalized and focal epilepsy | Focal epilepsy | Focal epilepsy | Focal epilepsy | Combined generalized and focal epilepsy | Combined generalized and focal epilepsy | Focal epilepsy | Focal epilepsy | Combined generalized and focal epilepsy | Focal epilepsy | Combined generalized and focal epilepsy | Unknown | Unknown | Combined generalized and focal epilepsy |
| SE (frequency) | frequent | infrequent | frequent | frequent | frequent | no | n.a. | n.a. | no | monthly | no | yes (twice) | no | frequent | yes (twice) | no | no |
| EEG | |||||||||||||||||
| Interictal EEG | Slow BG, multifocal SW (onset) | Slow BG, multifocal SW (onset) | Slow BG, multifocal SW | Slow BG, multifocal SW | Slow BG, multifocal SW | Discontinuous, multifocal SW (onset); increase of diffuse/multifocal SW; from 10m normal EEG (FU) | Slow BG left temporal SW (onset); slow BG and multifocal SW (FU) | Normal BG, multifocal spikes (onset); focal spikes (FU) | Slow BG, Frontal SW (onset); Slow BG, multifocal SW (FU) | Suppression burst (onset); slow BG with focal spikes (FU) | Slow BG, multifocal and diffuse SW (onset); slower BG multifocal SW (FU) | Normal BG, multifocal SW (onset); slow BG and multifocal SW (FU) | Discontinuous and multifocal SW (onset); slow BG with increase of diffuse/multifocal SW | Slow BG, multifocal SW (onset); Slow BG and multifocal and diffuse SW (FU) | Normal BG multifocal SW (onset) Slow BG and posterior SW (FU) | Normal | Normal (onset); generalized and focal paroxysmal in temporal regions (FU) |
| Ictal EEG | Generalized onset (tonic seizure) | Generalized onset (tonic seizure) | Focal to bilateral t-c | n.a. | n.a. | Generalized onset | Generalized onset (tonic seizure) | Generalized onset (tonic seizure) | Generalized onset (AS, TS, GTCS) Focal seizures: R or L hemisphere | n.a. | Generalized onset. Seizure activity migrated from one region to another | Diffuse onset | n.a. | L hemisphere; R frontal/frontotemporal | R central | n.a. | Generalized polyspikes, spike-SW complexes |
| TREATMENT | |||||||||||||||||
| ASM | PB, VPA, PHT, GVG, TPM, CZP; PN | PB, VPA, PHT, GVG, TPM | LEV, PB, KD | PHT, PER, VNS | PHT, PRG, PER, VNS | PB, LEV, TPM, PHT, CBZ | PB, TPM, LTG, RUF | PB, GVG, CBZ, CLB, ESM, KD | PB, CLB, VPA, KBr, PHT, LEV, NZP | VPA, PB, PHT, CZP, AZA, PHT, GBP | PB, PN, CBZ, CLB, VPA, ZNS, LEV, KBr, PHT | PB, PHT, CBZ, LEV, RTG, VPA | PB, LEV, PN/PLP, TPM, CBZ, PHT | PB, LEV, PHT, OXC, LCM, CLZ, PER, TPM, VNS, KD | VPA, CZP, LEV, GVG, CBZ, PN, PLP, PB, Folic Acid, Biotine | LEV, VPA, LTG | PB, CBZ, VPA, LEV, GVG, steroids, PHT |
| ASM efficacy | Resistant to ASMs; best response to PHT | Resistant to ASMs; best response to PHT | Resistant to ASMs | Resistant to ASMs; partially responsive to PHT and VNS | Resistant to ASMs | Responsive to PHT and CBZ | Responsive: to RUF and LTG, | Partially responsive to CBZ | Best response to high dose of PHT | Partially responsive to PHT, CZP and VPA | Best response to PHT and high-dose of PB | Partially responsive to VPA | Resistant to ASMs | Resistant to ASMs | ASMs-responsive | ASMs-responsive | Best response to PB and PHT |
| DEVELOPMENT | |||||||||||||||||
| ID | severe | severe | severe | severe | moderate | no | moderate | mild | severe | severe | severe | moderate | moderate | moderate | moderate | no | moderate |
| ASD and other disturbances | stereotypies, absent eye contact, acquired microcephaly | stereotypies, absent eye contact, acquired microcephaly | n.a. | n.a. | yes | no | yes | very tight | yes, stereotypies, absent eye contact | yes, stereotypies, absent eye contact | No, poor eye contact, congenital microcephaly | yes, stereotypies, absent eye contact | No, rapid mood swings, congenital microcephaly | yes, severe obsessive behaviour | yes, stereotypies, absent eye contact | no | yes |
| BRAIN MR | |||||||||||||||||
| First brain MR/age | Normal/6m | Normal/4m | Normal/5d | Normal/1y | Normal/21d | Normal/3d | Mild Chiari I /14d | Tight T2 weighted hyper intensity of the parietal region, cerebellum and brain stem/15d | Mild cerebral and cerebellar atrophy/3y | Mild enlargement of lateral ventricle/7y | Mild cerebral atrophy/6m | Mild cerebral atrophy/4m | Normal/5d | Normal/1y | Normal/21d | Normal/4m | Normal/4m |
| Second brain MR/age | Cerebellar atrophy/6y | Cerebellar atrophy/3y | Cerebral atrophy/2y | Cerebellar atrophy/8y | Bilateral mesial temporal sclerosis (R>L), mild prominence of cerebellar folia/12y | No | Mild Chiari I /2y | n.a. | Mild cerebral and cerebellar atrophy/8y | Mild enlargement of lateral ventricle/13y | Diffuse cerebral atrophy/1y7m | Mild cerebral atrophy/2y9m | Normal/10d | Normal/4y | Normal/2y | Normal/3y4m | No |
Table Legend:
= presumed gonadal mosaicism in unaffected parent;
= inherited from healthy mother (blood leukocyte with a variant allele fraction of 11.7% – 11/94 clones);
= inherited from affected father with onset of drug-resistant epilepsy at age 8 months (blood leukocyte mutant allele fraction of 7% – 10/1479 reads);
= inherited from affected mother who had epilepsy during infancy (blood leukocyte mutant allele fraction of 52% – 178/338 reads); A= Absences; AS= atonic seizure; ASD= autism spectrum disorder; ASM= anti-seizure medication; AZA= acetazolamide; BG= background activity; CBZ= carbamazepine; CZP= clonazepam; d= days; ES= epileptic spasm; ESM= etosuximide; F= female; FS= focal seizure; FTS=focal tonic seizure; FBTCS=focal to bilateral tonic clonic seizures; FU= follow-up; GBP= gabapentin; GTCS= generalized tonic-clonic seizure; GVG= vigabatrin; ID= intellectual disability; KBr= potassium bromide; KD= ketogenic diet; L= left; LEV= levetiracetam; LTG= lamotrigine; M= male; m= months; MS= myoclonic seizure; n.a.= not available; NZP= nitrazepam; OXC= oxcarbazepine; PB= phenobarbital; PER= perampanel; PHT= phenytoin; PLP= pyridoxal-5-phosphate; PN= pyridoxine; PRG= pregabalin; R= right; RTG= retigabine; RUF= rufinamide; SE=status epilepticus; SW= spike and wave; TPM= topiramate; TS= tonic seizure; VNS= vagal nerve stimulation; VPA= valproate; y=years; ZNS= zonisamide.