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36


A Severe Case of Streptococcus pneumoniae Meningoencephalitis in an Infant Resulting in Fatal Strokes [Case Report]

Goodman, Michelle; Garcia, Mekka R; Wang, Heidy; Borja, Maria J; Miller, Claire; Segal, Devorah
PMCID:11097696
PMID: 38766553
ISSN: 2329-048x
CID: 5654132

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

Neifert, Sean N; Khan, Hammad A; Kurland, David B; Kim, Nora C; Yohay, Kaleb; Segal, Devorah; Samdani, Amer; Hwang, Steven; Lau, Darryl
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.
PMID: 35535821
ISSN: 1092-0684
CID: 5866152

Bilateral Optic Disc Edema in Multisystem Inflammatory Syndrome in Children Associated With COVID-19

Dinkin, Marc; Segal, Devorah; Zyskind, Israel; Oliveira, Cristiano; Liu, Grace
PMID: 34417772
ISSN: 1536-5166
CID: 5189912

A Case of Infant-Type Hemispheric Glioma with NTRK1 Fusion [Case Report]

Garcia, Mekka R; Bell, Lena; Miller, Claire; Segal, Devorah
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.
PMCID:9806371
PMID: 36601394
ISSN: 2329-048x
CID: 5523962

PURA-Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum

Johannesen, Katrine M; Gardella, Elena; Gjerulfsen, Cathrine E; Bayat, Allan; Rouhl, Rob P W; Reijnders, Margot; Whalen, Sandra; Keren, Boris; Buratti, Julien; Courtin, Thomas; Wierenga, Klaas J; Isidor, Bertrand; Piton, Amélie; Faivre, Laurence; Garde, Aurore; Moutton, Sébastien; Tran-Mau-Them, Frédéric; Denommé-Pichon, Anne-Sophie; Coubes, Christine; Larson, Austin; Esser, Michael J; Appendino, Juan Pablo; Al-Hertani, Walla; Gamboni, Beatriz; Mampel, Alejandra; Mayorga, Lía; Orsini, Alessandro; Bonuccelli, Alice; Suppiej, Agnese; Van-Gils, Julien; Vogt, Julie; Damioli, Simona; Giordano, Lucio; Moortgat, Stephanie; Wirrell, Elaine; Hicks, Sarah; Kini, Usha; Noble, Nathan; Stewart, Helen; Asakar, Shailesh; Cohen, Julie S; Naidu, SakkuBai R; Collier, Ashley; Brilstra, Eva H; Li, Mindy H; Brew, Casey; Bigoni, Stefania; Ognibene, Davide; Ballardini, Elisa; Ruivenkamp, Claudia; Faggioli, Raffaella; Afenjar, Alexandra; Rodriguez, Diana; Bick, David; Segal, Devorah; Coman, David; Gunning, Boudewijn; Devinsky, Orrin; Demmer, Laurie A; Grebe, Theresa; Pruna, Dario; Cursio, Ida; Greenhalgh, Lynn; Graziano, Claudio; Singh, Rahul Raman; Cantalupo, Gaetano; Willems, Marjolaine; Yoganathan, Sangeetha; Góes, Fernanda; Leventer, Richard J; Colavito, Davide; Olivotto, Sara; Scelsa, Barbara; Andrade, Andrea V; Ratke, Kelly; Tokarz, Farha; Khan, Atiya S; Ormieres, Clothilde; Benko, William; Keough, Karen; Keros, Sotirios; Hussain, Shanawaz; Franques, Ashlea; Varsalone, Felicia; Grønborg, Sabine; Mignot, Cyril; Heron, Delphine; Nava, Caroline; Isapof, Arnaud; Borlot, Felippe; Whitney, Robyn; Ronan, Anne; Foulds, Nicola; Somorai, Marta; Brandsema, John; Helbig, Katherine L; Helbig, Ingo; Ortiz-González, Xilma R; Dubbs, Holly; Vitobello, Antonio; Anderson, Mel; Spadafore, Dominic; Hunt, David; Møller, Rikke S; Rubboli, Guido
Background and Objectives/UNASSIGNED:syndrome by collecting data, including EEG, from a large cohort of affected patients. Methods/UNASSIGNED:Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. Results/UNASSIGNED:without any clear genotype-phenotype associations. Discussion/UNASSIGNED:syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.
PMCID:8592566
PMID: 34790866
ISSN: 2376-7839
CID: 5049312

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

Ebrahimi-Fakhari, Darius; Teinert, Julian; Behne, Robert; Wimmer, Miriam; D'Amore, Angelica; Eberhardt, Kathrin; Brechmann, Barbara; Ziegler, Marvin; Jensen, Dana M; Nagabhyrava, Premsai; Geisel, Gregory; Carmody, Erin; Shamshad, Uzma; Dies, Kira A; Yuskaitis, Christopher J; Salussolia, Catherine L; Ebrahimi-Fakhari, Daniel; Pearson, Toni S; Saffari, Afshin; Ziegler, Andreas; Kölker, Stefan; Volkmann, Jens; Wiesener, Antje; Bearden, David R; Lakhani, Shenela; Segal, Devorah; Udwadia-Hegde, Anaita; Martinuzzi, Andrea; Hirst, Jennifer; Perlman, Seth; Takiyama, Yoshihisa; Xiromerisiou, Georgia; Vill, Katharina; Walker, William O; Shukla, Anju; Dubey Gupta, Rachana; Dahl, Niklas; Aksoy, Ayse; Verhelst, Helene; Delgado, Mauricio R; Kremlikova Pourova, Radka; Sadek, Abdelrahim A; Elkhateeb, Nour M; Blumkin, Lubov; Brea-Fernández, Alejandro J; Dacruz-Álvarez, David; Smol, Thomas; Ghoumid, Jamal; Miguel, Diego; Heine, Constanze; Schlump, Jan-Ulrich; Langen, Hendrik; Baets, Jonathan; Bulk, Saskia; Darvish, Hossein; Bakhtiari, Somayeh; Kruer, Michael C; Lim-Melia, Elizabeth; Aydinli, Nur; Alanay, Yasemin; El-Rashidy, Omnia; Nampoothiri, Sheela; Patel, Chirag; Beetz, Christian; Bauer, Peter; Yoon, Grace; Guillot, Mireille; Miller, Steven P; Bourinaris, Thomas; Houlden, Henry; Robelin, Laura; Anheim, Mathieu; Alamri, Abdullah S; Mahmoud, Adel A H; Inaloo, Soroor; Habibzadeh, Parham; Faghihi, Mohammad Ali; Jansen, Anna C; Brock, Stefanie; Roubertie, Agathe; Darras, Basil T; Agrawal, Pankaj B; Santorelli, Filippo M; Gleeson, Joseph; Zaki, Maha S; Sheikh, Sarah I; Bennett, James T; Sahin, Mustafa
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.
PMID: 32979048
ISSN: 1460-2156
CID: 4778732

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

Behne, Robert; Teinert, Julian; Wimmer, Miriam; D'Amore, Angelica; Davies, Alexandra K; Scarrott, Joseph M; Eberhardt, Kathrin; Brechmann, Barbara; Chen, Ivy Pin-Fang; Buttermore, Elizabeth D; Barrett, Lee; Dwyer, Sean; Chen, Teresa; Hirst, Jennifer; Wiesener, Antje; Segal, Devorah; Martinuzzi, Andrea; Duarte, Sofia T; Bennett, James T; Bourinaris, Thomas; Houlden, Henry; Roubertie, Agathe; Santorelli, Filippo M; Robinson, Margaret; Azzouz, Mimoun; Lipton, Jonathan O; Borner, Georg H H; Sahin, Mustafa; Ebrahimi-Fakhari, Darius
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.
PMCID:7001721
PMID: 31915823
ISSN: 1460-2083
CID: 4778722

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

Beck, David B; Subramanian, T; Vijayalingam, S; Ezekiel, Uthayashankar R; Donkervoort, Sandra; Yang, Michele L; Dubbs, Holly A; Ortiz-Gonzalez, Xilma R; Lakhani, Shenela; Segal, Devorah; Au, Margaret; Graham, John M; Verma, Sumit; Waggoner, Darrel; Shinawi, Marwan; Bönnemann, Carsten G; Chung, Wendy K; Chinnadurai, G
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.
PMID: 31041561
ISSN: 1364-6753
CID: 4778712

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals

Ng, Bobby G; Sosicka, Paulina; Agadi, Satish; Almannai, Mohammed; Bacino, Carlos A; Barone, Rita; Botto, Lorenzo D; Burton, Jennifer E; Carlston, Colleen; Chung, Brian Hon-Yin; Cohen, Julie S; Coman, David; Dipple, Katrina M; Dorrani, Naghmeh; Dobyns, William B; Elias, Abdallah F; Epstein, Leon; Gahl, William A; Garozzo, Domenico; Hammer, Trine Bjørg; Haven, Jaclyn; Héron, Delphine; Herzog, Matthew; Hoganson, George E; Hunter, Jesse M; Jain, Mahim; Juusola, Jane; Lakhani, Shenela; Lee, Hane; Lee, Joy; Lewis, Katherine; Longo, Nicola; Lourenço, Charles Marques; Mak, Christopher C Y; McKnight, Dianalee; Mendelsohn, Bryce A; Mignot, Cyril; Mirzaa, Ghayda; Mitchell, Wendy; Muhle, Hiltrud; Nelson, Stanley F; Olczak, Mariusz; Palmer, Christina G S; Partikian, Arthur; Patterson, Marc C; Pierson, Tyler M; Quinonez, Shane C; Regan, Brigid M; Ross, M Elizabeth; Guillen Sacoto, Maria J; Scaglia, Fernando; Scheffer, Ingrid E; Segal, Devorah; Singhal, Nilika Shah; Striano, Pasquale; Sturiale, Luisa; Symonds, Joseph D; Tang, Sha; Vilain, Eric; Willis, Mary; Wolfe, Lynne A; Yang, Hui; Yano, Shoji; Powis, Zöe; Suchy, Sharon F; Rosenfeld, Jill A; Edmondson, Andrew C; Grunewald, Stephanie; Freeze, Hudson H
Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.
PMCID:6661012
PMID: 30817854
ISSN: 1098-1004
CID: 4778702

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

Veerapandiyan, Aravindhan; Aravindhan, Akilandeswari; Takahashi, James Huynh; Segal, Devorah; Pecor, Keith; Ming, Xue
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.
PMID: 29987971
ISSN: 1708-8283
CID: 4778692