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PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

The clinical presentations of autoimmune encephalitides tend to be a mixture of neuropsychiatric and somatic symptoms. The focus of this chapter concerns these clinical problems: the clinical phenomenology, the prevalence, and the possible pathophysiologies of anti-NMDAR or the other types of autoimmune encephalitis. We also specifically address the psychopharmacologic and nonpsychopharmacologic treatments. Our main questions are: What are the most used and best justified drug treatments? What are the most frequent side effects? And which other treatment options, such as ECT, are available? We discuss the main findings, present limitations, and we conclude by giving recommendations and presenting two algorithms.

SummaryWe describe four children with Dravet syndrome treated with the combination of valproic acid (VPA) and topiramate (TPM) who developed transient liver toxicity. The time-interval between fever, administration of acetaminophen, epileptic status and liver enzyme disturbances in our four cases suggests that accumulation of toxic acetaminophen-metabolites is possibly responsible for liver toxicity. If acetaminophen and its metabolites cause those liver problems in children treated with the combination of VPA and TPM, the advice to use acetaminophen for treating fever in children using this combination, should be changed. Only future clinical observations and research can solve this clinical dilemma.

This review addresses the effects of subclinical localized epileptiform discharges during sleep in children with benign childhood epilepsy with centrotemporal spikes (BCECTS) on cognition and behavior. A diversity of educational deficits, behavioral impairments, language delay, and neuropsychological test results have been reported in children with BCECTS. The occurrence of atypical seizure characteristics seems to be related to language delay, and several atypical EEG characteristics are related to cognitive or behavioral problems. It remains to be shown whether treatment of nocturnal discharges in children with BCECTS is indicated to improve cognitive and behavioral problems.

In daily clinical practice, doctors are frequently confronted with the issue whether treatment is necessary when the patient is without (further) seizures, but nevertheless still shows interictal discharges on the EEG. Will these discharges influence cognition temporarily and in time correlated with the discharges or is there a longer-lasting or even cumulative impairment? Which children are most at risk and when? Based on available literature in this field and own research in patients with Benign Epilepsy with Centro-Temporal spikes (BECTS), an inventory has been made of all issues that has to be addressed to answer these crucial questions. Prospective studies in drug naive children with BECTS (with or without behavioral comorbidity) are highly recommended.

In December, 2009, a 9-year-old boy was admitted to our hospital with an acute onset of secondary generalised seizures. He had no medical or psychiatric history and functioned very well socially and academically. He presented with speech and swallowing diffi culties, which after 10 days developed into a severely agitated catatonic state with opisthotonic posturing, tonic posturing of limbs, insomnia, and dyskinesia. Initially the electroencephalogram showed a normal background pattern with epileptic discharges, and oligoclonal bands were present in cerebrospinal fl uid (CSF). Brain MRI and extensive blood tests were normal. The neurological diagnosis was atypical childhood epilepsy with centrotemporal spikes, for which oral corticosteroids and antiepileptic drugs were prescribed. His catatonia was treated with benzodiazepines. In January, 2010, our patient presented in a robotic state with complete mutism and negativism, and he did not respond to any form of contact. We provisionally diagnosed acute late onset autism with a diff erential diagnosis of childhood dis integrative disorder or early onset schizophrenia. Childhood disintegrative disorder, early onset schizophrenia, and late onset autism often share a fi nal common pathway: previous normal development, followed by sudden neuropsychiatric regression of social interaction and communication skills, and a decline in intelligence and daily activities. The disorders are sometimes misrecognised and collectively called as autistic disorder. Although judged to be functional psychiatric diagnoses, the marked deterioration and poor prognosis suggest an organic cause, especially in children with catatonia, a normal development up to at least 5 years of age, or both. In our patient, late onset autism was considered because: it is associated with neurological disorders; it is a known end stage of acquired brain injury; progression of symptoms was fast and severe, unlike in early onset schizophrenia; the absence of positive symptoms made schizophrenia less plausible; the age of onset and rare prevalence made chronic disintegrative disorder unlikely; and accompanying catatonic features were present. After extensive diagnostic assessments, our patient was fi nally diagnosed with anti-NMDA-receptor encephalitis on the basis of slightly raised anti-NMDA-receptor antibody titres in serum and highly raised titres in CSF. Clinical characteristics of this condition are acute major neuropsychiatric symptoms including anxiety, aggres sion, agitation, behavioural changes and catatonia, delusional thoughts, progressive speech deterioration, and hallucinations. Neurological symptoms such as dyskinesia, abnormal seizure-like movements, and diff use and profound autonomic instability have also been reported. Anti-NMDA-receptor encephalitis can occur in the context of malignant disease; however for our patient extensive oncological investigations were negative. Electroconvulsive therapy was given for the severe catatonic state, and monoclonal antibody treatment (rituximab) was started because of the unsatisfactory response to the initial treatment with benzodiazepines. The acquired autism gradually subsided, he spoke fl uently and was able to draw a happy picture (fi gure). In June, 2011, he only had some mild cognitive dysfunction. Childhood disintegrative disorder, early onset schizophrenia, late onset autism and all stages of anti-NMDAreceptor encephalitis share core symptoms, as in our patient. We suggest that anti-NMDA-receptor encephalitis might be a possible organic cause underlying these three disorders. Patients previously diagnosed with these diagnoses might need to be re-examined for anti-NMDAreceptor encephalitis. We suggest that forthcoming editions of DSM-5 and ICD-11 exclude and defi ne cases of regressive autism spectrum disorders due to anti-NMDAreceptor encephalitis.