Research Publications

A rare cause of infantile achalasia: GMPPA-congenital disorder of glycosylation with two novel compound heterozygous variants. Geiculescu I, Dranove J, Cosper G, Edmondson AC, Morava-Kozicz E, Carter LB. Am J Med Genet A. 2022 Jun 4. doi: 10.1002/ajmg.a.62859. Epub ahead of print. PMID: 35665995.

Achalasia is a disorder of the esophagus, the tube that carries food from the mouth to the stomach. It is characterized by enlargement of the esophagus, impaired ability of the esophagus to push food down toward the stomach (peristalsis), and failure of the ring-shaped muscle at the bottom of the esophagus (the lower esophageal sphincter) to relax. Because achalasia is rare in the pediatric population, clinicians should consider associated genetic disorders. This includes GMPPA-congenital disorder of glycosylation (CDG), a rare type of CDG that is caused by variants in the GMPPA gene. In this study, researchers describe a 9-month-old female with achalasia and alacrima (reduced or absent ability to produce tears). The patient was found to have two novel compound heterozygous variants in the GMPPA gene that are associated with GMPPA-CDG. Authors provide a brief review of GMPPA-CDG, including management of this condition.

ALG8-CDG: Molecular and phenotypic expansion suggests clinical management guidelines. Albokhari D, Ng BG, Guberinic A, Daniel EJP, Engelhardt NM, Barone R, Fiumara A, Garavelli L, Trimarchi G, Wolfe L, Raymond KM, Morava E, He M, Freeze HH, Lam C, Edmondson AC. J Inherit Metab Dis. 2022 Jun 18. doi: 10.1002/jimd.12527. Epub ahead of print. PMID: 35716054.

ALG8-congenital disorder of glycosylation (ALG8-CDG) is a rare, inherited disorder that affects multiple systems in the body. Patients with ALG8-CDG commonly present with decreased muscle tone, intestinal problems, and liver problems. In this study, researchers describe seven new individuals with ALG8-CDG, bringing the total to 26 individuals reported in medical literature. The team diagnosed these patients based on biochemical and molecular testing, identifying nine novel variants in ALG8. The cohort also includes the two oldest patients reported to date. This study expands the phenotype of ALG8-CDG to include stable intellectual disability, autism spectrum disorder, and other neuropsychiatric symptoms. Researchers also expand the clinical features in a variety of organ systems. To improve clinical management, authors suggest a comprehensive evaluation and monitoring strategy.

CDG or not CDG. Freeze HH, Jaeken J, Matthijs G. J Inherit Metab Dis. 2022 May;45(3):383-385. doi: 10.1002/jimd.12498. Epub 2022 Apr 1. PMID: 35338706; PMCID: PMC9121739.

In this letter to the editor, an expert team of authors explores a consensus on which genetic conditions should be identified as congenital disorders of glycosylation (CDG). “They are aiming to be inclusive; CDG should be used as the correct nomenclature in any disorders where the synthesis of glycans, glycoproteins, or glycolipids—including oligosaccharide transfer, glycan maturation, or trafficking—is affected,” says Eva Morava-Kozicz, MD, PhD, principal investigator of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC). “This is demonstrated by abnormal glycosylation in functional studies, and should be called a CDG.”

Clinical and molecular characterization of a third patient with a milder and a predominantly movement disorder phenotype. Elsharkawi I, Wongkittichote P, Daniel EJP, Starosta RT, Ueda K, Ng BG, Freeze HH, He M, Shinawi M. DDOST-CDG. J Inherit Metab Dis. 2022 Oct 10. doi: 10.1002/jimd.12565. Epub ahead of print. PMID: 36214423.

DDOST-CDG is an ultra-rare type of congenital disorder of glycosylation (CDG) that is caused by mutations in the gene DDOST. The metabolic disorder was previously reported in just two patients, whose clinical features included severe developmental delay, failure to thrive, and hypotonia (low muscle tone). Both patients also had abnormal transferrin glycosylation. In this study, researchers describe a new patient with DDOST-CDG. The 18-year-old male presented with moderate developmental delay, progressive opsoclonus (involuntary, rapid eye movements), myoclonus (involuntary, sudden muscle spasms), ataxia (impaired balance or coordination), tremor, and dystonia (involuntary muscle contractions that cause repetitive or twisting movements). The team performed several tests, including biochemical studies, exome sequencing, plasma N-glycan profiling, and western blot analysis, to learn more about the patient’s clinical features. Authors state that these insights—including new findings on the clinical variability, phenotypes, and genotypes of DDOST-CDG—are essential for diagnosing and managing patients with DDOST-CDG.

Defining the mild variant of leukocyte adhesion deficiency type II (SLC35C1-congenital disorder of glycosylation) and response to l-fucose therapy: Insights from two new families and review of the literature. Tahata S, Raymond K, Quade M, Barnes S, Boyer S, League S, Kumanovics A, Abraham R, Jacob E, Menon P, Morava E. Am J Med Genet A. 2022 Mar 26. doi: 10.1002/ajmg.a.62737. Epub ahead of print. PMID: 35338746.

Leukocyte adhesion deficiency type II (LAD II, also known as SLC35C1-congenital disorder of glycosylation) is an autosomal recessive disorder characterized by growth and cognitive impairment, peripheral neutrophilia, recurrent infections, and the Bombay blood phenotype. Among a subset of patients with a milder presentation, descriptions have also included short stature and developmental delay with minimal immune and hematologic (relating to blood) features. While some patients with LAD II benefit from oral fucose therapy, this has not yet been studied in patients with milder disease. In this study, researchers describe three new patients from two separate families with the milder variant of LAD II and review the published literature. After 27 months of oral fucose supplementation, one patient showed improvements in speech and cognition, CD15 expression, and core fucosylation of serum glycoproteins. Authors note that these patients support classification of this disorder into distinct subtypes—a classical severe and an attenuated variant—and provide preliminary evidence of benefit of fucose therapy in the latter group.

N-glycoproteomics reveals distinct glycosylation alterations in NGLY1-deficient patient-derived dermal fibroblasts. Budhraja R, Saraswat M, De Graef D, Ranatunga W, Ramarajan MG, Mousa J, Kozicz T, Pandey A, Morava E.. J Inherit Metab Dis. 2022 Sep 14. doi: 10.1002/jimd.12557. Epub ahead of print. PMID: 36102038

NGLY1-CDDG (congenital disorder of deglycosylation) is a multisystemic, inherited condition caused by a mutation in the NGLY1 gene. Although the NGLY1 enzyme plays an essential role in the process of deglycosylation, the effects of NGLY1 deficiency on protein glycosylation are not yet understood. In this study, researchers explored the hypothesis that NGLY1 deficiency leads to accumulation of misfolded glycoproteins. Using glycoproteomics and proteomics methods, the team analyzed fibroblasts from four patients with NGLY1 deficiency carrying different variants in NGLY1. Results showed no significant accumulation of glycoproteins in the NGLY1-deficient fibroblasts. However, researchers found distinct changes in specific glycoproteins. As the first study of its kind, authors note that these findings highlight new insights for understanding NGLY1-CDDG.

Origin of cytoplasmic GDP-fucose determines its contribution to glycosylation reactions. Sosicka P, Ng BG, Pepi LE, Shajahan A, Wong M, Scott DA, Matsumoto K, Xia ZJ, Lebrilla CB, Haltiwanger RS, Azadi P, Freeze HH. J Cell Biol. 2022 Oct 3;221(10):e202205038. doi: 10.1083/jcb.202205038. Epub 2022 Sep 2. PMID: 36053214.

Congenital disorders of glycosylation (CDG) are a group of inherited metabolic disorders that affect a process called glycosylation. This process uses monosaccharides (simple sugars) from multiple sources to produce nucleotide sugars (activated forms of monosaccharides). Since these sources of monosaccharides are assumed to contribute to one similar pool, their individual contributions are often overlooked. In this study, researchers explored the hypothesis that fucose (a type of monosaccharide) exists in multiple, distinct pools. The team measured the contribution of fucose from different sources. Findings show that cells identify and select from different pools of fucose for the process of glycosylation. Authors also present new perspectives on monosaccharide metabolism, which may have other applications beyond glycosylation.

A new D-galactose treatment monitoring index for PGM1-CDG. Perales-Clemente E, Liedtke K, Studinski A, Radenkovic S, Gavrilov D, Oglesbee D, Matern D, Rinaldo P, Tortorelli S, Morava E, Raymond K. J Inherit Metab Dis. 2021 Sep;44(5):1263-1271. doi: 10.1002/jimd.12406. Epub 2021 Jun 22.

ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes. 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. J Inherit Metab Dis. 2021 Mar 18. doi: 10.1002/jimd.12378. Online ahead of print.

Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings. Wilson MP, Garanto A, Pinto E Vairo F, Ng BG, Ranatunga WK, Ventouratou M, Baerenfaenger M, Huijben K, Thiel C, Ashikov A, Keldermans L, Souche E, Vuillaumier-Barrot S, Dupré T, Michelakakis H, Fiumara A, Pitt J, White SM, Lim SC, Gallacher L, Peters H, Rymen D, Witters P, Ribes A, Morales-Romero B, Rodríguez-Palmero A, Ballhausen D, de Lonlay P, Barone R, Janssen MCH, Jaeken J, Freeze HH, Matthijs G, Morava E, Lefeber DJ. Am J Hum Genet. 2021 Nov 4;108(11):2130-2144. doi: 10.1016/j.ajhg.2021.09.012. Epub 2021 Oct 14. PMID: 34653363; PMCID: PMC8595932.

Congenital disorders of glycosylation (CDGs) are a group of rare diseases characterized by hypoglycosylation. The STT3A gene plays an essential role in protein N-glycosylation. In this study, researchers identified 16 individuals from nine families who have variants in STT3A, leading to an autosomal-dominant CDG. They describe the features of these individuals including variable skeletal anomalies, short stature, large head, muscle cramps, and in some, intellectual disability. The authors also present data to support a dominant form of STT3A-CDG that is unusual among type I CDGs.

Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation. 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. Am J Hum Genet. 2021 Jul 1;108(7):1342-1349. doi: 10.1016/j.ajhg.2021.05.010. Epub 2021 Jun 17.

D-galactose supplementation in individuals with PMM2-CDG: results of a multicenter, open label, prospective pilot clinical trial. Witters P, Andersson H, Jaeken J, Tseng L, van Karnebeek CDM, Lefeber DJ, Cassiman D, Morava E. Orphanet J Rare Dis. 2021 Mar 20;16(1):138. doi: 10.1186/s13023-020-01609-z.

Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation. Radenkovic S, Fitzpatrick-Schmidt T, Byeon SK, Madugundu AK, Saraswat M, Lichty A, Wong SYW, McGee S, Kubiak K, Ligezka A, Ranatunga W, Zhang Y, Wood T, Friez MJ, Clarkson K, Pandey A, Jones JR, Morava E. Mol Genet Metab. 2021 Jan;132(1):27-37. doi: 10.1016/j.ymgme.2020.10.007. Epub 2020 Oct 17.

Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG. 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. J Inherit Metab Dis. 2021 Feb 13. doi: 10.1002/jimd.12367. Online ahead of print.

Genotype-Phenotype Correlations in PMM2-CDG. Vaes L, Rymen D, Cassiman D, Ligezka A, Vanhoutvin N, Quelhas D, Morava E, Witters P Genotype-Phenotype Correlations in PMM2-CDG . Genes (Basel). 2021 Oct 21;12(11):1658. doi: 10.3390/genes12111658. PMID: 34828263; PMCID: PMC8620515.

PMM2-CDG is a rare disease that causes hypoglycosylation of multiple proteins. Direct genotype-phenotype correlations are not yet identified. In this paper, researchers carried out a retrospective cohort study on 26 PMM2-CDG patients. They collected the identified genotype, as well as variables indicating the disease severity and patients' phenotype. By studying the phenotypic effects of patients' genotype, researchers gained a better insight in the phenotypic prognosis of PMM2-CDG, according to their molecular base. They concluded that specific pathogenic variants (p.Pro113Leu and p.Phe119Leu) have a significantly higher total NPCRS disease severity score which indicates a more severe clinical outcome. The Nijmegen Paediatric CDG Rating Scale (NPCRS) is a tool to objectively follow the clinical disease progression in clinical disorders of glycosylation (CDG). Pathogenic variants affecting the folding or stabilization domain of the PMM2 enzyme protein have a significantly lower total NPCRS and thus the genetic results could provide a good prognostic clinical outcome.

Immune dysfunction in MGAT2-CDG: A clinical report and review of the literature. Poskanzer SA, Schultz MJ, Turgeon CT, Vidal-Folch N, Liedtke K, Oglesbee D, Gavrilov DK, Tortorelli S, Matern D, Rinaldo P, Bennett JT, Thies JM, Chang IJ, Beck AE, Raymond K, Allenspach EJ, Lam C. Am J Med Genet A. 2021 Jan;185(1):213-218. doi: 10.1002/ajmg.a.61914. Epub 2020 Oct 12.

Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder. Morava E, Schatz UA, Torring PM, Abbott MA, Baumann M, Brasch-Andersen C, Chevalier N, Dunkhase-Heinl U, Fleger M, Haack TB, Nelson S, Potelle S, Radenkovic S, Bommer GT, Van Schaftingen E, Veiga-da-Cunha M. Am J Hum Genet. 2021 Jun 3;108(6):1151-1160. doi: 10.1016/j.ajhg.2021.04.017. Epub 2021 May 11.

Study authors describe a genetic syndrome due to PGM2L1 deficiency. The gene PGM2L1 is highly expressed in the brain. They report the identification of four children with PGM2L1 deficiency sharing a largely neurological phenotype. All four children had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals. Study authors concluded that, while analyses indicated PGM2L1 deficiency does not appear to be a glycosylation defect, the discovery of this developmental disorder highlights the importance of glucose-1,6-biophosphate in the brain.

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management. Altassan R, Radenkovic S, Edmondson AC, Barone R, Brasil S, Cechova A, Coman D, Donoghue S, Falkenstein K, Ferreira V, Ferreira C, Fiumara A, Francisco R, Freeze H, Grunewald S, Honzik T, Jaeken J, Krasnewich D, Lam C, Lee J, Lefeber D, Marques-da-Silva D, Pascoal C, Quelhas D, Raymond KM, Rymen D, Seroczynska M, Serrano M, Sykut-Cegielska J, Thiel C, Tort F, Vals MA, Videira P, Voermans N, Witters P, Morava E. J Inherit Metab Dis. 2021 Jan;44(1):148-163. doi: 10.1002/jimd.12286. Epub 2020 Sep 15.

Is X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy a congenital disorder of glycosylation?. Berry GT, Freeze HH, Morava E. Epilepsia. 2021 Feb;62(2):335-336. doi: 10.1111/epi.16817. Epub 2021 Feb 11.

Liver manifestations in a cohort of 39 patients with congenital disorders of glycosylation: pin-pointing the characteristics of liver injury and proposing recommendations for follow-up. Starosta RT, Boyer S, Tahata S, Raymond K, Lee HE, Wolfe LA, Lam C, Edmondson AC, Schwartz IVD, Morava E. Orphanet J Rare Dis. 2021 Jan 7;16(1):20. doi: 10.1186/s13023-020-01630-2.

Should patients with Phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency?. Čechová A, Honzík T, Edmondson AC, Ficicioglu C, Serrano M, Barone R, De Lonlay P, Schiff M, Witters P, Lam C, Patterson M, Janssen MCH, Correia J, Quelhas D, Sykut-Cegielska J, Plotkin H, Morava E, Sarafoglou K. Mol Genet Metab. 2021 Aug;133(4):397-399. doi: 10.1016/j.ymgme.2021.06.003. Epub 2021 Jun 11.

Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications. 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. Ann Neurol. 2021 Dec;90(6):887-900. doi: 10.1002/ana.26245. Epub 2021 Oct 26.

Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study. Witters P, Edmondson AC, Lam C, Johnsen C, Patterson MC, Raymond KM, He M, Freeze HH, Morava E. Orphanet J Rare Dis. 2021 Feb 25;16(1):102. doi: 10.1186/s13023-021-01751-2.

Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy. Del Caño-Ochoa F, Ng BG, Abedalthagafi M, Almannai M, Cohn RD, Costain G, Elpeleg O, Houlden H, Karimiani EG, Liu P, Manzini MC, Maroofian R, Muriello M, Al-Otaibi A, Patel H, Shimon E, Sutton VR, Toosi MB, Wolfe LA, Rosenfeld JA, Freeze HH, Ramón-Maiques S. Genet Med. 2020 Oct;22(10):1598-1605. doi: 10.1038/s41436-020-0833-2. Epub 2020 May 28.

Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG. 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. Genet Med. 2020 Jun;22(6):1102-1107. doi: 10.1038/s41436-020-0767-8. Epub 2020 Feb 27.

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation. Čechová A, Altassan R, Borgel D, Bruneel A, Correia J, Girard M, Harroche A, Kiec-Wilk B, Mohnike K, Pascreau T, Pawliński Ł, Radenkovic S, Vuillaumier-Barrot S, Aldamiz-Echevarria L, Couce ML, Martins EG, Quelhas D, Morava E, de Lonlay P, Witters P, Honzík T. J Inherit Metab Dis. 2020 Jul;43(4):671-693. doi: 10.1002/jimd.12241. Epub 2020 Apr 21.

Defining a new immune deficiency syndrome: MAN2B2-CDG. Verheijen J, Wong SY, Rowe JH, Raymond K, Stoddard J, Delmonte OM, Bosticardo M, Dobbs K, Niemela J, Calzoni E, Pai SY, Choi U, Yamazaki Y, Comeau AM, Janssen E, Henderson L, Hazen M, Berry G, Rosenzweig SD, Aldhekri HH, He M, Notarangelo LD, Morava E. J Allergy Clin Immunol. 2020 Mar;145(3):1008-1011. doi: 10.1016/j.jaci.2019.11.016. Epub 2019 Nov 24.

Fetal glycosylation defect due to ALG3 and COG5 variants detected via amniocentesis: Complex glycosylation defect with embryonic lethal phenotype. Ferrer A, Starosta RT, Ranatunga W, Ungar D, Kozicz T, Klee E, Rust LM, Wick M, Morava E. Mol Genet Metab. 2020 Dec;131(4):424-429. doi: 10.1016/j.ymgme.2020.11.003. Epub 2020 Nov 7.

Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function. 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. Brain. 2020 Apr 1;143(4):1114-1126. doi: 10.1093/brain/awaa063.

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions. Ng BG, Eklund EA, Shiryaev SA, Dong YY, Abbott MA, Asteggiano C, Bamshad MJ, Barr E, Bernstein JA, Chelakkadan S, Christodoulou J, Chung WK, Ciliberto MA, Cousin J, Gardiner F, Ghosh S, Graf WD, Grunewald S, Hammond K, Hauser NS, Hoganson GE, Houck KM, Kohler JN, Morava E, Larson AA, Liu P, Madathil S, McCormack C, Meeks NJL, Miller R, Monaghan KG, Nickerson DA, Palculict TB, Papazoglu GM, Pletcher BA, Scheffer IE, Schenone AB, Schnur RE, Si Y, Rowe LJ, Serrano Russi AH, Russo RS, Thabet F, Tuite A, Villanueva MM, Wang RY, Webster RI, Wilson D, Zalan A; Undiagnosed Diseases Network, University of Washington Center for Mendelian Genomics (UW-CMG), Wolfe LA, Rosenfeld JA, Rhodes L, Freeze HH. J Inherit Metab Dis. 2020 Nov;43(6):1333-1348. doi: 10.1002/jimd.12290. Epub 2020 Aug 5.

Vascular ring anomaly in a patient with phosphomannomutase 2 deficiency: A case report and review of the literature. Qian Z, Van den Eynde J, Heymans S, Mertens L, Morava E. JIMD Rep. 2020 Aug 19;56(1):27-33. doi: 10.1002/jmd2.12160. eCollection 2020 Nov.

Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG. Iyer S, Sam FS, DiPrimio N, Preston G, Verheijen J, Murthy K, Parton Z, Tsang H, Lao J, Morava E, Perlstein EO. Dis Model Mech. 2019 Nov 11;12(11):dmm040584. doi: 10.1242/dmm.040584.