Christian Korff

De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons.

A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation

A boy with a clinical history of pharmacologically resistant Dravet syndrome died suddenly after falling asleep. The autopsy concluded that the cause of death was sudden unexpected death in epilepsy (SUDEP). Postmortem molecular analysis of the SCN1A gene by multiplex ligation‐dependent probe amplification (MLPA), high‐resolution melting curve analysis (HRMCA), and sequencing revealed a frameshift duplication of adenosine at position 504. The incidence of this mutation is discussed as a potential cause of SUDEP.

Food poisoning as a cause of acute liver failure.

We report a 9-year-old girl with cereulide-producing Bacillus cereus food poisoning, who developed fulminant hepatitis, renal and pancreatic insufficiency, shock, and prolonged seizures. She was transferred to our institution for hepatic transplantation before her diagnosis was established. As a result of rapid identification of the microorganism and supportive care, liver transplantation was avoided, and she recovered fully.

Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for anti-N-methyl-d-aspartate receptor encephalitis

Aim  We report four cases of acquired severe encephalopathy with massive hyperkinesia, marked neurological and cognitive regression, sleep disturbance, prolonged mutism, and a remarkably delayed recovery (time to full recovery between 5 and 18mo) with an overall good outcome, and its association with anti‐N‐methyl‐d‐aspartate (anti‐NMDA) receptor antibodies.

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.

Yield of MRI, high-density electric source imaging (HD-ESI), SPECT and PET in epilepsy surgery candidates.

OBJECTIVE Preoperative workup aims at localizing the epileptogenic focus to achieve postoperative seizure-freedom. We studied the predictive value of non-invasive techniques, i.e. structural magnetic resonance imaging [MRI], high-density electric source imaging [HD-ESI] and metabolic imaging (positron emission tomography [PET]; single-photon emission computed tomography [SPECT]), in surgically treated patients. METHODS A prospective study of 190 epileptic operated patients, with >12 months follow-up and analyzed with state-of-the-art algorithms. 58 patients underwent all techniques. We computed sensitivity, specificity, predictive value and diagnostic odds ratio (OR) in relation to postoperative outcome. RESULTS Of 190 patients, 148 (77.9%) were seizure-free at follow-up. Resection of the epileptogenic focus was associated with favorable postsurgical outcome (p<0.05). Among 58 patients who underwent all tests, only MRI and HD-ESI were favorable outcome predictors (MRI: OR 10.9, p=0.004; HD-ESI: OR 13.1, p=0.004). Patients with concordant structural MRI and HD-ESI results had 92.3% (24/26) probability of favorable outcome. When both results were negative, probability was 0% (0/5); and when they disagreed, it was 63.0% (17/27). CONCLUSIONS Combination of MRI and HD-ESI offered the highest predictive value for postoperative seizure-freedom. SIGNIFICANCE This finding highlights the added value of HD-ESI in the presurgical workup, in particular in combination with an informative MRI.

Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

Objective We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations. Methods We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed. Results We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15. Conclusions SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Background We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Methods Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. Results Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. Conclusions In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

Do generalized tonic-clonic seizures in infancy exist?

Objective: To determine the frequency of generalized tonic-clonic seizures (GTCS) in infants (1 month to 2 years). Methods: From a total of 2,112 patients monitored in our video-EEG lab from May 2000 through January 2005, 109 distinct seizures in 77 infants were reviewed. Eight events in eight patients were excluded because of video files insufficiently reliable to determine the clinical characteristics with precision. The clinical manifestations and electrographic features of the remaining 101 seizures in 69 infants were retrospectively analyzed. Results: The authors did not observe a single GTCS. Four patients had icti that resembled GTCS, but careful analysis of these episodes revealed that three of them had a focal onset and that the fourth had a slightly different sequence of events. Conclusions: Generalized tonic-clonic seizures are rarely, if ever, seen in infants younger than age 2 in a tertiary-care pediatric epilepsy unit. Instead, they more commonly occur in older children, particularly in the well-characterized epilepsy syndromes of childhood and adolescence.

Towards the identification of a genetic basis for Landau‐Kleffner syndrome

To establish the genetic basis of Landau‐Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases.