Two types of early epileptic encephalopathy in a Pitt-Hopkins syndrome patient with a novel TCF4 mutation

IntroductionPitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by mutations in TCF4. Seizures have been found to vary among patients with PTHS. We report the case of a PTHS patient with a novel missense mutation in the gene TCF4, presenting with two types of early epileptic encephalopathy.Case reportThe patient was a Japanese boy. His first seizure was reported at 17 days of age, with twitching of the left eyelid and tonic-clonic seizures on either side of his body. An ictal electroencephalogram (EEG) showed epileptic discharges arising independently from both hemispheres, occasionally resembling migrating partial seizures of infancy (MPSI) that migrated from one side to the other. Brain magnetic resonance imaging revealed agenesis of the corpus callosum. His facial characteristics included a distinctive upper lip and thickened helices. His seizures were refractory, and psychomotor development was severely delayed. At the age of 10 months, he developed West syndrome with spasms and hypsarrhythmia. After being prescribed topiramate (TPM), his seizures and EEG abnormalities dramatically improved. Also, psychomotor development progressed. Whole-exome sequencing revealed a novel de novo missense mutation in exon 18 (NM_001083962.2:c.1718A > T, p.(Asn573Ile)), corresponding to the basic region of the basic helix-loop-helix domain, which may be a causative gene for epileptic encephalopathy.ConclusionsTo our knowledge, this is the first report of a patient with PTHS treated with TPM, who presented with both MPSI as well as West syndrome. This may help provide new insights regarding the phenotypes caused by mutations in TCF4.     

Predictive value of EEG findings at control of epileptic spasms for seizure relapse in patients with West syndrome

PurposeTo evaluate the prognostic importance of electroencephalography (EEG) findings at cessation of epileptic spasms for seizure outcome.MethodsWe reviewed 71 children with West syndrome (cryptogenic 14) who had obtained control of epileptic spasms with initial treatment (adrenocorticotropic hormone (ACTH) 37, high-dose vitamin B₆ 2, and antiepileptic drugs 32). According to the EEG findings at control of epileptic spasms, the subjects were divided into three groups: normal group (no epileptic activity, n = 12), abnormal group (residual epileptic activity without hypsarrhythmia, n = 53), and hypsarrhythmic group (persisting hypsarrhythmia, n = 6).ResultsOverall, 47 (66%) of the 71 patients (cryptogenic 4) had experienced relapses of seizures (epileptic spasms 23 and focal seizure 24) after initial control of epileptic spasms. Within symptomatic cases, seizure relapse rate varied widely from 0% (Down syndrome) to 100% (tuberous sclerosis), depending on underlying causes. Seizure relapse depended on the EEG findings at control of epileptic spasms. The normal group had a significantly lower seizure relapse rate (17%) in comparison with the abnormal group (75%), the hypsarrhythmic group (83%), and the epileptiform (abnormal plus hypsarrhythmic, 76%) group. No significant difference in seizure relapse rate was observed between non-hypsarrhythmic (normal plus abnormal, 65%) and hypsarrhythmic groups. At the last follow-up, normal group children also showed a favorable seizure prognosis (seizure control 100%).ConclusionsA favorable seizure prognosis is associated with the disappearance of epileptic activity, but not the resolution of hypsarrhythmic pattern on EEG at control of epileptic spasms. We suggest that effective treatment for West syndrome should produce both cessation of epileptic spasms and disappearance of epileptic activity on EEG.     

Epileptic apnea in a patient with inherited glycosylphosphatidylinositol anchor deficiency and PIGT mutations

We report an 11-month-old boy with acetazolamide-responsive epileptic apnea and inherited glycosylphosphatidylinositol (GPI)-anchor deficiency who presented with decreased serum alkaline phosphatase associated with compound PIGT mutations. The patient exhibited congenital anomalies, severe intellectual disability, and seizures, including epileptic apnea with epileptiform discharges from bilateral temporal areas. Brain magnetic resonance imaging revealed delayed myelination and progressive atrophy of the brainstem, cerebellum, and cerebrum. Whole-exome sequencing revealed compound heterozygous mutations in PIGT (c.250 G > T, p.Glu84X and c.1096 G > T, p.Gly366Trp), which encodes a subunit of the GPI transamidase complex. Flow cytometry revealed decreased expression of CD16 (a GPI anchor protein) on granulocytes, supporting the putative pathogenicity of the mutations. Phenobarbital, clonazepam, and potassium bromide decreased the frequency of tonic seizure and acetazolamide decreased epileptic apnea. To our knowledge, this is the first reported case of intractable seizures accompanied by epileptic apnea associated with GPI anchor deficiency and a compound PIGT mutation.     

Mutations in KCNT1 cause a spectrum of focal epilepsies

Autosomal dominant mutations in the sodium‐gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype–phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.     

Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy

The KCNT1 gene encodes for subunits contributing to the Na⁺-activated K⁺ current (K_Na), expressed in many cell types. Mutations in KCNT1 have been found in patients affected with a wide spectrum of early-onset epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI), a severe early-onset epileptic encephalopathy characterized by pharmacoresistant focal seizures migrating from one brain region or hemisphere to another and neurodevelopment arrest or regression, resulting in profound disability. In the present study we report identification by whole exome sequencing (WES) of two de novo, heterozygous KCNT1 mutations (G288S and, not previously reported, M516V) in two unrelated MMPSI probands. Functional studies in a heterologous expression system revealed that channels formed by mutant KCNT1 subunits carried larger currents when compared to wild-type KCNT1 channels, both as homo- and heteromers with these last. Both mutations induced a marked leftward shift in homomeric channel activation gating. Interestingly, the KCNT1 blockers quinidine (3–1000 μM) and bepridil (0.03–10 μM) inhibited both wild-type and mutant KCNT1 currents in a concentration-dependent manner, with mutant channels showing higher sensitivity to blockade. This latter result suggests two genotype-tailored pharmacological strategies to specifically counteract the dysfunction of KCNT1 activating mutations in MMPSI patients.     

Phenotypic manifestations between male and female children with CDKL5 mutations

BackgroundCyclin-dependent kinase-like 5 (CDKL5), which maps to chromosome Xp22.13 and contains 20 coding exons, has been recognized as the gene responsible for early-onset epileptic encephalopathy (EoEE). A retrospective study is carried out to analyze potential genotypic and phenotypic differences between male and female patients with CDKL5 mutations.Materials and methodsTargeted next-generation DNA sequencing was employed to search for mutations in patients with cryptogenic EE. A total of 44 patients with EoEE/infantile spasms (ISs)/West syndrome were enrolled for pathogenic mutation screening. The clinical phenotypes of patients with CDKL5 mutations were analyzed and compared with those of 166 published cases.ResultsOne novel and three recurrent mutations were found in four enrolled patients (two boys and two girls). One female patient had partial seizures during the early infantile period and epileptic spasms and tonic seizures several weeks thereafter. The other female patient had IS with hypsarrhythmia. The two male patients had IS without typical hypsarrhythmia and were bedridden. Brain MRIs of the male patients revealed brain atrophy and white matter hyperintensity. The female patients exhibited autistic features with hand stereotypies.ConclusionOur study highlights that both girls and boys with IS harbor CDKL5 mutations. Male children with CDKL5 mutations demonstrate a higher frequency of infantile spasms and brain atrophy, whereas female children often exhibit atypical Rett syndrome with EoEE. In addition, male children have a more severe phenotype than female children.     

A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures

Epilepsy of infancy with migrating focal seizures {a.k.a malignant migrating partial seizures of infancy (MMPSI)} is an uncommon epileptic encephalopathy with a poor prognosis. Migrating focal seizures with autonomic features, developmental stagnation and refractoriness to treatment are its key features. It is caused by genetic defects in various ion channels, most common being sodium activated potassium channel (KCNT1), found in up to 50% of cases. With advent of genetic diagnosis and precision medicine, many targeted therapies have been identified. Antagonist of KCNT1 coded ion channel like Quinidine has shown promising results in MMPSI. Here we report first mutation proven case of MMPSI from India. This child had a novel heterozygous missense mutation in exon10 of the KCNT1 gene (chr9:138650308; c.808C?>?C/G (p.Q270E)) which was pathogenic. Neither quinidine nor ketogenic diet could control his seizures. Ultimately, the child succumbed to his illness at nine months of age.     

ATP1A3-related early childhood onset developmental and epileptic encephalopathy responding to corpus callosotomy: A case report

BackgroundVarious ATP1A3 variant-related diseases have been reported, including alternating hemiplegia of childhood; rapid-onset dystonia–parkinsonism; and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome. Moreover, a few cases of developmental and epileptic encephalopathy (DEE) with none of these symptoms have been reported. Here, we present a case of DEE with early childhood onset caused by an ATP1A3 variant that was effectively treated using corpus callosotomy (CC).Case presentationAt the age of 3 years, the patient developed epileptic spasms, complicated by generalized and focal aware tonic seizures. Based on the seizure type and electroencephalographic findings showing a generalized spike and waves as well as interictal left frontal-dominant spikes, combined generalized and focal epilepsy was diagnosed. Whole-exome sequencing revealed a de novo missense variant in ATP1A3 (c.2888G > A, p.Gly963Asp), which was classified as likely pathogenic. At the age of 5 years, CC for generalized tonic seizures resulted in seizure-freedom using two anti-seizure medications. Subsequently, the patient achieved better verbal development.Discussion and conclusionEarly childhood onset DEE has not been reported in patients with ATP1A3 variants. Moreover, CC was extremely effective in our case. Although more research is needed to determine the etiology of epilepsy caused by the ATP1A3 variant, the clinical course of DEE caused by the ATP1A3 variant is diverse and its prognosis may be improved in early childhood onset cases using aggressive control of epilepsy, such as CC.     

Targeted treatment of migrating partial seizures of infancy with quinidine

Migrating partial seizures of infancy is an early onset epileptic encephalopathy syndrome that is typically resistant to treatment. The most common cause is a gain of function mutation in the potassium channel KCNT1. The antiarrhythmic drug quinidine is a partial antagonist of KCNT1 and hence may be a candidate drug for treatment of this condition. We report the case of a child with migrating partial seizures of infancy secondary to an activating mutation in KCNT1 treated with quinidine. Treatment with quinidine was correlated with a marked reduction in seizure frequency and improved psychomotor development. Ann Neurol 2014;76:457–461     

Epileptic phenotype of FGFR3-related bilateral medial temporal lobe dysgenesis

Hypochondroplasia (HCH) is a skeletal dysplasia, characterized by short stature and macrocephaly. Clinical symptoms and radiological and histopathological features of HCH are similar, but milder than those seen in achondroplasia. Particularly, HCH patients with Asn540Lys mutation in the FGFR3 gene are reported to have medial temporal lobe dysgenesis and epilepsy.We report a 3-year-old girl who developed recurrent epileptic apnea, which started immediately after birth. The apneic seizures were refractory to antiepileptic medications; ictal electroencephalography showed rhythmic activity originating from the left or right temporal areas and rarely from the right frontal area. Macrocephaly was noted since birth. Neuroimaging revealed bilateral dysgenesis and hypometabolism of the medial temporal structures as well as perfusion changes in the left lateral temporofrontal areas during the ictal period. Clonazepam was initiated and acetazolamide dosage was increased at 6 months, resulting in complete seizure control after 8 months of age. Genetic analysis identified an Asn540Lys (c.1620 C > A) mutation in the FGFR3 gene. Characteristic bone findings on the lumbar spine, iliac bone, and femur were retrospectively confirmed on X-rays during infancy.This was the first report that delineated the epilepsy phenotype in FGFR3-related bilateral medial temporal lobe dysgenesis; such findings would lead to an early diagnosis and better epilepsy management.     

Effect of adrenocorticotropic hormone therapy for epileptic spasms developing after the age of 1 year

PurposeEpileptic spasms sometimes begin after the first year of life, and such seizures are recognized as late-onset spasms (LOS). The prognosis of LOS is poor, and a treatment strategy has not been established. This study aimed to assess the short- and long-term effects of adrenocorticotropic hormone (ACTH) therapy for LOS.MethodsWe investigated the rate of LOS in 22 patients (14 boys and 8 girls) treated with ACTH therapy. The age at onset of LOS and at the start of ACTH therapy ranged from 12 to 94 months (median, 31.6 ± 22.1 months) and from 12.5 to 116 months (median, 37.5 ± 23.7 months), respectively. We investigated the response rate of LOS treated with ACTH therapy, and compared the clinical features between responders (short-term) and nonresponders.ResultsNine (41%) of the 22 patients showed cessation of epileptic spasms within 3 months. The epileptic spasms ceased in four of these nine patients for more than 1 year. The age at onset of LOS was significantly associated with short-term seizure cessation (p < 0.05). Patients who achieved short-term cessation of seizures received ACTH therapy within 6 months from the onset of LOS.ConclusionACTH therapy is a potentially effective treatment when started within 6 months from the onset of LOS. A younger age at onset of LOS is associated with a favorable outcome.     

Quinidine therapy and therapeutic drug monitoring in four patients with KCNT1 mutations

Aims. Several recent studies have reported potassium sodium‐activated channel subfamily T member 1 (KCNT1) mutations in epilepsy patients on quinidine therapy. The efficacy and safety of quinidine for epilepsy treatment, however, remains controversial. Methods. We herein report the cases of four patients with KCNT1 mutations treated with quinidine. Results. A reduction in seizures of more than 50% after quinidine treatment was observed in one patient with epilepsy of infancy with migrating focal seizures (EIMFS), whereas two patients with EIMFS and one with focal epilepsy did not achieve apparent seizure reduction. The relationship between quinidine dose and serum quinidine concentration was inconsistent, particularly at high quinidine doses. One patient with EIMFS developed ventricular tachycardia the day after an increase in quinidine dose from 114 to 126 mg/kg/day. The serum trough quinidine concentration and the corrected QT interval (QTc) before arrhythmia onset were 2.4 μg/ml and 420 ms, respectively, and peak serum quinidine concentration after arrhythmia onset was 9.4 μg/ml. Another patient with EIMFS showed aberrant intraventricular conduction with a quinidine dose of 74.5 mg/kg/day and a serum trough concentration of 3.2 μg/ml. Conclusions. Given that serum quinidine levels may elevate sharply after a dose increase, careful monitoring of electrocardiographs and serum concentrations is required. Based on a review of previous reports and our experience with this case, quinidine should be considered as a promising drug for patients with EIMFS harbouring KCNT1 mutations, however, its efficacy remains controversial due to the limited number of cases, and more information on optimal serum concentrations and appropriate titration methods is required.     

Clinical features of early myoclonic encephalopathy caused by a CDKL5 mutation

BackgroundCDKL5 deficiency is caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene and clinically manifests often in females as drug-resistant intractable epilepsy and severe psychomotor retardation.Case reportWe report the case of a girl with a CDKL5 mutation born at 39 weeks without neonatal asphyxia. She developed epilepsy at age 1 month with myoclonus of the face and limbs, and non-rhythmic and irregular opsoclonus. She developed tonic seizures and epileptic spasms at 6 months of age and was diagnosed with symptomatic West syndrome and underwent adrenocorticotropic hormone therapy but her seizures were refractory. At the age of 4, she was introduced to our hospital and development was at 2 months of age. We diagnosed her with early myoclonic encephalopathy (EME) due to the remaining suppression-burst pattern observed on an electroencephalogram and her symptoms since onset were mainly myoclonus. At 14 years of age, mutational analysis revealed a CDKL5 mutation (c.380A > G:p.His127Arg). She was diagnosed with epileptic encephalopathy exhibiting clinical features of early myoclonic epilepsy caused by CDKL5 deficiency.ConclusionsEarly onset epilepsy with severe psychomotor retardation without a known etiology may be caused by a mutation in CDKL5. More research investigating a genotype-phenotype correlation of CDKL5 mutations is necessary because clinical severity may be associated with the location and type of mutations.     

De novo gain‐of‐function variants in KCNT2 as a novel cause of developmental and epileptic encephalopathy

Variants in several potassium channel genes have been found in developmental and epileptic encephalopathies (DEE). We report on 2 females with de novo variants in KCNT2 with West syndrome followed by Lennox‐Gastaut syndrome or with DEE with migrating focal seizures. After in vitro analysis suggested quinidine‐responsive gain‐of‐function effects, we treated 1 of the girls with quinidine add‐on therapy and achieved marked clinical improvements. This suggests that the new spectrum of KCNT2‐related disorders do not only share similar phenotypic and in vitro functional and pharmacological features with previously known KCNT1‐related disorders, but also represents a further example for possible precision medicine approaches. Ann Neurol 2018;83:1198–1204     

Use of high b value diffusion-weighted magnetic resonance imaging in acute encephalopathy/encephalitis during childhood

Aim

To determine the use of high b value diffusion-weighted imaging (DWI) in the diagnosis and assessment of acute febrile encephalopathy/encephalitis in childhood.

Rufinamide for the treatment of epileptic spasms

ObjectiveThe purpose of this study was to determine the safety and efficacy of rufinamide for treatment of epileptic spasms.MethodsWe retrospectively reviewed patients treated with rufinamide for epileptic spasms from January 2009 to March 2010. Age, presence of hypsarrhythmia, change in seizure frequency following rufinamide initiation, and side effects were assessed. Patients who had a ≥ 50% reduction in spasm frequency were considered responders.ResultsOf all 107 children treated with rufinamide during the study period, 38 (36%) had epileptic spasms. Median patient age was 7 years (range: 17 months to 23). One patient had hypsarrhythmia at the time of treatment with rufinamide, and 9 other patients had a history of hypsarrhythmia. Median starting dose of rufinamide was 9 mg/kg/day (range: 2–18) and median final treatment dose was 39 mg/kg/day (range: 8–92). All patients were receiving concurrent antiepileptic drug therapy, with the median number of antiepileptic drugs being 3 (range: 2–6). Median duration of follow-up since starting rufinamide was 171 days (range: 10–408). Responder rate was 53%. Median reduction in spasm frequency was 50% (interquartile range = –56 to 85%, P < 0.05). Two patients (5%) achieved a > 99% reduction in spasms. Rufinamide was discontinued in 7 of 38 patients (18%) because of lack of efficacy, worsening seizures, or other side effects. Minor side effects were reported in 14 of 38 patients (37%).ConclusionsRufinamide appears to be a well-tolerated and efficacious adjunctive therapeutic option for children with epileptic spasms. A prospective study is warranted to validate our observations.     

Reduction of seizure frequency after epilepsy surgery in a patient with STXBP1 encephalopathy and clinical description of six novel mutation carriers

Mutations in STXBP1 have been identified in a subset of patients with early onset epileptic encephalopathy (EE), but the full phenotypic spectrum remains to be delineated. Therefore, we screened a cohort of 160 patients with an unexplained EE, including patients with early myoclonic encephalopathy (EME), Ohtahara syndrome, West syndrome, nonsyndromic EE with onset in the first year, and Lennox‐Gastaut syndrome (LGS). We found six de novo mutations in six patients presenting as Ohtahara syndrome (2/6, 33%), West syndrome (1/65, 2%), and nonsyndromic early onset EE (3/64, 5%). No mutations were found in LGS or EME. Only two of four mutation carriers with neonatal seizures had Ohtahara syndrome. Epileptic spasms were present in five of six patients. One patient with normal magnetic resonance imaging (MRI) but focal seizures underwent epilepsy surgery and seizure frequency dropped drastically. Neuropathology showed a focal cortical dysplasia type 1a. There is a need for additional neuropathologic studies to explore whether STXBP1 mutations can lead to structural brain abnormalities.     

De novo KCNT1 mutations in early‐onset epileptic encephalopathy

KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1‐targeted next‐generation sequencing (207 samples) and/or whole‐exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K⁺ conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1–4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS.     

SCN1A testing for epilepsy: Application in clinical practice

This report is a practical reference guide for genetic testing of SCN1A, the gene encoding the α1 subunit of neuronal voltage‐gated sodium channels (protein name: Na_v1.1). Mutations in this gene are frequently found in Dravet syndrome (DS), and are sometimes found in genetic epilepsy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. Recommendations for testing: (1) Testing is particularly useful for people with suspected DS and sometimes in other early onset infantile epileptic encephalopathies such as MPSI because genetic confirmation of the clinical diagnosis may allow optimization of antiepileptic therapy with the potential to improve seizure control and developmental outcome. In addition, a molecular diagnosis may prevent the need for unnecessary investigations, as well as inform genetic counseling. (2) SCN1A testing should be considered in people with possible DS where the typical initial presentation is of a developmentally normal infant presenting with recurrent, febrile or afebrile prolonged, hemiclonic seizures or generalized status epilepticus. After age 2, the clinical diagnosis of DS becomes more obvious, with the classical evolution of other seizure types and developmental slowing. (3) In contrast to DS, the clinical utility of SCN1A testing for GEFS+ remains questionable. (4) The test is not recommended for children with phenotypes that are not clearly associated with SCN1A mutations such as those characterized by abnormal development or neurologic deficits apparent at birth or structural abnormalities of the brain. Interpreting test results: (1) Mutational testing of SCN1A involves both conventional DNA sequencing of the coding regions and analyses to detect genomic rearrangements within the relevant chromosomal region: 2q24. Interpretation of the test results must always be done in the context of the electroclinical syndrome and often requires the assistance of a medical geneticist, since many genomic variations are possible and it is essential to differentiate benign polymorphisms from pathogenic mutations. (2) Missense variants may have no apparent effect on the phenotype (benign polymorphisms) or may represent mutations underlying DS, MPSI, GEFS+, and related syndromes and can provide a challenge in interpretation. (3) Conventional methods do not detect variations in introns or promoter or regulatory regions; therefore, a negative test does not exclude a pathogenic role of SCN1A in a specific phenotype. (4) It is important to note that a negative test does not rule out the clinical diagnosis of DS or other conditions because genes other than SCN1A may be involved. Obtaining written informed consent and genetic counseling should be considered prior to molecular testing, depending on the clinical situation and local regulations.     

KCNQ2 encephalopathy: A case due to a de novo deletion

KCNQ2 encephalopathy is characterized by severely abnormal EEG, neonatal-onset epilepsy and developmental delay. It is caused by mutations (typically missense) in the KCNQ2 gene, encoding the voltage gated potassium channel Kv7.2 and leading to a negative-dominant effect. We present one case experiencing recurrent neonatal seizures with changing hemispheres of origin, reminiscent of epilepsy of infancy with migrating focal seizures. At 9 months of age the patient is still seizure-free on carbamazepine, although he is developing a spastic-dystonic tetraplegia with severe dysphagia. He harbors a de novo deletion (c.913_915del [p.Phe305del)]), only described once in a couple of severely affected twins, and leading to the deletion of a phenylalanine residue in the pore domain of the channel. In conclusion, our case is the second described with encephalopathy due to this specific deletion (the one and only deletion so far reported in KCNQ2 encephalopathy). Thus, deletion is a newly described mechanism highlighting how not only missense mutations but also deletions in the channel hot spots can lead to a severe phenotype. Furthermore he presented ictal EEG features similar to epilepsy of infancy with migrating focal seizures not previously described.