@article {997, title = {Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG.}, journal = {J Inherit Metab Dis}, year = {2021}, month = {2021 Feb 13}, abstract = {

Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3-CDG, we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man GlcNAc consistent with their truncated lipid-linked precursor oligosaccharides. This spectrum of N-glycan changes is unique to ALG3-CDG. These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.

}, issn = {1573-2665}, doi = {10.1002/jimd.12367}, author = {Alsharhan, Hind and Ng, Bobby G and Daniel, Earnest James Paul and Friedman, Jennifer and Pivnick, Eniko K and Al-Hashem, Amal and Faqeih, Eissa Ali and Liu, Pengfei and Engelhardt, Nicole M and Keller, Kierstin N and Chen, Jie and Mazzeo, Pamela A and Rosenfeld, Jill A and Bamshad, Michael J and Nickerson, Deborah A and Raymond, Kimiyo M and Freeze, Hudson H and He, Miao and Edmondson, Andrew C and Lam, Christina} } @article {928, title = {Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 04 01}, pages = {1114-1126}, abstract = {

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

}, keywords = {Adolescent, Animals, Apolipoprotein C-III, Child, Child, Preschool, Developmental Disabilities, Female, Glycosylation, Humans, Loss of Function Mutation, Male, Mice, N-Acetylgalactosaminyltransferases, Pedigree, Rats, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awaa063}, author = {Zilmer, Monica and Edmondson, Andrew C and Khetarpal, Sumeet A and Alesi, Viola and Zaki, MAH S and Rostasy, Kevin and Madsen, Camilla G and Lepri, Francesca R and Sinibaldi, Lorenzo and Cusmai, Raffaella and Novelli, Antonio and Issa, Mahmoud Y and Fenger, Christina D and Abou Jamra, Rami and Reutter, Heiko and Briuglia, Silvana and Agolini, Emanuele and Hansen, Lars and Pet{\"a}j{\"a}-Repo, Ulla E and Hintze, John and Raymond, Kimiyo M and Liedtke, Kristen and Stanley, Valentina and Musaev, Damir and Gleeson, Joseph G and Vitali, Cecilia and O{\textquoteright}Brien, W Timothy and Gardella, Elena and Rubboli, Guido and Rader, Daniel J and Schjoldager, Katrine T and M{\o}ller, Rikke S} } @article {241, title = {PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Jul 03}, pages = {96-107}, abstract = {

Human phosphoglucomutase 3 (PGM3) catalyzes the conversion of N-acetyl-glucosamine (GlcNAc)-6-phosphate into GlcNAc-1-phosphate during the synthesis of uridine diphosphate (UDP)-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways. We identified three unrelated children with recurrent infections, congenital leukopenia including neutropenia, B and T~cell lymphopenia, and progression to bone marrow failure. Whole-exome sequencing demonstrated deleterious mutations in PGM3 in all three subjects, delineating their disease to be due to an unsuspected congenital disorder of glycosylation (CDG). Functional studies of the disease-associated PGM3 variants in E.~coli cells demonstrated reduced PGM3 activity for all mutants tested. Two of the three children had skeletal anomalies resembling Desbuquois dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability. However, these additional features were absent in the third child, showing the clinical variability of the disease. Two children received hematopoietic stem cell transplantation of cord blood and bone marrow from matched related donors; both had successful engraftment and correction of neutropenia and lymphopenia. We define PGM3-CDG as a treatable immunodeficiency, document the power of whole-exome sequencing in gene discoveries for rare disorders, and illustrate the utility of genomic analyses in studying combined and variable phenotypes.

}, keywords = {Bone Diseases, Developmental, Congenital Disorders of Glycosylation, Female, Humans, Immunologic Deficiency Syndromes, Male, Mutation, Pedigree, Phosphoglucomutase}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.05.007}, author = {Stray-Pedersen, Asbj{\o}rg and Backe, Paul H and Sorte, Hanne S and M{\o}rkrid, Lars and Chokshi, Niti Y and Erichsen, Hans Christian and Gambin, Tomasz and Elgst{\o}en, Katja B P and Bj{\o}r{\r a}s, Magnar and Wlodarski, Marcin W and Kr{\"u}ger, Marcus and Jhangiani, Shalini N and Muzny, Donna M and Patel, Ankita and Raymond, Kimiyo M and Sasa, Ghadir S and Krance, Robert A and Martinez, Caridad A and Abraham, Shirley M and Speckmann, Carsten and Ehl, Stephan and Hall, Patricia and Forbes, Lisa R and Merckoll, Else and Westvik, Jostein and Nishimura, Gen and Rustad, Cecilie F and Abrahamsen, Tore G and R{\o}nnestad, Arild and Osnes, Liv T and Egeland, Torstein and R{\o}dningen, Olaug K and Beck, Christine R and Boerwinkle, Eric A and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and Lausch, Ekkehart and Hanson, I Celine} }