Epilepsy and overgrowth-intellectual disability syndromes: a patient organization perspective on collaborating to accelerate pathways to treatment.

Overgrowth-intellectual disability (OGID) syndromes are a collection of rare genetic disorders with overlapping clinical profiles. In addition to the cardinal features of general overgrowth (height and/or head circumference at least two standard deviations above the mean) and some degree of intellectual disability, the OGID syndromes are often associated with neurological anomalies including seizures. In an effort to advance research in directions that will generate meaningful treatments for people with OGID syndromes, a new collaborative partnership called the Overgrowth Syndromes Alliance (OSA) formed in 2023. By taking a phenotype-first approach, OSA aims to unite research and patient communities traditionally siloed by genetic disorder. OSA has galvanized OGID patient organizations around shared interests and developed a research roadmap to identify and address our community's greatest unmet needs. Here, we describe the literature regarding seizures among those with overgrowth syndromes and present the OSA Research Roadmap. This patient-driven guide outlines the milestones essential to reaching the outcome of effective treatments for OGID syndromes and offers resources for reaching those milestones.

Working together to speed up treatments for rare genetic syndromes linked to excessive growth and intellectual disability To address the shared challenges experienced among those affected by overgrowth­intellectual disability (OGID) syndromes, we recently formed the Overgrowth Syndromes Alliance (OSA). The OSA unites patient advocacy organizations that have typically worked independently of one another, in hopes of accelerating our progress toward treatments. Here, we summarize the OGID syndromes represented by the OSA, the prevalence of seizures in these disorders, and efforts by the OSA to tackle the most pressing needs of the overgrowth community. We also present the steps patient organizations can take in pursuit of developing treatments. We hope the work of our alliance can be a template for creating collaborative, patient-led advances in diagnosis, management guidelines, and, eventually, treatment of rare genetic disorders.

MRI predictors of long-term outcomes of neonatal hypoxic ischaemic encephalopathy: a primer for radiologists.

This review aims to serve as a foundational resource for general radiologists, enhancing their understanding of the role of Magnetic Resonance Imaging (MRI) in early prognostication for newborns diagnosed with hypoxic ischaemic encephalopathy (HIE). The article explores the application of MRI as a predictive instrument for determining long-term outcomes in newborns affected by HIE. With HIE constituting a leading cause of neonatal mortality and severe long-term neurodevelopmental impairments, early identification of prognostic indicators is crucial for timely intervention and optimal clinical management. We examine current literature and recent advancements to provide an in-depth overview of MRI predictors, encompassing brain injury patterns, injury scoring systems, spectroscopy, and diffusion imaging. The potential of these MRI biomarkers in predicting long-term neurodevelopmental outcomes and the probability of epilepsy is also discussed.

Resting-State Functional Magnetic Resonance Imaging Network Association With Mortality, Epilepsy, Cognition, and Motor Two-Year Outcomes in Suspected Severe Neonatal Acute Brain Injury.

BACKGROUND AND OBJECTIVES: In acute brain injury of neonates, resting-state functional magnetic resonance imaging (MRI) (RS) showed incremental association with consciousness, mortality, cognitive and motor development, and epilepsy, with correction for multiple comparisons, at six months postgestation in neonates with suspected acute brain injury (ABI). However, there are relatively few developmental milestones at six months to benchmark against, thus, we extended this cohort study to evaluate two-year outcomes. METHODS: In 40 consecutive neonates with ABI and RS, ordinal scores of resting-state networks; MRI, magnetic resonance spectroscopy, and electroencephalography; and up to 42-month outcomes of mortality, general and motor development, Pediatric Cerebral Performance Category Scale (PCPC), and epilepsy informed associations between tests and outcomes. RESULTS: Mean gestational age was 37.8 weeks, 68% were male, and 60% had hypoxic-ischemic encephalopathy. Three died in-hospital, four at six to 42 months, and five were lost to follow-up. Associations included basal ganglia network with PCPC (P = 0.0003), all-mortality (P = 0.005), and motor (P = 0.0004); language/frontoparietal network with developmental delay (P = 0.009), PCPC (P = 0.006), and all-mortality (P = 0.01); default mode network with developmental delay (P = 0.003), PCPC (P = 0.004), neonatal intensive care unit mortality (P = 0.01), and motor (P = 0.009); RS seizure onset zone with epilepsy (P = 0.01); and anatomic MRI with epilepsy (P = 0.01). CONCLUSION: For the first time, at any age, resting state functional MRI in ABI is associated with long-term epilepsy and RSNs predicted mortality in neonates. Severity of RSN abnormality was associated with incrementally worsened neurodevelopment including cognition, language, and motor function over two years.

A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization.

The vast majority of severe (Type 0) spinal muscular atrophy (SMA) cases are caused by homozygous deletions of survival motor neuron 1 (SMN1). We report a case in which the patient has two copies of SMN1 but clinically presents as Type 0 SMA. The patient is an African American male carrying a homozygous maternally inherited missense variant (c.796T>C) in a cis-oriented SMN1 duplication on one chromosome and an SMN1 deletion on the other chromosome (genotype: 2*+0). Initial extensive genetic workups including exome sequencing were negative. Deletion analysis used in the initial testing for SMA also failed to detect SMA as the patient has two copies of SMN1. Because of high clinical suspicion, SMA diagnosis was finally confirmed based on full-length SMN1 sequencing. The patient was initially treated with risdiplam and later gene therapy with onasemnogene abeparvovec at 5 months without complications. The patient's muscular weakness has stabilized with mild improvement. The patient is now 28 months old and remains stable and diffusely weak, with stable respiratory ventilatory support. This case highlights challenges in the diagnosis of SMA with a non-deletion genotype and provides a clinical example demonstrating that disruption of functional SMN protein polymerization through an amino acid change in the YG-box domain represents a little known but important pathogenic mechanism for SMA. Clinicians need to be mindful about the limitations of the current diagnostic approach for SMA in detecting non-deletion genotypes.

Recurrent acute hemorrhagic necrotizing encephalopathy associated with RAN-binding protein-2 gene mutation in a pediatric patient.

A young male child presented with recurrent episodes of seizures and altered mental status following febrile episodes on three separate occasions between his first and third birthdays. Laboratory evaluations identified SARS-CoV-2 infection during the first episode and no infective agents or antibodies in the cerebrospinal fluid during all the episodes. Brain imaging with CT and MRI revealed bilaterally symmetric patchy hemorrhagic necrotic foci in the deep brain nuclei and medial temporal lobes, prompting suspicion for an underlying predisposition to recurrent acute hemorrhagic necrotizing encephalopathy. Gene analysis confirmed a mutation in the RAN-binding protein-2 (RANBP2) gene. The patient made good recovery following treatment with IVIG, steroids and plasmapheresis, and follow-up brain imaging showed no progression of brain lesions. Early suspicion from characteristic imaging features in appropriate clinical settings will inform timely appropriate treatment and better outcome. We therefore provided short review of imaging features of acute hemorrhagic necrotizing encephalopathy.

Wide range of perioperative drugs and doses used in inguinal hernia repairs for premature infants.

OBJECTIVE: Characterize the types and doses of commonly administered perioperative drugs in inguinal hernia (IH) repair for premature infants. STUDY DESIGN: Single-center, retrospective cohort study. RESULTS: In total, 112 premature infants underwent IH repair between 2010 and 2015. Twenty-one drugs were used during IH repair, with each infant receiving a median seven drugs. Acetaminophen (88%), bupivacaine (84%), cisatracurium (74%), sevoflurane (72%), and propofol (71%) were the most commonly used agents. Thirty-two infants underwent additional procedures with IH repair. Additional procedures were not associated with a higher number of perioperative drugs, however infants with additional procedures were exposed to higher cumulative doses of cisatracurium (p < 0.001) and fentanyl (p = 0.002). CONCLUSION: There is wide variability in the drugs and doses used for a common surgical procedure in this population, even within a single center. Future research should focus on the safety and efficacy of the most commonly used perioperative drugs described in this study.

Mitochondrial DNA damage induced autophagy, cell death, and disease.

Mammalian mitochondria contain multiple small genomes. While these organelles have efficient base excision removal of oxidative DNA lesions and alkylation damage, many DNA repair systems that work on nuclear DNA damage are not active in mitochondria. What is the fate of DNA damage in the mitochondria that cannot be repaired or that overwhelms the repair system? Some forms of mitochondrial DNA damage can apparently trigger mitochondrial DNA destruction, either via direct degradation or through specific forms of autophagy, such as mitophagy. However, accumulation of certain types of mitochondrial damage, in the absence of DNA ligase III (Lig3) or exonuclease G (EXOG), can directly trigger cell death. This review examines the cellular effects of persistent damage to mitochondrial genomes and discusses the very different cell fates that occur in response to different kinds of damage.

In vivo repair of alkylating and oxidative DNA damage in the mitochondrial and nuclear genomes of wild-type and glycosylase-deficient Caenorhabditis elegans.

Base excision repair (BER) is an evolutionarily conserved DNA repair pathway that is critical for repair of many of the most common types of DNA damage generated both by endogenous metabolic pathways and exposure to exogenous stressors such as pollutants. Caenorhabditis elegans is an increasingly important model organism for the study of DNA damage-related processes including DNA repair, genotoxicity, and apoptosis, but BER is not well understood in this organism, and has not previously been measured in vivo. We report robust BER in the nuclear genome and slightly slower damage removal from the mitochondrial genome; in both cases the removal rates are comparable to those observed in mammals. However we could detect no deficiency in BER in the nth-1 strain, which carries a deletion in the only glycosylase yet described in C. elegans that repairs oxidative DNA damage. We also failed to detect increased lethality or growth inhibition in nth-1 nematodes after exposure to oxidative or alkylating damage, suggesting the existence of at least one additional as-yet undetected glycosylase.

The QPCR assay for analysis of mitochondrial DNA damage, repair, and relative copy number.

The quantitative polymerase chain reaction (QPCR) assay allows measurement of DNA damage in the mitochondrial and nuclear genomes without isolation of mitochondria. It also permits measurement of relative mitochondrial genome copy number. Finally, it can be used for measurement of DNA repair in vivo when employed appropriately. In this manuscript we briefly review the methodology of the QPCR assay, discuss its strengths and limitations, address considerations for measurement of mitochondrial DNA repair, and describe methodological changes implemented in recent years. We present QPCR assay primers and reaction conditions for five species not previously described in a methods article: Caenorhabditis elegans, Fundulus heteroclitus, Danio rerio, Drosophila melanogaster, and adenovirus. Finally, we illustrate the use of the assay by measuring repair of ultraviolet C radiation-induced DNA damage in the nuclear but not mitochondrial genomes of a zebrafish cell culture.