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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
Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression
Olson, Heather E; Kelly, McKenna; LaCoursiere, Christopher M; Pinsky, Rebecca; Tambunan, Dimira; Shain, Catherine; Ramgopal, Sriram; Takeoka, Masanori; Libenson, Mark H; Julich, Kristina; Loddenkemper, Tobias; Marsh, Eric D; Segal, Devorah; Koh, Susan; Salman, Michael S; Paciorkowski, Alex R; Yang, Edward; Bergin, Ann M; Sheidley, Beth Rosen; Poduri, Annapurna
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/CONCLUSIONS: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.
PMCID:5366084
PMID: 28133863
ISSN: 1531-8249
CID: 4778682
ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMAS: A CLINICOPATHOLOGIC AND MOLECULAR PROFILE [Meeting Abstract]
Segal, Devorah; Thomas, Cheddhi; Bowman, Christopher; Kannan, Kasthuri; Wang, Shiyang; Heguy, Adriana; Liechty, Benjamin; Jones, David TW; Hovestadt, Volker; Pfister, Stefan M; Karajannis, Matthias; Snuderl, Matija
ISI:000398604103008
ISSN: 1523-5866
CID: 2545142
MIDBRAIN GLIOMAS: A LARGE SERIES THAT IDENTIFIES FEATURES CORRESPONDING WITH OUTCOME [Meeting Abstract]
Segal, Devorah; Rao, Harini; Thomas, Cheddhi; Cohen, Benjamin; Snuderl, Matija; Karajannis, Matthias; Allen, Jeffrey
ISI:000398604103102
ISSN: 1523-5866
CID: 2545152
Utility of MRI versus tumor markers for post-treatment surveillance of marker-positive CNS germ cell tumors
Cheung, Victoria; Segal, Devorah; Gardner, Sharon L; Zagzag, David; Wisoff, Jeffrey H; Allen, Jeffrey C; Karajannis, Matthias A
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.
PMID: 27406584
ISSN: 1573-7373
CID: 2180172
Severe holocord syrinx in a child with megalencephaly-capillary malformation syndrome
Segal, Devorah; Heary, Robert F; Sabharwal, Sanjeev; Barry, Maureen T; Ming, Xue
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.
PMID: 27035547
ISSN: 1933-0715
CID: 2188622
Pediatric Brain Tumors: An Update
Segal, Devorah; Karajannis, Matthias A
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.
PMID: 27230809
ISSN: 1538-3199
CID: 2115152
MIDBRAIN GLIOMAS: A LARGE SERIES OF CLINICALLY AND RADIOGRAPHICALLY HETEROGENEOUS TUMORS [Meeting Abstract]
Segal, Devorah; Rao, Harini; Thomas, Cheddhi; Cohen, Benjamin; Snuderl, Matija; Karajannis, Matthias; Allen, Jeffrey
ISI:000379749000370
ISSN: 1522-8517
CID: 2964232
ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMAS: A CLINICOPATHOLOGIC AND MOLECULAR PROFILE [Meeting Abstract]
Segal, Devorah; Thomas, Cheddhi; Bowman, Christopher; Kannan, Kasthuri; Wang, Shiyang; Heguy, Adriana; Liechty, Benjamin; Jones, David; Hovestadt, Volker; Pfister, Stefan; Karajannis, Matthias; Snuderl, Matija
ISI:000379749000302
ISSN: 1523-5866
CID: 2687542