Epilepsy Of Infancy With Migrating Focal Seizures Research Articles

Clinical features and gene mutations in epilepsy of infancy with migrating focal seizures

Objective: To summarize the clinical features and gene mutations of epilepsy of infancy with migrating focal seizures (EIMFS). Method: Clinical features and electroencephalograms(EEG)of 9 patients with EIMFS of Peking University First Hospital from May 2015 to January 2016 were analyzed. Candidate gene mutations were screened by next generation sequencing. Result: Among the 9 patients, 3 were males and 6 were females. Two patients had family history. Seizure onset age was 2 days to 3 months after birth (median age 35 days). Migrating focal seizure was presented. Seizures manifested as eyes and(or)head deviation, involuntary blinking, swallowing, trembling or stiffness of limbs, hand clenching, flushing and cyanosis of lips, etc. Four patients had a history of status epilepticus. All 9 patients had psychomotor delay. EEG of all patients presented relatively slow background; during interictal phase, there were multi-focal epileptic discharges, which dominated one hemisphere or brain region; seizures were recorded in all 9 cases, which manifested eyes or(and)head deviation, stiffening or trembling of limbs, lip smacking, etc. Corresponding EEG showed low-medium-amplitude fast waves that originated from some brain regions and migrated to other regions. Cranial magnetic resonance imaging (MRI) was abnormal in 4 cases, which predominantly showed white matter dysplasia and enlargement of subarachnoid spaces. Two cases carried heterozygous missense mutations of SCN1A gene, while 3 cases carried heterozygous missense mutations of KCNT1 gene, all of which were de novo. One case carried compound heterozygous mutation of TBC1D24 gene(p.Gln207*, p. Ala289Va). Gene mutation was not found in 3 cases. All patients used multiple antiepileptic drugs (AED) and their seizures were not controlled. Follow-up ranged from 2 months to 5 years and 8 months, during which 4 were found dead. Two were lost to follow-up. Conclusion: EIMFS is clinically characterized by early onset, which is usually within 3 months after birth, migrating focal seizures, psychomotor delay, bad response to AED and high death rate. The interictal EEG showed multi-focal discharges, while ictal EEG shows migrating multifocal discharges. Genetic analysis can assist in diagnosis and genetic counseling.

Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.

The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy.

SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures.

De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy. Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping. Patients were aged 0.7 to 22 years; 3 were deceased. Seizures commenced on day 1-4 in 8, week 2-6 in 2, and after 1 year in 2. Characteristic features included clusters of brief focal seizures with multiple hourly (9 patients), multiple daily (2), or multiple weekly (1) seizures, peaking at maximal frequency within 3 months of onset. Multifocal interictal epileptiform discharges were seen in all. Three of 12 patients had infantile spasms. The epileptic syndrome at presentation was epilepsy of infancy with migrating focal seizures (EIMFS) in 7 and Ohtahara syndrome in 2. Nine patients had improved seizure control with sodium channel blockers including supratherapeutic or high therapeutic phenytoin levels in 5. Eight had severe to profound developmental impairment. Other features included movement disorders (10), axial hypotonia (11) with intermittent or persistent appendicular spasticity, early handedness, and severe gastrointestinal symptoms. Mutations arose de novo in 11 patients; paternal DNA was unavailable in one. Review of our 12 and 34 other reported cases of SCN2A encephalopathy suggests 3 phenotypes: neonatal-infantile-onset groups with severe and intermediate outcomes, and a childhood-onset group. Here, we show that SCN2A is the second most common cause of EIMFS and, importantly, does not always have a poor developmental outcome. Sodium channel blockers, particularly phenytoin, may improve seizure control.

A novel KCNT1 mutation in a Japanese patient with epilepsy of infancy with migrating focal seizures.

Epilepsy of infancy with migrating focal seizures (EIFMS) is a rare, early-onset epileptic encephalopathy characterized by polymorphous focal seizures. De novo mutations of KCNT1 have been identified in cases of this disorder. We encountered a sporadic patient with EIFMS, who suffered tonic convulsions at the age of 9 days. Using Sanger sequencing, we identified a de novo missense mutation of the same amino acid affected by a previously identified mutation, c.1420C>T (p.Arg474Cys).

KCNT1 gain-of-function mutations linked to human epilepsy are modulated by quinidine

Epilepsy of infancy with migrating focal seizures (EIMFS) and a severe form of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) are strikingly different epilepsy syndromes, which have very recently been associated with mutations in the same gene. EIMFS is a rare early infantile epileptic encephalopathy characterised by heterogeneous migrating focal seizures, and associated with arrest or regression of development resulting in profound disability. In contrast, ADNFLE begins in mid-childhood and is characterized by clusters of motor seizures arising from sleep and is associated with major comorbidities of intellectual disability and psychiatric features. Whole exome sequencing of patients with EIMFS and severe ADNFLE has revealed a number of KCNT1 mutations with 100% penetrance, many of which are de novo . KCNT1 , widely expressed in the mammalian central nervous system, encodes a potassium channel that is activated by large elevations in intracellular sodium, which occur during normal physiological signalling in the nervous system. While KCNT1 channels are thought to play important roles in regulating neuronal excitability, their precise contribution to electrical activity differs in different neuronal cell types. KCNT1 disorders are resistant to standard anti-epileptic drugs and have a severe prognosis, creating an urgent need for novel therapies. Several studies have demonstrated that antiarrhythmic compounds, such as quinidine, bepridil and clofilium are effective blockers of KCNT1 channels and despite their known adverse effect profile our recent study suggests that they may hold promise as effective therapies in EIMFS. This research highlight describes this study, evaluating the electrophysiological and pharmacological gain-of-function phenotype of KCNT1 mutations in vitro and examining the neurodevelopmental time frame for the potential contribution of this channel to neuronal excitability in vivo .

Epilepsy of infancy with migrating focal seizures: Six patients treated with bromide

PurposeWe present six patients with epilepsy of infancy with migrating focal seizures (EIMFS) and provide a comprehensive evaluation of potassium bromide therapy. MethodBetween February 1, 2007 and July 31, 2012, six patients who met the diagnostic criteria of EIMFS were treated with potassium bromide. Potassium bromide was added to other antiepileptic drugs (AEDs) in doses ranging from 30 to 80mg/kg/day. Plasma bromide concentration was monitored. A therapeutic bromide concentration between 75 and 125mg/dL was considered to be ideal. ResultsFour of six children responded well to bromide. One of these patients became seizure free, but remained severely mentally impaired. Two boys, currently 4 and 6 years of age, respectively, have monthly seizures as well as axial hypotonia and severe language impairment. The fourth child responded well to bromide, having only weekly seizures and moderate psychomotor retardation. The patient who became seizure free improved visual contact and head control. In the other three patients with good control, the seizures became focal without secondary generalization and status epilepticus and hospital admission was not required. The remaining two patients did not respond well to bromide. Adverse effects were seen in three cases: vomiting in one, drowsiness in another, and acneiform eruption in the face in the remaining patient. Adverse effects resolved with dose reduction. ConclusionEarly treatment with bromides should be considered in EIMFS to control the seizures and status epilepticus and to avoid progressive cognitive impairment. Potassium bromide is an old AED. Plasma concentration monitoring should be considered.

KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine

Mutations in KCNT1 have been implicated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). More recently, a whole exome sequencing study of epileptic encephalopathies identified an additional de novo mutation in 1 proband with EIMFS. We aim to investigate the electrophysiological and pharmacological characteristics of hKCNT1 mutations and examine developmental expression levels. Here we use a Xenopus laevis oocyte-based automated 2-electrode voltage clamp assay. The effects of quinidine (100 and 300 μM) are also tested. Using quantitative reverse transcriptase polymerase chain reaction, the relative levels of mouse brain mKcnt1 mRNA expression are determined. We demonstrate that KCNT1 mutations implicated in epilepsy cause a marked increase in function. Importantly, there is a significant group difference in gain of function between mutations associated with ADNFLE and EIMFS. Finally, exposure to quinidine significantly reduces this gain of function for all mutations studied. These results establish direction for a targeted therapy and potentially exemplify a translational paradigm for in vitro studies informing novel therapies in a neuropsychiatric disease.