Developmental Regression Research Articles

Epileptic Encephalopathy GABRB Structural Variants Share Common Gating and Trafficking Defects.

Variants in the GABRB gene, which encodes the β subunit of the GABAA receptor, have been implicated in various epileptic encephalopathies and related neurodevelopmental disorders such as Dravet syndrome and Angelman syndrome. These conditions are often associated with early-onset seizures, developmental regression, and cognitive impairments. The severity and specific features of these encephalopathies can differ based on the nature of the genetic variant and its impact on GABAA receptor function. These variants can lead to dysfunction in GABAA receptor-mediated inhibition, resulting in an imbalance between neuronal excitation and inhibition that contributes to the development of seizures. Here, 13 de novo EE-associated GABRB variants, occurring as missense mutations, were analyzed to determine their impact on protein stability and flexibility, channel function, and receptor biogenesis. Our results showed that all mutations studied significantly impact the protein structure, altering protein stability, flexibility, and function to varying degrees. Variants mapped to the GABA-binding domain, coupling zone, and pore domain significantly impact the protein structure, modifying the β+/α- interface of the receptor and altering channel activation and receptor trafficking. Our study proposes that the extent of loss or gain of GABAA receptor function can be elucidated by identifying the specific structural domain impacted by mutation and assessing the variability in receptor structural dynamics. This paves the way for future studies to explore and uncover links between the incidence of a variant in the receptor topology and the severity of the related disease.

West Syndrome: A Case Report

Infantile spasms (IS), formerly known as West syndrome, are a type of seizure associated with the epileptic disorder known as West syndrome. Infants and children are affected by West syndrome. Mental deficits are associated with infantile spasms. A particular kind of seizure that starts in the first year of life is known as infantile spasms. Loss of developmental milestones or developmental regression. However, an electroencephalogram is required to confirm the diagnosis of west syndrome (EEG). We describe the unusual West syndrome case.

Management of Choroid Plexus Tumors and the Benefit of Preoperative Embolization in Pediatric Patients: Report of 46 Cases from a Single Institution

Optimal choroid plexus tumor (CPT) treatment involves gross total resection; however, intraoperative hemorrhage risk remains significant given tumor vascularity. This study describes pediatric CPT management and identifies patients most likely to benefit from preoperative embolization. CPTs resected from 1997 to 2021 were included. The characteristics of embolized patients were compared to nonembolized patients; nonembolized patients were further stratified based on open vascular control-pedicle feeder ligation versus no pedicle ligation prior to tumor debulking. Statistical analyses identified factors associated with estimated blood loss (EBL), transfusion, length of stay, and complications. Among the 46 CPT cases identified, 98% achieved gross total resection, and 15% received embolization. Embolized patients were younger, smaller, and had larger tumors compared to nonembolized patients (median: 0.8 vs. 2.1years; 9.3 vs. 14.4kg; 91.08 vs. 5.5cm3). Transfused patients were similarly younger and smaller (P < 0.05) than nontransfused patients. Among nonembolized patients, open vascular control was achieved in smaller tumors (<13cm3) with significantly lower EBL (P= 0.002). Higher EBL was observed in patients with larger tumors, hydrocephalus, transependymal edema, vomiting, lethargy, and developmental regression (all P < 0.05). Patients with lethargy had longer hospital stays and a higher likelihood of postoperative complications (P < 0.05). There were no significant differences in complication rates between the embolization and nonembolization groups. Despite higher surgical risk profiles, embolized patients had similar complication rates and postoperative hydrocephalus management as nonembolized patients. Embolization was particularly beneficial in patients at high risk for surgical morbidity, such as those <2years, weighing <10kg, and with a tumor volume >15cm3.

EPCO-44. RHABDOID TUMOR PREDISPOSITION SYNDROME DUE TO A GERMLINE SMARCB1 MUTATION IN TWO INFANT SIBLINGS

Abstract INTRODUCTION Rhabdoid tumors (RTs) are highly aggressive malignancies caused by a loss–of–function mutation in the SMARCB1 tumor suppressor gene on chromosome 22 that makes up the SW1/SNF chromatin remodeling complex involved in gene transcription. In rhabdoid tumor predisposition syndrome (RTPS), a biallelic germline SMARCB1 mutation markedly increases the risk of affected individuals developing early, aggressive, and rapidly progressing RTs, most commonly in the CNS, referred to as atypical teratoid rhabdoid tumors (AT/RT), and the kidneys, but oftentimes presents with synchronous lesions. In this case series, we present a family affected by RTPS with a recurrence of AT/RT in two infant siblings with the same germline SMARCB1 mutation. CASE SERIES DESCRIPTION An 8-month-old female was brought to the emergency department for 3 months of vomiting, developmental regression, and CN VI palsy. Brain imaging revealed a posterior fossa mass, acquired obstructive hydrocephalus, and spinal metastasis. Four years later, her 3-month-old sister was also brought in for evaluation for 2 months of vomiting, irritability, increasing head circumference, and vertical gaze palsy. Her brain imaging similarly showed a posterior fossa mass and acquired obstructive hydrocephalus, but no metastasis. Both siblings underwent subtotal tumor resections and ventriculoperitoneal shunt placement followed by chemotherapy. While on active treatment, they experienced rapid disease progression and ultimately succumbed to their illness. Genetic testing on the family identified the same in-frame deletion in the SNF5 homology domain of SMARCB1 and loss of heterozygosity of chromosome 22 in the two sisters; their mother was found to be a carrier. CONCLUSION This case series describes a family affected by RTPS, demonstrating the risk of familial recurrence in SMARCB1 germline mutations and emphasizing the need for genetic testing and counseling for these families should they wish to have additional children.

A Review on Rett Syndrome: A Debilitating Neurodevelopmental Disorder

Rett syndrome is a neurodevelopmental disorder primarily affecting females, characterised by slowed growth, developmental regression, loss of fine motor skills, communication difficulties, and stereotypical hand movements. It is strongly associated with mutations in the MECP2 gene, while other variations have been linked to FOXG1 and CDKL5 mutations. This review provides an in-depth understanding of Rett syndrome, including its causes, symptoms, and available treatments. The epidemiology of Rett syndrome indicates a varying prevalence across different regions. Males with Rett syndrome, though rare, have been reported. The aetiology of Rett syndrome involves MECP2 mutations that lead to functional loss, affecting synapse development and maintenance. Mitochondrial dysfunction and oxidative stress have also been implicated in the disorder. Neuropathological findings reveal specific abnormalities in various brain regions. The symptoms of Rett syndrome include slowed head growth, abnormal gait, loss of intentional hand movements, breathing difficulties, and loss of speech. Complications such as metabolic issues, epilepsy, scoliosis, and gastrointestinal dysfunction are common. The diagnosis relies on clinical criteria and genetic testing for MECP2 mutations. Treatment for Rett syndrome is symptomatic and includes individualised rehabilitation therapies such as physical therapy, applied behaviour analysis, environmental enrichment, hydrotherapy, and music therapy. The review emphasises the importance of early intervention and family involvement in rehabilitation programmes.

Classical imaging in cerebral folate transport deficiency

Cerebral folate transport deficiency is an inherited disorder with late infantile-onset caused by nonsense mutations in the folate receptor 1 gene coding for folate receptor alpha. We report a case of a 4-year-old female child, who presented with global neurodevelopmental regression with onset at 15 months of age with an electroencephalogram showing poorly modulated polymorphic delta sleep background. Based on the clinical features, age of onset, and imaging findings, the possibility of cerebral folate transport deficiency (OMIM#613068) was considered. Targeted gene sequencing confirmed the diagnosis.

66 Neuropsychological Profile of ROHHAD Syndrome: A Case Study

Objective:Rapid Onset Obesity with Hypoventilation, Hypothalamic Dysfunction, Autonomic Dysregulation (ROHHAD) is a rare and often progressive syndrome with unknown etiology and only 100 cases reported to date. The syndrome is characterized by generally normal development followed by rapid onset of pain, muscle weakness, personality changes, and developmental regression. Associated chronic pain and fatigue result in difficulty concentrating, slow information processing, and executive function challenges. Only one study has examined the neuropsychological profile of pediatric patients with this syndrome.Participants and Methods:Our patient was a 10-year-old, right-handed male with a history of ROHHAD syndrome, focal epilepsy, mild neurocognitive disorder, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) who underwent two comprehensive neuropsychological evaluations at our medical center.Results:Findings across multiple evaluations showed solid verbal skills and difficulty processing visual-spatial and nonverbal information, as well as problems with attention, executive functioning, and adaptive skills, and psychosocial functioning consistent with his diagnoses of ADHD and ASD. He exhibited fine-and gross-motor challenges associated with hypotonia. Chronic fatigue contributed to his challenges with attention and information processing. These findings are generally consistent with previous research examining the neuropsychological profile associated with ROHHAD syndrome.Conclusions:Results from our case study highlight the complexity and challenges associated with ROHHAD syndrome. Consistent with available information, etiology of our patients’ neuropsychological weakness and functional decline is unclear. Yearly neuropsychological evaluations are recommended for these patients to update interventions based on their variable abilities. More research is needed to firmly establish the neuropsychological profile in youth of varying ages afflicted with this syndrome.

Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the DNM1 gene have been associated with autosomal dominant DEE type 31A and autosomal recessive DEE type 31B. In the current study, a consanguineous Pakistani family consisting of a proband (IV-2) was clinically evaluated and genetically analyzed manifesting in severe neurodevelopmental phenotypes. WES followed by Sanger sequencing was performed to identify the disease-causing variant. Furthermore, 3D protein modeling and dynamic simulation of wild-type and mutant proteins along with reverse transcriptase (RT)-based mRNA expression were checked using standard methods. Data analysis of WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene that was predicted as pathogenic class I. Variants in the DNM1 gene have been associated with DEE types 31A and B. Different bioinformatics prediction tools and American College of Medical Genetics guidelines were used to verify the identified variant. Sanger sequencing was used to validate the disease-causing variant. Our approach validated the pathogenesis of the variant as a cause of heterogeneous neurodevelopmental disorders. In addition, 3D protein modeling showed that the mutant protein would lose most of the amino acids and might not perform the proper function if the surveillance non-sense-mediated decay mechanism was skipped. Molecular dynamics analysis showed varied trajectories of wild-type and mutant DNM1 proteins in terms of root mean square deviation, root mean square fluctuation and radius of gyration. Similarly, RT-qPCR revealed a substantial reduction of the DNM1 gene in the index patient. Our finding further confirms the association of homozygous, loss-of-function variants in DNM1 associated with DEE type 31B. The study expands the genotypic and phenotypic spectrum of pathogenic DNM1 variants related to DNM1-associated pathogenesis.

"Progressive myoclonic ataxia and developmental/epileptic encephalopathy associated with a novel homozygous mutation in TCN2 gene".

Transcobalamin II (TCN2) defect is a rare metabolic disorder associated with a range of neurological manifestations, including mild developmental delay, severe intellectual disability, ataxia, and, in some cases, seizures. Cobalamin, an essential nutrient, plays a crucial role in central nervous system myelination. We present a family with an index patient who exhibited progressive neurodevelopmental regression starting at 9 months of age, accompanied by myoclonic seizures, ataxia, and tremor. No significant hematological abnormalities were observed. Exome sequencing analysis identified a novel homozygous mutation, c.3G>A - P(Met1I), affecting the acceptor site of intron 4 of the TCN2 gene (chromosome 22: 31003321, NM_000355.4), leading to likely pathogenic variant potentially affecting translation. Following treatment with hydroxocobalamin, the patient demonstrated partial clinical improvement. He has a sibling with overt hematological abnormalities and subtle neurological abnormalities who is homozygous to the same mutation. Both parents are heterozygous for the same mutation. In infants presenting with unexplained non-specific neurological symptoms, irrespective of classical signs of vitamin B12 deficiency, evaluation for TCN2 defect should be considered. Early diagnosis and appropriate management can lead to favorable outcomes.

SAT673 Novel Mutation Of TBX3 Associated With Morbid Obesity In Human

Abstract Disclosure: H.R. Alkaissi: None. B. Ji: None. S. McFarlane: None. Background: TBX3 is a transcription involved in the development of the heart conduction system, apocrine and mammary glands, limbs, and lung development and maturation, with variable oncogenic roles. Recently, the role of TBX3 and body weight control has been demonstrated in animal models, showing an essential role for TBX3 in hypothalamic arcuate neuronal maturation, function, and identity [1]. Case: 26-year-old woman referred for the management of morbid obesity and menstrual irregularities. The patient weighed 330 lbs, with a BMI of 55 kg/m2, with hypertension T2DM. The patient had a normal development until age five, after which she experienced regression in milestones and lost the ability to communicate, and was diagnosed with autism. She had a history of food-seeking behavior, leading to progressive weight gain, which was managed by blocking access to food, such as locking the fridge. The patient's weight fluctuated from 290 lbs to 330 lbs. Family history of T2DM in her maternal relatives. She was diagnosed with T2DM at the age of 18, with HbA1c level of 9.4%. Autoantibody testing was negative for glutamic acid decarboxylase (GAD), islet cell antibody (ICA), and zinc transporter 8 (ZnT8). The fasting C-peptide level was detectable at 1.87 ng/mL. T2DM was well controlled with an HbA1C range of 6.0-6.7% with the use of short and long-acting insulin regimen. However, with improved glycemic control, short-acting insulin was stopped and she was started on liraglutide. Syndromic obesity was suspected due to early-onset of the disease and the developmental regression. Testing for Prader-Willi syndrome was negative, based on a normal chromosome 15 methylation study. Leptin levels were elevated at 66 ng/mL, prompting further testing for obesity-related genetic mutations. Next-generation sequencing and targeted Sanger sequencing for 79 genes associated with obesity in human and animal models was performed. A novel mutation was identified in TBX3 activation domain, c. C1513T (p.P505S). UniProt peptide sequence alignment analyzed for sequence conservation. ClinVar, HGMD and GWAS Catalogue databases screened for similar variants. Discussion: We present the first case in human, where novel TBX3 mutation results in hypothalamic dysfunction, leptin resistance manifesting as morbid obesity, hyperphagia, and menstrual irregularities. The reported mutation in the activation domain (A) of TBX3. In silico analysis showed high evolutionary conservation of the mutated domain (across vertebrate species), indicating the mutation is likely pathogenic.

Multi-dimensional Insight into the Coexistence of Pathogenic Genes for ADAR1 and TSC2: Careful Consideration is Essential for Interpretation of ADAR1 Variants.

Aicardi-Goutières syndrome 6 (AGS6) is a serious auto-immunization-associated acute neurologic decompensation. AGS6 manifests as acute onset of severe generalized dystonia of limbs and developmental regression secondary to febrile illness mostly. Dyschromatosis symmetrica hereditaria (DSH), as pigmentary genodermatosis, is a characterized mixture of hyperpigmented and hypopigmented macules. Both AGS6 and DSH are associated with ADAR1 pathogenic variants. To explore the etiology of a proband with developmental regression with mixture of hyperpigmentation and hypopigmentation macules, we used the trio-WES. Later, to clarify the association between variants and diseases, we used guidelines of ACMG for variants interpretation and quantitative Real-time PCR for verifying elevated expression levels of interferon-stimulated genes, separately. By WES, we detected 2 variants in ADAR1 and a variant in TSC2, respectively, were NM_001111.5:c.1096_1097del, NM_001111.5:c.518A>G, and NM_000548.5:c.1864C>T. Variants interpretation suggested that these 3 variants were both pathogenic. Expression levels of interferon-stimulated genes also elevated as expected. We verified the co-occurrence of pathogenic variants of ADAR1 and TSC2 in AGS6 patients with DSH. Our works contributed to the elucidation of ADAR1 pathogenic mechanism, given the specific pathogenic mechanism of ADAR1, and it is necessary to consider with caution when variants were found in ADAR1.

Treatment modalities for infantile spasms: current considerations and evolving strategies in clinical practice.

Infantile spasms, newly classified as infantile epileptic spasm syndrome (IESS), occur in children under 2 years of age and present as an occur as brief, symmetrical, contractions of the musculature of the neck, trunk, and extremities. When infantile spasms occur with a concomitant hypsarrhythmia on electroencephalogram (EEG) and developmental regression, it is known as West Syndrome. There is no universally accepted mainstay of treatment for this condition, but some options include synthetic adrenocorticotropic hormone (ACTH), repository corticotropin injection (RCI/Acthar Gel), corticosteroids, valproic acid, vigabatrin, and surgery. Without effective treatment, infantile spasms can cause an impairment of psychomotor development and/or cognitive and behavioral functions. The first-line treatment in the USA is ACTH related to high efficacy for cessation of infantile spasms long-term and low-cost profile. Acthar Gel is a repository corticotropin intramuscular injection that became FDA-approved for the treatment of IESS in 2010. Though it is believed that ACTH, Acthar Gel, and corticosteroids all work via a negative feedback pathway to decrease corticotropin-releasing hormone (CRH) release, their safety and efficacy profiles all vary. Vigabatrin and valproic acid are both anti-seizure medications that work by increasing GABA concentrations in the CNS and decreasing excitatory activity. Acthar Gel has been shown to have superior efficacy and a diminished side effect profile when compared with other treatment modalities.

A rare case of Yhwag gene mutation causing developmental and epileptic encephalopathy

Background: epileptic encephalopathy 56 or DEE is a rare disease characterized by early-onset treatment-refractory epilepsy accompanied by global developmental regression that has been shown to be caused by various mutations of the YWHAG gene. Case presentation: We report a novel of a heterozygous mutation of YHWAG c.170G&gt;A, p.(Arg57His), in a Caucasian male. Conclusions: Our report further confirms that mutation of YWHAG results in developmental and epileptic encephalopathy.

Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice.

Sanfilippo syndrome Type-B, also known as mucopolysaccharidosis IIIB (MPS IIIB), accounts for approximately one-third of all Sanfilippo syndrome patients and is characterized by a similar natural history as Type-A. Patients suffer from developmental regression, bone malformation, organomegaly, GI distress, and profound neurological deficits. Despite human trials of enzyme replacement therapy (ERT) (SBC-103, AX250) in MPS IIIB, there is currently no FDA approved treatment and a few palliative options. The major concerns of ERT and gene therapy for the treatment of bone malformation are the inadequate biodistribution of the missing enzyme, N-acetyl-α-glucosaminidase (NAGLU), and that the skeleton is a poorly hit target tissue in ERT and gene therapy. Each of the four known human types of MPS III (A, B, C, and D) is usually regarded as having mild bone manifestations, yet it remains poorly characterized. This study aimed to determine bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties in femurs MPS IIIB C57BL/6 mice compared to phenotypic control C57BL/6 mice. Significant differences were observed in MPS IIIB mice within various cortical and cancellous bone parameters for both males and females (p < 0.05). Here, we establish some osteogenic manifestations of MPS IIIB within the mouse model by radiographic and biomechanical tests, which are also differentially affected by age and sex. This suggests that some skeletal features of the MPS IIIB mouse model may be used as biomarkers of peripheral disease correction for preclinical treatment of MPS IIIB.

Expanding the genotypic and phenotypic spectrum associated with TBL1XR1 de novo variants

BackgroundThe TBL1XR1 gene encodes the protein transducin-beta-like 1 receptor1, widely distributed in the pituitary, hypothalamus, white and brown adipose tissue, muscle, and liver. Current evidence suggests that heterozygous TBL1XR1 pathogenic variants can lead to a wide spectrum of phenotypes. This study aims to reveal the clinical phenotype and genetic profiles of de novo TBL1XR1 variations and summarize the relevant clinical and genetic features. MethodsWe analyzed four new cases harboring de novo TBL1XR1 variants and reviewed all reported cases. ResultsAll probands suffered from global developmental delay. Moreover, patient 1 exhibited susceptibility to startle, patient 2 had hypovitaminosis D, short stature and hyponatremia, and patients 3 and 4 both presented with ASD (Autism spectrum disorder) and short stature. They all had a de novo TBL1XR1 variant (NM_024665.7), c.1184A > G (p.Tyr395Cys), c.1108G > A (p.Asp370Asn), c.1047 + 1G > C, and c.1097C > T (p.Ser366Phe) respectively. In addition, pooled analysis of 51 cases showed that they had speech impairment (38/39), intellectual developmental disorder (28/28), global developmental delay (42/42), and hypotonia (24/27), and some of them had epilepsy (10/22), ASD (13/25), and developmental regression (4/13). ConclusionsWe report four new patients with de novo TBL1XR1 variants and provide a comprehensive overview of 47 previously reported individuals with TBL1XR1 variants, enriching the genotypic and phenotypic spectrum of TBL1XR1-related disease. This report further validates the pathogenicity de novo TBL1XR1 variants.

Rett Syndrome-Associated Scoliosis: Analysis of National Trends and Treatment Patterns of a Rare Indication for Posterior Instrumented Fusion.

Retrospective database cohort study. To evaluate U.S. treatment trends and inpatient outcomes for children undergoing posterior spinal fusion (PSF) for Rett syndrome (RTT)-associated scoliosis (RAS). RTT is a rare, sporadic neurodevelopmental disorder presenting in childhood with developmental regression, ataxia, and seizures. RAS occurs in 50% to 80% of cases of RTT, but little is known about the case volume and perioperative experience for children undergoing PSF. Using the International Classification of Diseases Ninth and 10th revision codes in the national Kids' Inpatient Database, we identified children with RTT who underwent PSF from 2000 to 2019. Annual case volumes were analyzed. Clinical characteristics and outcomes were compared with those of a cohort of patients with neuromuscular scoliosis (NMS). Among 220 patients with RAS, 216 (98.2%) were females (mean age at surgery: 12.3±3.3yr). Surgical case incidence steadily increased over 19 years, with more RAS admissions in the South (31.4%). Overall, patients with RAS demonstrated a higher mean Elixhauser Comorbidity Index score (2 vs . 1, P < 0.001) and had more perioperative complications (41.4% vs . 18%, P < 0.001) than patients with NMS. RTT diagnosis independently predicted higher odds of any complications (odds ratio: 1.98, P < 0.001) and increased length of stay (odds ratio: 1.18, P = 0.009) for admissions for PSF. Surgical treatment for RAS is rare but increased over a 19-year period. Cases appear to be clustering by region, with the highest proportion in the South. The higher Elixhauser Comorbidity Index in RAS patients predicted higher costs, longer hospital stays, more complications (particularly respiratory), and more nonroutine discharge disposition than in other patients with NMS. RTT was independently associated with higher odds of complications and longer length of stay. Because RAS cases appear to be increasing in number, future studies should emphasize methods to reduce morbidity and investigate deformity-specific metrics to help better understand this population.

Alternative Diagnoses in the Work Up of Down Syndrome Regression Disorder.

Down Syndrome Regression Disorder (DSRD) is a diagnosis of exclusion. Psychiatric and neuroimmunologic etiologies have been proposed although the exact etiology remains unknown. This study sought to review non-DSRD diagnoses at a large quaternary medical center specializing in the diagnosis of DSRD and compare clinical characteristics between those diagnosed with DSRD and those with non-DSRD diagnoses. The authors performed a single-center retrospective, chart-based, review of referrals for developmental regression in individuals with Down syndrome. Two hundred and sixty-six individuals were evaluated for DSRD and of these, 54 (20%) ultimately had alternative diagnoses. Individuals with DSRD were more likely to have shorter nadir to clinical symptoms (p = 0.01, 95% CI: 0.36-0.47) and have preceding triggers (p < 0.001, 95% CI: 1.13-1.43) compared to those with alternative diagnoses. Individuals with non-DSRD diagnoses were more likely to be born premature (p = 0.01, 95% CI: 0.51-0.87) and have a history of epilepsy (p = 0.01, 95% CI: 0.23-0.77) but were also less likely to have a history of cytokine abnormalities on bloodwork (p < 0.001, 95% CI: 1.19-1.43) and have catatonia (p < 0.001, 95% CI: 1.54-2.17). The majority of alternative diagnoses (41/54, 76%) were autism spectrum disorder. In these cases, symptoms were more likely to be longstanding (symptoms > 12months) and earlier onset (median 8years, IQR: 6-11). Other diagnoses included epilepsy (5/54, 9%), Celiac disease (5/54, 9%), cerebrovascular disease (3/54, 6%). This study identifies that 20% of individuals referred with concerns for DSRD have alternative diagnoses. The majority of these diagnoses were autism, but rare treatable conditions were also identified, highlighting the importance of a thorough neurodiagnostic assessment.

West Syndrome in an Infant with Complete Corpus Callosal Agenesis

West syndrome is a severe form of epilepsy with onset in infancy and early childhood. The characteristic triad described includes infantile spasms (IS), an abnormal electroencephalogram (EEG) pattern referred to as hypsarrhythmia, and developmental regression. It comprises 2% of childhood epilepsies. Etiologically, West syndrome can be classified into symptomatic with known etiology and cryptogenic with unknown etiology. Hypsarrhythmia is defined as chaotic, asynchronous, disorganized slow background activity with high-voltage spike activity. Burst-suppression pattern is a rarely described pattern of modified hypsarrhythmia, which denotes severe disease. Hereby, we describe the case of a female infant who presented with IS; EEG showed a modified hypsarrhythmia pattern in the form of burst suppression, and magnetic resonance imaging brain showed complete corpus callosal agenesis. She was initiated on injection of adrenocorticotropic hormone and showed marked improvement in epileptic spasms.

Predictive factors of genetic diagnosis and real-life impact of next-generation sequencing for children with epilepsy.

Identify the predictive variables of genetic pathogenic results and the impact of test results on epilepsy diagnosis and management. Analytical observational design evaluated 130 patients with epilepsy that had performed genetic testing over January 2017 to July 2022. There was a gradual increase in the number of exams performed over the years. The frequency of pathogenic results was 34% (n = 44/130), 8 altered genes with 54% (n = 24/44) of the results. The tests were more positive in patients with developmental delay and/or regression (p = .01). None of the other factors analyzed were associated with higher diagnostic yield. The age at onset of epilepsy brought diagnostic yield to the test (p = .041). Patients with negative genetic test had a reduction in the number of electroencephalograms performed before and after the test (respectively, 3.80 ± 6.37 and .84 ± 1.67; p < .001). Facing a large proportion of patients with unexplained epilepsy have a genetic cause a genetic test has the potential to reduce the use of unnecessary diagnostic tests, improve patient outcomes by identifying targeted treatments, and provide families with genetic counseling and risk assessment. But an early genetic testing can be crucial to reach these goals. Even in cases where the genetic test is negative, the study suggests that it still has important implications for patient care and management.

Subacute Partially Reversible Leukoencephalopathy Expands the Aicardi-Goutières Syndrome Phenotype.

To report a series of atypical presentations of Aicardi-Goutières syndrome. Clinical, neuroimaging, and genetic data. We report a series of six unrelated patients (five males) with a subacute loss of developmental milestones, pyramidal signs, and regression of communication abilities, with onset at ages ranging from 7 to 20 months, reaching a nadir after 4 to 24 weeks. A remarkable improvement of lost abilities occurred in the follow-up, and they remained with residual spasticity and dysarthria but preserved cognitive function. Immunization or febrile illness occurred before disease onset in all patients. CSF was normal in two patients, and in four, borderline or mild lymphocytosis was present. A brain CT scan disclosed a subtle basal ganglia calcification in one of six patients. Brain MRI showed asymmetric signal abnormalities of white matter with centrum semi-ovale involvement in five patients and a diffuse white matter abnormality with contrast enhancement in one. Four patients were diagnosed and treated for acute demyelinating encephalomyelitis (ADEM). Brain imaging was markedly improved with one year or more of follow-up (average of 7 years), but patients remained with residual spasticity and dysarthria without cognitive impairment. Demyelination relapse occurred in a single patient four years after the first event. Whole-exome sequencing (WES) was performed in all patients: four of them disclosed biallelic pathogenic variants in RNASEH2B (three homozygous p.Ala177Thr and one compound heterozygous p.Ala177Thr/p.Gln58*) and in two of them the same homozygous deleterious variants in RNASEH2A (p.Ala249Val). This report expands the phenotype of AGS to include subacute developmental regression with partial clinical and neuroimaging improvement. Those clinical features might be misdiagnosed as ADEM.