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A congenital disorder of glycosylation (previously called carbohydrate-deficient glycoprotein syndrome) is one of several rare
inborn errors of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substra ...
in which
glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not al ...
of a variety of tissue
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s and/or
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
s is deficient or defective.
Congenital disorder A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...
s of glycosylation are sometimes known as CDG
syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek σύνδρομον, meaning "concurrence". When a syndrome is paired ...
s. They often cause serious, sometimes fatal, malfunction of several different
organ system An organ system is a biological system consisting of a group of organs that work together to perform one or more functions. Each organ has a specialized role in a plant or animal body, and is made up of distinct tissues. Plants Plants have ...
s (especially the
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
,
muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
s, and
intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...
s) in affected infants. The most common sub-type is
PMM2-CDG PMM2 deficiency or PMM2-CDG is a very rare genetic disorder caused by mutations in PMM2. It is an autosomal recessive disorder. A defective copy of the PMM2 gene is the most common cause of a disease called “ congenital disorders of glycosylati ...
(formally known as CDG-Ia) where the genetic defect leads to the loss of phosphomannomutase 2 (
PMM2 Phosphomannomutase 2 is an enzyme that in humans is encoded by the ''PMM2'' gene. Function Phosphomannomutase 2 catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate. Mannose 1-phosphate is a precursor to GDP-mannose nece ...
), the enzyme responsible for the conversion of
mannose-6-phosphate Mannose-6-phosphate (M6P) is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase. M6P is a key targeting signal for acid hydrolase precursor proteins that are destined for transp ...
into
mannose-1-phosphate Mannose 1-phosphate is a molecule involved in glycosylation. See also

* Congenital disorder of glycosylation * Mannose-6-phosphate Organophosphates Monosaccharide derivatives {{organic-compound-stub ...
.


Presentation

The specific problems produced differ according to the particular abnormal synthesis involved. Common manifestations include
ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
;
seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
s;
retinopathy Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically inc ...
;
liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the sig ...
; coagulopathies; failure to thrive (FTT);
dysmorphic feature A dysmorphic feature is an abnormal difference in body structure. It can be an isolated finding in an otherwise normal individual, or it can be related to a congenital disorder, Genetics, genetic syndrome or birth defect. Dysmorphology is the stud ...
s (''e.g.,''
inverted nipple An inverted nipple (occasionally invaginated nipple) is a condition where the nipple, instead of pointing outward, is retracted into the breast. In some cases, the nipple will be temporarily protruded if stimulated. Both women and men can have inv ...
s and subcutaneous
fat pad A fat pad (aka haversian gland) is a mass of closely packed fat cells surrounded by fibrous tissue septa.TheFreeDictionary > Fat padCiting: Mosby's Medical Dictionary, 8th edition. 2009 They may be extensively supplied with capillaries and nerve end ...
s),
pericardial effusion A pericardial effusion is an abnormal accumulation of fluid in the pericardial cavity. The pericardium is a two-part membrane surrounding the heart: the outer fibrous connective membrane and an inner two-layered serous membrane. The two layers of t ...
, and
hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...
. If an MRI is obtained;
cerebellar hypoplasia Cerebellar hypoplasia is characterized by reduced cerebellar volume, even though cerebellar shape is (near) normal. It consists of a heterogeneous group of disorders of cerebellar maldevelopment presenting as early-onset non–progressive conge ...
is a common finding. Ocular abnormalities of CDG-Ia include:
myopia Near-sightedness, also known as myopia and short-sightedness, is an eye disease where light focuses in front of, instead of on, the retina. As a result, distant objects appear blurry while close objects appear normal. Other symptoms may include ...
,
infantile esotropia Infantile esotropia is an ocular condition of early onset in which one or either eye turns inward. It is a specific sub-type of esotropia and has been a subject of much debate amongst ophthalmologists with regard to its naming, diagnostic features ...
,
delayed visual maturation Cortical visual impairment (CVI) is a form of visual impairment that is caused by a brain problem rather than an eye problem. (The latter is sometimes termed "ocular visual impairment" when discussed in contrast to cortical visual impairment.) Some ...
, peripheral neuropathy (PN),
strabismus Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...
,
nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...
,
optic disc pallor Optic disc pallor refers to an abnormal coloration of the optic disc as visualized by a fundoscopic examination. The disc normally has a pink hue In color theory, hue is one of the main properties (called color appearance parameters) of ...
, and reduced rod function on
electroretinography Electroretinography measures the electrical responses of various cell types in the retina, including the photoreceptors ( rods and cones), inner retinal cells ( bipolar and amacrine cells), and the ganglion cells. Electrodes are placed on the ...
.Three subtypes PMM2-CDG, PMI-CDG, ALG6-CDG can cause
congenital hyperinsulinism Congenital hyperinsulinism is a medical term referring to a variety of congenital disorders in which hypoglycemia is caused by excessive insulin secretion.update 2013 Congenital forms of hyperinsulinemic hypoglycemia can be transient or persiste ...
with
hyperinsulinemic hypoglycemia Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin ...
in infancy.


''N''-Glycosylation and known defects

A biologically very important group of
carbohydrates In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or may ...
is the
asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
( Asn)-linked, or N-linked,
oligosaccharide An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sugar ...
s. Their
biosynthetic pathway Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
is very complex and involves a hundred or more
glycosyltransferase Glycosyltransferases (GTFs, Gtfs) are enzymes ( EC 2.4) that establish natural glycosidic linkages. They catalyze the transfer of saccharide moieties from an activated nucleotide sugar (also known as the "glycosyl donor") to a nucleophilic glycos ...
s,
glycosidase Glycoside hydrolases (also called glycosidases or glycosyl hydrolases) catalyze the hydrolysis of glycosidic bonds in complex sugars. They are extremely common enzymes with roles in nature including degradation of biomass such as cellulose (cel ...
s, transporters and synthases. This plethora allows for the formation of a multitude of different final oligosaccharide structures, involved in
protein folding Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduci ...
,
intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
transport/localization, protein activity, and degradation/half-life. A vast amount of carbohydrate binding molecules (
lectins Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in rec ...
) depend on correct glycosylation for appropriate binding; the
selectins The selectins (cluster of differentiation 62 or CD62) are a family of cell adhesion molecules (or CAMs). All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus a ...
, involved in
leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
extravasation __NOTOC__ Extravasation is the leakage of a fluid out of its container into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells from the capillaries to th ...
, is a prime example. Their binding depends on a correct fucosylation of cell surface
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
s. Lack thereof leads to leukocytosis and increase sensitivity to infections as seen in SLC35C1-CDG(CDG-IIc); caused by a GDP-fucose (Fuc) transporter deficiency. All N-linked oligosaccharides originate from a common lipid-linked oligosaccharide (LLO) precursor, synthesized in the ER on a dolichol-phosphate (Dol-P) anchor. The mature LLO is transferred co-translationally to consensus sequence Asn residues in the nascent protein, and is further modified by trimming and re-building in the Golgi. Deficiencies in the
genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
involved in
N-linked glycosylation ''N''-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein), ...
constitute the molecular background to most of the CDGs. * Type I defects involve the synthesis and transfer of the LLO * Type II defects impair the modification process of protein-bound oligosaccharides.


Type I


Type II

The mature LLO chain is next transferred to the growing protein chain, a process catalysed by the
oligosaccharyl transferase Oligosaccharyltransferase or OST () is a membrane protein complex that transfers a 14-sugar oligosaccharide from dolichol to nascent protein. It is a type of glycosyltransferase. The sugar Glc3Man9GlcNAc2 (where Glc=Glucose, Man=Mannose, and Gl ...
(OST) complex. * Once transferred to the protein chain, the oligosaccharide is trimmed by specific glycosidases. This process is vital since the
lectin Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in rec ...
chaperones
calnexin Calnexin (CNX) is 67kDaintegral protein (that appears variously as a 90kDa, 80kDa, or 75kDa band on western blotting depending on the source of the antibody) of the endoplasmic reticulum (ER). It consists of a large (50 kDa) N-terminal calcium- bi ...
and
calreticulin Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the ''CALR'' gene. Calreticulin is a multifunctional soluble prote ...
, involved in protein quality, bind to the Glc1Man9GlcNAc-structure and assure proper folding. Lack of the first glycosidase ( GCS1) causes CDG-IIb. * Removal of the Glc residues and the first Man residue occurs in the ER. * The glycoprotein then travels to the Golgi, where a multitude of different structures with different biological activities are formed. *
Mannosidase Mannosidase is an enzyme which hydrolyses mannose. There are two types: * alpha-Mannosidase * beta-Mannosidase Beta-mannosidase (, ''mannanase'', ''mannase'', ''beta-D-mannosidase'', ''beta-mannoside mannohydrolase'', ''exo-beta-D-mannanase'' ...
I creates a Man5GlcNAc2-structure on the protein, but note that this has a different structure than the one made on LLO. * Next, a GlcNAc residue forms GlcNAc1Man5GlcNAc2, the substrate for a-mannosidase II (aManII). * aManII then removes two Man residues, creating the substrate for GlcNAc transferase II, which adds a GlcNAc to the second Man branch. This structure serves as substrate for additional galactosylation,
fucosylation Fucosylation is the process of adding fucose sugar units to a molecule. It is a type of glycosylation. It is important clinically, and high levels of fucosylation have been reported in cancer. In cancer and inflammation there are significant chan ...
and
sialylation Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" (from the Greek for saliva, - ''síalon'') was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this g ...
reactions. Additionally, substitution with more GlcNAc residues can yield tri- and tetra-antennary molecules. Not all structures are fully modified, some remain as high-mannose structures, others as hybrids (one unmodified Man branch and one modified), but the majority become fully modified complex type oligosaccharides. In addition to glycosidase I, mutations have been found: * in
MGAT2 Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the ''MGAT2'' gene. The product of this gene is a Golgi enzyme catalyzing an essential step in the conversion of oligomannose to comp ...
, in GlcNAc transferase II (CDG-IIa) * in
SLC35C1 GDP-fucose transporter 1 is a protein that in humans is encoded by the ''SLC35C1'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' ...
, the GDP-Fuc transporter (CDG-IIc) * in
B4GALT1 Beta-1,4-galactosyltransferase 1 is an enzyme that in humans is encoded by the ''B4GALT1'' gene. This gene is one of seven beta-1,4-galactosyltransferase (beta4GalT) genes. They encode type II membrane-bound glycoproteins that appear to have excl ...
, a
galactosyltransferase Galactosyltransferase is a type of glycosyltransferase which catalyzes the transfer of galactose. An example is B-N-acetylglucosaminyl-glycopeptide b-1,4-galactosyltransferase. The biosynthesis of disaccharides, oligosaccharides and polysacchar ...
(CDG-IId) * in
COG7 Conserved oligomeric Golgi complex subunit 7 is a protein that in humans is encoded by the ''COG7'' gene. Multiprotein complexes are key determinants of Golgi apparatus structure and its capacity for intracellular transport and glycoprotein modi ...
, the conserved oligomeric Golgi complex-7 (CDG-IIe) * in SLC35A1, the CMP-sialic acid (NeuAc) transporter (CDG-IIf) However, the use of >100 genes in this process, presumably means that many more defects are to be found.


Diagnosis


Classification

Historically, CDGs are classified as Types I and II (CDG-I and CDG-II), depending on the nature and location of the biochemical defect in the
metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
relative to the action of
oligosaccharyltransferase Oligosaccharyltransferase or OST () is a membrane protein protein complex, complex that transfers a 14-sugar oligosaccharide from dolichol to nascent protein. It is a type of glycosyltransferase. The sugar Glc3Man9GlcNAc2 (where Glc=Glucose, Man= ...
. The most commonly used screening method for CDG, analysis of transferrin glycosylation status by
isoelectric focusing Isoelectric focusing (IEF), also known as electrofocusing, is a technique for separating different molecules by differences in their isoelectric point (pI). It is a type of zone electrophoresis usually performed on proteins in a gel that takes ad ...
, ESI-MS, or other techniques, distinguish between these subtypes in so called Type I and Type II patterns. Currently, twenty-two CDG Type-I and fourteen Type-II subtypes of CDG have been described. Since 2009, most researchers use a different nomenclature based on the gene defect (''e.g.'' CDG-Ia = PMM2-CDG, CDG-Ib = PMI-CDG, CDG-Ic = ALG6-CDG etc.). The reason for the new nomenclature was the fact that proteins not directly involved in glycan synthesis (such as members of the COG-family and vesicular H+-ATPase) were found to be causing the glycosylation defect in some CDG patients. Also, defects disturbing other glycosylation pathways than the ''N''-linked one are included in this classification. Examples are the α- dystroglycanopathies (''e.g.'' POMT1/POMT2-CDG ( Walker-Warburg syndrome and Muscle-Eye-Brain syndrome)) with deficiencies in ''O''-mannosylation of proteins; ''O''-xylosylglycan synthesis defects (EXT1/EXT2-CDG (
hereditary multiple exostoses Hereditary multiple osteochondromas (HMO), also known as hereditary multiple exostoses, is a disorder characterized by the development of multiple benign osteocartilaginous masses ( exostoses) in relation to the ends of long bones of the lower li ...
) and B4GALT7-CDG ( Ehlers-Danlos syndrome, progeroid variant)); ''O''-fucosylglycan synthesis (B3GALTL-CDG (Peter's plus syndrome) and LFNG-CDG (
spondylocostal dysostosis Spondylocostal dysostosis, also known as Jarcho-Levin syndrome (JLS), is a rare, heritable axial skeleton growth disorder. It is characterized by widespread and sometimes severe malformations of the vertebral column and ribs, shortened thorax, an ...
III)).


Type I

* Type I disorders involve disrupted synthesis of the
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
-linked
oligosaccharide An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sugar ...
precursor (LLO) or its transfer to the protein. Types include:


Type II

* Type II disorders involve malfunctioning trimming/processing of the protein-bound oligosaccharide chain. Types include:


Disorders of ''O''-mannosylation

* Disorders with deficient α-
dystroglycan Dystroglycan is a protein that in humans is encoded by the ''DAG1'' gene. Dystroglycan is one of the dystrophin-associated glycoproteins, which is encoded by a 5.5 kb transcript in ''Homo sapiens'' on chromosome 3. There are two exons that are s ...
''O''-mannosylation. Mutations in several genes have been associated with the traditional clinical syndromes, termed
muscular dystrophy Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affe ...
-dystroglycanopathies (MDDG). A new nomenclature based on clinical severity and genetic cause was recently proposed by OMIM. The severity classifications are A (severe), B (intermediate), and C (mild). The subtypes are numbered one to six according to the genetic cause, in the following order: (1)
POMT1 Protein O-mannosyl-transferase 1 is an enzyme that in humans is encoded by the ''POMT1'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generat ...
, (2)
POMT2 Protein O-mannosyl-transferase 2 is an enzyme that in humans is encoded by the ''POMT2'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generati ...
, (3) POMGNT1, (4) FKTN, (5)
FKRP Fukutin-related protein (FKRP) is also known as FKRP_HUMAN, LGMD2I, MDC1C, MDDGA5, MDDGB5, and MDDGC5. FKRP can be located in the brain, cardiac muscle and skeletal muscle, and in cells it is found in the Golgi apparatus. Fukutin is expressed in t ...
, and (6)
LARGE Large means of great size. Large may also refer to: Mathematics * Arbitrarily large, a phrase in mathematics * Large cardinal, a property of certain transfinite numbers * Large category, a category with a proper class of objects and morphisms (or ...
. Most common severe types include:


Treatment

No treatment is available for most of these disorders.
Mannose Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylation ...
supplementation relieves the symptoms in MPI-CDG for the most part, even though the hepatic fibrosis may persist.
Fucose Fucose is a hexose deoxy sugar with the chemical formula C6H12O5. It is found on ''N''-linked glycans on the mammalian, insect and plant cell surface. Fucose is the fundamental sub-unit of the seaweed polysaccharide fucoidan. The α(1→3) link ...
supplementation has had a partial effect on some SLC35C1-CDG patients.


History

The first CDG patients (twin sisters) were described in 1980 by Jaeken et al.Jaeken, J., Vanderschueren-Lodeweyckx, M., Casaer, P., Snoeck, L., Corbeel, L., Eggermont, E., and Eeckels, R. (1980) Pediatr Res 14, 179 Their main features were
psychomotor retardation Psychomotor may refer to: * Psychomotor learning, the relationship between cognitive functions and physical movement * Psychomotor retardation, a slowing-down of thought and a reduction of physical movements in an individual * Psychomotor agitatio ...
, cerebral and cerebellar atrophy and fluctuating
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
levels (''e.g.''prolactin, FSH and GH). During the next 15 years the underlying defect remained unknown but since the plasmaprotein
transferrin Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encode ...
was underglycosylated (as shown by ''e.g.'' ''isoelectric focusing''), the new syndrome was named carbohydrate-deficient glycoprotein syndrome (CDGS) Its "classical"
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
included
psychomotor retardation Psychomotor may refer to: * Psychomotor learning, the relationship between cognitive functions and physical movement * Psychomotor retardation, a slowing-down of thought and a reduction of physical movements in an individual * Psychomotor agitatio ...
,
ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
,
strabismus Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...
, anomalies (fat pads and inverted
nipples The nipple is a raised region of tissue on the surface of the breast from which, in females, milk leaves the breast through the lactiferous ducts to feed an infant. The milk can flow through the nipple passively or it can be ejected by smooth mu ...
) and
coagulopathy Coagulopathy (also called a bleeding disorder) is a condition in which the blood's ability to coagulate (form clots) is impaired. This condition can cause a tendency toward prolonged or excessive bleeding (bleeding diathesis), which may occur spo ...
. In 1994, a new phenotype was described and named CDGS-II. In 1995, Van Schaftingen and Jaeken showed that CDGS-I (now PMM2-CDG) was caused by the deficiency of the enzyme phosphomannomutase. This enzyme is responsible for the interconversion of
mannose-6-phosphate Mannose-6-phosphate (M6P) is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase. M6P is a key targeting signal for acid hydrolase precursor proteins that are destined for transp ...
and
mannose-1-phosphate Mannose 1-phosphate is a molecule involved in glycosylation. See also

* Congenital disorder of glycosylation * Mannose-6-phosphate Organophosphates Monosaccharide derivatives {{organic-compound-stub ...
, and its deficiency leads to a shortage in
GDP-mannose Guanosine diphosphate mannose or GDP-mannose is a nucleotide sugar that is a substrate for glycosyltransferase reactions in metabolism. This compound is a substrate for enzymes called mannosyltransferases. Known as donor of activated mannose in al ...
and
dolichol Dolichol refers to any of a group of long-chain mostly unsaturated organic compounds that are made up of varying numbers of isoprene units terminating in an α-saturated isoprenoid group, containing an alcohol functional group. Functions Dolich ...
(Dol)-
mannose Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylation ...
(Man), two donors required for the synthesis of the lipid-linked oligosaccharide precursor of N-linked glycosylation. In 1998, Niehues described a new CDG syndrome, MPI-CDG, which is caused by
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s in the enzyme metabolically upstream of PMM2, phosphomannose isomerase (PMI). A functional therapy for MPI-CDG, alimentary mannose was also described. The characterization of new defects took increased and several new Type I and Type II defects were delineated. In 2012, Need described the first case of a congenital disorder of deglycosylation,
NGLY1 deficiency NGLY1 deficiency is a very rare genetic disorder caused by biallelic pathogenic variants in ''NGLY1''. It is an autosomal recessive disorder. Errors in deglycosylation are responsible for the symptoms of this condition. Clinically, most affecte ...
. A 2014 study of
NGLY1 PNGase also known as N-glycanase 1 (EC 3.5.1.52) or peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase is an enzyme that in humans is encoded by the NGLY1 gene. PNGase is a de-''N''-glycosylating enzyme that removes ''N-''linked or aspar ...
deficient patients found similarities with traditional congenital disorders of glycosylation.


See also

*
Inborn error of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrat ...
*
Leukocyte adhesion deficiency Leukocyte adhesion deficiency (LAD) is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections. LAD is currently divided into three subtypes: LAD1, LAD2, and the recently described LAD3, also kno ...
* PMM2 deficiency


References


External links


GeneReviews/NIH/NCBI/UW entry on PMM2-CDG (CDG-Ia)Carbohydrate-Deficient Glycoprotein Syndrome, Type 1a; Congenital Disorder of Glycosylation Type 1a; Jaeken Syndrome

OMIM entries on Carbohydrate-Deficient Glycoprotein Syndrome, Type 1a; Congenital Disorder of Glycosylation Type 1a; Jaeken Syndrome

GeneReviews/NIH/NCBI/UW entry on Congenital Disorders of Glycosylation Overview
{{DEFAULTSORT:Congenital Disorder Of Glycosylation Inborn errors of metabolism Glycoprotein metabolism disorders Membrane transport protein disorders Congenital disorders of glycosylation