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Congenital disorder of glycosylation

Rita Francisco, Carlota Pascoal, Dorinda Marques-da-Silva, Eva Morava, Glen A Gole, David Coman, Jaak Jaeken, Vanessa Dos Reis Ferreira
Congenital disorders of glycosylation (CDG) are a rapidly growing family comprising >100 genetic diseases. Some 25 CDG are pure O-glycosylation defects. Even among this CDG subgroup, phenotypic diversity is broad, ranging from mild to severe poly-organ/system dysfunction. Ophthalmic manifestations are present in 60% of these CDG. The ophthalmic manifestations in N-glycosylation-deficient patients have been described elsewhere. The present review documents the spectrum and incidence of eye disorders in patients with pure O-glycosylation defects with the aim of assisting diagnosis and management and promoting research...
January 2019: Journal of Inherited Metabolic Disease
Ruqaiah Altassan, Romain Péanne, Jaak Jaeken, Rita Barone, Muad Bidet, Delphine Borgel, Sandra Brasil, David Cassiman, Anna Cechova, David Coman, Javier Corral, Joana Correia, María Eugenia de la Morena-Barrio, Pascale de Lonlay, Vanessa Dos Reis, Carlos R Ferreira, Agata Fiumara, Rita Francisco, Hudson Freeze, Simone Funke, Thatjana Gardeitchik, Matthijs Gert, Muriel Girad, Marisa Giros, Stephanie Grünewald, Trinidad Hernández-Caselles, Tomas Honzik, Marlen Hutter, Donna Krasnewich, Christina Lam, Joy Lee, Dirk Lefeber, Dorinda Marques-de-Silva, Antonio F Martinez, Hossein Moravej, Katrin Õunap, Carlota Pascoal, Tiffany Pascreau, Marc Patterson, Dulce Quelhas, Kimiyo Raymond, Peymaneh Sarkhail, Manuel Schiff, Małgorzata Seroczyńska, Mercedes Serrano, Nathalie Seta, Jolanta Sykut-Cegielska, Christian Thiel, Federic Tort, Mari-Anne Vals, Paula Videira, Peter Witters, Renate Zeevaert, Eva Morava
Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG...
January 2019: Journal of Inherited Metabolic Disease
Irene J Chang, Miao He, Christina T Lam
Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of >130 diseases caused by defects in various steps along glycan modification pathways. The vast majority of these monogenic diseases are autosomal recessive and have multi-systemic manifestations, mainly growth failure, developmental delay, facial dysmorphisms, and variable coagulation and endocrine abnormalities. Carbohydrate deficient transferrin (CDT) and protein-linked glycan analysis with mass spectrometry can diagnose some subtypes of congenital disorders of glycosylation (CDG), while many currently rely on massively parallel genomic sequencing for diagnosis...
December 2018: Annals of Translational Medicine
Wo-Tu Tian, Xing-Hua Luan, Hai-Yan Zhou, Chao Zhang, Xiao-Jun Huang, Xiao-Li Liu, Sheng-Di Chen, Hui-Dong Tang, Li Cao
The congenital disorders of glycosylation are a group of clinically and biochemically heterogeneous diseases characterized by multisystem involvement due to glycosylation defect of protein and lipid. Here we report a 49-year-old man with exercise-induced fatigue and pain of muscle, tachypnea, cleft palate and bifid uvula. Exercise induced elevation of serum creatine kinase (CK), ammonia and lactic acid was recorded. The abnormal levels of myoglobin, CK-MB and LDH as well as S-T elevation in electrocardiogram were observed in repeated hospitalization recordings...
January 6, 2019: Neuromuscular Disorders: NMD
Walinka van Tol, Hans Wessels, Dirk J Lefeber
Over 100 human Congenital Disorders of Glycosylation (CDG) have been described. Of these, about 30% reside in the O-glycosylation pathway. O-glycosylation disorders are characterized by a high phenotypic variability, reflecting the large diversity of O-glycan structures. In contrast to N-glycosylation disorders, a generic biochemical screening test is lacking, which limits the identification of novel O-glycosylation disorders. The emergence of next generation sequencing (NGS) and O-glycoproteomics technologies have changed this situation, resulting in significant progress to link disease phenotypes with underlying biochemical mechanisms...
January 29, 2019: Current Opinion in Structural Biology
Helena Moreira-Silva, Inês Maio, Anabela Bandeira, Esmeralda Gomes-Martins, Ermelinda Santos-Silva
Metabolic liver diseases (MLD) are an important group of disorders presenting with neonatal cholestasis (NC). The spectrum of liver involvement is wide and the presumptive diagnosis is traditionally based on clinical and laboratory findings. Recently, next-generation sequencing (NGS) panels have emerged as an appealing tool to diagnose neonatal/infantile cholestatic disorders. The aim of this study was to identify clinical phenotypes of liver injury and contribute to find a diagnostic methodology that integrates new molecular diagnostic tools...
January 28, 2019: European Journal of Pediatrics
Veronica Arora, Ratna Dua Puri, Pratibha Bhai, Nidhish Sharma, Sunita Bijarnia-Mahay, Nandita Dimri, Ashok Baijal, Renu Saxena, Ishwar Verma
Congenital disorders of glycosylation (CDG) are an extremely rapidly growing and phenotypically versatile group of disorders. Conserved oligomeric Golgi (COG) complexes are hetero-octameric proteins involved in retrograde trafficking within the Golgi. Seven of its eight subunits have a causal role in CDG. To date, only three cases of COG8-CDG have been published but none in the antenatal period. We present the first case of antenatally diagnosed COG8-CDG with facial dysmorphism and additional features such as Dandy-Walker malformation and arthrogryposis multiplex congenita, thus expanding the phenotype of this rare disorder...
January 28, 2019: American Journal of Medical Genetics. Part A
Maria K Haanpää, Bobby G Ng, Natalie M Gallant, Kathryn E Singh, Candida Brown, Virginia Kimonis, Hudson H Freeze, Eric A Muller
ALG11-Congenital Disorder of Glycosylation (ALG11-CDG, also known as congenital disorder of glycosylation type Ip) is an inherited inborn error of metabolism due to abnormal protein and lipid glycosylation. We describe two unrelated patients with ALG11-CDG due to novel mutations, review the literature of previously described affected individuals, and further expand the clinical phenotype. Both affected individuals reported here had severe psychomotor disabilities and epilepsy. Their fibroblasts synthesized truncated precursor glycan structures, consistent with ALG11-CDG, while also showing hypoglycosylation of a novel biomarker, GP130...
January 24, 2019: American Journal of Medical Genetics. Part A
C Medrano, A Vega, R Navarrete, M J Ecay, R Calvo, S I Pascual, M Ruiz-Pons, L Toledo, I García Jiménez, I Arroyo, A Campo, M L Couce, R Domingo-Jiménez, M T García Silva, L González G-Solana, L Hierro, E Martín-Hernández, M Martínez-Pardo, S Roldán, M Tomás, J C Cabrera, F MártinezBugallo, L Martín Viota, I Vitoria, D Lefeber, M L Girós, M Serrano, M Ugarte, B Perez, C Perez-Cerdá
The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems but non-specific symptoms render the diagnosis of the different CDG very challenging. PMM2-CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non-PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%)...
January 17, 2019: Clinical Genetics
Anna B Wolking, Julien H Park, Marianne Grüneberg, Janine Reunert, Ralph Fingerhut, Manfred Fobker, Thorsten Marquardt
BACKGROUND: Congenital disorders of glycosylation (CDG) are a growing group of inherited diseases causing manifold symptoms. Routine diagnostic procedures are high performance liquid chromatography (HPLC) or isoelectric focusing (IEF) of serum transferrin. METHODS: We introduce a modified method to screen for glycosylation abnormalities from dried blood spot (DBS) samples based on isoelectric focusing. In PGM1-CDG, glycosylation analysis and enzyme activity measurement were performed from a single DBS sample...
February 1, 2019: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Guy Helman, Suvasini Sharma, Joanna Crawford, Bijoy Patra, Puneet Jain, Stephen J Bent, J Andoni Urtizberea, Ravindra K Saran, Ryan J Taft, Marjo S van der Knaap, Cas Simons
OBJECTIVE: To determine the molecular etiology of disease in 4 individuals from 2 unrelated families who presented with proximal muscle weakness and features suggestive of mitochondrial disease. METHODS: Clinical information and neuroimaging were reviewed. Genome sequencing was performed on affected individuals and biological parents. RESULTS: All affected individuals presented with muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress while the other family had 2 children with episodic deteriorations...
January 11, 2019: Neurology
Min Li, Yuanyuan Xu, Yajian Wang, Xiu-An Yang, Danqun Jin
This study is to present two Chinese siblings who were diagnosed with congenital disorders of glycosylation (CDG) IIb because of mannosyl-oligosaccharide glucosidase (MOGS) deficiency. The siblings visited our hospital due to "pulmonary infection". Facial dysmorphism including long eyelashes, blepharophimosis, depressed nasal bridge, and high palate was noted. Head MRI of the elder sister showed increased signals on T1W1, bilateral frontal gyrus stenosis, and thin corpus callosum. Both cases presented progressive hepatomegaly and elevated hepatic enzymes...
December 26, 2018: Journal of Human Genetics
Rossella Indellicato, Rossella Parini, Ruben Domenighini, Nadia Malagolini, Maria Iascone, Serena Gasperini, Nicoletta Masera, Fabio dall'Olio, Marco Trinchera
ST3GAL5-CDG is a rare syndrome which is caused by variant GM3 synthases, the enzyme involved in the biosynthesis of a-b-c-series gangliosides. Here we report a novel homozygous ST3GAL5 variant, p.Gly342Ser, in a patient suffering from failure to thrive, severe hearing, visual, motor, and cognitive impairment, and respiratory chain dysfunction. A GM3 synthase assay towards the natural acceptor substrate lactosylceramide was performed upon transfection in HEK-293T cells of expression plasmids carrying wild type and mutated ST3GAL5 cDNAs...
December 20, 2018: Glycobiology
Jonathan J Lyons, Joshua D Milner
Dynamic changes in metabolism have long been understood as critical for both the initiation and maintenance of innate and adaptive immune responses. A number of recent advances have clarified details of how metabolic pathways can specifically affect cellular function in immune cells. Critical to this understanding is ongoing study of the congenital disorders of glycosylation and other genetic disorders of metabolism that lead to altered immune function in humans. While there are a number of immune phenotypes associated with metabolic derangements caused by single gene disorders, several genetic mutations have begun to link discrete alterations in metabolism and growth specifically with allergic disease...
January 2019: Immunological Reviews
Jessica P Lao, Nina DiPrimio, Madeleine Prangley, Feba S Sam, Joshua D Mast, Ethan O Perlstein
Phosphomannomutase 2 Deficiency (PMM2-CDG) is the most common monogenic congenital disorder of glycosylation (CDG) affecting at least 800 patients globally. PMM2 orthologs are present in model organisms, including the budding yeast Saccharomyces cerevisiae gene SEC53. Here we describe conserved genotype-phenotype relationships across yeast and human patients between five PMM2 loss-of-function missense mutations and their orthologous SEC53 mutations. These alleles range in severity from folding defective (hypomorph) to dimerization defective (severe hypomorph) to catalytic dead (null)...
December 7, 2018: G3: Genes—Genomes—Genetics
Bobby G Ng, Jill A Rosenfeld, Lisa Emrick, Mahim Jain, Lindsay C Burrage, Brendan Lee, William J Craigen, David R Bearden, Brett H Graham, Hudson H Freeze
FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia...
December 6, 2018: American Journal of Human Genetics
Albert Kelly, Aisling O'Malley, Mohammad Redha, Gerard W O'Keeffe, Denis S Barry
Glycosylation is a major post-translational modification in which a carbohydrate known as a glycan is enzymatically attached to target proteins which regulate protein folding and stability. Glycans are strongly expressed in the developing nervous system where they play multiple roles during development. The importance of these glycan epitopes in neural development is highlighted by a group of conditions known as congenital disorders of glycosylation which lead to psychomotor difficulties, mental retardation, lissencephaly, microencephaly and epilepsy...
November 25, 2018: Journal of Anatomy
R Francisco, D Marques-da-Silva, S Brasil, C Pascoal, V Dos Reis Ferreira, E Morava, J Jaeken
Congenital disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases that currently includes some 130 different types. CDG diagnosis is a challenge, not only because of this large number but also because of the huge clinical heterogeneity even within a number of CDG. In addition, the classical screening test, serum transferrin isoelectrofocusing, is only positive in about 60% of CDG, and can even become negative in some CDG particularly in PMM2-CDG, the most frequent N-glycosylation defect...
November 9, 2018: Molecular Genetics and Metabolism
Pengzhi Hu, Lamei Yuan, Hao Deng
Protein O-mannosyltransferase 1 (POMT1) is a critical enzyme participating in the first step of protein O-mannosylation. Mutations in the coding gene, POMT1, have been described to be related to a series of autosomal recessive disorders associated with defective alpha-dystroglycan glycosylation, later termed muscular dystrophy-dystroglycanopathies (MDDGs). MDDGs are characterized by a broad phenotypic spectrum of congenital muscular dystrophy or later-onset limb-girdle muscular dystrophy, accompanied by variable degrees of intellectual disability, brain defects, and ocular abnormalities...
October 2018: Mutation Research
Nanako Kanaki, Ayako Matsuda, Katsufumi Dejima, Daisuke Murata, Kazuko H Nomura, Takashi Ohkura, Keiko Gengyo-Ando, Sawako Yoshina, Shohei Mitani, Kazuya Nomura
N-linked glycosylation of proteins is the most common post-translational modification of proteins. The enzyme UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) catalyses the first step of N-glycosylation, and DPAGT1 knockout is embryonic lethal in mice. In this study, we identified the sole orthologue (algn-7) of the human DPAGT1 in the nematode C. elegans. The gene activity was disrupted by RNAi and deletion mutagenesis, which resulted in larval lethality, defects in oogenesis and oocyte-to-embryo transition...
February 1, 2019: Glycobiology
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