The Experts below are selected from a list of 16683 Experts worldwide ranked by ideXlab platform
Bobby G Ng - One of the best experts on this subject based on the ideXlab platform.
-
arrest of fetal brain development in alg11 Congenital Disorder of glycosylation
Pediatric Neurology, 2019Co-Authors: Sarah B Mulkey, Bobby G Ng, Gilbert Vezina, Dorothy I Bulas, Lynne A Wolfe, Hudson H Freeze, Carlos R FerreiraAbstract:Abstract Background Arrest of fetal brain development and the fetal brain disruption sequence describe a severe phenotype involving microcephaly, occipital bone prominence, and scalp rugae. Congenital Disorders of glycosylation are a heterogeneous group of inherited Disorders involved in glycoprotein and glycolipid biosynthesis, which can cause microcephaly and severe neurodevelopmental disability. Methods We report an example of fetal microcephaly diagnosed at 36 weeks' gestation with a history of normal fetal biometry at 20 weeks' gestation. Postnatal genetic testing was performed. Results Fetal magnetic resonance imaging at 36 weeks' gestational age showed severe cortical thinning with a simplified gyral pattern for gestational age, ventriculomegaly, and agenesis of the corpus callosum. The fetal skull had a posterior shelf at the level of the lambdoid suture, characteristic of fetal brain disruption sequence. Postnatal brain magnetic resonance imaging found no brain growth during the interval from the fetal to postnatal study. The infant was found to have biallelic pathologic mutations in ALG11. Conclusions Arrest of fetal brain development, with image findings consistent with fetal brain disruption sequence, is a previously unreported phenotype of Congenital microcephaly in ALG11-Congenital Disorder of glycosylation. ALG11-Congenital Disorder of glycosylation should be considered in the differential diagnosis of this rare form of Congenital microcephaly.
-
mutations in the translocon associated protein complex subunit ssr3 cause a novel Congenital Disorder of glycosylation
Journal of Inherited Metabolic Disease, 2019Co-Authors: Bobby G Ng, Kati J Buckingham, Martin Kircher, Marie Estelle Losfeld, Charles Marques Lourenco, Deborah A Nickerson, Jay Shendure, Michael J Bamshad, Hudson H FreezeAbstract:: The translocon-associated protein (TRAP) complex facilitates the translocation of proteins across the endoplasmic reticulum membrane and associates with the oligosaccharyl transferase (OST) complex to maintain proper glycosylation of nascent polypeptides. Pathogenic variants in either complex cause a group of rare genetic Disorders termed, Congenital Disorders of glycosylation (CDG). We report an individual who presented with severe intellectual and developmental disabilities and sensorineural deafness with an unsolved type I CDG, and sought to identify the underlying genetic basis. Exome sequencing identified a novel homozygous variant c.278_281delAGGA [p.Glu93Valfs*7] in the signal sequence receptor 3 (SSR3) subunit of the TRAP complex. Biochemical studies in patient fibroblasts showed the variant destabilized the TRAP complex with a complete loss of SSR3 protein and partial loss of SSR1 and SSR4. Importantly, all subunit levels were corrected by expression of wild-type SSR3. Abnormal glycosylation status in fibroblasts was confirmed using two markers proteins, GP130 and ICAM1. Our findings confirm mutations in SSR3 cause a novel CDG. A novel frameshift variant in the translocon associated protein, SSR3, disrupts the stability of the TRAP complex and causes a novel Congenital Disorder of Glycosylation.
-
pathogenic variants in fucokinase cause a Congenital Disorder of glycosylation
American Journal of Human Genetics, 2018Co-Authors: Bobby G Ng, Jill A Rosenfeld, Lisa T Emrick, Mahim Jain, Lindsay C Burrage, William J Craigen, David R Bearden, Brett H Graham, Hudson H FreezeAbstract: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. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a Congenital glycosylation Disorder characterized by a defective fucose-salvage pathway.
-
biallelic mutations in fut8 cause a Congenital Disorder of glycosylation with defective fucosylation
American Journal of Human Genetics, 2018Co-Authors: Bobby G Ng, Kimiyo Raymond, Gege Xu, Nandini Chandy, Joan Steyermark, Deepali N Shinde, Kelly Radtke, Carlito B Lebrilla, Ali Alasmari, Sharon F SuchyAbstract:Fucosyltransferase 8 ( FUT8 ) encodes a Golgi-localized α1,6 fucosyltransferase that is essential for transferring the monosaccharide fucose into N-linked glycoproteins, a process known as "core fucosylation." Here we describe three unrelated individuals, who presented with intrauterine growth retardation, severe developmental and growth delays with shortened limbs, neurological impairments, and respiratory complications. Each underwent whole-exome sequencing and was found to carry pathogenic variants in FUT8. The first individual (consanguineous family) was homozygous for c.715C>T (p.Arg239 ∗ ), while the second (non-consanguineous family) was compound heterozygous for c.1009C>G (p.Arg337Gly) and a splice site variant c.1259+5G>T. The third individual (consanguineous family) was homozygous for a c.943C>T (p.Arg315 ∗ ). Splicing analysis confirmed the c.1259+5G>T resulted in expression of an abnormal FUT8 transcript lacking exon 9. Functional studies using primary fibroblasts from two affected individuals revealed a complete lack of FUT8 protein expression that ultimately resulted in substantial deficiencies in total core fucosylated N-glycans. Furthermore, serum samples from all three individuals showed a complete loss of core fucosylation. Here, we show that loss of function mutations in FUT8 cause a Congenital Disorder of glycosylation (FUT8-CDG) characterized by defective core fucosylation that phenotypically parallels some aspects of the Fut8 −/− knockout mouse. Importantly, identification of additional affected individuals can be easily achieved through analysis of core fucosylation of N-glycans.
-
severe fatal multisystem manifestations in a patient with dolichol kinase Congenital Disorder of glycosylation
Molecular Genetics and Metabolism, 2013Co-Authors: Michelle T Lieu, Bobby G Ng, Hudson H Freeze, Jeffrey S Rush, Tim Wood, Monica J Basehore, Madhuri Hegde, Richard Chang, Jose E Abdenur, Raymond Y WangAbstract:Abstract Congenital Disorders of glycosylation are a group of metabolic Disorders with an expansive and highly variable clinical presentation caused by abnormal glycosylation of proteins and lipids. Dolichol kinase (DOLK) catalyzes the final step in biosynthesis of dolichol phosphate (Dol-P), which is the oligosaccharide carrier required for protein N-glycosylation. Human DOLK deficiency, also known as DOLK-CDG or CDG-Im, results in a syndrome that has been reported to manifest with dilated cardiomyopathy of variable severity. A male neonate born to non-consanguineous parents of Palestinian origin presented with dysmorphic features, genital abnormalities, talipes equinovarus, and severe, refractory generalized seizures. Additional multi-systemic manifestations developed including dilated cardiomyopathy, hepatomegaly, severe insulin-resistant hyperglycemia, and renal failure, which were ultimately fatal at age 9months. Electrospray ionization mass spectrometric (ESI-MS) analysis of transferrin identified a type I Congenital Disorder of glycosylation; next-generation sequencing demonstrated homozygous p.Q483K DOLK mutations that were confirmed in patient fibroblasts to result in severely reduced substrate binding and catalytic activity. This patient expands the phenotype of DOLK-CDG to include anatomic malformations and multi-systemic dysfunction.
Hudson H Freeze - One of the best experts on this subject based on the ideXlab platform.
-
arrest of fetal brain development in alg11 Congenital Disorder of glycosylation
Pediatric Neurology, 2019Co-Authors: Sarah B Mulkey, Bobby G Ng, Gilbert Vezina, Dorothy I Bulas, Lynne A Wolfe, Hudson H Freeze, Carlos R FerreiraAbstract:Abstract Background Arrest of fetal brain development and the fetal brain disruption sequence describe a severe phenotype involving microcephaly, occipital bone prominence, and scalp rugae. Congenital Disorders of glycosylation are a heterogeneous group of inherited Disorders involved in glycoprotein and glycolipid biosynthesis, which can cause microcephaly and severe neurodevelopmental disability. Methods We report an example of fetal microcephaly diagnosed at 36 weeks' gestation with a history of normal fetal biometry at 20 weeks' gestation. Postnatal genetic testing was performed. Results Fetal magnetic resonance imaging at 36 weeks' gestational age showed severe cortical thinning with a simplified gyral pattern for gestational age, ventriculomegaly, and agenesis of the corpus callosum. The fetal skull had a posterior shelf at the level of the lambdoid suture, characteristic of fetal brain disruption sequence. Postnatal brain magnetic resonance imaging found no brain growth during the interval from the fetal to postnatal study. The infant was found to have biallelic pathologic mutations in ALG11. Conclusions Arrest of fetal brain development, with image findings consistent with fetal brain disruption sequence, is a previously unreported phenotype of Congenital microcephaly in ALG11-Congenital Disorder of glycosylation. ALG11-Congenital Disorder of glycosylation should be considered in the differential diagnosis of this rare form of Congenital microcephaly.
-
mutations in the translocon associated protein complex subunit ssr3 cause a novel Congenital Disorder of glycosylation
Journal of Inherited Metabolic Disease, 2019Co-Authors: Bobby G Ng, Kati J Buckingham, Martin Kircher, Marie Estelle Losfeld, Charles Marques Lourenco, Deborah A Nickerson, Jay Shendure, Michael J Bamshad, Hudson H FreezeAbstract:: The translocon-associated protein (TRAP) complex facilitates the translocation of proteins across the endoplasmic reticulum membrane and associates with the oligosaccharyl transferase (OST) complex to maintain proper glycosylation of nascent polypeptides. Pathogenic variants in either complex cause a group of rare genetic Disorders termed, Congenital Disorders of glycosylation (CDG). We report an individual who presented with severe intellectual and developmental disabilities and sensorineural deafness with an unsolved type I CDG, and sought to identify the underlying genetic basis. Exome sequencing identified a novel homozygous variant c.278_281delAGGA [p.Glu93Valfs*7] in the signal sequence receptor 3 (SSR3) subunit of the TRAP complex. Biochemical studies in patient fibroblasts showed the variant destabilized the TRAP complex with a complete loss of SSR3 protein and partial loss of SSR1 and SSR4. Importantly, all subunit levels were corrected by expression of wild-type SSR3. Abnormal glycosylation status in fibroblasts was confirmed using two markers proteins, GP130 and ICAM1. Our findings confirm mutations in SSR3 cause a novel CDG. A novel frameshift variant in the translocon associated protein, SSR3, disrupts the stability of the TRAP complex and causes a novel Congenital Disorder of Glycosylation.
-
pathogenic variants in fucokinase cause a Congenital Disorder of glycosylation
American Journal of Human Genetics, 2018Co-Authors: Bobby G Ng, Jill A Rosenfeld, Lisa T Emrick, Mahim Jain, Lindsay C Burrage, William J Craigen, David R Bearden, Brett H Graham, Hudson H FreezeAbstract: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. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a Congenital glycosylation Disorder characterized by a defective fucose-salvage pathway.
-
severe fatal multisystem manifestations in a patient with dolichol kinase Congenital Disorder of glycosylation
Molecular Genetics and Metabolism, 2013Co-Authors: Michelle T Lieu, Bobby G Ng, Hudson H Freeze, Jeffrey S Rush, Tim Wood, Monica J Basehore, Madhuri Hegde, Richard Chang, Jose E Abdenur, Raymond Y WangAbstract:Abstract Congenital Disorders of glycosylation are a group of metabolic Disorders with an expansive and highly variable clinical presentation caused by abnormal glycosylation of proteins and lipids. Dolichol kinase (DOLK) catalyzes the final step in biosynthesis of dolichol phosphate (Dol-P), which is the oligosaccharide carrier required for protein N-glycosylation. Human DOLK deficiency, also known as DOLK-CDG or CDG-Im, results in a syndrome that has been reported to manifest with dilated cardiomyopathy of variable severity. A male neonate born to non-consanguineous parents of Palestinian origin presented with dysmorphic features, genital abnormalities, talipes equinovarus, and severe, refractory generalized seizures. Additional multi-systemic manifestations developed including dilated cardiomyopathy, hepatomegaly, severe insulin-resistant hyperglycemia, and renal failure, which were ultimately fatal at age 9months. Electrospray ionization mass spectrometric (ESI-MS) analysis of transferrin identified a type I Congenital Disorder of glycosylation; next-generation sequencing demonstrated homozygous p.Q483K DOLK mutations that were confirmed in patient fibroblasts to result in severely reduced substrate binding and catalytic activity. This patient expands the phenotype of DOLK-CDG to include anatomic malformations and multi-systemic dysfunction.
-
cryptogenic liver disease in four children a novel Congenital Disorder of glycosylation
Pediatric Research, 2006Co-Authors: Claudia Mandato, Yoshiaki Miura, Lena Brive, Joseph Alex Davis, Nicolina Di Cosmo, S Lucariello, Severo Pagliardini, Giancarlo Parenti, R Vecchione, Hudson H FreezeAbstract:We investigated the metabolic defect(s) of four children who presented with isolated cryptogenic chronic liver disease, coagulopathy, and abnormalities of several unrelated serum glycoproteins. Analysis of the patients' serum glycoproteins and fibroblasts suggest they have a novel Congenital Disorder of glycosylation (CDG). All had abnormal transferrin (Tf) isoelectric focusing (IEF) profiles. More detailed analysis of Tf by electrospray ionization mass spectrometry (ESI-MS) showed a plethora of abnormal glycosylations that included loss of 1-2 sialic acids and 1-2 galactose units, typical of Group II defects. Tf from two patients also lacked 1-2 entire oligosaccharide chains, typical of Group One Disorders. Total serum N-glycans were analyzed by HPLC and matrix-assisted laser desorption/ionization mass spectrometry and also showed increased proportion of neutral glycan chains lacking sialic acids and galactose units. Analysis of patient fibroblasts eliminated CDG-Ia, through CDG-Ih, -IL and CDG-IId. Our results suggest that a subset of children with clinically asymptomatic, cryptogenic hypertransaminasemia and/or liver steato-fibrosis may represent a novel type of CDG-X with an unknown defect(s). Clinicians are encouraged to test such patients for abnormal Tf glycosylation by ESI-MS.
Gert Matthijs - One of the best experts on this subject based on the ideXlab platform.
-
Clinical utility gene card for: DPAGT1 defective Congenital Disorder of glycosylation
European Journal of Human Genetics, 2015Co-Authors: Jaak Jaeken, Dirk Lefeber, Gert MatthijsAbstract:1.Name of the Disease ( Synonyms ): Deficiency of UDP-GlcNAc:Dol-P-GlcNAc-P transferase 1, deficiency of Dol-P:GlcNAc-P transferase 1, deficiency of GlcNAc-1-P transferase 1 Congenital myasthenic syndrome with tubular aggregates 2, CMSTA2, DPAGT1-CDG, CDG-Ij 2. OMIM# of the Disease: 608093 614750 3. Name of the Analysed Genes or DNA/Chromosome Segments: DPAGT1 4. OMIM# of the Gene(s): 191350 Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in DPAGT1 gene in diagnostic, predictive and prenatal settings, and for risk assessment in relatives.
-
clinical utility gene card for dpagt1 defective Congenital Disorder of glycosylation
European Journal of Human Genetics, 2015Co-Authors: Jaak Jaeken, Dirk Lefeber, Gert MatthijsAbstract:Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in PGM3 in diagnostic, predictive and prenatal settings, and for risk assessment in relatives.
-
Congenital Disorder of glycosylation type ia presenting with hydrops fetalis
Journal of Medical Genetics, 2007Co-Authors: J M Van De Kamp, Sylke J Steggerda, N Den S Hollander, Stefan M Willems, George J. G. Ruijter, Gert Matthijs, B J H M Poorthuis, Dirk J. Lefeber, Ron A. WeversAbstract:There is a growing awareness that inborn errors of metabolism can be a cause of non-immune hydrops fetalis. The association between Congenital Disorders of glycosylation (CDG) and hydrops fetalis has been based on one case report concerning two sibs with hydrops fetalis and CDG-Ik. Since then two patients with hydrops-like features and CDG-Ia have been reported. Two more unrelated patients with CDG-Ia who presented with hydrops fetalis are reported here, providing definite evidence that non-immune hydrops fetalis can be caused by CDG-Ia. The presence of Congenital thrombocytopenia and high ferritin levels in both patients was remarkable. These might be common features in this severe form of CDG. Both patients had one severe mutation in the phosphomannomutase 2 gene, probably fully inactivating the enzyme, and one milder mutation with residual activity, as had the patients reported in literature. The presence of one severe mutation might be required for the development of hydrops fetalis. CDG-Ia should be considered in the differential diagnosis of hydrops fetalis and analysis of PMM activity in chorionic villi or amniocytes should also be considered.
-
Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized Congenital Disorder of glycosylation type II
P NATL ACAD SCI USA, 2006Co-Authors: Gert MatthijsAbstract:The conserved oligomeric Golgi (COG) complex is a hetero-octameric complex that regulates intraGolgi trafficking and the integrity of the Golgi compartment in eukaryotic cells. Here, we describe a patient with a mild form of Congenital Disorder of glycosylation type II (CDG-II) that is caused by a deficiency in the Cog1 subunit of the complex. This patient has a defect in both Nand O-glycosylation. Mass spectrometric analysis of the structures of the N-linked glycans released from glycoproteins from the patient's serum revealed a reduction in sialic acid and galactose residues. Peanut agglutinin (PNA) lectin staining revealed a decrease in sialic acids on core 1 mucin type O-glycans, indicating a combined defect in N- and O-glycosylation. Sequence analysis of the COG1 cDNA and gene identified a homozygous insertion of a single nucleotide (2659-2660insC), which is predicted to lead to a premature translation stop and truncation of the C terminus of the Cog1 protein by 80 amino acids. This mutation destabilizes several other COG subunits and alters their subcellular localization and hence the overall integrity of the COG complex. This results in reduced levels and/or altered Golgi localization of alpha-mannosidase II and beta-1,4 galactosyltransferase 1, which links it to the glycosylation deficiency. Transfection of primary fibroblasts of this patient with the full length hemagglutinin-tagged Cog1 indeed restored beta-1,4 galactosyltransferase Golgi localization. We propose naming this Disorder CDG-II/Cog1, or CDG-II caused by Cog1 deficiency.
-
Congenital Disorder of glycosylation cdg type ie a new patient
Journal of Inherited Metabolic Disease, 2004Co-Authors: Maria Teresa Garciasilva, Gert Matthijs, E Schollen, Jimena Cabrera, Sanchez J Del Pozo, Marti M Herreros, R Simon, M Maties, Martin E Hernandez, Thierry HennetAbstract:Summary: CDG Ie is caused by a deficiency of dolichol-phosphate-mannose synthase 1 (DPM1), an enzyme involved in N-glycan assembly in the endoplasmic reticulum. Three proteins are known to be part of the synthase complex: DPM1, DPM2 and DPM3. Only mutations in DPM1, the catalytic subunit, have been described in three families. One was homozygous for the c274C>;G (R92G) mutation in DPM1 and two others were compound heterozygous for R92G and a c628delC deletion or a c331–343del13, respectively. Clinical features were a severe infantile encephalopathy, early intractable seizures, acquired microcephaly, and some dysmorphic features. We report a patient with milder symptoms: microcephaly, dysmorphic features, developmental delay, optic atrophy, and cerebellar dysfunction without cerebellar atrophy. The patient is homozygous for a new mutation in exon 9 of the DPM1 gene (c742T>;C (S248P)). Our findings extend the spectrum of CDG Ie.
Marie Estelle Losfeld - One of the best experts on this subject based on the ideXlab platform.
-
mutations in the translocon associated protein complex subunit ssr3 cause a novel Congenital Disorder of glycosylation
Journal of Inherited Metabolic Disease, 2019Co-Authors: Bobby G Ng, Kati J Buckingham, Martin Kircher, Marie Estelle Losfeld, Charles Marques Lourenco, Deborah A Nickerson, Jay Shendure, Michael J Bamshad, Hudson H FreezeAbstract:: The translocon-associated protein (TRAP) complex facilitates the translocation of proteins across the endoplasmic reticulum membrane and associates with the oligosaccharyl transferase (OST) complex to maintain proper glycosylation of nascent polypeptides. Pathogenic variants in either complex cause a group of rare genetic Disorders termed, Congenital Disorders of glycosylation (CDG). We report an individual who presented with severe intellectual and developmental disabilities and sensorineural deafness with an unsolved type I CDG, and sought to identify the underlying genetic basis. Exome sequencing identified a novel homozygous variant c.278_281delAGGA [p.Glu93Valfs*7] in the signal sequence receptor 3 (SSR3) subunit of the TRAP complex. Biochemical studies in patient fibroblasts showed the variant destabilized the TRAP complex with a complete loss of SSR3 protein and partial loss of SSR1 and SSR4. Importantly, all subunit levels were corrected by expression of wild-type SSR3. Abnormal glycosylation status in fibroblasts was confirmed using two markers proteins, GP130 and ICAM1. Our findings confirm mutations in SSR3 cause a novel CDG. A novel frameshift variant in the translocon associated protein, SSR3, disrupts the stability of the TRAP complex and causes a novel Congenital Disorder of Glycosylation.
-
mosaicism of the udp galactose transporter slc35a2 causes a Congenital Disorder of glycosylation
American Journal of Human Genetics, 2013Co-Authors: Bobby G Ng, Kati J Buckingham, Kimiyo Raymond, Martin Kircher, Emily H Turner, Miao He, Joshua D Smith, Alexey Eroshkin, Marta Szybowska, Marie Estelle LosfeldAbstract:Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked Congenital Disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses.
Dirk Lefeber - One of the best experts on this subject based on the ideXlab platform.
-
Clinical utility gene card for: DPAGT1 defective Congenital Disorder of glycosylation
European Journal of Human Genetics, 2015Co-Authors: Jaak Jaeken, Dirk Lefeber, Gert MatthijsAbstract:1.Name of the Disease ( Synonyms ): Deficiency of UDP-GlcNAc:Dol-P-GlcNAc-P transferase 1, deficiency of Dol-P:GlcNAc-P transferase 1, deficiency of GlcNAc-1-P transferase 1 Congenital myasthenic syndrome with tubular aggregates 2, CMSTA2, DPAGT1-CDG, CDG-Ij 2. OMIM# of the Disease: 608093 614750 3. Name of the Analysed Genes or DNA/Chromosome Segments: DPAGT1 4. OMIM# of the Gene(s): 191350 Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in DPAGT1 gene in diagnostic, predictive and prenatal settings, and for risk assessment in relatives.
-
clinical utility gene card for dpagt1 defective Congenital Disorder of glycosylation
European Journal of Human Genetics, 2015Co-Authors: Jaak Jaeken, Dirk Lefeber, Gert MatthijsAbstract:Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in PGM3 in diagnostic, predictive and prenatal settings, and for risk assessment in relatives.
-
defining the phenotype in Congenital Disorder of glycosylation due to alg1 mutations
Pediatrics, 2012Co-Authors: Eva Morava, Julia Vodopiutz, Dirk Lefeber, Andreas R Janecke, Wolfgang M Schmidt, Silvia Lechner, Chike B Item, Jolanta Sykutcegielska, Maciej Adamowicz, Jolanta WierzbaAbstract:Deficiency of β-1,4 mannosyltransferase (MT-1) Congenital Disorder of glycosylation (CDG), due to ALG1 gene mutations. Features in 9 patients reported previously consisted of prenatal growth retardation, pregnancy-induced maternal hypertension and fetal hydrops. Four patients died before 5 years of age, and survivors showed a severe psychomotor retardation. We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution. Four children had a stable clinical course, two had visual impairment, and 1 had hearing loss. Thrombotic and vascular events led to deterioration of the clinical outcome in 2 patients. Four novel ALG1 mutations were identified. Pathogenicity was determined in alg1 yeast mutants transformed with hALG1. Functional analyses showed all novel mutations representing hypomorphs associated with residual enzyme activity. We extend the phenotypic spectrum including the first description of deafness in MT1 deficiency, and report on mildly affected patients, surviving to adulthood. The dysmorphic features, including abnormal fat distribution and strabismus highly resemble CDG due to phosphomannomutase-2 deficiency (PMM2-CDG), the most common type of CDG. We suggest testing for ALG1 mutations in unsolved CDG patients with a type 1 transferrin isoelectric focusing pattern, especially with epilepsy, severe visual loss and hemorrhagic/thrombotic events. * Abbreviations: ALG — : asparagine-linked glycosylation CDG — : Congenital Disorders of glycosylation CPY — : carboxypeptidase Y GDP-mannose — : GlcNAc2-PP-dolichol β1,4-mannosyltransferase LLO — : lipid-linked oligosaccharides MT-1 — : β-1,4 mannosyltransferase PMM — : phosphomannomutase TIEF — : transferrin isoelectric focusing
-
pericardial and abdominal fluid accumulation in Congenital Disorder of glycosylation type ia
Molecular Genetics and Metabolism, 2008Co-Authors: Gerben Truin, Ron A. Wevers, Dirk Lefeber, Jolanta Sykutcegielska, Maciej Adamowicz, Mailys Guillard, Esther P A H Hoppenreijs, R C A Sengers, Eva MoravaAbstract:Abstract The association of fetal hydrops with Congenital Disorders of Glycosylation (CDG) has been reported previously. Pericardial fluid accumulation and ascites were also observed in a few young patients with CDG type Ia. Here we describe the clinical and biochemical features in three children developing life-threatening extravascular fluid accumulation. All patients carried severe PMM2 mutations comparable to the earlier reported patients with fetal hydrops. One patient was successfully treated with a pericardial–pleural shunt placement. Pericardial fluid accumulation and generalized oedema resolved temporarily in the other two children on regular albumin infusions and the use of diuretics. Sequential abdominal punctures were unsuccessful in the treatment of the extensive ascites production. The use of non-steroid anti-inflammatory agents and the application of high dose steroids had no clinical effect. Severe extravascular fluid accumulation progressed to decompensation and death. Biochemical investigations of the abdominal fluid and pericardial fluid demonstrated a high extracellular protein concentration, increased cytokine concentrations and an abnormal transferrin isoelectric focusing pattern characteristic of CDG type I. Our results are consistent with a local activation of the cytokine pathways and subsequent protein transport through the endothelial surface to the extravascular space. Normal glycosylation of cell surface proteins is essential for the normal fluid balance and protein transport through the pericardial and peritoneal membrane. Future therapeutic efforts should be directed to inhibit the abnormal immune response and excessive protein transport in this life-threatening complication of CDG syndrome.
-
Congenital Disorder of glycosylation type ix review of clinical spectrum and diagnostic steps
Journal of Inherited Metabolic Disease, 2008Co-Authors: Eva Morava, Ron A. Wevers, Jolanta Sykutcegielska, Maciej Adamowicz, H Wosik, Judit Karteszi, Mailys Guillard, Kinga Hadzsiev, Dirk LefeberAbstract:Congenital Disorder of glycosylation type I (CDG I) represent a rapidly growing group of inherited multisystem Disorders with 13 genetically established subtypes (CDG Ia to CDG Im), and a high number of biochemically unresolved cases (CDG Ix). Further diagnostic effort and prognosis counselling are very challenging in these children. In the current study, we reviewed the clinical records of 10 CDG Ix patients and compared the data with 13 CDG Ix patients published in the literature in search for specific symptoms to create clinical subgroups. The most frequent findings were rather nonspecific, including developmental delay and axial hypotonia. Several features were found that are uncommon in CDG syndrome, such as elevated creatine kinase or arthrogryposis. Distinct ophthalmological abnormalities were observed including optic nerve atrophy, cataract and glaucoma. Two subgroups could be established: one with a pure neurological presentation and the other with a neurological-multivisceral form. The first group had a significantly better prognosis. The unique presentation of microcephaly, seizures, ascites, hepatomegaly, nephrotic syndrome and severe developmental delay was observed in one child diagnosed with CDG Ik. Establishing clinical subgroups and increasing the number of patients within the subgroups may lead the way towards the genetic defect in children with a so far unsolved type of the Congenital Disorders of glycosylation. Raising awareness for less common, non-CDG specific clinical features such as Congenital joint contractures, movement Disorders or ophthalmological anomalies will encourage clinicians to think of CDG in its more unusual presentation. Clinical grouping also helps to determine the prognosis and provide better counselling for the families.