Andrew C. Edmondson, MD, PhD

faculty photo
Assistant Professor of Pediatrics (Human Genetics)
Department: Pediatrics
Graduate Group Affiliations

Contact information
Children's Hospital of Philadelphia
Abramson Research Building, 1007C
3615 Civic Center Boulevard
Philadelphia, PA 19104
Office: 2155901177
Fax: 2155904297
Lab: 2674265423
BS (Microbiology and Russian, minors in Molecular Biology and Chemistry, University Honors)
Brigham Young University, 2004.
MD/PhD (Cell and Molecular Biology)
University of Pennsylvania, 2013.
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Description of Research Expertise

Research Interests: We use model systems (primary cells, iPSCs, mouse) of rare genetic neurodevelopmental disorders that disrupt glycosylation (known as Congenital Disorders of Glycosylation, or CDG) and glycoproteomics to study glycosylation in the brain.

Keywords: biochemical genetics, CDG, epilepsy, gene discovery, genetics, genomics, glycoproteomics, glycosylation, mouse models, neurogenetics, neuroscience, targeted therapeutics

Research Details: Glycosylation is the enzyme-mediated process by which a carbohydrate (or “glycan”) is covalently attached to a target macromolecule (typically a protein or lipid). As the most abundant post-translational modification, glycosylation generates immense biological variability and mediates fundamental biological processes. The biological significance of glycosylation is emphasized by the Congenital Disorders of Glycosylation (CDG), a group of ~170 rare genetic diseases that disrupt glycosylation. CDG patients exhibit multiorgan dysfunction, including neurological deficits such as epilepsy and neurodevelopmental abnormalities. The pathophysiology of CDG is attributed to disrupted protein glycosylation. However, the specific identities of the hypoglycosylated proteins responsible for most disease manifestations are unknown. In the nervous system, key proteins involved in neurotransmitter release, neuronal cell signaling, and cellular migration events are glycosylated, yet our understanding of the role of glycosylation in these processes is rudimentary. The genetic basis of CDG provides an opportunity to identify the neurobiological functions of glycosylation using model systems and glycoproteomics. Disruptions in glycosylation have also been implicated in the pathophysiology of complex neurologic and psychiatric diseases, including Alzheimer disease, amyotrophic lateral sclerosis (AML), and schizophrenia. The goal of my lab is to elucidate the biological roles of glycosylation in the brain and to develop novel therapeutic approaches to treating glycosylation-related disease manifestations. We currently focus on two major types of glycosylation, N-linked and O-linked.

N-linked glycosylation: Most CDG disrupt N-glycosylation. The single most common genetic cause of CDG results from biallelic mutations in PMM2. Patients with PMM2-CDG typically suffer from multi-systemic symptoms, including prominent and progressive neurological symptoms, such as intellectual disability, seizures, and cerebellar hypoplasia with resulting ataxia. Lifelong neurological impairment is the largest source of morbidity for PMM2-CDG patients. Currently, there is no effective treatment. We have several mouse models that recapitulate various aspects of the disease. Currently, we are employing mass spectrometry-based approaches to identify disrupted glycosylation for identification and validation of the molecular pathophysiology of disease mechanisms.

O-linked glycosylation: Our lab recently identified a new genetic cause of CDG, caused by biallelic mutations in GALNT2, which encodes a Golgi-localized glycosyltransferase that initiates mucin-type O-glycosylation. Patients with GALNT2-CDG exhibit global developmental delay, multi-focal treatment-resistant epilepsy, autistic features, and white matter changes on brain MRI. Currently, there is no effective treatment. We developed a mouse model for this disorder, with mice exhibiting spontaneous seizures and deficits across numerous behavioral and learning domains. Time-locked video EEG recordings identify seizures in the majority of these mice, which increase in prevalence as the mice age. Genetic dissection of the circuit suggests that molecular events in both excitatory and inhibitory neurons contribute to development of spontaneous seizures. These findings implicate a role of O-glycosylation in diverse neurological processes, including learning, memory, and neurotransmission. Glycoproteomic analysis of brains from these mice identified candidate glycoproteins and disrupted O-glycosites that likely underlie these abnormalities.

Rotation Projects: Rotation projects will be tailored to the goals and strengths of rotation students in discussion with Dr. Edmondson, but may fall into a number of broad categories, each with potential for contribution to lab publications and development into a larger PhD thesis project.
1) N-glycosylation (PMM2-CDG): Identification and validation of the molecular pathophysiology of disease mechanisms using primary cells, iPSCs, or collected mouse tissues
2) O-glycosylation (GALNT2-CDG): Identification and validation of the molecular pathophysiology of disease mechanisms using cellular models or collected mouse tissues
3) Other key glycosylation genes: More than 170 rare genetic diseases that disrupt glycosylation have been identified. The lab is interested in why disruptions of glycosylation at different points in the process produce varying disease symptoms. We are validating key genes for future project development.
4) Novel genetic syndrome discovery: In collaboration with the CHOP Center for Computational and Genomic Medicine (CCGM, https://www.research.chop.edu/center-for-computational-and-genomic-medicine), the lab is validating a novel diagnostic tool using long-read RNA-seq technologies. This tool is being applied to RNA samples from patients without a known genetic diagnosis, despite state-of-the-art clinical genetic diagnostic evaluations, exome and genome sequencing. Projects relate to functional laboratory validation of novel gene discoveries from these efforts.
5) GlycoRNA: Using Nobel Prize-winning bioorthogonal chemistry approaches, a new RNA modification, endogenously N-glycosylated RNA (glycoRNA), was recently discovered (Flynn et al. 2021. Cell. PMCID: PMC9097497) How N-glycosylation pathways contribute to glycoRNA production remains largely unexplored and the physiological functions of glycoRNA remain entirely unknown, presenting an exciting area for new discovery.

Lab Personnel:
We currently have a postdoc, a technician, two undergraduate students, and a physician scientist in the lab. We also have a clinical research coordinator and two clinical fellows pursuing clinical research investigations translating findings from the lab into clinical care of patients.

Lab Alumni (role while in the lab), current position:
Hind Alsharhan, MD (Clinical Biochemical Fellow), Assistant Professor of Genetic Medicine at Johns Hopkins University and Kuwait University
Hana Alharbi, MD (Clinical Biochemical Fellow), Attending Physician at University of Tabuk, Saudi Arabia
Daniah Albokhari, MD (Medical Biochemical Fellow), Attending Physician at Taibah University College of Medicine, Saudi Arabia
Shagun Kaur, MD (Medical Biochemical Fellow), Attending Physician at Phoenix Children’s Hospital, Arizona
Maria Patino (Clinical Research Coordinator), Research Coordinator at University of Pennsylvania

Selected Publications

Polla DL, Edmondson AC, Duvet S, March ME, Sousa AB, Lehman A; CAUSES Study, Niyazov D, van Dijk F, Demirdas S, van Slegtenhorst MA, Kievit AJA, Schulz C, Armstrong L, Bi X, Rader DJ, Izumi K, Zackai EH, de Franco E, Jorge P, Huffels SC, Hommersom M, Ellard S, Lefeber DJ, Santani A, Hand NJ, van Bokhoven H, He M, de Brouwer APM.: Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation. Am J Hum Genet 108: 1342-1349, Jul 2021.

Zilmer M, Edmondson AC, Khetarpal SA, Alesi V, Zaki MS, Rostasy K, Madsen CG, Lepri FR, Sinibaldi L, Cusmai R, Novelli A, Issa MY, Fenger CD, Abou Jamra R, Reutter H, Briuglia S, Agolini E, Hansen L, Petäjä-Repo UE, Hintze J, Raymond KM, Liedtke K, Stanley V, Musaev D, Gleeson JG, Vitali C, O'Brien WT, Gardella E, Rubboli G, Rader DJ, Schjoldager KT, Møller RS.: Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function. Brain 143: 1114-1126, Apr 2020.

Ligezka AN, Radenkovic S, Saraswat M, Garapati K, Ranatunga W, Krzysciak W, Yanaihara H, Preston G, Brucker W, McGovern RM, Reid JM, Cassiman D, Muthusamy K, Johnsen C, Mercimek-Andrews S, Larson A, Lam C, Edmondson AC, Ghesquière B, Witters P, Raymond K, Oglesbee D, Pandey A, Perlstein EO, Kozicz T, Morava E.: Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications. Ann Neurol 90(6): 887-900, Dec 2021.

Radenkovic S, Bird MJ, Emmerzaal TL, Wong SY, Felgueira C, Stiers KM, Sabbagh L, Himmelreich N, Poschet G, Windmolders P, Verheijen J, Witters P, Altassan R, Honzik T, Eminoglu TF, James PM, Edmondson AC, Hertecant J, Kozicz T, Thiel C, Vermeersch P, Cassiman D, Beamer L, Morava E, Ghesquière B.: The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG. Am J Hum Genet 104: 835-846, May 2019.

Terzic B, Cui Y, Edmondson AC, Tang S, Sarmiento N, Zaitseva D, Marsh ED, Coulter DA, Zhou Z.: X-linked cellular mosaicism underlies age-dependent occurrence of seizure-like events in mouse models of CDKL5 deficiency disorder. Neurobiol Dis 148(1): 105176, Jan 2021.

Tremblay-Laganière C, Maroofian R, Nguyen TTM, Karimiani EG, Kirmani S, Akbar F, Ibrahim S, Afroze B, Doosti M, Ashrafzadeh F, Babaei M, Efthymiou S, Christoforou M, Sultan T, Ladda RL, McLaughlin HM, Truty R, Mahida S, Cohen JS, Baranano K, Ismail FY, Patel MS, Lehman A, Edmondson AC, Nagy A, Walker MA, Mercimek-Andrews S, Maki Y, Sachdev R, Macintosh R, Palmer EE, Mancini GMS, Barakat TS, Steinfeld R, Rüsch CT, Stettner GM, Wagner M, Wortmann SB, Kini U, Brady AF, Stals KL, Ismayilova N, Ellard S, Bernardo D, Nugent K, McLean SD, Antonarakis SE, Houlden H, Kinoshita T, Campeau PM, Murakami Y.: PIGG variant pathogenicity assessment reveals characteristic features within 19 families. Genet Med 23(10): 1873-188, Oct 2021.

Alsharhan H, He M, Edmondson AC, Daniel EJP, Chen J, Donald T, Bakhtiari S, Amor DJ, Jones EA, Vassallo G, Vincent M, Cogné B, Deb W, Werners AH, Jin SC, Bilguvar K, Christodoulou J, Webster RI, Yearwood KR, Ng BG, Freeze HH, Kruer MC, Li D, Raymond KM, Bhoj EJ, Sobering AK.: ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes. J Inherit Metab Dis 44(4): 1001-1012, Jul 2021.

Witters P, Tahata S, Barone R, Õunap K, Salvarinova R, Grønborg S, Hoganson G, Scaglia F, Lewis AM, Mori M, Sykut-Cegielska J, Edmondson A, He M, Morava E.: Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG. Genetics in Medicine 22(6): 1102-1107, June 2020.

Chen J, Li X, Edmondson A, Meyers GD, Izumi K, Ackermann AM, Morava E, Ficicioglu C, Bennett MJ, He M.: Increased Clinical Sensitivity and Specificity of Plasma Protein N-Glycan Profiling for Diagnosing Congenital Disorders of Glycosylation by Use of Flow Injection-Electrospray Ionization-Quadrupole Time-of-Flight Mass Spectrometry. Clin Chem 65(5): 653–663, May 2019.

Alsharhan H, Ng BG, Daniel EJP, Friedman J, Pivnick EK, Al-Hashem A, Faqeih EA, Liu P, Engelhardt NM, Keller KN, Chen J, Mazzeo PA; University of Washington Center for Mendelian Genomics (UW-CMG), Rosenfeld JA, Bamshad MJ, Nickerson DA, Raymond KM, Freeze HH, He M, Edmondson AC, Lam C.: Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG. J Inherit Metab Dis 44(4): 987-1000, Jul 2021.

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Last updated: 05/15/2024
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