Current Literature In Basic Science

Locus Heterogeneity in Epilepsy of Infancy with Migrating Focal Seizures

Mutations in SLC12A5 in Epilepsy of Infancy With Migrating Focal Seizures. Stödberg T, McTague A, Ruiz AJ, Hirata H, Zhen J, Long P, Farabella I, Meyer E, Kawahara A, Vassallo G, Stivaros SM, Bjursell MK, Stranneheim H, Tigerschiöld S, Persson B, Bangash I, Das K, Hughes D, Lesko N, Lundeberg J, Scott RC, Poduri A, Scheffer IE, Smith H, Gissen P, Schorge S, Reith ME, Topf M, Kullmann DM, Harvey RJ, Wedell A, Kurian MA. Nat Commun 2015;6:8038. doi: 10.1038/ncomms9038.

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-offunction 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. Howell KB, McMahon JM, Carvill GL, Tambunan D, Mackay MT, Rodriguez-Casero V, Webster R, Clark D, Freeman JL, Calvert S, Olson HE, Mandelstam S, Poduri A, Mefford HC, Harvey AS, Scheffer IE. Neurology 2015;85:958–966. doi: 10.1212/ WNL.0000000000001926. Epub 2015 Aug 19.

OBJECTIVE: De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy. METHODS: Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping. RESULTS: 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. CONCLUSIONS: 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.

Commentary Epilepsy of infancy with migrating focal seizures (EIMFS) is characterized by onset before 6 months of age of nearly continuous electrographic seizures with multiple areas of onset in Epilepsy Currents, Vol. 16, No. 1 (January/February) 2016 pp. 43–45 © American Epilepsy Society

both hemispheres (1). Migration of ictal focal discharges is the hallmark of EIMFS. In addition to seizures, there is severe psychomotor deterioration, and outcomes are generally poor. The syndrome progresses through three distinct phases: In the first phase, seizures are often sporadic and begin as focal but often evolve to generalized. In the second phase, seizures become very frequent, occurring in clusters or being almost continuous. The third phase is relatively seizure-free, although seizure clusters or status epilepticus may be precipitated by illness.

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Locus Heterogeneity in Infants with Migrating Focal Seizures

Seizure control, particularly during the second stormy phase, may improve outcomes. The etiology of EIMFS is genetic, with a number of genes implicated to date, including KCNT1, SLC25A22, SCN1A, and SCN8A (2–6). The list of EIMFS genes continues to expand with the addition of SLC12A5 and SCN2A in recent publications. Stödberg and colleagues reported recessive mutations in SLC12A5, which encodes the potassium-chloride co-transporter KCC2. From a cohort of 42 patients with EIMFS, the authors identified two families that each had two affected children with pharmacoresistant EIMFS. They performed exome sequencing and identified SLC12A5 mutations in both families. In family A, the affected children were compound heterozygotes for missense mutations L246P and G551D, inherited from unrelated healthy parents. The affected children in family B were homozygous for the missense mutation L331H, inherited from healthy first cousin parents. No potentially pathogenic variants were identified in other genes associated with EIMFS or epileptic encephalopathy. Screening of 38 additional patients did not reveal any other SLC12A5 variants. KCC2 is the major potassium-chloride co-transporter that extrudes chloride from neurons and establishes low intracellular chloride concentrations that are essential for hyperpolarizing GABAA receptor-mediated inhibition. Impaired chloride homeostasis due to KCC2 dysfunction may result in a depolarizing effect of GABA. Homology modeling predicted damaging effects of the missense variants on KCC2 structure. The authors investigated the functional effects of the mutations on chloride homeostasis in HEK293 cells expressing a glycine receptor and wild-type or mutant KCC2. In cells expressing the KCC2 mutants, they observed a depolarized reversal potential for chloride relative to wild-type KCC2. The rate of recovery following chloride load was significantly slower for cells expressing mutant versus wild-type KCC2. For two of the mutations (L426P, G551D), the rate of recovery was similar to cells expressing no KCC2, suggesting almost complete loss of KCC2 function. Whereas one of the mutants (L311H) had an intermediate rate, suggesting reduced but not absent KCC2 function. The mechanism of reduced function may be due to impaired post-translational modification and reduced expression of mutant KCC2 at the cell surface. To model the effect of KCC2 deficiency in vivo, the authors generated a knockout zebrafish model by genome editing with TALENs. They observed impairment of motor behavior, characterized by jerky spasmodic movements. This was consistent with phenotypes observed in other species with loss of KCC2 function, including a mouse model with only 5% KCC2 function that has frequent spontaneous seizures and premature lethality (7). The identification of autosomal recessive loss-of-function SLC12A5 mutations in two independent families with EIFMS supports a contribution of this gene to epileptic encephalopathy. This is perhaps not surprising give the critical function of KCC2 in establishing inhibitory GABAergic signaling during development. Other rare variants had previously been described in association with familial febrile seizures and genetic generalized epilepsy (8, 9). However, in those cases, the genetic evidence was not strong. The current report solidifies SLC12A5 as an epilepsy gene. Identification of SLC12A5 variants in additional patients will determine the range of clinical phenotypes

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and the frequency of KCC2 mutations as a cause of EIFMS and other epilepsy types. Mutations in SCN2A have previously been associated with a wide range of epilepsies, including a number of epileptic encephalopathy syndromes. Howell and colleagues sought to determine the phenotypic spectrum of SCN2A-associated encephalopathy and screened for SCN2A variants in a cohort of 580 heterogeneous epileptic encephalopathy patients. They identified heterozygous SCN2A variants in 12 patients, including eleven missense variants and one frameshift mutation. They confirmed that the SCN2A variants arose de novo in 11 of the patients, while it was undetermined for the other case. Nine of the cases had an identifiable clinical syndrome, of which seven were EIFMS and two were Otahara syndrome. Of the patients with EIFMS and SCN2A mutations, developmental outcome was normal in one case, mild in one case, while there was severe to profound intellectual disability in the remaining five cases. In the total cohort of 580 patients, there were 27 cases of EIFMS and SCN2A mutations were identified in seven of them (26%). This makes SCN2A the second most commonly mutated gene for EIFMS, following KCNT1. Features that discriminate cases with SCN2A mutations from those with KCNT1 mutations include severe movement disorders and positive response to phenytoin or other sodium channel blockers. There is considerable locus heterogeneity for EIFMS, although mutations in KCNT1 appear to be the most frequent cause (2, 3). If prioritization is necessary for genetic testing, KCNT1 screening should be considered first. However, screening a panel of genes associated with EIFMS and epileptic encephalopathies may be the most efficient strategy for a molecular diagnosis in this genetically heterogeneous disorder. Understanding the genetic basis has implications for treatment since children with SCN2A mutations may respond to sodium channel blockers, while patients with mutations in SLC12A5, KCNT1, or other genes require a different therapeutic approach. by Jennifer A. Kearney, PhD References 1. Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures of infancy: A malignant disorder with developmental arrest. Epilepsia 1995;36:1017–1024. 2. Barcia G, Fleming MR, Deligniere A, Gazula V-R, Brown MR, Langouet M, Chen H, Kronengold J, Abhyankar A, Cilio R, Nitschke P, Kaminska A, Boddaert N, Casanova J-L, Desguerre I, Munnich A, Dulac O, Kaczmarek LK, Colleaux L, Nabbout R. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nature Genet 2012;44:1255–1259. 3. Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, Oliver KL, Mazarib A, Afawi Z, Korczyn A, Plazzi G, Petrou S, Berkovic SF, Scheffer IE, Dibbens LM. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nature Genet 2012;44:1188–1190. 4. Poduri A, Heinzen EL, Chitsazzadeh V, Lasorsa FM, Elhosary PC, LaCoursiere CM, Martin E, Yuskaitis CJ, Hill RS, Atabay KD, Barry B, Partlow JN, Bashiri FA, Zeidan RM, Elmalik SA, Kabiraj MM, Kothare S, Stödberg T, McTague A, Kurian MA, Scheffer IE, Barkovich AJ, Palmieri

Locus Heterogeneity in Infants with Migrating Focal Seizures

F, Salih MA, Walsh CA. SLC25A22 is a novel gene for migrating partial seizures in infancy. Ann Neurol 2013;74:873–882. 5. Ohba C1, Kato M, Takahashi S, Lerman-Sagie T, Lev D, Terashima H, Kubota M, Kawawaki H, Matsufuji M, Kojima Y, Tateno A, GoldbergStern H, Straussberg R, Marom D, Leshinsky-Silver E, Nakashima M, Nishiyama K, Tsurusaki Y, Miyake N, Tanaka F, Matsumoto N, Saitsu H. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia 2014;55:994–1000. 6. Freilich ER, Jones JM, Gaillard WD, Conry JA, Tsuchida TN, Reyes C, Dib-Hajj S, Waxman SG, Meisler MH, Pearl PL. Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. Arch Neurol 2011;68:665–671. 7. Woo NS, Lu J, England R, McClellan R, Dufour S, Mount DB, Deutch AY, Lovinger DM, Delpire E. Hyperexcitability and epilepsy associated

with disruption of the mouse neuronal-specific K-Cl cotransporter gene. Hippocampus 2002;12:258–268. 8. Puskarjov M, Seja P, Heron SE, Williams TC, Ahmad F, Iona X, Oliver KL, Grinton BE, Vutskits L, Scheffer IE, Petrou S, Blaesse P, Dibbens LM, Berkovic SF, Kaila K. A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. EMBO Rep 2014;15:723–729. 9. Kahle KT, Merner ND, Friedel P, Silayeva L, Liang B, Khanna A, Shang Y, Lachance-Touchette P, Bourassa C, Levert A, Dion PA, Walcott B, Spiegelman D, Dionne-Laporte A, Hodgkinson A, Awadalla P, Nikbakht H, Majewski J, Cossette P, Deeb TZ, Moss SJ, Medina I, Rouleau GA. Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy. EMBO Rep 2014;15:766–774.

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Locus Heterogeneity in Epilepsy of Infancy with Migrating Focal Seizures.

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