Metabolic causes of pediatric developmental & epileptic encephalopathies (DEE)- genetic variant analysis in a south Indian cohort.

PURPOSE: Drug-resistant epilepsy is seen in patients with inborn errors of metabolism and metabolic dysfunction in neurons is crucial to brain disorders associated with psychomotor impairment. Diagnostic rates of metabolic causes of developmental and epileptic encephalopathy (DEE) using next generation sequencing have been rarely studied in literature. METHODS: A prospective hospital study was carried out in 384 children with DEE, who underwent genetic testing. Metabolic disorders were evaluated with biochemical blood/urine assays and when required CSF estimations performed. RESULTS: A total of 154 pathogenic/likely pathogenic variants in 384 children were identified. Out of 384 children, 89 were clinically suspected to have probable or possible metabolic disorders. Pathogenic/likely pathogenic variants in metabolic genes were identified in 39 out of 89 (43.8 %) and promising VUS in 28 (31.4 %). These included variants for progressive myoclonus epilepsies (21; 53.8 %), DEE with focal/multifocal seizures (8; 20.5 %), generalized epilepsy (5;12.8 %), early myoclonic encephalopathy (2; 5.1 %), LGS (1; 2.6 %) and West syndrome (2; 5.1 %). CONCLUSION: Our cohort demonstrates for the first time from the Indian subcontinent that identification of metabolic variants can guide investigations and has therapeutic implications in patients with variable DEE phenotypes. A high utility is noted with regard to diagnosis and prognostication, given the low yield of available biochemical tests, indicating cost-effectiveness of this approach.

Arginase deficiency-An unheralded cause of developmental epileptic encephalopathy.

Arginase deficiency, which leads to hyperargininaemia is a rare urea cycle disorder caused by a mutation in the ARG1 gene. It is an under-recognized cause of pediatric developmental epileptic encephalopathy, with the key coexistent clinical features being developmental delay or regression and spasticity. Detection of ARG1 gene mutation on genetic testing is the confirmatory diagnostic test. However, elevated levels of plasma arginine and low plasma arginase level can be considered as biochemical markers for diagnosis. We present two cases of arginase deficiency with genetically confirmed ARG1 mutation in one and biochemical confirmation in both. As the spectrum of epilepsy in arginase deficiency has been less explored, we attempted to elucidate the novel electroclinical features and syndromic presentations in these patients. Informed consent was obtained from families of patients. Electroclinical diagnosis was consistent with Lennox Gastaut syndrome (LGS) in the first patient while the second patient had refractory atonic seizures with electrophysiological features consistent with developmental and epileptic encephalopathy. Though primary hyperammonaemia is not a consistent feature, secondary hyperammonaemia in the setting of infectious triggers and drugs like valproate (valproate sensitivity) has been well described as also observed in our patient. In the absence of an overt antecedent in a child with spasticity and seizure disorder, with a progressive course consistent with a developmental epileptic encephalopathy, arginase deficiency merits consideration. Diagnosis often has important therapeutic implications with respect to dietary management and choice of the appropriate antiseizure medications.

Clinical Reasoning: A Teenager With Chronic Meningitis-Does Occam's Razor Apply?

A 14-year-old girl presented with subacute onset headache, fever, and vomiting and was managed initially with antibiotics for suspected bacterial meningitis. Her symptoms further evolved over the next few weeks with systemic signs and symptoms favoring chronic meningitis with raised intracranial pressure. After the etiologic workup was unrevealing, she was started on empirical antituberculous therapy. After a period of partial improvement, symptoms recurred with a new-onset focal seizure. Her imaging findings evolved from features suggestive of focal leptomeningitis to multifocal heterogeneous enhancing cortical and subcortical lesions with hemorrhagic foci, leading to brain biopsy that confirmed diagnosis. Our case highlights the utility of diagnostic biopsy in patients with "chronic meningitis" in uncertain cases rather than confining the approach to the law of parsimony. The decision to initiate empirical therapy in chronic meningitis should be considered on a case-by-case basis and take into account factors, such as clinical examination findings, immune status, recent exposures, and potential risks of treatment. Atypical MRI features should lower the threshold for meningocortical biopsy when indicated.

Weekly methotrexate may reduce valproate levels causing relapse of genetic generalized epilepsy.

•Seizures have been observed in epilepsy patients receiving high dose intravenous or intrathecal Methotrexate (Mtx) therapy for the treatment of leukemias, due to reduction in valproic acid (VPA) levels.•Prolonged low dose weekly Mtx exposure can also produce reduction in VPA levels causing seizure relapse as reported in this case.•Mtx competes with VPA for binding to albumin as a result of which a larger proportion of VPA become unbound and is rapidly metabolized by the liver causing decline in VPA levels.•Awareness about pharmacological interactions of anti-epileptic drugs (AEDs) is essential in epilepsy management.

The Dysfunctional Gangway: SZT2-associated Epilepsy with Thick Corpus Callosum.

Mutations in seizure threshold 2 (SZT2) gene on chromosome 1p34.2 are an of late identified cause of epilepsy and epileptic encephalopathy. We report a 3-year-old girl who presented with developmental delay, dysmorphic facies, refractory seizures, and subsequent developmental regression. Despite significant multifocal epileptiform abnormalities on her electroencephalogram, she had a paucity of generalized discharges indicating a functional deficiency of corpus callosum inspite of its increased thickness seen on magnetic resonance imaging. Her clinical exome sequencing revealed a homozygous single base pair duplication in the SZT2 gene that resulted in a frameshift mutation and premature truncation of the protein. Our case emphasizes the role of SZT2 gene in the diagnostic algorithm of early childhood refractory epilepsy especially in the context of a thick yet dysfunctional corpus callosum.