Safety and tolerability of intravenous immunoglobulin infusion in Down syndrome regression disorder.

Three large multi-center studies have identified the clinical utility of intravenous immunoglobulin (IVIg) in the treatment of Down syndrome regression disorder (DSRD). Yet the tolerability of infusions in individuals with DS and the safety of IVIg remains unknown in this population. This study sought to evaluate the safety and tolerability of IVIg in individuals with DSRD compared to a real-world cohort of individuals with pediatric onset neuroimmunologic disorders. A single-center, retrospective chart review evaluating clinically documented infusion reactions was performed for individuals meeting international consensus criteria for DSRD and having IVIg infusions between 2019 and 2023. Infusion reactions were evaluated for severity and need for alterations in infusion plan. This cohort was compared against an age and sex matched cohort of children with neuroimmunologic conditions who had also received IVIg infusions. In total, 127 individuals with DSRD and 186 individuals with other neuroimmunologic disorders were enrolled. There was no difference in the overall rate of adverse reactions (AEs) between the DSRD and general neuroimmunology cohorts (p = 0.31, 95% CI: 0.80-2.00), but cardiac-related AEs specifically were more common among the DSRD group (p = 0.02, 95% CI: 1.23-17.54). When AEs did occur, there was no difference in frequency of pharmacologic intervention (p = 0.12, 95% CI: 0.34-1.13) or discontinuation of therapy (p = 0.74, 95% CI: 0.06-7.44). There was a higher incidence of lab abnormalities on IVIG among the general neuroimmunology cohort (p = 0.03, 95% CI: 0.24-0.94) compared to the DSRD cohort. Transaminitis was the most common laboratory abnormality in the DSRD group. In a large cohort of individuals with DSRD, there were no significant differences in the safety and tolerability of IVIg compared to a cohort of children and young adults with neuroimmunologic conditions.

Impact of endocrine dysregulation on disability and non-motor symptoms in pediatric onset multiple sclerosis.

Background: Pediatric onset multiple sclerosis (POMS) commonly occurs at the time of various endocrine changes. Evaluation of the impact of endocrine status on disease severity in POMS has not been previously explored. Objective: This study sought to evaluate if sex and stress hormones in children with POMS impact motor and non-motor diseases severity. Methods: A single-center case control study was performed. Individuals with POMS were compared to individuals without neurologic disease. Each individual had three blood draws assessing stress and sex hormones between 07:00 and 09:00. Measures of fatigue (Epworth sleepiness scale), depression (PHQ-9), and quality of life (PedsQL) assessed at each visit. Results: Forty individuals with POMS and 40 controls were enrolled. Individuals with POMS had lower free testosterone (p = 0.003), cortisol (p < 0.001), and ACTH (p < 0.001) and had higher progesterone (p = 0.025) levels than controls. Relapses and EDSS were not impacted by endocrine variables. The POMS cohort had a significantly higher Epworth score (p < 0.001), PHQ-9 score (p < 0.001), and lower PQL score (p < 0.001) than controls. Non-motor measures were not associated with endocrine status. Conclusion: Free testosterone, cortisol, ACTH, and progesterone were abnormal in children with POMS although there was no association between endocrine status and markers of disease severity or non-motor symptoms of MS.

Autism voices: Perspectives of the needs, challenges, and hopes for the future of autistic youth.

LAY ABSTRACT: Currently, our understanding of the adolescent period for autistic youth has relied on the expertise of researchers, clinicians, parents, and teachers, yet rarely involves their unique first-person experiences. Our study attempted to understand the experiences and perspectives of autistic adolescents in their home, school, and community environments using the Autism Voices protocol, a semi-structured interview specifically designed and tailored to engage with autistic youth with various language and intellectual levels. The analysis of the 31 interviews conducted with autistic adolescents aged 11-18 years highlighted six themes: (1) autistic identities, (2) thinking about the future, (3) seeking social connection on their own terms, (4) seeking autonomy, (5) school as both a stressor and social facilitator, and (6) experiences of stress and anxiety. These results highlight similarities and differences in the adolescent experiences of autistic youth compared to their typically developing peers. Our findings suggest that by removing assumptions about the experiences of autistic individuals and investing in inclusive interview methods, we can faithfully capture the experiences of autistic youth regardless of their communication and cognitive abilities. Being able to capture and amplify these diverse voices will facilitate the active involvement of autistic communities in research and clinical and policy decisions that impact them.

Examining the Impacts of the COVID-19 Pandemic on Service Providers Working with Children and Youth with Neuro-developmental Disabilities and their Families: Results of a Focus Group Study.

The COVID-19 pandemic has imposed unprecedented service interruptions in many sectors including services for children and youth with neuro-developmental disabilities (NDD). We examined the experiences of service providers as they supported this population during the pandemic. Five focus groups were convened with 24 service providers offering support to children/youth with NDD and their families. Results highlight substantial service changes and challenges, as observed by service providers. Service closures and program delivery modification resulted in the rapid adoption of virtual services and reduced program delivery. Service providers have faced heightened workloads, personal weariness and 'burn out', and new levels of conflict at work, yet with little opportunity and support for self-care. Beyond challenges, new learning and growth have emerged, with heightened collaboration amongst organizations. Strains in service delivery during the pandemic have exposed programming and systems gaps, for which proactive capacity building is warranted and recommended.

Maximising the engagement of older people with mental health needs and dementia with social care.

Older people with mental health needs and dementia often face difficulties with daily living and community participation, requiring the intervention of social care services. However, cognitive and emotional needs often mean that mainstream support is not appropriate. In England, mental health support workers may attempt to address these concerns, to prevent mounting care needs and the potential for institutional care. Yet, their work has not been researched to identify good practices and to understand the mechanisms through which they engage older people. A new qualitative study used semi-structured interviews and focus groups with specialist support workers (n = 22), managers (n = 7), homecare staff (n = 4) and service users and carers (n = 6). The latter group were interviewed by co-authors with lived experiences of dementia and care. Participants were recruited from mental health services, home care organisations and third-sector agencies across the North of England in 2020-2021. The study identified three themes that described support worker activities. First, 'building trusting relationships' identified steps to establish the foundations of later interventions. Paradoxically, these may involve misleading clients if this was necessary to overcome initial reluctance, such as by feigning a previous meeting. Second, 're-framing care' referred to how the provision of care was positioned within a narrative that made support easier to engage with. Care framed as reciprocal, as led by clients, and having a positive, non-threatening description would more likely be accepted. Third, 'building supportive networks' described how older people were enabled to draw upon other community resources and services. This required careful staging of support, joint visits alongside workers in other services, and recognition of social stigma. The study was limited by constrained samples and covid context requiring online data collection. The study recommends that support workers have more opportunity for sharing good practice across team boundaries, and improved access to specialist training.

Association of rare variants in genes of immune regulation with pediatric autoimmune CNS diseases.

BACKGROUND: There is a gap in the literature regarding genetic underpinnings of pediatric autoimmune CNS diseases. This study explored rare gene variants implicated in immune dysregulation within these disorders. METHODS: This was a single-center observational study of children with inflammatory CNS disorder who had genetic testing through next generation focused exome sequencing targeting 155 genes associated with innate or adaptive immunity. For in silico prediction of functional effects of single-nucleotide variants, Polymorphism Phenotyping v2, and Sorting Intolerant from Tolerant were used, and Combined Annotation Dependent Depletion (CADD) scores were calculated. Identified genes were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. RESULTS: Of 54 patients, 42 (77.8%) carried variant(s), among which 12 (22.2%) had 3-8 variants. Eighty-eight unique single-nucleotide variants of 55 genes were identified. The most variants were detected in UNC13D, LRBA, LYST, NOD2, DOCK8, RNASEH2A, STAT5B, and AIRE. The majority of variants (62, 70.4%) had CADD > 10. KEGG pathway analysis revealed seven genes associated with primary immunodeficiency (Benjamini 1.40E - 06), six genes with NOD-like receptor signaling (Benjamini 4.10E - 04), five genes with Inflammatory Bowel Disease (Benjamini 9.80E - 03), and five genes with NF-kappa B signaling pathway (Benjamini 1.90E - 02). DISCUSSION: We observed a high rate of identification of rare and low-frequency variants in immune regulatory genes in pediatric neuroinflammatory CNS disorders. We identified 88 unique single-nucleotide variants of 55 genes with pathway analysis revealing an enrichment of NOD2-receptor signaling, consistent with involvement of the pathway within other autoinflammatory conditions and warranting further investigation.

A Qualitative Examination of the Impact of the COVID-19 Pandemic on Individuals with Neuro-developmental Disabilities and their Families.

Individuals with neuro-developmental disabilities (NDD) have been profoundly affected by the COVID-19 pandemic. Based on focus groups with 24 service providers supporting this population, using an Interpretive Description approach, we examined perceived impacts of the pandemic on individuals with NDD and their families. The results highlight pandemic-related experiences which include: service reduction, the need for financial supports, relying on natural supports, and school-related challenges. Interruptions in services have resulted in intensified mental health issues for individuals with NDD and family caregivers, with particular concern for those with added social determinants of health-related barriers. Mitigating factors have also emerged, such as resilience and technology utilization to facilitate communication. Recommendations for resource flexibility and sufficiency as well as navigational support are offered.

SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance.

Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.

Diagnosis and Management of Opsoclonus-Myoclonus-Ataxia Syndrome in Children: An International Perspective.

BACKGROUND AND OBJECTIVES: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder of the nervous system that classically presents with a combination of characteristic eye movement disorder and myoclonus, in addition to ataxia, irritability, and sleep disturbance. There is good evidence that OMAS is an immune-mediated condition that may be paraneoplastic in the context of neuroblastoma. This syndrome may be associated with long-term cognitive impairment, yet it remains unclear how this is influenced by disease course and treatment. Treatment is largely predicated on immune suppression, but there is limited evidence to indicate an optimal regimen. METHODS: Following an international multiprofessional workshop in 2004, a body of clinicians and scientists comprising the International OMS Study group continued to meet biennially in a joint professionals and family workshop focusing on pediatric OMAS. Seventeen years after publication of the first report, a writing group was convened to provide a clinical update on the definitions and clinical presentation of OMAS, biomarkers and the role of investigations in a child presenting with OMAS, treatment and management strategies including identification and support of long-term sequelae. RESULTS: The clinical criteria for diagnosis were reviewed, with a proposed approach to laboratory and radiologic investigation of a child presenting with possible OMAS. The evidence for an upfront vs escalating treatment regimen was reviewed, and a treatment algorithm proposed to recognize both these approaches. Importantly, recommendations on monitoring of immunotherapy response and longer-term follow-up based on an expert consensus are provided. DISCUSSION: OMAS is a rare neurologic condition that can be associated with poor cognitive outcomes. This report proposes an approach to investigation and treatment of children presenting with OMAS, based on expert international opinion recognizing the limited data available.

m.3685T > C is a novel mitochondrial DNA variant that causes Leigh syndrome.

Variants in the mitochondrial genome can result in dysfunction of Complex I within the electron transport chain, thus causing disruptions in oxidative phosphorylation. Pathogenic variants in the MT-ND1 (NADH:ubiquinone oxidoreductase core subunit 1) gene that result in Complex I dysfunction are a known cause of Leigh syndrome. The patient is a 4-yr-old female who initially presented with generalized tonic-clonic seizures, with other symptoms of Leigh syndrome becoming apparent after the seizures. A three-generation pedigree revealed no family history of mitochondrial disorders. Laboratory studies were remarkable for elevated blood lactate, alanine, and GDF15. T2-weighted magnetic resonance imaging (MRI) revealed bilateral asymmetric signal hyperintensities in the basal ganglia, specifically in the bilateral putamen and right caudate. Magnetic resonance spectroscopy showed regionally elevated glucose and lactate. Mitochondrial respiratory chain enzyme analysis on skin fibroblasts demonstrated slightly reduced Complex I function. A 16-gene dystonia panel and chromosomal microarray analysis did not identify any disease-causing variants. Combined exome and mitochondrial genome sequencing identified the m.3685T > C (MT-ND1 p.Tyr127His) variant with 62.3% heteroplasmy with no alternative cause for the patient's condition. Mitochondrial genome sequencing of the mother demonstrated that the m.3685T > C variant occurred de novo. The m.3685T > C variant is absent from population databases. The tyrosine 127 residue is highly conserved, and several nearby pathogenic variants in the MT-ND1 gene have been previously associated with Leigh syndrome. We propose that the m.3685T > C variant is a novel mitochondrial DNA variant that causes Leigh syndrome, and we classify this variant as likely pathogenic based on currently available information.

Comparison of Cosyntropin, Vigabatrin, and Combination Therapy in New-Onset Infantile Spasms in a Prospective Randomized Trial.

Objective: In a randomized trial, we aimed to evaluate the efficacy of cosyntropin injectable suspension, 1 mg/mL, compared to vigabatrin for infantile spasms syndrome. An additional arm was included to assess the efficacy of combination therapy (cosyntropin and vigabatrin) compared with cosyntropin monotherapy. Methods: Children (2 months to 2 years) with new-onset infantile spasms syndrome and hypsarhythmia were randomized into 3 arms: cosyntropin, vigabatrin, and cosyntropin and vigabatrin combined. Daily seizures and adverse events were recorded, and EEG was repeated at day 14 to assess for resolution of hypsarhythmia. The primary outcome measure was the composite of resolution of hypsarhythmia and absence of clinical spasms at day 14. Fisher exact test was used to compare outcomes. Results: 37 children were enrolled and 34 were included in the final efficacy analysis (1 withdrew prior to treatment and 2 did not return seizure diaries). Resolution of both hypsarhythmia and clinical spasms was achieved in in 9 of 12 participants (75%) treated with cosyntropin, 1/9 (11%) vigabatrin, and 5/13 (38%) cosyntropin and vigabatrin combined. The primary comparison of cosyntropin versus vigabatrin was significant (64% [95% confidence interval 21, 82], P < .01). Adverse events were reported in all 3 treatment arms: 31 (86%) had an adverse event, 7 (19%) had a serious adverse event, and 15 (42%) had an adverse event of special interest with no difference between treatment arms. Significance: This randomized trial was underpowered because of incomplete enrollment, yet it demonstrated that cosyntropin was more effective for short-term outcomes than vigabatrin as initial treatment for infantile spasms.

Autism Voices: A novel method to access first-person perspective of autistic youth.

LAY ABSTRACT: The perspective of autistic individuals is often left uncaptured, and as a result they are often excluded from making decisions that impact them. Conventional communication can be challenging for many autistic individuals, especially those who are minimally verbal or who have an associated intellectual disability. Currently, a lack of appropriate methods to capture voices across the spectrum is a barrier. In the present study, we developed the Autism Voices protocol using universal design principles to capture the perspectives and experiences of autistic youth with a range of language or intellectual abilities. This protocol was then used with 33 autistic youth aged 11 to 18 years. A scoring rubric was developed to capture the unconventional communication used by the participants and the mitigation strategies used by interviewers to facilitate the interview. Many components of the protocol were found to effectively facilitate communication between the participant and interviewer, including the use of picture cards to support verbal questions/prompts, the fact that participants could respond with their preferred communication methods (writing, texting, pointing), and the fact that interviews were applied flexibly to adapt to each participant. Unconventional communication and mitigation strategies were mostly observed in interviews with minimally verbal individuals, but a fine-grained analysis showed participants were still communicating something through this unconventional communication. Our protocol could help promote the inclusion of more autistic individuals in research and showed that unconventional modes of communication like echolalia provide an understanding that participants' are invested in conversations and certain topics are more meaningful than others.

Acceptability of employment readiness measures in youth and young adults on the autism spectrum: a mixed-methods study.

PURPOSE: Reliable, valid, and pragmatic measures are essential for monitoring and evaluating employment readiness and comparing the effectiveness of alternative implementation strategies. The Work Readiness Inventory (WRI) and Ansell-Casey Life Skills Assessment (ACLSA) are valid measures of employment readiness in neurotypical populations; however, their acceptability (i.e., user perception of measure as agreeable/satisfactory) for persons on the autism spectrum is not yet known. This investigation assesses the acceptability of the WRI and a modified ACLSA (ACLSA-M) in measuring employment readiness in youth/young adults on the spectrum. METHODS: A concurrent triangulation mixed-methods study design utilizing quantitative pre-post measurement of a community-based employment readiness program alongside qualitative survey assessment was employed to determine concurrent acceptability. For robustness, further explication through peer debriefing of experts evaluated the retrospective acceptability via interview and acceptability-rate assessment. RESULTS: Findings indicated that both measures are acceptable, although individual- and job-specific item modifications are advised, particularly due to disability-specific needs. Significant change in employment readiness in youth/young adults on the spectrum supports concurrent acceptability. Peer debriefing provided rich data on retrospective acceptability. Acceptability-rates of 0.84 and 0.91 confirm broad acceptability of these measures. CONCLUSIONS: Implications are presented for clinicians and researchers, highlighting the relevance for autism-specific measurement development and acceptability.Implications for rehabilitationGiven the lower labor force participation of persons on the autism spectrum, a combination of measures should be used in the assessment of an individual's employment readiness.In youth and young adults on the spectrum, employment readiness can be measured using the Work Readiness Inventory (WRI) and a modified version of the Ansell-Casey Life Skills Assessment (ACLSA-M).In clinical practice and research, modifying the contents of these measures may be advised to minimize language complexity, and maximize ease in self report.When designing, developing, and testing new measures in rehabilitation practice or research, the intent should be broadened by involving diverse representation from the project outset, by engaging both those on the spectrum and neurotypical populations.

Comparative Effectiveness of Initial Treatment for Infantile Spasms in a Contemporary US Cohort.

OBJECTIVE: Compare the effectiveness of initial treatment for infantile spasms. METHODS: The National Infantile Spasms Consortium prospectively followed children with new onset infantile spasms that began at age 2-24 months at 23 US centers (2012-2018). Freedom from treatment failure at 60 days required no second treatment for infantile spasms and no clinical spasms after 30 days of treatment initiation. We managed treatment selection bias with propensity score weighting and within-center correlation with generalized estimating equations. RESULTS: Freedom from treatment failure rates were: ACTH 88/190 (46%), oral steroids 42/95 (44%), vigabatrin 32/87 (37%), and non-standard therapy 4/51 (8%). Changing from oral steroids to ACTH was not estimated to affect response (observed 44% estimated to change to 44% [95% CI 34-54]). Changing from non-standard therapy to ACTH would improve response from 8% to 39 [17-67]%, and to oral steroids from 8% to 38 [15-68]%. There were large but not statistically significant estimated effects of changing from vigabatrin to ACTH (29% to 42 [15-75]%), vigabatrin to oral steroids (29% to 42 [28-57]%), and non-standard therapy to vigabatrin (8% to 20 [6-50]%). Among children treated with vigabatrin, those with tuberous sclerosis complex (TSC) responded more often than others (62% vs 29%; p<0.05) CONCLUSION: Compared to non-standard therapy, ACTH and oral steroids are superior for initial treatment of infantile spasms. The estimated effectiveness of vigabatrin is between ACTH / oral steroids and non-standard therapy, though the sample was underpowered for statistical confidence. When used, vigabatrin worked best for TSC. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for children with new onset infantile spasms, ACTH or oral steroids were superior to non-standard therapies.

Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long-term open-label extension trial.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. METHODS: Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. RESULTS: Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.

Deep-Phenotyping the Less Severe Spectrum of PIGT Deficiency and Linking the Gene to Myoclonic Atonic Seizures.

The two aims of this study were (i) to describe and expand the phenotypic spectrum of PIGT deficiency in affected individuals harboring the c.1582G>A; p.Val528Met or the c.1580A > G; p.Asn527Ser variant in either homozygous or compound heterozygous state, and (ii) to identify potential genotype-phenotype correlations and any differences in disease severity among individuals with and without the PIGT variants. The existing literature was searched to identify individuals with and without the two variants. A detailed phenotypic assessment was performed of 25 individuals (both novel and previously published) with the two PIGT variants. We compared severity of disease between individuals with and without these PIGT variants. Twenty-four individuals carried the PIGT variant Val528Met in either homozygous or compound heterozygous state, and one individual displayed the Asn527Ser variant in a compound heterozygous state. Disease severity in the individual with the Asn527Ser variant was compatible with that in the individuals harboring the Val528Met variant. While individuals without the Asn527Ser or Val528Met variant had focal epilepsy, profound developmental delay (DD), and risk of premature death, those with either of the two variants had moderate to severe DD and later onset of epilepsy with both focal and generalized seizures. Individuals homozygous for the Val528Met variant generally became seizure-free on monotherapy with antiepileptic drugs, compared to other PIGT individuals who were pharmaco-resistant. Two patients were diagnosed with myoclonic-atonic seizures, and a single patient was diagnosed with eyelid myoclonia. Our comprehensive analysis of this large cohort of previously published and novel individuals with PIGT variants broadens the phenotypical spectrum and shows that both Asn527Ser and Val528Met are associated with a milder phenotype and less severe outcome. Our data show that PIGT is a new candidate gene for myoclonic atonic epilepsy. Our genotype-phenotype correlation will be useful for future genetic counseling. Natural history studies of this mild spectrum of PIGT-related disorder may shed light on hitherto unknown aspects of this rare disorder.

Immunotherapy responsive SARS-CoV-2 infection exacerbating opsoclonus myoclonus syndrome.

The global pandemic of SARS-CoV-2 has been known to have diverse neurologic complications among adult patients. The neurologic effects of SARS-CoV-2 in the pediatric population is poorly described, especially in those with rare underlying neurologic conditions. We describe the first known case of SARS-CoV-2 in a pediatric patient with refractory opsoclonus-myoclonus syndrome. A 25-month-old female with progressive opsoclonus-myoclonus syndrome secondary to metastatic neuroblastoma status-post resection and chemotherapy presented with worsening opsoclonus, tremor, and breakthrough seizures. She had no fever or respiratory symptoms at presentation. Urine catecholamines were unchanged, with low suspicion for tumor recurrence. She was found to have SARS-CoV-2 via nasopharnygeal PCR assay. She received intravenous immunoglobulin and dexamethasone therapy with improvement in opsoclonus-myoclonus syndrome symptoms and was discharged home at her neurologic baseline. Patients with opsoclonus-myoclonus syndrome may present with exacerbation of symptoms in the context of SARS-CoV-2. This case describes a sentinel report of a child with opsoclonus-myoclonus syndrome presenting with worsening symptoms with concomitant SARS-CoV-2. Improvement in symptoms was achieved with standard of care therapies.

Custom Pediatric Oncology Next-Generation Sequencing Panel Identifies Somatic Mosaicism in Archival Tissue and Enhances Targeted Clinical Care.

BACKGROUND: Disorders in the PIK3CA-related overgrowth spectrum because of somatic mosaicism are associated with segmental overgrowth of the body in conjunction with vascular, skeletal, and brain malformations such as hemimegalencephaly. A pathogenic variant may only be detectable in affected tissue and not in peripheral blood or saliva samples; therefore archival tissue may be the only relevant available specimen for testing. Although this is a common approach for cancer testing, it is not typically used for constitutional genetic disorders. METHODS: PIK3CA mosaicism was assessed with a custom pediatric oncology next-generation sequencing panel (OncoKids) designed to capture somatic mutations in pediatric malignancies. The panel covers a wide range of targets including PIK3CA and AKT1 hotspots. We used OncoKids on archival formalin-fixed, paraffin-embedded or frozen samples from seven patients with facial hemihypertrophy and lipomas, hemimegalencephaly, or hemihypertrophy with a lymphovascular malformation. The age of the archival tissue examined by next-generation sequencing ranged from two to 13 years (median 5 years). Every patient had clinical manifestations within the PIK3CA-related overgrowth spectrum and had a sample of an affected tissue available for testing from a prior surgical intervention. RESULTS: PIK3CA mosaicism was detected in all seven patients and the mutant allele fraction was lower in the lymphovascular malformation tissues (8% to 11%) than in brain (20% to 32%) and lipomatous (16% to 23%) tissues. CONCLUSIONS: Our study highlights the clinical utility of using a robust, oncology-focused next-generation sequencing assay to identify PIK3CA mosaicism in noncancer cases. It is feasible to use archival samples that are more than a decade old to obtain a molecular diagnosis, which can then be used to improve health care management.