Mowat-Wilson syndrome: literature review and case series

Mowat-Wilson syndrome (MWS) is a rare genetic disorder characterized by a combination of the following signs: 1) facial dysmorphism (wide nose, broad medial eyebrows, pronounced chin, and open mouth); 2) mental retardation; 3) abnormalities of internal organs (congenital heart defects, Hirschsprung's disease, hypospadias/cryptorchidism). The disease is associated with a heterozygous pathogenic mutation in the ZEB2 gene. More than 80 % of MWS patients are diagnosed with epilepsy, the onset of which is usually observed in infancy. Patents have focal motor seizures, atypical absence seizures, generalized convulsive seizures. Epileptic seizures are often triggered by fever; some children are resistant to therapy. MWS patients have a specific phenotype (blue eyes, fair hair, wide-based gait, frequent laughter, limited or absent expressive language) that requires differential diagnosis with Angelman syndrome (caused by a mutation in the UBE3A gene). MWS was described in 1998, but there have been no case reports in the Russian literature yet. We report 4 cases of MWS in children aged 2 to 13 years treated in the Svt. Luka's Institute of Neurology and Epilepsy. In all of these patients, we identified a heterozygous de novo deletion in the ZEB2 gene. Epilepsy was observed in all patients. Mean age at onset was 13 months. All children had focal motor seizures and atypical absence seizures. None of them had tonic-clonic seizures or status epilepticus. The analysis of electroencephalograms showed that patients with a lower index of epileptiform activity tend to have better development and vice versa: children with a high index of epileptiform activity during sleep had more severe developmental delay.

Children With Trisomy 21 and Lennox-Gastaut Syndrome With Predominant Myoclonic Seizures

Introduction: Lennox-Gastaut syndrome is a severe form of pediatric epilepsy that is classically defined by a triad of drug-resistant seizures, including atonic, tonic, and atypical absence seizures; slow spike-and-wave discharges and paroxysmal fast activity on electroencephalography (EEG); and cognitive and behavioral dysfunction. In the vast majority, Lennox-Gastaut syndrome develops in patients with an identified etiology, including genetic or structural brain abnormalities. Long-term prognosis is generally poor with progressive intellectual deterioration and persistent seizures. At present, there are few reported cases of Lennox-Gastaut syndrome and trisomy 21 in the literature. To further delineate the spectrum of epilepsy in trisomy 21, we reviewed children with trisomy 21 and Lennox-Gastaut syndrome at one center over 28 years. Methods: This is a retrospective case series. At our institution, all EEG results are entered into a database, which was queried for patients with trisomy 21 from 1992 to 2019. Pertinent electroclinical data was obtained from medical records. Results: Of 63 patients with trisomy 21 and epilepsy, 6 (10%) had Lennox-Gastaut syndrome and were included in the study. Four of the 6 patients were male and 5 of 6 had neuroimaging, which was normal. Follow-up ranged from 3 to 20 years. Notably, 5 of 6 had predominant myoclonic seizures throughout the course of their epilepsy, associated with generalized spike-wave discharges, <100 milliseconds. Conclusion: We observed myoclonic seizures to be a predominant seizure type in patients with trisomy 21, suggestive that trisomy 21 patients may have a unique pattern of Lennox-Gastaut syndrome.

Phenotypes of GNAO1 Variants in a Chinese Cohort

This study aimed to analyze the genotypes and phenotypes of GNAO1 variants in a Chinese cohort. Seven male and four female patients with GNAO1 variants were enrolled, including siblings of brothers. Ten different GNAO1 variants (nine missense and one splicing site) were identified, among which six were novel. All the variants were confirmed to be de novo in peripheral blood DNA. Eight (73%, 8/11) patients had epilepsy; the seizure onset age ranged from 6 h after birth to 4 months (median age, 2.5 months). Focal seizures were observed in all eight patients, epileptic spasms occurred in six (75%, 6/8), tonic spasm in four (50%, 4/8), tonic seizures in two, atypical absence in one, and generalized tonic–clonic seizures in one. Seven patients had multiple seizure types. Eight (73%, 8/11) patients had movement disorders, seven of them having only dystonia, and one having dystonia with choreoathetosis. Varying degrees of developmental delay (DD) were present in all 11 patients. The phenotypes were diagnosed as early infantile epileptic encephalopathy (EIEE) in two (18%) patients, which were further diagnosed as West syndrome. Movement disorders (MD) with developmental delay were diagnosed in two (18%) brothers. EIEE and MD were overlapped in six (55%) patients, among which two were diagnosed with West syndrome, one with Ohtahara syndrome, and the other three with non-specific EIEE. One (9%) patient was diagnosed as DD alone. The onset age of GNAO1-related disorders was early infancy. The phenotypic spectrum of GNAO1 included EIEE, MD with DD, and DD alone.

Diagnostic Procedure and Therapeutic Approaches in Nonconvulsive Status Epilepticus (NCSE)

Nonconvulsive epileptic seizures are major type of seizures of all patients with predominantly focal epilepsy. However, this problem is still insufficiently studied, the literature presents a few data on the diagnosis and treatment of nonconvulsive status epilepticus (NCSE). NCSE is a prolonged seizure, not accompanied by severe motor presentation. Such attacks occur much more often than previously thought. NCSE is divided into focal NCSE (complex partial status epilepticus), and generalized NCSE, often referred as absence status. The absence status divides into a typical absence status (presents with suppression of consciousness of various depths, myoclonic twitching of the eyelids, impoverishment of speech production and hallucinations), atypical absence status (presents with retardation of mental processes and eyelid myoclonus) and late absence status (long-term disorientation accompanied by cognitive deficiency and presents mainly in elderly patients). According to the available sources, more than 30% of patients in the intensive care units with impaired consciousness of unclear genesis are patients with NCSE. Use of antiepileptic drugs for intravenous administration opens better opportunities in the treatment of patients with status epilepticus and NCSE.

MON-110 Utilization of GluCEST, a Novel Neuroimaging Technique, to Characterize the Brain Phenotype in Hyperinsulinism/Hyperammonemia Syndrome

BACKGROUND: Hyperinsulinism/Hyperammonemia (HI/HA) syndrome is the second most common form of congenital hyperinsulinism. It is caused by gain-of-function mutations in glutamate dehydrogenase (GDH), a mitochondrial enzyme expressed in pancreatic β-cells, liver, kidney, and brain, and is responsible for metabolizing glutamate into α-ketoglutarate and ammonia. In addition to hyperinsulinemic hypoglycemia due to abnormal GDH activity in pancreatic β-cells, ~80% of patients have developmental delays, learning, or behavioral disorders and &gt;60% have atypical absence seizures (Bahi-Buisson, 2008). These neurologic symptoms are not fully explained by hypoglycemia and are hypothesized to result from central nervous system (CNS) glutamate imbalance due to CNS GDH overactivity. Newer magnetic resonance imaging (MRI) techniques have allowed for sensitive estimation of CNS glutamate using Glutamate Chemical Exchange Saturation Transfer (GluCEST). We aimed to comprehensively characterize the biochemical and clinical neurologic phenotype of HI/HA leveraging GluCEST MRI. Methods: Subjects with confirmed HI/HA diagnosis and without contraindication to MRI had electroencephalogram (EEG), serum ammonia, and the following validated neurodevelopmental assessments: ABAS-3, BRIEF, and ASEBA CBCL (if &lt;18 years) or ASR (if &gt;18 years) completed. GluCEST MRI axial hippocampal and midsagittal slices were acquired on a 7.0T Siemens scanner and reported as GluCEST % contrast. Healthy control GluCEST % contrast data were obtained from a separate study using the same neuroimaging protocol. Results: 8 HI/HA subjects (4 female; mean age 28 years [range 16-56] years) participated to date. Median serum ammonia was 58 umol/L (IQR 39-89). 50% self-reported learning impairments and 37.5% self-reported prior ADHD diagnosis. Marked unilateral increase in hippocampal GluCEST % contrast was observed in 3/6 subjects (2 L&gt;R; 1 R&gt;L). Overall, median peak GluCEST % contrast level was significantly higher in HI/HA subjects than controls (10.3% [IQR 8.9-11.3] v. 8.0% [IQR 7.8-8.4], p=0.0013, n=6). Conclusions: This is the first study to evaluate CNS glutamate via GluCEST in HI/HA. Hippocampal glutamate, measured by GluCEST % contrast, was significantly higher in HI/HA subjects than healthy controls. Laterality in hippocampal glutamate was observed in half of subjects. These findings are remarkable given the known role of abnormal glutamate signaling in the development of epilepsy and neurocognitive impairment. Next steps are to complete midsagittal GluCEST image processing, EEG and neurodevelopmental assessment interpretations to explore correlations between CNS phenotype and brain glutamate pattern. GluCEST holds promise for elucidating the pathophysiology of CNS manifestations in HI/HA syndrome.

Dravet Syndrome -A case report from Aseer, Saudi Arabia

Dravet syndrome (DS) is an epileptic encephalopathy that presents with protracted seizures in infancy, associated with fever, and frequently categorized as febrile seizure at first presentation. In the second year, myoclonia, atypical absence and complex partial seizures develop. The correct diagnosis of DS and appropriate follow-up are delayed until after appearance of signs of developmental regression in the second year of life. Timely detection and diagnosis of DS followed by management with suitable anticonvulsants and treatment plan may reduce the seizure burden and improve long-term developmental outcome. We present a case of 2 years old female with recurrent attacks of generalized tonic colonic convulsion after 1st febrile convulsion diagnosed as Dravet syndrome. The diagnosis was based on history and gene study (SCN1A). Bangladesh Journal of Medical Science Vol.19(2) 2020 p.315-318

GABAA receptor β3 subunit mutation D120N causes Lennox–Gastaut syndrome in knock-in mice

The Lennox–Gastaut syndrome is a devastating early-onset epileptic encephalopathy, associated with severe behavioural abnormalities. Its pathophysiology, however, is largely unknown. A de novo mutation (c.G358A, p.D120N) in the human GABA type-A receptor β3 subunit gene (GABRB3) has been identified in a patient with Lennox–Gastaut syndrome. To determine whether the mutation causes Lennox–Gastaut syndrome in vivo in mice and to elucidate its mechanistic effects, we generated the heterozygous Gabrb3+/D120N knock-in mouse and found that it had frequent spontaneous atypical absence seizures, as well as less frequent tonic, myoclonic, atonic and generalized tonic–clonic seizures. Each of these seizure types had a unique and characteristic ictal EEG. In addition, knock-in mice displayed abnormal behaviours seen in patients with Lennox–Gastaut syndrome including impaired learning and memory, hyperactivity, impaired social interactions and increased anxiety. This Gabrb3 mutation did not alter GABA type-A receptor trafficking or expression in knock-in mice. However, cortical neurons in thalamocortical slices from knock-in mice had reduced miniature inhibitory post-synaptic current amplitude and prolonged spontaneous thalamocortical oscillations. Thus, the Gabrb3+/D120N knock-in mouse recapitulated human Lennox–Gastaut syndrome seizure types and behavioural abnormalities and was caused by impaired inhibitory GABAergic signalling in the thalamocortical loop. In addition, treatment with antiepileptic drugs and cannabinoids ameliorated atypical absence seizures in knock-in mice. This congenic knock-in mouse demonstrates that a single-point mutation in a single gene can cause development of multiple types of seizures and multiple behavioural abnormalities. The knock-in mouse will be useful for further investigation of the mechanisms of Lennox–Gastaut syndrome development and for the development of new antiepileptic drugs and treatments.

Pharmacoresistant Atypical Benign Partial Epilepsy of Childhood: Early Introduction of Specific Therapies to Prevent Cognitive Decline

Atypical benign partial epilepsy (ABPE) of childhood is a special type of epileptic syndrome characterized by the combination of epileptic negative myoclonus, atypical absence seizures, focal motor seizures, and a continuous spike–wave during slow sleep (CSWS). Although the seizures are resistant to antiseizure drugs (ASDs) effective for focal epilepsy, they are markedly responsive to ethosuximide (ESM). An incorrect ASD choice may aggravate the seizures and CSWS, resulting in a pseudo-catastrophic state or nonconvulsive status epilepticus. In this study, we retrospectively investigated the effectiveness of steroid and ketogenic diet (KD) therapies for children with ABPE resistant to ASDs, including ESM. Adrenocorticotropic hormone (ACTH) therapy (n = 4), KD therapy (n = 4), and an oral steroid (n = 2) were tried for eight patients (two patients tried two therapies). An excellent response (seizure-free period > 1 year) was achieved by four out of four patients undergoing ACTH therapy, two out of four undergoing KD therapy, and one out of two receiving oral steroid therapy. In conclusion, steroid and KD therapies are reasonable treatment options early in the course of treatment of children with pharmacoresistant ABPE to prevent a decline in cognitive function due to the persistence of epileptic encephalopathy. The majority of patients in our case series had an excellent response, though further studies are warranted to confirm their efficacy and safety.