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BACKGROUND AND OBJECTIVES: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age METHODS: In this article, we report key safety and early outcome data from the first 21 children (age 1–23 months) treated in the state of Ohio. RESULTS: In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. CONCLUSIONS: In this population, with thorough screening and careful post–gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.

Fanconi anemia (FA) is a hereditary genomic instability disorder with a predisposition to leukemia and oral squamous cell carcinomas (OSCCs). Hematopoietic stem cell transplantation (HSCT) facilitates cure of bone marrow failure and leukemia and thus extends life expectancy in FA patients; however, survival of hematologic malignancies increases the risk of OSCC in these patients. We developed a "cytology-on-a-chip" (COC)-based brush biopsy assay for monitoring patients with oral potentially malignant disorders (OPMDs). Using this COC assay, we measured and correlated the cellular morphometry and Minichromosome Maintenance Complex Component 2 (MCM2) expression levels in brush biopsy samples of FA patients' OPMD with clinical risk indicators such as loss of autofluorescence (LOF), HSCT status, and mutational profiles identified by next-generation sequencing. Statistically significant differences were found in several cytology measurements based on high-risk indicators such as LOF-positive and HSCT-positive status, including greater variation in cell area and chromatin distribution, higher MCM2 expression levels, and greater numbers of white blood cells and cells with enlarged nuclei. Higher OPMD risk scores were associated with differences in the frequency of nuclear aberrations and differed based on LOF and HSCT statuses. We identified mutation of FAT1 gene in five and NOTCH-2 and TP53 genes in two cases of FA patients' OPMD. The high-risk OPMD of a non-FA patient harbored FAT1, CASP8, and TP63 mutations. Use of COC assay in combination with visualization of LOF holds promise for the early diagnosis of high-risk OPMD. These minimally invasive diagnostic tools are valuable for long-term surveillance of OSCC in FA patients and avoidance of unwarranted scalpel biopsies.

Background Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder often causing progressive brain injury that is not confined to large arterial territories. Severe insults ultimately lead to gyral necrosis affecting the cortex and juxtacortical white matter; the neuroimaging correlate is partial gyral signal suppression on T2/FLAIR sequences that resemble black toenails. We aimed to characterize the imaging features and the natural history of MELAS-related gyral necrosis. Materials and Methods Databases at two children's hospitals were searched for brain magnetic resonance imaging studies of individuals with MELAS. Examinations with motion artifact and those lacking T2/FLAIR sequences were excluded. The location, the cumulative number, and the maximum transverse diameter of necrotic gyral lesions were assessed using T2-weighted images and T2/FLAIR sequences. Wilcoxon signed-rank test was employed to evaluate the relationship between disease duration and the number of necrotic lesions. Results One hundred twenty-four examinations from patients with 14 unique MELAS patients (16 ± 3 years) were evaluated. Six of the eight patients who developed brain lesions also developed gyral necroses (mean 13, range 0 to 44). Necrotic lesions varied in maximal diameter from 4 to 25 mm. Cumulative necrotic lesions correlated with disease duration ( P Conclusions The black toenail sign signifying gyral necrosis is a common imaging feature in individuals with MELAS syndrome. The extent of gyral necrosis correlates with disease duration.

MELAS syndrome is a mitochondrial disorder typified by recurrent stroke-like episodes, seizures, and progressive brain injury. Abnormal mitochondria have been found in arterial walls implicating a vasculogenic etiology. We have observed abnormal cortical vein T2/FLAIR signal in MELAS patients, potentially representing wall thickening and sluggish flow. We sought to examine the relationship of hyperintense veins and brain lesions in MELAS.Imaging databases at two children's hospitals were searched for brain MRIs from MELAS patients. Artifact, sedated exams, and lack of 2D-T2/FLAIR sequences were exclusion criteria. Each exam was assigned a venous score based on number of T2/FLAIR hyperintense veins: 1 = 10, 2 = 10 to 20, 3 = 20. Cumulative brain lesions and venous score in MELAS and aged-matched normal exams were compared by Mann-Whitney test.A total of 106 exams from 14 unique MELAS patients (mean 16 ± 3 years) and 30 exams from normal aged-matched patients (mean 15 ± 3 years) were evaluated. Median venous score between MELAS and control patients significantly differed (3 versus 1; p 0.001). In the MELAS group, venous score correlated with presence (median = 3) or absence (median = 1) of cumulative brain lesions. In all 8 MELAS patients who developed lesions, venous hyperintensity was present prior to, during, and after lesion onset. Venous score did not correlate with brain lesion acuity.Abnormal venous signal correlates with cumulative brain lesion severity in MELAS syndrome. Cortical venous stenosis, congestion, and venous ischemia may be mechanisms of brain injury. Identification of cortical venous pathology may aid in diagnosis and could be predictive of lesion development.

Early detection of oral cancer and oral premalignant lesions (OPL) containing dysplasia could improve oral cancer outcomes. However, general dental practitioners have difficulty distinguishing dysplastic OPLs from confounder oral mucosal lesions in low-risk populations. We evaluated the ability of two optical imaging technologies, autofluorescence imaging (AFI) and high-resolution microendoscopy (HRME), to diagnose moderate dysplasia or worse (ModDys+) in 56 oral mucosal lesions in a low-risk patient population, using histopathology as the gold standard, and in 46 clinically normal sites. AFI correctly diagnosed 91% of ModDys+ lesions, 89% of clinically normal sites, and 33% of benign lesions. Benign lesions with severe inflammation were less likely to be correctly diagnosed by AFI (13%) than those without (42%). Multimodal imaging (AFI+HRME) had higher accuracy than either modality alone; 91% of ModDys+ lesions, 93% of clinically normal sites, and 64% of benign lesions were correctly diagnosed. Photos of the 56 lesions were evaluated by 28 dentists of varied training levels, including 26 dental residents. We compared the area under the receiver operator curve (AUC) of clinical impression alone to clinical impression plus AFI and clinical impression plus multimodal imaging using k-Nearest Neighbors models. The mean AUC of the dental residents was 0.71 (range: 0.45–0.86). The addition of AFI alone to clinical impression slightly lowered the mean AUC (0.68; range: 0.40–0.82), whereas the addition of multimodal imaging to clinical impression increased the mean AUC (0.79; range: 0.61–0.90). On the basis of these findings, multimodal imaging could improve the evaluation of oral mucosal lesions in community dental settings. Cancer Prev Res; 11(8); 465–76. ©2018 AACR.

Cornelia de Lange syndrome (CdLS) is a rare dominantly inherited genetic multisystem developmental condition with considerable phenotypic and allelic heterogeneity. Missense and in-frame deletions within the SMC1A gene can be associated with epilepsy and milder craniofacial features. We report two females who presented with developmental delay and developed isolated medically refractory seizures with unrevealing initial laboratory, imaging and genetic evaluations. Whole exome sequencing (WES) analyses were performed and were instrumental in uncovering the genetic etiology for their conditions. WES identified two novel de novo heterozygous frameshift mutations in the SMC1A gene [c.2853_2856delTCAG (p.Ser951Argfs*12) and c.3549_3552dupGGCC (p.Ile1185Glyfs*23)]. We also observed marked skewing of X-inactivation in one patient. The individual with the p.Ser951Argfs*12 mutation represents an extreme on the CdLS phenotypic spectrum, with prominent neurological involvement of severe developmental delay and refractory epilepsy, with mild craniofacial features. Both individuals eventually had incomplete clinical responses to therapy with valproic acid. We review previous reports of SMC1A mutations with epilepsy. SMC1A should be included in clinical gene panels for early infantile and early childhood epileptic encephalopathy.

Aphasia is an important presenting symptom of acute stroke. With increasing reliance on electronic communication, incoherent texting or “dystextia,” which is a subset of aphasia that is reflected in text messages, can be a useful tool for symptom recognition and analysis. It can be a red flag for the family and therefore can help in early identification of an acute neurological deficit. It is also useful for providers to reliably analyze the deficit as well as establish a timeline of evolution of symptoms. There have been case reports where dystextia has been the presenting feature of stroke or complicated migraine and in one case of meningioma. We present the case of a teenage patient that in our knowledge is the youngest reported case of dystextia, whose aphasia recorded in a text message assisted with stroke localization. This also adds to the literature of dystextia which so far has only seven other cases reported.

Objective:To investigate the common thinking, as reinforced by the International Classification of Headache Disorders, 3rd edition (beta), that occipital headaches in children are rare and suggestive of serious intracranial pathology.Methods:We performed a retrospective chart review cohort study of all patients ≤18 years of age referred to a university child neurology clinic for headache in 2009. Patients were stratified by headache location: solely occipital, occipital plus other area(s) of head pain, or no occipital involvement. Children with abnormal neurologic examinations were excluded. We assessed location as a predictor of whether neuroimaging was ordered and whether intracranial pathology was found. Analyses were performed with cohort study tools in Stata/SE 13.0 (StataCorp, College Station, TX).Results:A total of 308 patients were included. Median age was 12 years (32 months–18 years), and 57% were female. Headaches were solely occipital in 7% and occipital-plus in 14%. Patients with occipital head pain were more likely to undergo neuroimaging than those without occipital involvement (solely occipital: 95%, relative risk [RR] 10.5, 95% confidence interval [CI] 1.4–77.3; occipital-plus: 88%, RR 3.7, 95% CI 1.5–9.2; no occipital pain: 63%, referent). Occipital pain alone or with other locations was not significantly associated with radiographic evidence of clinically significant intracranial pathology.Conclusions:Children with occipital headache are more likely to undergo neuroimaging. In the absence of concerning features on the history and in the setting of a normal neurologic examination, neuroimaging can be deferred in most pediatric patients when occipital pain is present.

Oral premalignant lesions (OPLs), such as leukoplakia, are at risk of malignant transformation to oral cancer. Clinicians can elect to biopsy OPLs and assess them for dysplasia, a marker of increased risk. However, it is challenging to decide which OPLs need a biopsy and to select a biopsy site. We developed a multimodal optical imaging system (MMIS) that fully integrates the acquisition, display, and analysis of macroscopic white-light (WL), autofluorescence (AF), and high-resolution microendoscopy (HRME) images to noninvasively evaluate OPLs. WL and AF images identify suspicious regions with high sensitivity, which are explored at higher resolution with the HRME to improve specificity. Key features include a heat map that delineates suspicious regions according to AF images, and real-time image analysis algorithms that predict pathologic diagnosis at imaged sites. Representative examples from ongoing studies of the MMIS demonstrate its ability to identify high-grade dysplasia in OPLs that are not clinically suspicious, and to avoid unnecessary biopsies of benign OPLs that are clinically suspicious. The MMIS successfully integrates optical imaging approaches (WL, AF, and HRME) at multiple scales for the noninvasive evaluation of OPLs.

Object Although survival for extremely low gestational age newborns (ELGANs) has improved in the past 3 decades, these infants remain prone to complications of prematurity, including intraventricular hemorrhage (IVH). The authors reviewed the outcomes for an entire cohort of ELGANs who suffered severe IVH at their institution during the past 12 years to gain a better understanding of the natural history of IVH and frequency of ventriculoperitoneal (VP) shunt placement in this population. Methods Data from the neonatal ICU (NICU) database, neurosurgery operative log, and medical records were used to identify and follow up all ELGANs who suffered a severe IVH between 1997 and 2008. Trends between Period 1 (1997–2001) and Period 2 (2004–2008) were analyzed using the Pearson chi-square test. Results Between 1997 and 2008, 1335 ELGANs were admitted to the NICU at the authors' institution within 3 days of birth, and 111 (8.3%) of these infants suffered a severe IVH. Survival to 2 years, incidence of severe IVH, neonatal risk factors (gestational age, birth weight, and incidence of necrotizing enterocolitis), ventriculomegaly on cranial ultrasonography, and use of serial lumbar punctures for symptomatic hydrocephalus were all stable. Infants from Period 2 had a significantly lower incidence of bronchopulmonary dysplasia and sepsis than infants from Period 1 (both p < 0.001). All ELGANs with severe IVH and ventriculomegaly underwent long-term follow-up to identify shunt status at late follow-up. Twenty-two ELGANs (20%) with severe IVH required a temporary ventriculosubgaleal (VSG) shunt. Three infants with VSG shunts showed spontaneous hydrocephalus resolution, and 2 infants died of unrelated causes during the neonatal admission. The temporary VSG shunt complication rate was 20% (12% infection and 8% malfunction). Sixteen percent of all ELGANs (18 of 111) with severe IVH eventually required permanent ventricular shunt insertion. Six (35%) of 17 infants with a permanent VP shunt required at least 1 permanent shunt revision during the 1st year. The proportion of ELGANs with severe IVH who required a temporary VSG (35%) or permanent VP shunt (30%) during Period 1 decreased by more than 60% in Period 2 (10% [p = 0.005] and 8.3% [p = 0.009], respectively). Conclusions The authors report for the first time a marked reduction over the past 12 years in the proportion of ELGANs with severe IVH who required surgical intervention for hydrocephalus. Using the NICU database, the authors were able to identify and follow all ELGANs with severe IVH and ventriculomegaly. They speculate that the reduction in ventricular shunt rate results from improved neonatal medical care, including reduced infection, improved bronchopulmonary dysplasia, and postnatal steroid avoidance, which may aid innate repair mechanisms. Multicenter prospective trials and detailed analyses of NICU parameters of neonatal well-being are needed to understand how perinatal factors influence the propensity to require ventricular shunting.

Hypophosphatasia is a rare metabolic bone disorder that predisposes patients to craniosynostosis. Typically, patients born with hypophosphatasia will exhibit fused cranial sutures at birth. This is the first reported case of delayed onset of pancraniosynostosis in a patient with infantile hypophosphatasia. The severity of onset and delayed presentation in this patient are of interest and should give pause to those care providers who treat and evaluate patients with hypophosphatasia.

OBJECTIVE: The goal was to assess awareness of the choking game among physicians who care for adolescents and to explore their opinions regarding its inclusion in anticipatory guidance. METHODS: We surveyed 865 pediatricians and family practitioners. The survey was designed to assess physicians' awareness of the choking game and its warning signs, the suspected prevalence of patients' participation in the activity, and the willingness of physicians to include the choking game in adolescent anticipatory guidance. Information on the general use of anticipatory guidance also was collected. RESULTS: The survey was completed by 163 physicians (response rate: 21.8%). One-hundred eleven (68.1%) had heard of the choking game, 68 of them (61.3%) through sources in the popular media. General pediatricians were significantly more likely to report being aware of the choking game than were family practitioners or pediatric subspecialists (P = .004). Of physicians who were aware of the choking game, 75.7% identified ≥1 warning sign and 52.3% identified ≥3. Only 7.6% of physicians who were aware of the choking game reported that they cared for a patient they suspected was participating in the activity, and 2 (1.9%) reported that they include the choking game in anticipatory guidance for adolescents. However, 64.9% of all respondents agreed that the choking game should be included in anticipatory guidance. CONCLUSIONS: Close to one third of physicians surveyed were unaware of the choking game, a potentially life-threatening activity practiced by adolescents. Despite acknowledging that the choking game should be included in adolescent anticipatory guidance, few physicians reported actually discussing it. To provide better care for their adolescent patients, pediatricians and family practitioners should be knowledgable about risky behaviors encountered by their patients, including the choking game, and provide timely guidance about its dangers.

Cerebral palsy refers to a neurologic disorder of motor skills that is static in nature and is the result of injury to the brain before its development is complete. Many neurodegenerative or metabolic disorders have a slow rate of progression and can be misdiagnosed as cerebral palsy. Diseases that have been misdiagnosed as cerebral palsy are presented here to provide the clinician with framework for the complex evaluation of these patients.

Fanconi Anemia (FA) is an autosomal recessive disorder caused by mutations of DNA repair genes. The risk of oral cancer (OC) among FA patients is 800-times higher than in the general population, occurring at younger ages. Hematopoietic stem cell transplantation (HSCT), which greatly extends the life-expectancy in FA patients further increases the risk of OC in these patients. Patients with FA cannot tolerate chemo-and radiation therapy; hence, early detection of OC is critical to improve survival. Objective: To investigate the role of a numerical index for monitoring OC progression applied to FA patients in combination with a microfluidic “cytology-on-chip” assay and autofluorescence visualization (AFV) using VELscope (Visually Enhanced Lesion scope). Methods: Patients attending the Meeting for Adults with FA, held in Baltimore, Maryland in March 2014 underwent a conventional oral examination followed by AFV. Transepithelial brush samples of mucosal lesions suspected of being oral potentially malignant disorders (OPMD) were obtained using Orcellex® brush (Rovers Medical Devices, Oss, The Netherlands) and transported in ThinPrep® CytoLyt® for cytology-on-chip assays. A numerical OC risk index (0-100) developed and validated on 506 prospectively recruited non-FA patients with OPMD was applied to site-matched brush biopsy samples of FA patients. Results: A total of 28 FA patients (Age range: 18-61 yrs., M = 9, F = 19) participated in this study, of whom 13 have had HSCT. The majority of these lesions (89%) revealed loss of fluorescence (LOF+ve) with AFV. Compared to a cohort of prospectively recruited non-FA patients with OPMD (mean = 36.71, SD = 33.60), the mean OC risk index score for FA patients was 50.66 (SD = 32.83). Additionally, HSCT-recipient FA patients exhibited higher risk index scores (mean = 58.69, SD = 32.16) compared to non -HSCT-recipient FA patients (mean = 40.34, SD = 33.08). The frequency of nuclear aberrations such as micronuclei, bi- and poly-nucleated cells was significantly higher in FA patient cells than healthy controls and significantly higher in LOF+ve compared to LOV-negative OPMD. Two samples exhibited significantly higher WBC (white blood cell) counts, an indicator of inflammation; both were from LOF+ve OPMD found in HSCT-recipient FA patients. Conclusion: FA patients who are HSCT recipients have significantly higher OC risk index scores as well as increased prevalence of LOF+ve OPMD that demonstrate higher incidence of nuclear aberrations and inflammation. These findings are consistent with recent reports that HSCT in FA patients increases their risk for oral cancer. Therefore, use of the OC numerical index and cytology-on-chip assay in combination with AFV may improve the efficacy of conventional oral examination for long-term surveillance of OC in this high-risk patient population, while minimizing unwarranted scalpel biopsies. Citation Format: Timothy J. Abram, Pierre N. Floriano, Rameez Raja, Nancy Bass, Anne Gillenwater, Nadarajah Vigneswaran, John T. McDevitt. Minimally-invasive “cytology-on-chip” assay combined with continuous risk index for screening and surveillance of oral cancer in patients with Fanconi anemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-248.

Sudden unexpected death in epilepsy is the sudden, unexplained, unexpected death of an individual with epilepsy in which postmortem examination does not reveal an anatomic or toxicologic cause of death. Patients with congenital long QT syndrome and catecholaminergic polymorphic ventricular tachycardia have been frequently initially diagnosed with epilepsy. A cardiac channel molecular autopsy of the common long QT syndrome and catecholaminergic polymorphic ventricular tachycardia-susceptibility genes was performed on an archived necropsy specimen from an 8-year-old victim of sudden unexpected death in epilepsy. A novel, sporadic missense mutation in exon 104 of the RYR2-encoded ryanodine receptor/calcium release channel (c. 14806G>A, p.Gly4936Arg) was discovered. This mutation was absent in >600 reference alleles including both parents, involved a highly conserved amino acid, and localized to a key structure-function domain. To our knowledge, this is the first postmortem molecular diagnosis of catecholaminergic polymorphic ventricular tachycardia in a patient with sudden unexpected death in epilepsy.

Uniparental disomy is a genetic cause of disease implicated in a wide variety of neurologic disorders. A recently identified condition is maternal uniparental disomy for chromosome 14 (mUPD14) syndrome. A child with hypotonia and developmental delay was found to have mUPD14 after identification of a balanced karyotypic rearrangement involving both chromosomes 14. We explore the genetic mechanisms by which uniparental disomy can cause clinical abnormalities and karyotypic findings that should raise suspicion for uniparental disomy, review the literature on the mUPD14, and discuss clinical indications on which to suspect this diagnosis. Although it is more difficult to establish a diagnosis in the absence of visible karyotypic abnormalities involving chromosome 14, a distinct phenotype exists in mUPD14 syndrome: in utero growth restriction, congenital hypotonia, gross motor delay, arrested hydrocephalus, mild to moderate mental retardation, joint hyperextensibility, short stature, and precocious puberty. Testing for mUPD14 should be considered in infants with generalized hypotonia who have a history of in utero growth restriction.

Various paraneoplastic autoantibodies have been linked to discrete neurologic syndromes and tumors in adults, but little is known about their incidence in children. We report a cross-sectional study of known paraneoplastic antibodies in 59 children with opsoclonus-myoclonus-ataxia, 86% of whom were moderately or severely symptomatic, and 68% of whom had relapsed at the time of testing. This total number of patients includes 18 children with low-stage neuroblastoma (tested after tumor resection), six of whom had never been treated with immunosuppressants. All were seronegative for anti-Hu, anti-Ri, and anti-Yo, the three paraneoplastic antibodies most associated with opsoclonus-myoclonus or ataxia in adults. These data contrast with reports of anti-Hu-positive sera in children with high-stage tumors and suggest that anti-Hu, anti-Ri, and anti-Yo do not explain relapses in pediatric opsoclonus-myoclonus-ataxia. They underscore the need to search for unique autoantibodies, as well as cellular mechanisms of pediatric paraneoplastic disease.

Baylisascaris procyonis is a common and widespread parasite of raccoons in the United States and Canada. With large raccoon populations occurring in many areas, the potential risk of human infection with B procyonis is high. We report a case of severe raccoon roundworm (B procyonis) encephalitis in a young child to illustrate the unique clinical, diagnostic, and treatment aspects, as well as public health concerns ofB procyonis infection. Acute and convalescent serum and cerebrospinal fluid samples from the patient were tested for antibodies against B procyonis to assist in documenting infection. An extensive field survey of the patient's residence and the surrounding community was performed to investigate raccoon abundance and to determine the extent of raccoon fecal contamination and B procyonis eggs in the environment. The patient evidenced serologic conversion, and the field investigation demonstrated a raccoon population far in excess of anything previously reported. There was abundant evidence of B procyonis eggs associated with numerous sites of raccoon defecation around the patient's residence and elsewhere in the community. Because B procyonis can produce such severe central nervous system disease in young children, it is important that pediatricians are familiar with this infection. The public should be made aware of the hazards associated with raccoons and B procyonis to hopefully prevent future cases of B procyonisinfection.