Table 3.
Review of the KCNQ2 gene mutations involving the pore region of the voltage-gated potassium channel subfamily Q member 2.
| Nucleotide/protein changes | Phenotype | Inheritance | Seizures onset | Semiology of seizures | EEG appearance at onset | First brain MRI | Medications trialed | Drug control | Outcome | References |
|---|---|---|---|---|---|---|---|---|---|---|
| c.761_770del10insA in KCNQ2 gene + c.2687A>G (p.N821S) in KCNQ3 gene | BFNC (patient, mother, sister), West syndrome (maternal aunt) | c.761_770del10insA in KCNQ2 gene: maternally inherited; c.2687A>G in KCNQ3 gene: paternally inherited | 3rd day | C seizures, right head and eyes rotation, palpebral myoclonias, oro-alimentary automatisms, and cyanosis | Fast polyspikes on the left centro-temporal areas with diffusion; normal organization background | Normal | PB | PB | SF. At 18 months of age normal neurological examination and psychomotor development | (44) |
| c.766G>T p.G256W | EE | (45) | ||||||||
| c.773A>G p.N258S | BFNC | (46) | ||||||||
| c.775G>T p.D259Y | BFNC | Inherited | 3rd day | Eye rolling, joint stiffness, and upper limb clonus | Normal | Normal | PB, VA | PB, VA | SF. Normal psychomotor development | (34) |
| c.790T>A p.Y264N | Seizures during neonatal period and infancy | (47) | ||||||||
| c.793G>A p.A265T | EE | De novo | Before 2nd day | T and/or C, T with apnea, ES, F hypermotor | Bursts of asynchronous spikes and sharp waves, discontinuity/BS | T1 hypersignal of the pallida, caudate nuclei, and hyppocampi; T2 hypersignal of the parietal occipital white matter/Normal | PB, MDZ, LVT, PH, ZNS, VA, VGB, CLB, BTN, FLT, KD, TPM, B6, ACTH, EZO | Improvement with EZO | M jerks /ES/SF since early adolescence. Poor psychomotor development | (27), (18), (42), (34) |
| c.793G>C p.A265P | EE | De novo | 7th day | T flexion spasms | Multifocal epileptic activity | Small frontal and temporal lobes, thin CC, hyper-T2, and hypo-T1 signals in cerebellum, frontal ventriculomegaly, increased frontotemporal extra-axial CSF spaces | VGB, VA, TPM | VGB temporary response | SF since age 2 y 6 m. Poor psychomotor development | (11) |
| c.794C>T p.A265V | EE | De novo | 1st-5th day | Apneic spells, T spasms with right opsoclonus-like movement, T seizures, left-sided seizures | BS/ Multifocal sharp waves | Mildly delayed myelination, T2 high signal on GP/Normal | CBZ, DZP, MDZ, PB, PLP, VA, B6, ZNS, CLN, CLB, VGB | DZP, MDZ, PB partially effective; CBZ effective | Myoclonus at the bilateral upper extremities/SF/Intractable seizures. Poor psychomotor development | (13), (12) |
| c.802C>T p.L268F | EE | De novo | 1st day | F seizures | Multifocal epileptiform discharges | Diffuse hypomielination with volumetric reduction of the frontal lobe | PB, PH, LVT, TPM | LEV+TPM | Mild global impairment | (24) |
| c.803T>C p.L268P | EE (Ohtahara-type), multifocal epilepsy | De novo | <24 hrs of life | T, TC, and F seizures | BS | Delayed myelination | PB, LVT, PH, TPM, OXC, BTN, FLT | OXC+TPM | SF. Poor psychomotor delay | (34) |
| p.W269L | EE | EZO | Improvement with EZO | (42) | ||||||
| c.807G>A p.W269Ter | BFNC | Inherited | 3rd day | F, initial T phase followed by asynchronous C phase | Normal background with centrotemporal sharp waves | CBZ | CBZ | SF. Normal psychomotor development | (21) | |
| c.807G>A p.W269X | BFNC, febrile seizures, generalized epilepsy in adulthood | (9) | ||||||||
| c.811C>T p.A294V | EE | 1st day | Discontinuity, asymmetric low voltage suppression, interictal epileptiform discharges, poorly organized background | Small focus of reduced diffusion in the left posterior parietal white matter | PB, LVT, B6, TPM, PH | PB, LVT, TPM | Reemergence of seizure activity upon attempt to wean AED | (48) | ||
| c.812G>T p.G271V | BFIC, choreoathetosis, myokymia | (30) | ||||||||
| c.821C>T p.T274M | EE | De novo | 2nd-3rd day | Stiffening, head, and eye deviation, T posturing, T and hypoT seizures, ES | BS, hypsarrhythmia, right temporal asymptomatic seizures | Hyperintensity of basal ganglia, irregular right thalamus, small frontal lobe, reduced white matter volume, thin CC, giant perivascular spaces/Normal | LVT, PB, PH, CLN, VGB, GBP, TPM, PRD, VA, OXC, EZO, CLB | OXC; some improvement with TPM; SF, reduced frequency of ES, increased alertness, and tone with EZO | SF/ES. Poor psychomotor development | (11), (27), (42), (34) |
| c.827C>T p.T276I | EE (Ohtahara-type) | De novo | 1st day | BS | Reduced posterior white matter volume, thin CC | Poor psychomotor development | (49) | |||
| c.830C>T p.T277I | EE | De novo | 2nd day | T seizures, FC activity | DNV | Normal | PB, MDZ, PN, LVT, LDN, CLN, TPM, VA | LVT and LDN acutely effective, VA effective | SF since 1.5m, one febrile seizure at 1y. Poor psychomotor development | (23) |
| c.835G>T p.G279C | EE | Intellectual disability | (50) | |||||||
| c.841G>A p.G281R | EE | De novo | 2nd day | T, T spasm-like, M, and hemiC seizures | BS | Atrophy of frontal lobe, thin CC, delayed myelination | PB, VGB, VA, PH, TPM, LVT, LTG, KD, ZNS | PB transient response, KD some response | Daily M seizures, clusters of T seizures, poor psychomotor development | (18) |
| c.841G>C p.G281R | EE | De novo | 1st day | T, C seizures | BS | Small thalami | PB, KD, RTG, TPM, steroids, VGB, VA, LVT, LCM | PB+KD+ high dose RTG (strong reduction in seizures); TPM and steroids some response | Weekly T seizures. Poor psychomotor development | (18) |
| c.841G>T p.G281W | EE | De novo | 2nd day | SE, T asymmetric seizures | Multifocal epileptiform discharges | Hyperintensity in the basal ganglia, thalami/hippocampus | PB, LVT, CBZ | CBZ | Poor psychomotor delay | (24) |
| c.847_848insGT p.K283SfsTer36 | BFNC | Inherited | (5) | |||||||
| c.850T>C p.Y284H | EE | De novo | <1 m of life | F, M, G seizures; spasms | SF. Poor psychomotor development | (51) | ||||
| c.850T>G p.Y284D | EE | De novo | 48 hrs | F seizures, startle episodes, ES, T seizures | Hypsarrhythmia | Cortical-subcortical atrophy with altered white matter, thin CC | PB, PN, VA, VGB, ZNS, CLB, CBZ, LVT | None | ES, T seizures. Poor psychomotor development | (34) |
| c.851A>G p.Y284C | BFNC | (5) | ||||||||
| c.854C>A p.P285H | OS | Inherited (mother: idiopathic epilepsy since neonate, medicated with VA) | 2nd day | T seizures | BS, asymmetric | T1 and T2 high signal on GP | VA, PLP, PB | VA | SF. Poor psychomotor development | (12) |
| p.P285S | OS | De novo | 1st day | T, simple partial seizures | BS | Normal | PB, TPM, VA | None | Refractory epilepsy | (17) |
| c.860C>A p.T287N | EE | 1st day | C, T seizures | BS | Normal | PB, VGB | SF. Poor psychomotor development | (27) | ||
| c.868G>A p.G290S | EE | De novo | 1st day | T seizures | BS, multifocal slow waves, frontal, and occipital spikes, generalized flattening | Normal | PB, VGB, CBZ, PH, LDN, CLN | PH | SF. Poor psychomotor development | (12), (27) |
| c.869G>A p.G290D | EE | De novo | 2nd day | T; myoclonias of arms and eyelid, C movements | BS/ Multifocal epileptic activity | Thin CC/ Hyperintensity of basal ganglia | PB, LVT, VA, CLN | VA+CLN | Monthly T or TC seizures, often with fever; SF since then. Poor psychomotor development | (11) |
| c.875T>C p.L292P | EE | 1st day | Discontinuity with epochs of complete suppression in either or both hemisphere and epileptiform discharges, poorly organized background | Normal | PB, LVT, TPM, CBZ | CBZ, LVT | At the 9 m follow-up visit the patient was meeting the developmental milestones. SF but difficulty in balancing seizure control with sedation and feeding | (48) | ||
| c.881C>G p.A294G | BFNC | (52) | ||||||||
| c.881C>T p.A294V | Mostly EE; EIMFS evolving to IS | Mostly de novo | 10 h-14th day | Excessive paroxysmal fetal movements; neonatal jitteriness; M, T, C, GTC seizures; spasms; SE; startle episodes | BS; hypsarrhythmia, multifocal/bilateral discharges, attenuation, discontinuity, asynchrony, slow background activity | Normal/ Increased signal over lentiform nuclei bilaterally/ T2 high signal on GP | PB, LVT, MDZ, VA, PH, TPM, VGB, CLN, BTN, FLT, PDN, ACTH, B6, CBZ, ZNS, PLP, NZP | PH (initial response), LVT (minimal response), ACTH (partially effective), VA, CBZ, ZNS, TPM | SF/ Uncontrollable seizure. Poor psychomotor development | (53), (12), (27), (54), (52), (24), (34), (28) |
BFNS-causing mutations are often non-sense, whereas OS/EOEE-causing mutations are all missense, as previously described by Millichap et al. (42).
AED, anti-epileptic drugs; BFIC benign familial infantile convulsions; BFNC, benign familial neonatal convulsions; BS, burst suppression; BTN, biotin; B6, vitamin B6; C, clonic; CBZ, carbamazepine; CC, corpus callosum; CLB, clobazam; CLN, clonazepam; DNV, discontinuous normal voltage; DZP, diazepam; EE, epileptic encephalopathy; EIMFS, epilepsy of infancy with migrating focal seizures; ES, epileptic spasms; EZO, ezogabine; F, focal; FC, focal clonic; FLT, folate; G, generalized; GP, globus pallidus; GBP, gabapentin; hr, hour; IS, infantile spasms; KD, ketogenic diet; LCM, lacosamide; LDN, lidocaine; LTG, lamotrigine; LVT, levetiracetam; M, myoclonic; m month; MDZ, midazolam; NZP, nitrazepam; OS, Ohtahara syndrome; OXC, oxcarbazepine; PB, phenobarbital; PDN, prednisone; PH, phenytoin; PLP, pyridoxal 5' phosphate; PN, pyridoxine; RTG, retiagabine; SE, status epilepticus; SF, seizure-free; T, tonic; TC, tonic-clonic; TPM, topiramate; VA, valproic acid; VGB, vigabatrin; wks, weeks; y, year; ZNS, zonisamide.