Developmental and epileptic encephalopathy 44 due to compound heterozygous variants in the UBA5 gene:a case report

Background Developmental and epileptic encephalopathy(DEE)is a group of rare inherited disorders characterized by intellectual disability,delayed development,epileptic seizures,and other related symptoms.DEE44 is caused by mutations in the UBA5 gene,which encodes a ubiquitin-like protein involved in protein degradation and cell signaling.However,there is limited information on the genotype–phenotype correlation of DEE44,and its clinical features remain to be fully characterized.Case presentation We report a 12-month-old infant who presented with epileptic spastic seizures beginning at 4 months of age,accompanied by overall developmental delay,short stature,microcephaly,inability to hold his head upright,chasing vision,and high muscle tone in the extremities.Genetic findings showed compound heterozygous mutations of the UBA5 gene:NM_024818 c.562C>T(p.R188X)from the mother and NM_024818 c.214C>T(p.R72C)from the father.Conclusions This case report expands the clinical spectrum of DEE44 and highlights the importance of considering DEE44 in the differential diagnosis of developmental delay and epilepsy,even in the absence of classical symptoms suggestive of the condition.We hope that this case report will advance the understanding of DEE44 and improve the expertise of clinicians and early diagnose of this disease.

Ion channels in neurodevelopment:lessons from the Integrin-KCNB1 channel complex

Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes.Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide.Epilepsies are trigge red by an imbalance between excitatory and inhibitory conductances.However,pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function va riants,all able to trigger epilepsy.Furthermore,certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype.This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought.Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox.The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes,including neuronal migration,neurite outgrowth,and synapse formation.Thus,pathogenic channel mutants can not only cause epileptic disorders by alte ring excitability,but further,by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.

Revealing the complex role of CDKL5 in developmental epilepsy through a calcium channel related vision

Developmental and epileptic encephalopathies are severe neurological conditions in clinical practice,among which loss-of-function mutations in brain-enriched serine-threonine kinase cyclin dependent kinase like-5(CDKL5)exists as one of the most common types.It is unknown,therefore,how precisely CDKL5 mutations lead to neuronal hyper-excitation.A recent study that looked at the connection between voltage-gated calcium channel Cav2.3 and CDKL5 in an experimental context was published in Nature Communications.This study has revealed that Cav2.3,a physi-ological phosphorylation target of CDKL5,would show delayed inactivation and increased cholinergic stimulation in CDKL5 knock out conditions.This would in turn cause neuronal hyperexcitability and related enhanced seizure susceptibility.This work,in our opinion,provided fresh insight into the epileptic encephalopathies linked to CDKL5 and highlighted Cav2.3 as a possible target for it.

Is tuberous sclerosis complex-associated autism a preventable andtreatabledisorder?

Background Tuberous sclerosis complex(TSC)is a genetic disorder caused by inactivating mutations in the TSCl and TSC2 genes,causing overactivation of the mechanistic(previously referred to as mammalian)target of rapamycin(mTOR)signaling pathway in fetal life.The mTOR pathway plays a crucial role in several brain processes leading to TSC-related epilepsy,intellectual disability,and autism spectrum disorder(ASD).Pre-natal or early post-natal diagnosis of TSC is now possible in a growing number of pre-symptomatic infants.Data sources We searched PubMed for peer-reviewed publications published between January 2010 and April 2023 with the terms“tuberous sclerosis",“autism",or“autism spectrum disorder""animal models",“preclinical studies",“neurobiology",and“treatment".Results Prospective studies have highlighted that developmental trajectories in TSC infants who were later diagnosed with ASD already show motor,visual and social communication skills in the first year of life delays.Reliable genetic,cellular,electroencephalography and magnetic resonance imaging biomarkers can identify pre-symptomatic TSC infants at high risk for having autism and epilepsy.Conclusions Preventing epilepsy or improving therapy for seizures associated with prompt and tailored treatment strategies for autism in a sensitive developmental time window could have the potential to mitigate autistic symptoms in infants with TSC.

Gene variations of glutamate metabolism pathway and epilepsy

Background Epilepsy is a paroxysmal disorder of the brain,caused by an imbalance of neuronal excitation and inhibition.Glutamate is the most important excitatory neurotransmitter in the brain and plays an important role in epileptogenesis.Mutations in genes at any step/component of the glutamate metabolic pathway may lead to the development of epilepsy or epileptic encephalopathy.Methods Clinical history of 3 epilepsy patients with genetic variations of the glutamate metabolism pathway was collected.Electroencephalogram recording and magnetic resonance imaging were performed in each patient.We also reviewed recent literature for a variety of the genetic variations involved in epilepsy.Results Case 1 was a SLC1A2 mutation-carrier diagnosed with developmental and epileptic encephalopathy(DEE)41,whose seizures decreased after start of the ketogenic diet.Case 2 carried a GRIN2A gene mutation and was seizure-free for three years after taking levetiracetam and vitamin B6.Case 3 was a GRIN2B mutation-carrier diagnosed with DEE 27,who seizures diminished after taking oxcarbazepine.Conclusions Preclinical and clinical evidence supports the therapeutic potential of glutamatergic signaling-targeting treatments for epilepsy.More studies are needed to discover novel DEE-related genetic mutations in the glutamate metabolic pathway.