Case Report: Traumatic Stress and Developmental Regression: An Unintended Consequence of Complex Cardiac Care

This brief case report outlines a novel approach to supporting the development of a pediatric complex cardiac care patient. Patient X is a 19-month old patient who spent 5.5 months in hospital and underwent multiple surgeries including heart transplantation. This case report explores the impacts of his condition and care on his development and family functioning within the framework of an integrated care model. This case report is uniquely complimented by outpatient neurodevelopmental follow up, dyadic trauma-informed intervention and use of telemedicine allowing for a deeper understanding of the family adaptation that provide novel insight into long-term trajectory beyond discharge. Throughout care Patient X met criteria for both a traumatic stress disorder and global developmental delay. This case study highlights the threat complex care poses to neurodevelopment, pediatric mental health and family dynamics as well as opportunities for intervention.

SSPE (SUBACUTE SCLEROSING PANENCEPHALITIS) - THE GREAT MASQUERADER

Background: SSPE is chronic progressive encephalitis affecting children and young adults which usually presents with cognitive decline and behavioural changes followed by periodic myoclonic jerks, seizures, vision loss and ataxia. High degree of suspicion is required as the presentation can be variable and can have many differentials. Aim: We aim to study various presentations of SSPE Methods and Material: Retrospective study was done to analyse various presentations in patients diagnosed with SSPE as per modied Dykens criteria from a tertairy care centre over a period of 2 years (1st January 2018-31st December 2020). Results: 6 cases of SSPE were identied. Case1 - 22 months old presented with subacute history of ataxia, multical myoclonus and developmental regression. Gradually myoclonus worsened to involve trunk and developed drop attacks. Case 2 - 17 years boy presented with single episode of seizure. Case 3- 25 years female with 5 months gestation presented with subacute vision loss followed by progressive cognitive decline, behavioural changes, Parkinsonism, Dystonia and stimulus sensitive myoclonus. Case4- 28 years female presented with rapidly progressive cognitive decline and behavioural changes. Case 5- 32 years male presented with history of myoclonic jerks and dropping of objects. Gradually developed progressive behavioural changes and cognitive decline and became vegetative. Case6 - 9 year old child presented with faciobrachial seizures (myoclonic jerks) and scholastic backwardness. Conclusions: SSPE can manifest with varied presenting complaints. Also, Results of EEG, MRI and CSF examination can change during the disease course. Therefore, high degree of suspicion is required for early diagnosis of this challenging entity.

Experience in Diagnosing Neuronal Ceroid Lipofuscinosis Type-2

Introduction: Developmental regression is always an alarming symptom in children as it is an early sign of some genetic disorders, one of which is neuronal ceroid lipofuscinosis (NCL). NCL is a group of rare neurodegenerative disorder caused by accumulation of intracellular ceroid lipofuscin. Since 2017 an enzyme replacement therapy (ERT) has been approved by Food and Drug Administration (FDA) for this disease. The symptoms of NCL could be managed by ERT if detected early, and the child could live normally.Case: We present a case of a 6-year-and-5-month-old boy with developmental regression, speech delay, recurrent seizure, and visual impairment, who was diagnosed with NCL type 2 after genetic testing. Compound heterozygous mutations in tripeptidyl-peptidase 1 (TPP1) gene was revealed, consistent with very low level of TPP1 enzyme in this patient.Discussion: NCL is a fatal disease which is often misdiagnosed in early stage. Diagnostic delay of NCL often occurs due to lack of awareness which often leads to premature death.Conclusion: Knowledge regarding the disease is important for early detection and to slow down the disease progression.

Approach to Neurological Channelopathies and Neurometabolic Disorders in Newborns

Ion channel disorders (channelopathies) can affect any organ system in newborns before 2 months of life, including the skeletal muscle and central nervous system. Channelopathies in newborns can manifest as seizure disorders, which is a critical issue as early onset seizures can mimic the presentation of neurometabolic disorders. Seizures in channelopathies can either be focal or generalized, and range in severity from benign to epileptic encephalopathies that may lead to developmental regression and eventually premature death. The presenting symptoms of channelopathies are challenging for clinicians to decipher, such that an extensive diagnostic survey through a precise step-by-step process is vital. Early diagnosis of a newborn’s disease, either as a channelopathy or neurometabolic disorder, is important for the long-term neurodevelopment of the child.

P.098 The Epilepsy Surgery Experience in Children with Infantile Spasms at the Hospital for Sick Children

Background: Infantile spasms (IS) is an epileptic encephalopathy, characterized by epileptic spasms, hypsarrhythmia, and developmental regression. This is a retrospective case series detailing the experience in children with IS who have undergone epilepsy surgery at The Hospital for Sick Children (HSC). Methods: Records of 223 patients from HSC were reviewed. Patients were included if they had a current or previous history of IS with a lesion detected on MRI/PET scan who underwent epilepsy surgery. Results: Nineteen patients were included. The etiology of IS was encephalomalacia in six patients (32%), malformations of cortical development in 11 patients (58%), atypical hypoglycaemic injury in one patient (0.5%), and partial hemimegalencephaly in one patient (0.5%). The median age at the onset of IS was five months. The median age at surgery was 18 months. Nine patients (47%) underwent hemispherectomy and 10 patients (53%) underwent lobectomy/lesionectomy. Fifteen patients (79%) were considered ILAE Seizure Outcome Class 1. Developmental outcome was improved in 14/19 (74%) and stable in 5/19 (26%) patients. Conclusions: Even with a generalized EEG pattern such as hypsarrhythmia, patients should be considered for focal resective surgery. Early surgical intervention shortens the duration of active epilepsy thus limiting the potentially irreversible effects of on-going seizures.

De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures

Background De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. Methods Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. Results We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype–phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. Limitations The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. Conclusions Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.

Infantile Developmental Delay Caused by Pathogenic Mutation in WDR45 Gene and Literature Review

Background The reasons of infantile developmental delay are varied and complexity. The mode of BPAN inheritance clinical manifestation and imaging findings of childhood BPAN patients are not typical. The reason of WDR45 mutation is still elusive. This study has the objective to give a comprehensive overview of the genetic and phenotypic spectrum of WDR45 mutations. Methods This study recruited 258 infants with developmental delay of the babies from Shengjing Hospital of China Medical University and performed a customdesigned gene panel to capture all exons and 5 base pairs of flanking intronic sequence. We reviewed the WDR45 mutation cases reported before. Results We identified two de novo variants in WDR45 mutation and listed the clinical manifestation and treatments. This study summarized variants of the gene WDR45 mutation expression in previous investigations. Childhood patients have the clinical features as generalized developmental delay, seizures, intellectual disorder. By contrast, adolescence and early adulthood patient have the features like developmental regression, dystonia and parkinsonism. Conclusion Our study suggest WDR45 mutations cause a series spectrum of neurodegeneration disorders and are most important etiology of BPAN. The developmental delay of infant is not obvious and rarely to be attention. The mode of BPAN inheritance clinical manifestation and imaging findings of infantile BPAN patients are not typical. WDR45 gene mutaion has closely relationship with the function of endoplasmic reticulum and mitochondria.

Clinical Attributes and Electroencephalogram Analysis of Patients With Varying Alpers’ Syndrome Genotypes

Alpers’ syndrome is an early inceptive neurodegenerative disorder with a poor prognosis, characterized by developmental regression, intractable epilepsy, and hepatic dysfunction. Candidate genes, such as POLG, PARS2, CARS2, FARS2, NARS2, and GABRB2 are distinguished and registered following research on large cohorts that portray the clinical phenotype in such patients using expanded access to whole-exome sequencing (WES). In this study, we aimed to better understand the electroencephalogram (EEG) characteristics and clinical phenotype of different genotypes of the Alpers’ syndrome, which are currently insufficiently studied. We conducted a study on seven patients with Alpers’ syndrome who received treatment in Beijing Children’s Hospital and had a detailed clinical EEG. Furthermore, a substantial literature search of the Chinese Biomedical Literature Database, PubMed, and Cochrane Central Register of Controlled Trials EMBASE was also conducted, which revealed a total of 22 reported cases between January 2008 to January 2021. We analyzed 29 cases of Alpers’ syndrome caused by different gene variants, of which 22 cases were related to POLG gene mutation and 7 cases were related to PARS2, CARS2, FARS2, NARS2, and GABRB2 gene mutation, and found that patients with distinctive pathogenic variants exhibited comparable phenotypes and similar EEG patterns. And we defined EEG characteristics found specifically in Alpers’ syndrome. Rhythmic high-amplitude delta with superimposed (poly) spikes (RHADS) is a characteristic EEG finding in the early stages of Alpers’ syndrome and is a kind of epileptic phenomenon, which can provide clues for the early diagnosis of the disease.