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The Expanding Spectrum of Congenital Disorders of Glycosylation

2005; Elsevier BV; Volume: 147; Issue: 6 Linguagem: Inglês

10.1016/j.jpeds.2005.08.064

1097-6833

Abigail E. Collins, Donna M. Ferriero,

Ubiquitin and proteasome pathways

Since the recognition of congenital disorders of glycosylation (CDG) by Jaeken et al in 1980, there has been a dramatic expansion in the description of disease phenotypes and genetic defects responsible for this diverse spectrum of disorders.1Jaeken J. Vanderschueren-Lodewyckx M. Caeser P. Snoeck L. Corbeel L. Eggermont E. et al.Familial psychomotor retardation with markedly fluctuating serum proloactin, FSH and GH levels, partial TGB deficiency, increased serum arylsulfatase A and increased CSF protein: a new syndrome?.Pediatr Res. 1980; 14: 179Crossref Google Scholar Glycosylation abnormalities are responsible for diseases including CDG (previously known as carbohydrate-deficient glycoprotein syndrome), limb girdle muscular dystrophy,2Longman C. Brockington M. Torelli S. Jimenez-Mallebrera C. Kennedy C. Khalil N. et al.Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan.Hum Mol Genet. 2003; 12: 2853-2861Crossref PubMed Scopus (372) Google Scholar, 3Michele D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. et al.Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies.Nature. 2002; 418: 417-422Crossref PubMed Scopus (685) Google Scholar muscle-eye-brain diseases,4Beltran-Valero de Bernabe D. Currier S. Steinbrecher A. Celli J. van Beusekom E. van der Zwaag B. et al.Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome.Am J Hum Genet. 2002; 71: 1033-1043Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar chondrodysplasias, mucoliposidoses I and II, and hereditary multiple exostoses syndrome.5Zak B.M. Crawford B.E. Esko J.D. Hereditary multiple exostoses and heparan sulfate polymerization.Biochim Biophys Acta. 2002; 1573: 346-355Crossref PubMed Scopus (144) Google Scholar Furthermore, continuing research has resulted in a growing list of disorders linked to defects in glycosylation, making this an exciting and important disease category.6Grunewald S. Matthijs G. Jaeken J. Congenital disorders of glycosylation: a review.Pediatr Res. 2002; 52: 618-624Crossref PubMed Google Scholar, 7Jaeken J. Congenital disorders of glycosylation (CDG): update and new developments.J Inherit Metab Dis. 2004; 27: 423-426Crossref PubMed Scopus (30) Google Scholar The basic defect present in all glycosylation disorders is an impaired synthesis and attachment of sugar chains, called glycans, to proteins or lipids. Glycans have very important roles in aiding protein production and communication both inside and outside of the cell.8Yarema K.J. Bertozzi C.R. Characterizing glycosylation pathways.Genome Biol. 2001; 2 (REVIEWS0004)Crossref PubMed Google Scholar The incredible versatility of glycans is evidenced by the ability of the same glycan chain to have widely different functions depending on the protein to which it is bound. This allows for an extraordinary degree of specificity, yet also complexity, in the regulation of diverse physiological processes beyond what is specified in the genome.8Yarema K.J. Bertozzi C.R. Characterizing glycosylation pathways.Genome Biol. 2001; 2 (REVIEWS0004)Crossref PubMed Google Scholar, 9Freeze H. Patterson M. Disorders of Glycosylation.in: Swaiman K. Ashwal S. Ferriero D. Pediatric neurology: principles and practice. 4th ed. Mosby, St. Louis2005: 2112Google Scholar, 10Marquardt T. Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies.Eur J Pediatr. 2003; 162: 359-379Crossref PubMed Scopus (239) Google Scholar Among the several types of glycosylation, the disorders of N- and O-linked glycosylation are the ones most commonly implicated in disease states. The N- and O-linkages specify the different conserved amino acid sequences to which the glycan is attached. N-linked disorders include the CDG, whereas O-linked disorders include the muscle-eye-brain diseases and some muscular dystrophies.2Longman C. Brockington M. Torelli S. Jimenez-Mallebrera C. Kennedy C. Khalil N. et al.Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan.Hum Mol Genet. 2003; 12: 2853-2861Crossref PubMed Scopus (372) Google Scholar, 3Michele D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. et al.Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies.Nature. 2002; 418: 417-422Crossref PubMed Scopus (685) Google Scholar, 4Beltran-Valero de Bernabe D. Currier S. Steinbrecher A. Celli J. van Beusekom E. van der Zwaag B. et al.Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome.Am J Hum Genet. 2002; 71: 1033-1043Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar Almost all of the glycosylation disorders are transmitted in an autosomal recessive pattern.11Jaeken J. Carchon H. Congenital disorders of glycosylation: a booming chapter of pediatrics.Curr Opin Pediatr. 2004; 16: 434-439Crossref PubMed Scopus (83) Google Scholar Protein glycosylation occurs in the endoplasmic reticulum and Golgi apparatus of eukaryotic cells. A simple glycan, the 14-sugar lipid linked oligosaccharides (LLO), is synthesized in the membrane of the endoplasmic reticulum. LLO are then transferred to an asparagine of the N-consensus sequence in the nascent polypeptide chain as it is being translated into the lumen of the endoplasmic reticulum. After ensuring proper protein folding, the glycan chains are then extensively remodeled in the endoplasmic reticulum and the Golgi appartus to endow further specificity to their function.8Yarema K.J. Bertozzi C.R. Characterizing glycosylation pathways.Genome Biol. 2001; 2 (REVIEWS0004)Crossref PubMed Google Scholar, 10Marquardt T. Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies.Eur J Pediatr. 2003; 162: 359-379Crossref PubMed Scopus (239) Google Scholar Congenital disorders of glycosylation are divided into 2 groups based on which aspect of this process is defective. The group I disorders include problems in the biosynthesis and addition of the glycan chain to the growing protein, whereas group II disorders include problems with the subsequent remodeling of the glycan chain. CDG are named by group number and a letter categorizing the gene defect. Those CDG without a known gene defect are designated with an “x”.8Yarema K.J. Bertozzi C.R. Characterizing glycosylation pathways.Genome Biol. 2001; 2 (REVIEWS0004)Crossref PubMed Google Scholar, 9Freeze H. Patterson M. Disorders of Glycosylation.in: Swaiman K. Ashwal S. Ferriero D. Pediatric neurology: principles and practice. 4th ed. Mosby, St. Louis2005: 2112Google Scholar, 10Marquardt T. Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies.Eur J Pediatr. 2003; 162: 359-379Crossref PubMed Scopus (239) Google Scholar The clinical presentation of CDG is nonspecific and may mimic mitochondrial disorders, although they lack a maternal inheritance pattern.12Briones P. Vilaseca M.A. Garcia-Silva M.T. Pineda M. Colomer J. Ferrer I. et al.Congenital disorders of glycosylation (CDG) may be underdiagnosed when mimicking mitochondrial disease.Europ J Paediatr Neurol. 2001; 5: 127-131Abstract Full Text PDF PubMed Scopus (45) Google Scholar, 13de Lonlay P. Seta N. Barrot S. Chabrol B. Drouin V. Gabriel B.M. et al.A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases.J Med Genet. 2001; 38: 14-19Crossref PubMed Scopus (180) Google Scholar Commonly, these patients have problems of the gastrointestinal tract, including poor feeding, vomiting and diarrhea, elevated serum aminotransferase levels or cirrhosis, and coagulation abnormalities. Dysmorphic features may be present, but typically are mild or not evident. Hypotonia and failure to thrive are common, as is mental retardation to varying degrees. Many other organs systems also may be involved.6Grunewald S. Matthijs G. Jaeken J. Congenital disorders of glycosylation: a review.Pediatr Res. 2002; 52: 618-624Crossref PubMed Google Scholar, 7Jaeken J. Congenital disorders of glycosylation (CDG): update and new developments.J Inherit Metab Dis. 2004; 27: 423-426Crossref PubMed Scopus (30) Google Scholar, 9Freeze H. Patterson M. Disorders of Glycosylation.in: Swaiman K. Ashwal S. Ferriero D. Pediatric neurology: principles and practice. 4th ed. Mosby, St. Louis2005: 2112Google Scholar, 11Jaeken J. Carchon H. Congenital disorders of glycosylation: a booming chapter of pediatrics.Curr Opin Pediatr. 2004; 16: 434-439Crossref PubMed Scopus (83) Google Scholar Any patient with this constellation of findings and an otherwise nondiagnostic workup should have testing performed to exclude CDG.7Jaeken J. Congenital disorders of glycosylation (CDG): update and new developments.J Inherit Metab Dis. 2004; 27: 423-426Crossref PubMed Scopus (30) Google Scholar, 9Freeze H. Patterson M. Disorders of Glycosylation.in: Swaiman K. Ashwal S. Ferriero D. Pediatric neurology: principles and practice. 4th ed. Mosby, St. Louis2005: 2112Google Scholar Several modalities are available to test for CDG, most of which rely on analyzing the number and type of glycan chains present on serum transferrin, termed transferrin isoforms. The methods for evaluating these transferrin isoforms include isoelectric focusing (IEF-Tf), mass spectrometry, zone electropheresis, high-pressure liquid chromatography, and electrospray ionization-mass spectrometry (ESI-MS).8Yarema K.J. Bertozzi C.R. Characterizing glycosylation pathways.Genome Biol. 2001; 2 (REVIEWS0004)Crossref PubMed Google Scholar, 14Carchon H.A. Chevigne R. Falmagne J.B. Jaeken J. Diagnosis of congenital disorders of glycosylation by capillary zone electrophoresis of serum transferrin.Clin Chem. 2004; 50: 101-111Crossref PubMed Scopus (85) Google Scholar, 15Fang J. Peters V. Körner C. Hoffmann G.F. Improvement of CDG diagnosis by combined examination of several glycoproteins.J Inherit Metab Dis. 2004; 27: 581-590Crossref PubMed Scopus (23) Google Scholar, 16Kleinert P. Kuster T. Durka S. Ballhausen D. Bosshard N.U. Steinmann B. et al.Mass spectrometric analysis of human transferrin in different body fluids.Clin Chem Lab Med. 2003; 41: 1580-1588Crossref PubMed Scopus (34) Google Scholar, 17Lacey J.M. Bergen H.R. Magera M.J. Naylor S. O'Brien J.F. Rapid determination of transferrin isoforms by immunoaffinity liquid chromatography and electrospray mass spectrometry.Clin Chem. 2001; 47: 513-518PubMed Google Scholar In group I CDG, these tests demonstrate a shift in the pattern from tetra-, penta- and hexasialotransferrins to di- and asialotransferrins.11Jaeken J. Carchon H. Congenital disorders of glycosylation: a booming chapter of pediatrics.Curr Opin Pediatr. 2004; 16: 434-439Crossref PubMed Scopus (83) Google Scholar This change reflects the inability to effectively synthesize or transfer the glycan chain to the protein. In group II CDG, the defects in glycan modification are evident by an increase in the tri- and monosialotransferrins, reflecting structurally abnormal glycans.11Jaeken J. Carchon H. Congenital disorders of glycosylation: a booming chapter of pediatrics.Curr Opin Pediatr. 2004; 16: 434-439Crossref PubMed Scopus (83) Google Scholar Despite the diversity of testing methods available, there are problems with both false-positive and false-negative results. False-positive results occur in individuals with uncontrolled galactose or fructose intolerance, or high alcohol consumption. Neonates may have an abnormal pattern that may later normalize on follow-up testing. False-negative results have been noted in patients who have genetically verified CDG but no abnormality of the IEF-Tf profiles.18Dupre T. Cuer M. Barrot S. Barnier A. Cormier-Daire V. Munnich A. et al.Congenital disorder of glycosylation Ia with deficient phosphomannomutase activity but normal plasma glycoprotein pattern.Clin Chem. 2001; 47: 132-134PubMed Google Scholar Therefore, a normal transferrin isoform pattern in a patient with features highly suggestive of CDG should undergo further enzymatic, biochemical, or genetic testing.9Freeze H. Patterson M. Disorders of Glycosylation.in: Swaiman K. Ashwal S. Ferriero D. Pediatric neurology: principles and practice. 4th ed. Mosby, St. Louis2005: 2112Google Scholar In this issue of The Journal, 2 patients are described who further expand the known spectrum of CDG. Eklund et al19Eklund E. Sun L. Westphal V. Northrop J. Freeze H. Scaglia F. Congenital disorder of glycosylation (CDG) Ih patient with a severe hepato-intestinal and evolving central nervous system pathology.J Pediatr. 2005; 147: 847-850Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar report a patient with CDG-Ih with gastrointestinal and renal involvement; this is the first patient described with neurologic features, including hypotonia, seizures, deceleration of head growth, and a markedly abnormal magnetic resonance imaging scan. Interestingly, this patient not only tested positive for the point mutation known to cause CDG-Ih in the ALG8 gene, but also had a polymorphism within the gene known to cause CDG-Ic, ALG6. Eklund et al raise the hypothesis that ALG6 might function as a modifier gene of ALG8; this is an interesting speculation regarding the poor phenotypic presentation in this patient. Also in this issue, Miura et al20Miura Y. Tay S. Aw M. Eklund E. Freeze H. Clinical and biochemical characterization of a patient with congenital disorder of glycosylation (CDG) IIx.J Pediatr. 2005; 147: 851-853Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar report a patient with CDG-IIx in whom the gene defect has not yet been identified. This patient's workup initially demonstrated a loss of sialic acids by ESI-MS, suggestive of a sialyltransferase defect, a group II CDG. Further genetic testing failed to reveal a point mutation in the suspected ST6Gal1 gene, which encodes the predominant liver sialyltransferase enzyme. Subsequent testing revealed extensive abnormalities in other glycans, suggestive of a CDG-IIx diagnosis. This report highlights the difficulties involved in using currently available testing methodologies to define this complex group of disorders. The patients reported in this issue of The Journal add to the rapidly expanding spectrum of CDG. Although treatment is not yet available for most of these conditions, it is nonetheless important to maintain a high suspicion for CDG in any patient with an unexplained neurologic and gastrointestinal condition. Although many methods are available for detecting transferrin isoforms, better testing methods are needed to consistently identify patients with CDG. The prospect of effective treatment in the future for families with this condition and other enzyme deficiencies makes accurate diagnosis of these disorders vital.