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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.
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.
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.
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.
PMID: 28133863
ISSN: 1531-8249
CID: 4778682


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
ISSN: 1523-5866
CID: 2545142


Segal, Devorah; Rao, Harini; Thomas, Cheddhi; Cohen, Benjamin; Snuderl, Matija; Karajannis, Matthias; Allen, Jeffrey
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