Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking.

Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3-5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

Management and surgical outcomes of dystrophic scoliosis in neurofibromatosis type 1: a systematic review.

OBJECTIVE: Neurofibromatosis type 1 (NF1) dystrophic scoliosis is an early-onset, rapidly progressive multiplanar deformity. There are few studies on the surgical management of this patient population. Specifically, perioperative morbidity, instrument-related complications, and quality-of-life outcomes associated with surgical management have not been systematically evaluated. In this study, the authors aimed to perform a systematic review on the natural history, management options, and surgical outcomes in patients who underwent NF1 dystrophic scoliosis surgery. METHODS: A PubMed search for articles with "neurofibromatosis" and either "dystrophic" or "scoliosis" in the title or abstract was performed. Articles with 10 or more patients undergoing surgery for NF1 dystrophic scoliosis were included. Data regarding indications, treatment details, morbidity, and outcomes were summarized and analyzed with descriptive statistics. RESULTS: A total of 310 articles were identified, 48 of which were selected for full-text review; 30 studies describing 761 patients met the inclusion criteria. The mean age ranged from 7 to 22 years, and 99.7% of patients were younger than 18 years. The mean preoperative coronal Cobb angle was 75.2°, and the average correction achieved was 40.3°. The mean clinical follow-up in each study was at least 2 years (range 2.2-19 years). All patients underwent surgery with the intent of deformity correction. The scoliosis regions addressed were thoracic curves (69.6%) and thoracolumbar (11.1%) and lumbar (14.3%) regions. The authors reported on a variety of approaches: posterior-only, combined anterior-posterior, and growth-friendly surgery. For fixation techniques, 42.5% of patients were treated with hybrid constructs, 51.5% with pedicle screw-only constructs, and 6.0% with hook-based constructs. Only 0.9% of patients underwent a vertebral column resection. The nonneurological complication rate was 14.0%, primarily dural tears and wound infections. The immediate postoperative neurological deficit rate was 2.1%, and the permanent neurological deficit rate was 1.2%. Ultimately, 21.5% required revision surgery, most commonly for implant-related complications. Loss of correction in both the sagittal and coronal planes commonly occurred at follow-up. Five papers supplied validated patient-reported outcome measures, showing improvement in the mental health, self-image, and activity domains. CONCLUSIONS: Data on the surgical outcomes of dystrophic scoliosis correction are heterogeneous and sparse. The perioperative complication rate appears to be high, although reported rates of neurological deficits appear to be lower than clinically observed and may be underreported. The incidence of implant-related failures requiring revision surgery is high. There is a great need for multicenter prospective studies of this complex type of deformity.

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity.

We previously reported a pathogenic de novo p.R342W mutation in the transcriptional corepressor CTBP1 in four independent patients with neurodevelopmental disabilities [1]. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CTBP1 mutation. Within this cohort, we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia, and tooth enamel defects present in most patients. The R342W mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin-modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cell lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes.

Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression.

OBJECTIVE: We sought to identify genetic causes of early onset epileptic encephalopathies with burst suppression (Ohtahara syndrome and early myoclonic encephalopathy) and evaluate genotype-phenotype correlations. METHODS: We enrolled 33 patients with a referral diagnosis of Ohtahara syndrome or early myoclonic encephalopathy without malformations of cortical development. We performed detailed phenotypic assessment including seizure presentation, electroencephalography, and magnetic resonance imaging. We confirmed burst suppression in 28 of 33 patients. Research-based exome sequencing was performed for patients without a previously identified molecular diagnosis from clinical evaluation or a research-based epilepsy gene panel. RESULTS: In 17 of 28 (61%) patients with confirmed early burst suppression, we identified variants predicted to be pathogenic in KCNQ2 (n = 10), STXBP1 (n = 2), SCN2A (n = 2), PNPO (n = 1), PIGA (n = 1), and SEPSECS (n = 1). In 3 of 5 (60%) patients without confirmed early burst suppression, we identified variants predicted to be pathogenic in STXBP1 (n = 2) and SCN2A (n = 1). The patient with the homozygous PNPO variant had a low cerebrospinal fluid pyridoxal-5-phosphate level. Otherwise, no early laboratory or clinical features distinguished the cases associated with pathogenic variants in specific genes from each other or from those with no prior genetic cause identified. INTERPRETATION: We characterize the genetic landscape of epileptic encephalopathy with burst suppression, without brain malformations, and demonstrate feasibility of genetic diagnosis with clinically available testing in >60% of our cohort, with KCNQ2 implicated in one-third. This electroclinical syndrome is associated with pathogenic variation in SEPSECS. Ann Neurol 2017;81:419-429.

Utility of MRI versus tumor markers for post-treatment surveillance of marker-positive CNS germ cell tumors.

Patients with marker-positive central nervous system (CNS) germ cell tumors are typically monitored for tumor recurrence with both tumor markers (AFP and b-hCG) and MRI. We hypothesize that the recurrence of these tumors will always be accompanied by an elevation in tumor markers, and that surveillance MRI may not be necessary. We retrospectively identified 28 patients with CNS germ cell tumors treated at our institution that presented with an elevated serum or cerebrospinal fluid (CSF) tumor marker at the time of diagnosis. We then identified those who had a tumor recurrence after having been in remission and whether each recurrence was detected via MRI changes, elevated tumor markers, or both. Four patients suffered a tumor recurrence. Only one patient had simultaneously elevated tumor markers and MRI evidence of recurrence. Two patients had evidence of recurrence on MRI without corresponding elevations in serum or CSF tumor markers. One patient had abnormal tumor markers with no evidence of recurrence on MRI until 6 months later. We conclude that in patients with marker-positive CNS germ cell tumors who achieve complete remission, continued surveillance imaging in addition to measurement of tumor markers is indicated to detect recurrences.

Identifying Lesions of the Corpus Callosum in Patients With Neurofibromatosis Type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a multisystemic autosomal dominant disorder that includes intracranial lesions such as unidentified bright objects (UBOs)-areas of increased T2 signal on magnetic resonance imaging (MRI)-and tumors known as gliomas. The presence of these lesions in the corpus callosum (CC) has not been previously studied in a large cohort. METHODS: We reviewed medical records of 681 patients (aged three months to 86 years) followed at our institution from 2000 to 2023 with NF1 and one or more brain MRI. Patients with lesions in the CC were identified, and RAPNO/RANO criteria were used to determine changes in size over time, where a change of 25% in the product of perpendicular measurements indicates growth or shrinkage. RESULTS: Forty-seven patients had CC UBOs, most of which were in the splenium (66.0%). Seventeen patients had CC gliomas (10% of those with any glioma), two of whom had two gliomas. Seventeen of 19 gliomas were in the splenium. Over follow-up, eight of 19 remained stable, three shrunk, and eight grew. The mean percentage change in the product of the dimensions was 311.5% (ranging from -46.7% to 2566.6%). Of the eight lesions that grew, one required treatment. CONCLUSIONS: There is a 6.9% and 2.5% prevalence of CC UBOs and gliomas, respectively, in our cohort of patients with NF1. Most lesions are present in the splenium, and although some gliomas demonstrate significant growth, they rarely require treatment. This work is the largest series of CC lesions in NF1 and adds to the growing data to inform appropriate follow-up.

A Severe Case of Streptococcus pneumoniae Meningoencephalitis in an Infant Resulting in Fatal Strokes.

Streptococcus pneumoniae (S. Pneumoniae) is a common cause of bacterial meningitis in the pediatric population, but rarely causes complications such as encephalitis, abscess, and seizures with the prompt initiation of proper antimicrobial therapy. In this report, we present a rare and severe case of S. Pneumoniae meningoencephalitis in a full term 6-month-old which progressed to multiple cerebral and cerebellar infarcts with concomitant cerebellar tonsillar herniation and hypercarbic respiratory failure requiring intubation and mechanical ventilation despite early initiation of antibiotics. Given the patient's clinical status and poor neurological prognosis, the family eventually opted for palliative extubation.

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial.

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m-2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .

A Case of Infant-Type Hemispheric Glioma with NTRK1 Fusion.

The incidence of childhood central nervous system tumors in infants is about 6 per 100 000 children. Recent studies have showed recurrent fusion of the neurotrophic tyrosine receptor kinase (NTRK) gene in 10% of non-brainstem high grade glioma in very young children suggesting an oncogenic effect of the NTRK fusion genes. In this report, we present a rare, severe case of a full-term neonate who was noted to have widely splayed sutures and a bulging fontanelle at birth who was found to have infant-type hemispheric glioma with NTRK1 fusion with course complicated by seizures refractory to medical treatment. Patient was deemed a poor surgical candidate due to the size of the mass and thus parents opted for comfort care.

Diffusion tensor anisotropy in the cingulate gyrus in schizophrenia.

It has been proposed that schizophrenia results partly from altered brain connectivity. The anterior cingulate cortex in particular has been demonstrated to be affected in schizophrenia, with studies reporting reduced volume, altered neuronal arrangement, decreased anisotropy in diffusion tensor images, and hypometabolism. We used a 3T Siemens scanner to acquire structural and diffusion tensor imaging in age-and sex-matched groups of 41 adults with chronic schizophrenia, 6 adults with recent-onset schizophrenia, and 38 healthy control subjects. We manually traced the anterior and posterior cingulate gyri on all subjects and then compared the volume and anisotropy across groups for the left and right anterior and posterior cingulate gyri. The anterior cingulate gyrus was divided axially into six equal segments, and the posterior cingulate gyrus into two segments. Volume was calculated for the anterior and posterior gyri, and average anisotropy was then calculated for each individual segment, looking separately at gray and white matter. We found decreased overall relative left and right gray matter volume in the anterior cingulate gyrus in persons with schizophrenia compared with healthy controls. Additionally, in both gray and white matter of the cingulate, we found that recent-onset patients had the highest anisotropy, chronic patients had the lowest, and controls were intermediate. These results provide additional evidence for the presence of both white and gray matter abnormalities in the cingulate gyrus, which has been implicated in schizophrenia.

Spatial distribution and density of oligodendrocytes in the cingulum bundle are unaltered in schizophrenia.

It has been proposed that schizophrenia results partly from altered brain connectivity. Gene microarray analyses performed in gray matter have indicated that several myelin-related genes normally expressed in oligodendrocytes have decreased expression levels in schizophrenia. These data suggest that oligodendrocytes may be involved in the deficits of schizophrenia and may be decreased in number in the case of disease. The anterior cingulate cortex in particular has been demonstrated to be affected in schizophrenia, with studies reporting altered neuronal arrangement, decreased anisotropy in diffusion tensor images, and hypometabolism. We used a stereologic nearest-neighbor estimator of spatial distribution to investigate oligodendrocytes in the anterior cingulum bundle using postmortem tissue from 13 chronic schizophrenics and 13 age-matched controls. Using a spatial point pattern analysis, we measured the degree of oligodendrocyte clustering by comparing the probability of finding a nearest-neighbor at a given distance in schizophrenics and controls. At the same time, we also estimated the number and density of oligodendrocytes in the region of interest. In the present study, we found no significant differences in the oligodendrocyte distribution or density in the cingulum bundle between the two groups, in contrast to earlier data from the prefrontal subcortical white matter. These results suggest that a subtler oligodendrocyte or myelin anomaly may underlie the structural deficits observed by brain imaging in the cingulum bundle in schizophrenia.

Use of Head Computed Tomography (CT) in the Pediatric Emergency Department in Evaluation of Children With New-Onset Afebrile Seizure.

OBJECTIVE: Cranial computed tomography (CT) is not recommended in the routine evaluation of children with first afebrile seizure due to its low yield. The objective was to assess the current practice in our pediatric emergency department regarding the use of head CT in children with first afebrile seizure and to identify the factors that lead to ordering a head CT. METHODS: Medical records of patients between 1 month and 18 years old evaluated at our emergency department for presentation of first afebrile seizure between 2010 and 2014 were retrospectively reviewed. Data extracted include age, gender, seizure type, single or multiple seizures at presentation, seizure duration, predisposing conditions to seizures (ie, history of developmental delay), and whether a head CT was performed. Contingency tables with chi-square analyses were used to determine which variables were associated with increased use of head CT. RESULTS: Of 155 patients (88M/67F) included in the study, 72 (46.5%) underwent head CT and only 3 had clinically significant findings that did not require acute management. There were no differences in CT use by age, sex, seizure type, seizure number, seizure risk factors, or findings on physical examination. Head CT was performed more frequently in cases with seizures ≥5 minutes and unknown seizure duration ( P = .04). CONCLUSION: Despite existing evidence, the emergent head CT rate was high in our cohort. Children with seizure duration of ≥5 minutes or of unknown duration were more likely to undergo head CT in our emergency department.

Pediatric Brain Tumors: An Update.

Brain tumors collectively represent the most common solid tumors in childhood and account for significant morbidity and mortality. Until recently, pediatric brain tumors were diagnosed and classified solely based on histologic criteria, and treatments were chosen empirically. Recent research has greatly enhanced our understanding of the diverse biology of pediatric brain tumors, their molecular and genetic underpinnings, leading to improved diagnostic accuracy and risk stratification, as well as the development of novel biomarkers and molecular targeted therapies. For subsets of patients, these new treatment options have already resulted in improved survival and decreased treatment toxicity. In this article, we provide an overview of the most common childhood brain tumors, describe recent key advances in the field, and discuss the therapeutic challenges that remain.

Severe holocord syrinx in a child with megalencephaly-capillary malformation syndrome.

The authors present the case of a child with megalencephaly-capillary malformation syndrome who developed a rapidly progressive holocord syringomyelia that was treated surgically. A 3-year-old boy with megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome presented with several months of right leg weakness, worsening scoliosis, and increased seizures. An MRI study of the brain demonstrated a Chiari I malformation and massively dilated syringomyelia extending from C-2 to the conus medullaris. The patient underwent an urgent suboccipital craniectomy with C1-3 laminectomies to relieve the CSF outflow obstruction with significant clinical improvement. Surgery was complicated by bleeding from intracranial vascular malformations. This report describes a very rapidly developing, massive holocord syringomyelia related to CSF obstruction due to an unusual congenital brain malformation and associated vascular overgrowth at the site. Serial, premorbid MRI studies demonstrated the very rapid progression from no Chiari malformation, to progressively greater cerebellar tonsillar herniation, to holocord syrinx. This complication has never been reported in MCAP syndrome and should be considered in any affected MCAP patient with a progressive neurological decline, even if previous spine imaging findings were normal. Surgical complications due to hemorrhage also need to be considered in this vascular brain malformation.

Call-Fleming syndrome: headache in a 16-year-old girl.

BACKGROUND: Call-Fleming syndrome, also known as reversible cerebral vasoconstriction syndrome, is an important cause of severe headache characterized by segmental constriction of cerebral arteries in multiple vascular distributions. It is commonly described in adults, with a female predominance. PATIENT: We report a case of a 16-year-old girl with history of anxiety, attention deficit hyperactivity disorder, and migraines on several medications presenting with 2 weeks of worsening headaches. RESULTS: Cranial computed tomography was normal, but magnetic resonance imaging revealed cortical subarachnoid hemorrhage. Follow-up imaging demonstrated extensive vasoconstriction of small- to medium-sized cerebral arteries. Sertraline and methylphenidate were discontinued, and nifedipine was started. Symptoms rapidly improved, and repeat angiography at 2 months showed no vasoconstriction. CONCLUSIONS: Call-Fleming syndrome is an important cause of thunderclap headache and should be considered in the pediatric population, especially in the setting of certain medication usage and other known risk factors.

Linking white and grey matter in schizophrenia: oligodendrocyte and neuron pathology in the prefrontal cortex.

Neuronal circuitry relies to a large extent on the presence of functional myelin produced in the brain by oligodendrocytes. Schizophrenia has been proposed to arise partly from altered brain connectivity. Brain imaging and neuropathologic studies have revealed changes in white matter and reduction in myelin content in patients with schizophrenia. In particular, alterations in the directionality and alignment of axons have been documented in schizophrenia. Moreover, the expression levels of several myelin-related genes are decreased in postmortem brains obtained from patients with schizophrenia. These findings have led to the formulation of the oligodendrocyte/myelin dysfunction hypothesis of schizophrenia. In this review, we present a brief overview of the neuropathologic findings obtained on white matter and oligodendrocyte status observed in schizophrenia patients, and relate these changes to the processes of brain maturation and myelination. We also review recent data on oligodendrocyte/myelin genes, and present some recent mouse models of myelin deficiencies. The use of transgenic and mutant animal models offers a unique opportunity to analyze oligodendrocyte and neuronal changes that may have a clinical impact. Lastly, we present some recent morphological findings supporting possible causal involvement of white and grey matter abnormalities, in the aim of determining the morphologic characteristics of the circuits whose alteration leads to the cortical dysfunction that possibly underlies the pathogenesis of schizophrenia.