Congenital disorders of N-linked glycosylation (abbreviated here as CDG-N-linked), are a group of disorders of N-linked oligosaccharides caused by deficiency in 42 different enzymes in the N-linked synthetic pathway. Most commonly, the disorders begin in infancy; manifestations range from severe developmental delay and hypotonia with multiple organ system involvement to hypoglycemia and protein-losing enteropathy with normal development. However, most types have been described in only a few individuals, and thus understanding of the phenotypes is limited. In PMM2-CDG (CDG-Ia), the most common type reported, the clinical presentation and course are highly variable, ranging from death in infancy to mild involvement in adults.
The diagnostic test for almost all types of CDG-N-linked is transferrin isoform analysis to determine the number and /or incomplete composition of sialylated N-linked oligosaccharide residues linked to serum transferrin. While the enzyme is known in most CDG types, the enzymatic assays have not been developed for most. Thus, clarification of type requires molecular genetic testing.
Most types of CDG-N-linked are inherited in an autosomal recessive manner; the exceptions are MAGT1-CDG, ALG13-CDG, SLC35A2-CDG, and SSR4-CDG, which are inherited in an X-linked manner. In the autosomal recessive disorders, the theoretic risks to each sib of an affected individual are, at conception: a 25% risk of being affected, a 50% risk of being an asymptomatic carrier, and a 25% risk of being unaffected and not a carrier. However, based on outcomes of at-risk pregnancies in families with a child with PMM2-CDG (CDG-Ia), the risk of having an affected child is closer to 1/3 than to the expected 1/4. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible through laboratories offering either testing for the gene of interest or custom testing.
Treatment of manifestations: Infants and children with all types of CDG N-linked except MPI-CDG (CDG-Ib) require nutrition supplements for maximal caloric intake and/or nasogastric tube or gastrostomy tube feedings. Routine therapies are used for gastroesophageal reflux and/or persistent vomiting, developmental delays, ocular findings, and hypothyroidism. IV hydration and physical therapy are used for stroke-like episodes. Orthopedic issues in adults require physical therapy, wheel chairs, transfer devices, and surgical treatment of scoliosis as needed.
Prevention of primary manifestations: MPI-CDG (CDG-Ib), characterized by hepatic-intestinal disease, is the most common type of CDG for which therapy exists. Mannose given as 1.0 gm per kg body weight per day divided into five oral doses normalizes hypoproteinemia and coagulation defects and rapidly improves the protein-losing enteropathy and hypoglycemia.
Prevention of secondary complications: Attention to coagulation status before surgery because of increased risk of deep venous thrombosis and bleeding.
Agents/circumstances to avoid: Acetominophen and other agents metabolized by the liver.
Note: There are now many human disorders of glycosylation pathways, including defects in synthetic pathways for N-linked oligosaccharides, O-linked oligosaccharides, shared substrates, GPI anchors, and dolichols. This overview will focus on (1) disorders of the N-linked glycan synthetic pathway and (2) some disorders that overlap this metabolic network, referred to here as CDG-N-linked and multiple pathway disorders, respectively.
Almost all types of congenital disorders of glycosylation (CDG) present in infancy. Manifestations range from severe developmental delay and hypotonia with multiple organ system involvement to hypoglycemia and protein-losing enteropathy with normal development.
Establishing the Diagnosis
CDG-N-linked are a group of disorders caused by the defective synthesis of N-linked oligosaccharides, sugars linked together in a specific pattern and attached to proteins and lipids (N-linked glycans link to the amide group of asparagine via an N-acetylglucosamine residue) [Jaeken & Matthijs 2001, Grunewald et al 2002, Freeze 2006, Grunewald 2007].
The diagnostic test for all N-linked types of CDG is analysis of serum transferrin glycoforms, also called "transferrin isoforms analysis" or "carbohydrate-deficient transferrin analysis." This diagnostic test is performed by isoelectric focusing (IEF) or by capillary electrophoresis, GC/MS, CE-ESI-MS, MALDI-MS to determine the number and presence of incomplete sialylated N-linked oligosaccharide residues linked to serum transferrin [Jaeken & Carchon 2001, Marklová & Albahri 2007, Sanz-Nebot et al 2007].
Results of such testing may reveal the following:
- Normal transferrin isoform pattern. Two biantennary glycans linked to asparagine with four sialic acid residues
- Type I transferrin isoform pattern. Decrease of tetrasialotransferrin and increased asialotransferrin and disialotransferrin. The pattern indicates defects in the earliest synthetic steps of the N-linked oligosaccharide synthetic pathway.
- Type II transferrin isoform pattern. Increased trisialo- and monosialo- fractions, most likely because of the incorporation of truncated or monoantennary sugar chains, defects in the terminal portion of the pathway [Jaeken & Matthijs 2001].
Note: (1) The diagnostic validity of analysis of serum transferrin glycoforms before age three weeks is controversial [Clayton et al 1992, Stibler & Skovby 1994]. (2) The use of Guthrie cards with whole blood samples is not suggested; however, the use of Guthrie cards with blotted serum yields accurate results [Carchon et al 2006]. (3) Rarely, individuals with the diagnosis of PMM enzyme deficiency with normal transferrin glycosylation have been reported [Fletcher et al 2000, Marquardt & Denecke 2003, Hahn et al 2006]. (4) Results are expected to be normal in MOGS-CDG (CDG-IIb) and SLC35C1-CDG (CDG-IIc). (5) The possibility that an abnormal transferrin glycoform analysis is the result of a transferrin protein variant can be confirmed with a glycoform analysis of a serum sample from the parents.
In PMM2-CDG (CDG-Ia)
- An enlarged cisterna magna and superior cerebellar cistern are observed in late infancy to early childhood.
- Occasionally both infratentorial and supratentorial changes compatible with atrophy are present.
- Dandy-Walker malformations and small white matter cysts have been reported [Peters et al 2002].
- Myelination varies from normal to delayed maturation or insufficient [Holzbach et al 1995].
- Imaging post stroke-like episodes can reveal ischemic areas or edema followed by focal necrosis [Ishikawa et al 2009].
In other types of CDG, MRI may range from normal to non-cerebellar findings.
Other genetic disorders to consider:
The following metabolic disorders are in the differential diagnosis of hypotonia, developmental delay, and failure to thrive:
- Peroxisome biogenesis disorders, Zellweger syndrome spectrum. Children with peroxisomal disorders are likely to present with seizures and/or hearing loss.
- Urea cycle defects. Children with urea cycle defects are likely to be ill at presentation.
The following genetic disorder has abnormal transferrin glycosylation and presents as cutis laxa, severe developmental delay, seizures and regression.
In 2009 the nomenclature for all types of CDG was changed to include the official gene symbol (not in italics) followed by “-CDG”. If the type has a known letter name, it follows in parenthesis; for example, the new nomenclature is PMM2-CDG (CDG-Ia) [Jaeken et al 2009a].
PMM2-CDG (CDG-Ia) is the most common type of CDG-N-linked reported to date, with more 700 affected individuals worldwide. The prevalence may be as high as 1:20,000 [Jaeken & Matthijs 2001]. The expected carrier frequency of PMM2 mutations in the Danish population is 1:60-1:79 [Matthijs et al 2000].
MPI-CDG (CDG-Ib). At least 20 individuals have been diagnosed.
ALG6-CDG (CDG-Ic). At least 30 individuals have been diagnosed.
All other types of CDG-N-linked and multiple pathway disorders are case reports of a small number of individuals.
Types of CDG-N-Linked and Multiple Pathway Disorders
Note: This list includes (1) disorders of the N-linked glycan synthetic pathway (CDG-N-linked) and (2) some disorders that involve both the N-linked and O-linked oligosaccharide synthetic pathways (“multiple pathway disorders”).
Clinical findings. Because of the important biologic functions of the oligosaccharides in both glycoproteins and glycolipids, incorrect synthesis of these compounds results in multisystem clinical manifestations [Varki 1993]. The clinical spectrum of the group of disorders included in congenital disorders of glycosylation (CDG) is broad.
For many types, the phenotype is not completely known because only a few affected individuals have been reported.
- PMM2-CDG (CDG-Ia). The typical clinical course of CDG-Ia has been divided into an infantile multisystem stage, late-infantile and childhood ataxia-intellectual disability stage, and adult stable disability stage; see PMM2-CDG (CDG-Ia). Recent reports have widened the phenotypic spectrum to include hydrops fetalis at the severe end [van de Kamp et al 2007] and a mild neurologic phenotype in adults with multisystemic involvement at the mild end [Barone et al 2007, Coman et al 2007].
The infantile multisystem stage, the most commonly seen stage, is characterized by failure to thrive, inverted nipples, abnormal subcutaneous fat distribution, and cerebellar hypoplasia, in combination with facial dysmorphism and developmental delay.
- MPI-CDG (CDG-Ib). Cyclic vomiting, profound hypoglycemia, failure to thrive, liver fibrosis, and protein-losing enteropathy, occasionally associated with coagulation disturbances without neurologic involvement, are characteristic [de Koning et al 1998, Jaeken et al 1998, Niehues et al 1998, Babovic-Vuksanovic et al 1999, de Lonlay et al 1999, Adamowicz et al 2000, DeLonlay & Seta 2009]. The clinical course is variable even within families.
- ALG6-CDG (CDG-Ic). Previously classified as carbohydrate-deficient glycoprotein syndrome type V [Korner et al 1998], ALG6-CDG (CDG-Ic) is characterized by mild-to-moderate neurologic involvement with hypotonia, poor head control, developmental delay, ataxia, strabismus, and seizures, ranging from febrile convulsions to epilepsy [Grunewald et al 2000, Hanefeld et al 2000, Imbach et al 2000a, Kahook et al 2006]. Retinal degeneration has been reported [Kahook et al 2006]. The clinical presentation may be milder than in PMM2-CDG (CDG-Ia); stroke-like episodes and peripheral neuropathy have not been reported. An adult with ALG6-CDG (CDG-Ic) had brachydactyly, deep vein thrombosis, pseudotumor cerebri with normal brain MRI, and endocrine abnormalities including hyperandrogenism with virilization [Sun et al 2005]. Pubertal abnormalities have been described in an individual with ALG6-CDG (CDG-Ic) [Miller et al 2011].
- ALG3-CDG (CDG-Id)
- One child had arthrogryposis multiplex congenita (AMC), severe developmental delay, microcephaly, seizures, and severe vision impairment, but not iris coloboma [Denecke et al 2005].
- Two sibs had severe developmental delay, failure to thrive, microcephaly, hypotonia, and seizures [Kranz et al 2007d]. One had significant digestive issues; the other was more neurologically impaired.
- DPM1-CDG (CDG-Ie)
- Two sibs had a milder phenotype with developmental delay, microcephaly, ataxia, and peripheral neuropathy without dysmorphic features or severe seizures [Dancourt et al 2006]. They had nystagmus and strabismus; one had a retinopathy.
- ALG12-CDG (CDG-Ig). Seven individuals had dysmorphic features, generalized hypotonia, feeding difficulties, moderate to severe developmental delay, progressive microcephaly, frequent upper respiratory tract infections, impaired immunity with decreased immunoglobulin levels, and decreased coagulation factors [Chantret et al 2002, Grubenmann et al 2002, Thiel et al 2002, Zdebska et al 2003, Di Rocco et al 2005, Eklund et al 2005a, Eklund et al 2005b, Kranz et al 2007a]. Additional features included hypogonadism with or without hypospadias in the males, seizures in two individuals, and cardiac anomalies in two sibs.
- ALG8-CDG (CDG-Ih)
- A four-month-old female had moderate hepatomegaly, severe diarrhea, and hypoalbuminemia from protein-losing enteropathy, normal facial features, and normal development [Chantret et al 2003]. She had decreased levels of factor XI, protein C, and antithrombin III.
- Three other affected individuals had cardiorespiratory difficulties with lung hypoplasia, a severe hepatointestinal disorder, and hypotonia [Schollen et al 2004a, Eklund et al 2005b]. A fourth individual had seizures and developmental delay. All four individuals had hematopoeitic issues with anemia and thrombocytopenia, and early death between ages three days and 16 months.
- ALG2-CDG (CDG-Ii). A six-year-old had bilateral iris colobomas, unilateral cataract, infantile spasms beginning at age four months, and severe developmental delay; coagulation factors were abnormal [Thiel et al 2003].
- DPAGT1-CDG (CDG-Ij). The one affected individual described had hypotonia, intractable seizures, developmental delay, and microcephaly [Wu et al 2003]. Subsequently two additional individuals were reported with similar features and early death prior to age one year [Wurde et al 2012]. One individual was described with features of severe fetal hypokinenesia [Carrera et al 2012]. A fifth child, who died at age 2.5 years, was identified with apnea and respiratory deficiency, cataracts, joint contractures, and feeding difficulties who died at 2.5 years [Timal et al 2012].
- ALG1-CDG (CDG-Ik). Four affected individuals had severe developmental delay, hypotonia, and early-onset seizures; the latter were intractable in three. Three individuals died between ages two weeks and ten months. As in ALG3-CDG (CDG-Id) and ALG12-CDG (CDG-Ig), also caused by mannosyltransferase defects, microcephaly was rapidly progressive. Other features included severe coagulation defects, nephrotic syndrome, liver dysfunction, coagulation abnormalities, cardiomyopathy, and immunodeficiency [Grubenmann et al 2004, Kranz et al 2004, Schwarz et al 2004]. Brain imaging showed cerebral atrophy in two individuals and was normal in a third individual. Further studies have shown that ALG1-CDG (CDG-Ik) and MPI-CDG (CDG-Ib) may be the most frequent after PMM2-CDG (CDG-Ia) and present at the severe end of the CDG I clinical spectrum [Dupré et al 2010].
- DOLK-CDG (CDG-Im). Four affected infants had hypotonia and ichthyosis, and died between ages four and nine months [Kranz et al 2007b]. Additional features included seizures and progressive microcephaly in one and dilated cardiomyopathy in two sibs.
- RFT1-CDG (CDG-In). An infant born preterm to unrelated parents had a poorly coordinated suck resulting in difficulty feeding and failure to thrive. Myoclonic jerks were noted at three weeks with hypotonia and brisk reflexes progressing to a seizure disorder. Eye movements were roving; ERG was normal and VEP was reduced. At age two years the child continued to have marked developmental delay [Imtiaz et al 2000, Haeuptle et al 2008, Clayton & Grunewald 2009]. Five additional affected individuals have been described [Vleugels et al 2009, Jaeken et al 2009b]. The common features in all six include severe developmental delay, hypotonia, visual disturbances, seizures, feeding difficulties, and sensorineural hearing loss, as well as features similar to other types of CDG including inverted nipples and microcephaly.
- DPM3-CDG (CDG-Io). A single described individual diagnosed with CDG at age 27 years had a low normal IQ and mild muscle weakness. She presented initially at age 11 years with mild muscle weakness and waddling gait. She was found to have dilated cardiomyopathy without signs of cardiac muscle hypertrophy at age 20 years followed by a stroke-like episode at age 21 years [Lefeber et al 2009].
- ALG11-CDG (CDG-Ip). A single infant presented with distinctive features (microcephaly, high forehead, and low posterior hairline), hypotonia, and failure to thrive. She had severe neurologic impairment with frequent and difficult-to-treat seizures. She developed an unusual fat pattern around age six months. She had persistent vomiting and gastric bleeding; she died at age two years [Rind et al 2010]. Subsequently, three additional individuals were identified with developmental delay, strabismus, and seizures in the first year of life [Thiel et al 2012].
- SRD5A3-CDG (CDG-Iq)
- Individuals from seven families were identified with common features including congenital eye malformations (ocular coloboma, optic nerve hypoplasia, and variable degree of visual loss), nystagmus, hypotonia, and developmental delay/intellectual disability. Dermatologic complications and/or congenital cardiac defects were identified in some [Cantagrel et al 2010].
- An additional 12 individuals from nine families were described with cerebellar ataxia and congenital eye malformations [Morava et al 2010].
- Additional mutations in SRD5A3 have been identified in people with Kahrizi syndrome, which consists of coloboma, cataract, kyphosis, and intellectual disability [Kahrizi et al 2011].
- DDOST-CDG (CDG-Ir). A single child was described, presenting with failure to thrive, developmental delay, hypotonia, strabismus and hepatic dysfunction. At three years the child walked but continued to have fine motor delays and minimal speech development. Brain MRI showed dysmyelination [Jones et al 2012].
- MAGT1-CDG. Reported in a family with two girls with mild cognitive impairment and two boys with more severe cognitive involvement. The mother is reported to have mild cognitive impairment [Molinari et al 2008].
- TUSC3-CDG. Described in 12 individuals (including two French sibs and three Iranian sibs) with nonsyndromic moderate to severe cognitive impairment and normal brain MRI [Garshasbi et al 2011].
- ALG13-CDG. Described in one child with microcephaly, hepatomegaly, edema of the extremities, intractable seizures, recurrent infections and increased bleeding tendency who died at age one year [Timal et al 2012].
- PGM1-CDG. Two individuals were described with dilated cardiomyopathy. One patient also had Pierre Robin sequence with cleft palate, fatigue, and chronic hepatitis [Timal et al 2012]. PGM1 deficiency has also been described in patients with a diagnosis of glycogen storage disease type 14 with recurrent rhabdomyolysis [Stojkovic et al 2009].
- MGAT2-CDG (CDG-IIa). Individuals have facial dysmorphism, stereotypic hand movements, seizures, and varying degrees of developmental delay, but no peripheral neuropathy or cerebellar hypoplasia. A bleeding disorder is caused by diminished platelet aggregation [Van Geet et al 2001].
- MOGS-CDG (CDG-IIb). An infant with generalized hypotonia, craniofacial dysmorphism, hypoplastic genitalia, seizures, feeding difficulties, hypoventilation, and generalized edema died at age 2.5 months [De Praeter et al 2000].
- SLC35C1-CDG (CDG-IIc). Severe growth and developmental delay, microcephaly, hypotonia, distinctive cranofacial features, and recurrent bacterial infections with persistent, highly elevated peripheral blood leukocyte count are characteristic [Etzioni et al 2002].
- B4GALT1-CDG (CDG-IId). Mild developmental delay, Dandy-Walker malformation, progressive hydrocephalus, coagulation abnormalities, and elevated serum creatine kinase concentration have been observed [Peters et al 2002].
- SLC35A2-CDG. An X-linked disorder leading to severe early-onset encephalopathy [Kodera et al 2013].
- GMPPA-CDG. Identified in several individuals with cognitive impairment and autonomic dysfunction including achalasia and alacrima. Gait abnormalities were also seen [Koehler et al 2013].
- SSR4-CDG. An X-linked disorder described in a male age 16 years with microcephaly, cognitive impairment and a seizure disorder [Losfeld et al 2013].
- STT3A-CDG and STT3B-CDG. Described in different individuals with hypotonia, developmental delay, feeding issues and failure to thrive [Shrimal et al 2013].
- COG7-CDG (CDG-IIe). Six affected infants had dysmorphic features with a small mouth (although one had full lips), micro- and retrognathia, short neck, wrinkled and loose skin, adducted thumbs, and overlapping long fingers; hypotonia; skeletal abnormalities; hepatosplenomegaly; progressive jaundice; seizures; and early death [Wu et al 2004, Spaapen et al 2005, Morava et al 2007, Ng et al 2007].
- SLC35A1-CDG (CDG-IIf). One affected infant presented at age four months with macrothrombocytopenia, neutropenia, and immunodeficiency, and died at age 37 months of complications from bone marrow transplantation [Martinez-Duncker et al 2005].
- COG1-CDG (CDG-IIg). An affected infant presented in the first month of life with feeding difficulties, failure to thrive, and hypotonia. She had mild developmental delays, rhizomelic short stature, and progressive microcephaly with slight cerebral and cerebellar atrophy on brain MRI, as well as cardiac abnormalities and hepatosplenomegaly [Foulquier et al 2006].
- COG8-CDG (CDG-IIh)
- More recently, a pair of sibs were described who had a milder presentation with pseudo-gynecomastia, hypotonia, intellectual disability, and ataxia [Stolting et al 2009].
- COG5-CDG (CDG-Iii). A single individual with mild delay in motor and language development was described [Paesold-Burda et al 2009].
- COG4-CDG (CDG-IIj). A single child has been described who presented at age four months with a complex seizure disorder that was treated with phenobarbital. At age three years, additional findings included hypotonia, microcephaly, ataxia, brisk uncoordinated movements, absent speech, motor delays, and recurrent respiratory infections [Reynders et al 2009].
- TMEM165-CDG (CDGIIk). Sibs with a skeletal dysplasia presentation affecting the epiphyses, metaphyses, and diaphyse were described. Additional features included abnormal white matter and pituitary hypoplasia on brain MRI. One of the sibs also had recurrent, unexplained fevers and died at age 14 months. Evaluation of unsolved cases with a type II transferrin isoelectric focusing pattern identified three additional patients, one of whom had no skeletal abnormalities [Foulquier et al 2012].
- COG6-CDG (CDG-IIL). A single infant presented with severe neurologic disease including intractable seizures; vitamin K deficiency and intracranial bleeding; vomiting; and early death [Lubbehusen et al 2010].
- DPM2-CDG. Failure to thrive, developmental delay, osteopenia, hypotonia, liver dysfunction, increased creatine kinase, and early death have been observed [Barone et al 2012].
- DHDDS-CDG. Retinitis pigmentosa is the only clinical manifestation reported [Willer et al 2012].
- MAN1B1-CDG. Nonsyndromic intellectual disability [Rafiq et al 2011].
Molecular genetics. Forty-two different enzymes in the N-linked oligosaccharide synthetic pathway or interactive pathways are currently recognized to be deficient in each of the types of CDG-N-linked or among the mixed pathway disorders (See Table 1).
Transferrin isoform analysis. The diagnostic test for almost all types of CDG-N-linked disorders is serum transferrin isoelectric focusing (IEF) or other serum transferrin isoform analysis to determine the number and/or incomplete composition of sialylated N-linked oligosaccharide residues linked to serum transferrin [Jaeken & Carchon 2001, Marklová & Albahri 2007, Sanz-Nebot et al 2007].
Molecular genetic testing. Whereas the enzyme is known in most CDG-N-linked types, the enzymatic assays have not been developed for most. Thus, clarification of type requires molecular genetic testing using either single gene testing or a multi-gene panel. Note that mutation detection frequency is up to 100% for PMM2 and MPI in individuals with an enzymatically confirmed diagnosis [G Matthijs, personal communication].
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
Mode of Inheritance
Congenital disorders of N-linked glycosylation (CDG -N-linked) are inherited in an autosomal recessive manner except for MGAT1-CDG, ALG13-CDG,SLC35A2-CDG, and SSR4-CDG which are inherited in an X-linked manner.
Risk to Family Members - Autosomal Recessive Inheritance
Parents of a proband
- The parents of the proband are obligate carriers and thus carry one mutant allele.
- Carriers are asymptomatic.
Sibs of a proband
- At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. See, however, Related Genetic Counseling Issues, Increased recurrence risk for PMM2-CDG (CDG-Ia).
- Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
- Heterozygotes (carriers) are asymptomatic.
Offspring of a proband
- Adults with CDG – except for those with MPI-CDG (CDG-Ib) – have not been reported to reproduce. (One woman with MPI-CDG (CDG-Ib) had a child without complications.)
- The offspring of an individual with MPI-CDG (CDG-Ib) are obligate heterozygotes (carriers).
Carrier testing for at-risk family members is possible if the mutation(s) have been identified in the family.
Related Genetic Counseling Issues
Increased recurrence risk for PMM2-CDG (CDG-Ia). Studies of the outcomes of prenatal testing suggest that the percentage of affected fetuses is higher than predicted by Mendel’s second law. The risk to sibs of a proband is estimated to be closer to 1/3 than to the expected 1/4. This finding of an apparent increased recurrence risk as a result of transmission ratio distortion continues to be validated [Schollen et al 2004b].
- The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
- It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) have been identified.
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- CDG CARE (Community Alliance and Resource Exchange)
- Foundation Glycosylation (FoG)Canada
Treatment of Manifestations
For all congenital disorders of N-linked glycosylation (CDG-N-linked) and most mixed pathway disorders except MPI-CDG (CDG-Ib)
- Failure to thrive. Infants and children can be fed any type of formula for maximal caloric intake. They can tolerate carbohydrates, fats, and protein. Early in life, children may do better on elemental formulas. Their feeding may be advanced based on their oral motor function. Some children require placement of a nasogastric tube or gastrostomy tube for nutritional support until oral motor skills improve.
- Oral motor dysfunction with persistent vomiting. Thickening of feeds, maintenance of an upright position after eating, and antacids can be helpful for children with gastroesophageal reflux and/or persistent vomiting. Consultation with a gastroenterologist and nutritionist is often necessary. Children with a gastrostomy tube should be encouraged to eat by mouth if the risk of aspiration is low. Continued speech and oral motor therapy aids transition to oral feeds and encourages speech when the child is developmentally ready.
- Developmental delay. Occupational therapy, physical therapy, and speech therapy should be instituted. As the developmental gap widens between children with CDG and their unaffected peers, parents need continued counseling and support.
- "Infantile catastrophic phase." Very rarely, infants may have a complicated early course presenting with infection, seizure, or hypoalbuminemia with third spacing that may progress to anasarca. Some children are responsive to aggressive albumin replacement with Lasix®; others may have a more refractory course. Symptomatic treatment in a pediatric tertiary care center is recommended. Parents should also be advised that some infants with PMM2-CDG (CDG-Ia) never experience a hospital visit while others may require frequent hospitalizations.
- Strabismus. Consultation with a pediatric ophthalmologist early in life is important so that therapies that preserve vision (glasses, patching, or surgery) can be instituted as needed.
- Hypothyroidism. Although children with CDG are usually chemically euthyroid [Martin & Freeze 2003], thyroid function tests are frequently abnormal. However, free thyroxine analyzed by equilibrium dialysis, the most accurate method, has been reported as normal in seven individuals with CDG. Diagnosis of hypothyroidism and L-thyroxine supplementation should be reserved for those children and adults with elevated TSH and low free thyroxine measured by equilibrium dialysis.
- Stroke-like episodes. Supportive therapy includes intravenous hydration as needed and physical therapy during the recovery period.
- Coagulopathy. Low levels of coagulation factors, both pro- and anti-coagulant, rarely cause clinical problems in daily activities but must be addressed when an individual with CDG undergoes surgery. Consultation with a hematologist to document the coagulation status and clotting factor levels and discussion of management issues with the surgeon are important. When necessary, infusion of fresh frozen plasma corrects the factor deficiency and clinical bleeding. The potential for imbalance of the level of both pro- and anti-coagulant factors may lead to either bleeding or thrombosis. Care givers, especially of older affected individuals, should be taught the signs of deep venous thrombosis.
- Immunologic status. Most individuals affected with CDGs have functional immune systems; however, rare children with CDG with recurrent or unexpectedly severe infections should be evaluated by an immunologist. Unless otherwise indicated, full pediatric vaccinations are recommended for affected children and adults.
Additional management issues of adults with CDG
- Orthopedic issues — thorax shortening, scoliosis/kyphosis. Management involves appropriate orthopedic and physical medicine management, well-supported wheel chairs, appropriate transfer devices for the home, and physical therapy. Occasionally, surgical treatment of spinal curvature is warranted.
- Independent living issues. Young adults with CDG and their parents need to address issues of independent living. Aggressive education in functional life skills and/or vocational training help the transition when schooling is completed. Independence in self care and the activities of daily living should be encouraged. Support and resources for parents of a disabled adult are important aspects of management.
- Deep venous thrombosis (DVT). DVT has been reported in two adults with PMM2-CDG (CDG-Ia). Rapid diagnosis and treatment of DVT are essential to minimize the risk of pulmonary emboli; sedentary affected adults and children are at increased risk for DVT.
Prevention of Primary Manifestations
MPI-CDG (CDG-Ib), characterized by hepatic-intestinal disease, is the most common type of CDG for which therapy exists. Because so few individuals have been treated and the natural history of this disorder is variable, careful monitoring and discussion among physicians treating these individuals are warranted [Jaeken et al 1998, Niehues et al 1998, de Lonlay et al 1999, Hendriksz et al 2001, DeLonlay & Seta 2009]:
- In the first reported case, mannose normalized hypoproteinemia and coagulation defects and rapidly improved the protein-losing enteropathy and hypoglycemia [Harms et al 2002]. One gram of mannose per kg body weight was given per day, divided into five oral doses.
- In two children with MPI-CDG (CDG-Ib) treated from infancy with mannose, protein-losing enteropathy and vomiting improved significantly; however, the two children were recently reported to have progressive liver fibrosis [Mention et al 2008].
- Recurrent episodes of thrombo-embolism and consumptive coagulopathy did not recur in an individual with MPI-CDG (CDG-Ib) treated with mannose [Tamminga et al 2008].
- For some individuals with MPI-CDG (CDG-Ib), heparin therapy can be an alternative to mannose in the treatment of the enteropathy [de Lonlay & Seta 2009].
Prevention of Secondary Complications
Because infants with CDG have more limited reserves than their peers, parents should have a low threshold for evaluation by a physician for prolonged fever, vomiting, or diarrhea. Aggressive intervention with antipyretics, antibiotics if warranted, and hydration may prevent the morbidity associated with the "infantile catastrophic phase" and may decrease the risk of “stroke-like episodes.”
- Assessment by a physician with attention to overall health and possible need for referral for speech, occupational, and physical therapy
- Eye examination
- Liver function tests; thyroid panel; serum concentrations of the clotting factors protein C, protein S, factor IX, and antithrombin III
- Periodic assessment of bleeding and clotting parameters by a hematologist
- Follow up with an orthopedist when scoliosis becomes evident
Agents/Circumstances to Avoid
Acetominophen and other agents metabolized by the liver should be used with caution.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
- Adamowicz M, Matthijs G, Van Schaftingen E. et al. New case of phosphomannose isomerase deficiency. J Inherit Metab Dis. 2000;23 Suppl 1:184.
- Aebi M, Helenius A, Schenk B, Barone R, Fiumara A, Berger EG, Hennet T, Imbach T, Stutz A, Bjursell C, Uller A, Wahlström JG, Briones P, Cardo E, Clayton P, Winchester B, Cormier-Dalre V, de Lonlay P, Cuer M, Dupré T, Seta N, de Koning T, Dorland L, de Loos F, Kupers L, et al (1999) Carbohydrate-deficient glycoprotein syndromes become congenital disorders of glycosylation: an updated nomenclature for CDG. First International Workshop on CDGS. Glycoconj J. 16:669-71. [PubMed: 11003549]
- Babovic-Vuksanovic D, Patterson MC, Schwenk WF, O'Brien JF, Vockley J, Freeze HH, Mehta DP, Michels VV. Severe hypoglycemia as a presenting symptom of carbohydrate-deficient glycoprotein syndrome. J Pediatr. 1999;135:775–81. [PubMed: 10586187]
- Barone R, Sturiale L, Fiumara A, Uziel G, Garozzo D, Jaeken J. Borderline mental development in a congenital disorder of glycosylation (CDG) type Ia patient with multisystemic involvement (intermediate phenotype). J Inherit Metab Dis. 2007;30:107. [PubMed: 17186415]
- Barone R, Aiello C, Race V, Morava E, Foulquier F, Riemersma M, Passarelli C, Concolino D, Carella M, Santorelli F, Vleugels W, Mercuri E, Garozzo D, Sturiale L, Messina S, Jaeken J, Fiumara A, Wevers RA, Bertini E, Matthijs G, Lefeber DJ. DPM2-CDG: A muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. Ann Neurol. 2012;72:550–8. [PubMed: 23109149]
- Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Blümel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 2010;142:203–17. [PMC free article: PMC2940322] [PubMed: 20637498]
- Carchon HA, Nsibu Ndosimao C, Van Aerschot S, Jaeken J. Use of serum on Guthrie cards in screening for congenital disorders of glycosylation. Clin Chem. 2006;52:774–5. [PubMed: 16595835]
- Carrera IA, Matthijs G, Perez B, Cerda CP. DPAGT1-CDG: Report of a patient with fetal hypokinesia phenotype. Am J Med Genet A. 2012;158A:2027–30. [PubMed: 22786653]
- Chantret I, Dancourt J, Dupre T, Delenda C, Bucher S, Vuillaumier-Barrot S, Ogier de Baulny H, Peletan C, Danos O, Seta N, Durand G, Oriol R, Codogno P, Moore SE. A deficiency in dolichyl-P-glucose:Glc1Man9GlcNAc2-PP-dolichyl alpha3-glucosyltransferase defines a new subtype of congenital disorders of glycosylation. J Biol Chem. 2003;278:9962–71. [PubMed: 12480927]
- Chantret I, Dupre T, Delenda C, Bucher S, Dancourt J, Barnier A, Charollais A, Heron D, Bader-Meunier B, Danos O, Seta N, Durand G, Oriol R, Codogno P, Moore SE. Congenital disorders of glycosylation type Ig is defined by a deficiency in dolichyl-P-mannose:Man7GlcNAc2-PP-dolichyl mannosyltransferase. J Biol Chem. 2002;277:25815–22. [PubMed: 11983712]
- Clayton PT, Grunewald S. Comprehensive description of the phenotype of the first case of congenital disorder of glycosylation due to RFT1 deficiency (CDG In). J Inherit Metab Dis. 2009;32 Suppl 1:S137–9. [PubMed: 19267216]
- Clayton PT, Winchester BG, Keir G. Hypertrophic obstructive cardiomyopathy in a neonate with the carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis. 1992;15:857–61. [PubMed: 1293380]
- Coman D, McGill J, MacDonald R, Morris D, Klingberg S, Jaeken J, Appleton D. Congenital disorder of glycosylation type 1a: Three siblings with a mild neurological phenotype. Journal of Clinical Neuroscience. 2007;14:668–72. [PubMed: 17451957]
- Dancourt J, Vuillaumier-Barrot S, de Baulny HO, Sfaello I, Barnier A, le Bizec C, Dupre T, Durand G, Seta N, Moore SE. A new intronic mutation in the DPM1 gene is associated with a milder form of CDG Ie in two French siblings. Pediatr Res. 2006;59:835–9. [PubMed: 16641202]
- de Koning TJ, Dorland L, van Diggelen OP, Boonman AM, de Jong GJ, van Noort WL, De Schryver J, Duran M, van den Berg IE, Gerwig GJ, Berger R, Poll-The BT. A novel disorder of N-glycosylation due to phosphomannose isomerase deficiency. Biochem Biophys Res Commun. 1998;245:38–42. [PubMed: 9535779]
- de Lonlay P, Cuer M, Vuillaumier-Barrot S, Beaune G, Castelnau P, Kretz M, Durand G, Saudubray JM, Seta N. Hyperinsulinemic hypoglycemia as a presenting sign in phosphomannose isomerase deficiency: A new manifestation of carbohydrate-deficient glycoprotein syndrome treatable with mannose. J Pediatr. 1999;135:379–83. [PubMed: 10484808]
- de Lonlay P, Seta N. The clinical spectrum of phosphomannose isomerase deficiency, with an evaluation of mannose treatment for CDG-Ib. Biochim Biophys Acta. 2009;1792:841–3. [PubMed: 19101627]
- De Praeter CM, Gerwig GJ, Bause E, Nuytinck LK, Vliegenthart JF, Breuer W, Kamerling JP, Espeel MF, Martin JJ, De Paepe AM, Chan NW, Dacremont GA, Van Coster RN. A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. Am J Hum Genet. 2000;66:1744–56. [PMC free article: PMC1378052] [PubMed: 10788335]
- Denecke J, Kranz C, von Kleist-Retzow JCh, Bosse K, Herkenrath P, Debus O, Harms E, Marquardt T. Congenital disorder of glycosylation type Id: clinical phenotype, molecular analysis, prenatal diagnosis, and glycosylation of fetal proteins. Pediatr Res. 2005;58:248–53. [PubMed: 16006436]
- Di Rocco M, Hennet T, Grubenmann CE, Pagliardini S, Allegri AE, Frank CG, Aebi M, Vignola S, Jaeken J. Congenital disorder of glycosylation (CDG) Ig: report on a patient and review of the literature. J Inherit Metab Dis. 2005;28:1162–4. [PubMed: 16435218]
- Dupré T, Vuillaumier-Barrot S, Chantret I, Yayé HS, Le Bizec C, Afenjar A, Altuzarra C, Barnérias C, Burglen L, de Lonlay P, Feillet F, Napuri S, Seta N, Moore SE. Guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase deficiency (congenital disorders of glycosylation type Ik): five new patients and seven novel mutations. J Med Genet. 2010;47:729–35. [PubMed: 20679665]
- Eklund EA, Newell JW, Sun L, Seo NS, Alper G, Willert J, Freeze HH. Molecular and clinical description of the first US patients with congenital disorder of glycosylation Ig. Mol Genet Metab. 2005a;84:25–31. [PubMed: 15639192]
- Eklund EA, Sun L, Westphal V, Northrop JL, Freeze HH, Scaglia F. Congenital disorder of glycosylation (CDG)-Ih patient with a severe hepato-intestinal phenotype and evolving central nervous system pathology. J Pediatr. 2005b;147:847–50. [PubMed: 16356445]
- Etzioni A, Sturla L, Antonellis A, Green ED, Gershoni-Baruch R, Berninsone PM, Hirschberg CB, Tonetti M. Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc founder effect and genotype/phenotype correlation. Am J Med Genet. 2002;110:131–5. [PubMed: 12116250]
- Fletcher JM, Matthijs G, Jaeken J, Van Schaftingen E, Nelson PV. Carbohydrate-deficient glycoprotein syndrome: beyond the screen. J Inherit Metab Dis. 2000;23:396–8. [PubMed: 10896303]
- Foulquier F, Amyere M, Jaeken J, Zeevaert R, Schollen E, Race V, Bammens R, Morelle W, Rosnoblet C, Legrand D, Demaegd D, Buist N, Cheillan D, Guffon N, Morsomme P, Annaert W, Freeze HH, Van Schaftingen E, Vikkula M, Matthijs G. TMEM165 deficiency causes a congenital disorder of glycosylation. Am J Hum Genet. 2012;91:15–26. [PMC free article: PMC3397274] [PubMed: 22683087]
- Foulquier F, Ungar D, Reynders E, Zeevaert R, Mills P, Garcia-Silva MT, Briones P, Winchester B, Morelle W, Krieger M, Annaert W, Matthijs G. A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation. Hum Mol Genet. 2007;16:717–30. [PubMed: 17220172]
- Foulquier F, Vasile E, Schollen E, Callewaert N, Raemaekers T, Quelhas D, Jaeken J, Mills P, Winchester B, Krieger M, Annaert W, Matthijs G. Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II. Proc Nat Acad Sci USA. 2006;103:3764–9. [PMC free article: PMC1450151] [PubMed: 16537452]
- Freeze H. Genetic defects in the human glycome. Nat Rev Genet. 2006;7:537–51. [PubMed: 16755287]
- Garcia-Silva MT, Matthijs G, Schollen E, Cabrera JC, Sanchez del Pozo J, Martí Herreros M, Simón R, Maties M, Martín Hernández E, Hennet T, Briones P. Congenital disorder of glycosylation (CDG) type Ie. A new patient. J Inherit Metab Dis. 2004;27:591–600. [PubMed: 15669674]
- Garshasbi M, Kahrizi K, Hosseini M, Nouri Vahid L, Falah M, Hemmati S, Hu H, Tzschach A, Ropers HH, Najmabadi H, Kuss AW. A novel nonsense mutation in TUSC3 is responsible for non-syndromic autosomal recessive mental retardation in a consanguineous Iranian family. Am J Med Genet. 2011;155A:1976–80. [PubMed: 21739581]
- Grubenmann CE, Frank CG, Hülsmeier AJ, Schollen E, Matthijs G, Mayatepek E, Berger EG, Aebi M, Hennet T. Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik. Hum Mol Genet. 2004;13:535–42. [PubMed: 14709599]
- Grubenmann CE, Frank CG, Kjaergaard S, Berger EG, Aebi M, Hennet T. ALG12 mannosyltransferase defect in congenital disorder of glycosylation type lg. Hum Mol Genet. 2002;11:2331–9. [PubMed: 12217961]
- Grunewald S. Congenital disorders of glycosylation: Rapidly enlarging group of (neuro)metabolic disorders. Early Human Development. 2007;83:825–30. [PubMed: 17959325]
- Grunewald S, Imbach T, Huijben K, Rubio-Gozalbo ME, Verrips A, de Klerk JB, Stroink H, de Rijk-van Andel JF, Van Hove JL, Wendel U, Matthijs G, Hennet T, Jaeken J, Wevers RA. Clinical and biochemical characteristics of congenital disorder of glycosylation type Ic, the first recognized endoplasmic reticulum defect in N-glycan synthesis. Ann Neurol. 2000;47:776–81. [PubMed: 10852543]
- Grunewald S, Matthijs G, Jaeken J. Congenital disorders of glycosylation: a review. Pediatr Res. 2002;52:618–24. [PubMed: 12409504]
- Hahn SH, Minnich SJ, O’Brien JF. Stabilization of hypoglycosylation in a patient with congenital disorder of glycosylation type Ia. J Inherit Metab Dis. 2006;29:235–7. [PubMed: 16601903]
- Hanefeld F, Korner C, Holzbach-Eberle U, von Figura K. Congenital disorder of glycosylation-Ic: case report and genetic defect. Neuropediatrics. 2000;31:60–2. [PubMed: 10832578]
- Harms HK, Zimmer KP, Kurnik K. Oral mannose therapy persistently corrects the severe clinical symptoms and biochemical abnormalities of phosphomannose isomerase deficiency. Acta Paediatr. 2002;91:1065–72. [PubMed: 12434892]
- Holzbach U, Hanefeld F, Helms G, Hanicke W, Frahm J. Localized proton magnetic resonance spectroscopy of cerebral abnormalities in children with carbohydrate-deficient glycoprotein syndrome. Acta Paediatr. 1995;84:781–6. [PubMed: 7549297]
- Imbach T, Grunewald S, Schenk B, Burda P, Schollen E, Wevers RA, Jaeken J, de Klerk JB, Berger EG, Matthijs G, Aebi M, Hennet T. Multi-allelic origin of congenital disorder of glycosylation (CDG)-Ic. Hum Genet. 2000a;106:538–45. [PubMed: 10914684]
- Imbach T, Schenk B, Schollen E, Burda P, Stutz A, Grunewald S, Bailie NM, King MD, Jaeken J, Matthijs G, Berger EG, Aebi M, Hennet T. Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie. J Clin Invest. 2000b;105:233–9. [PMC free article: PMC377434] [PubMed: 10642602]
- Imtiaz F, Worthington V, Champion M, Beesley C, Charlwood J, Clayton P, Keir G, Mian N, Winchester B. Genotypes and phenotypes of patients in the UK with carbohydrate-deficient glycoprotein syndrome type 1. J Inherit Metab Dis. 2000;23:162–74. [PubMed: 10801058]
- Ishikawa N, Tajima G, Ono H, Kobayashi M. Different neuroradiological findings during two stroke-like episodes in a patient with congenital disorder of glycosylation type Ia. Brain Dev. 2009;31:240–3. [PubMed: 18485644]
- Jaeken J. Congenital disorders of glycosylation. Ann. N.Y. Acad. Sci. 2010;1214:190–198. [PubMed: 21175687]
- Jaeken J, Carchon H. Congenital disorders of glycosylation: the rapidly growing tip of the iceberg. Curr Opin Neurol. 2001;14:811–5. [PubMed: 11723393]
- Jaeken J, Imbach T. et al. A newly recognized glycosylation defect with psychomotor retardation, ichthyosis and dwarfism. J Inherit Metab Dis. 2000;23 Suppl 1:186.
- Jaeken J, Matthijs G. Congenital disorders of glycosylation. Annu Rev Genomics Hum Genet. 2001;2:129–51. [PubMed: 11701646]
- Jaeken J, Matthijs G, Saudubray JM, Dionisi-Vici C, Bertini E, de Lonlay P, Henri H, Carchon H, Schollen E, Van Schaftingen E. Phosphomannose isomerase deficiency: a carbohydrate-deficient glycoprotein syndrome with hepatic-intestinal presentation. Am J Hum Genet. 1998;62:1535–9. [PMC free article: PMC1377152] [PubMed: 9585601]
- Jaeken J, Vleugels W, Régal L, Corchia C, Goemans N, Haeuptle MA, Foulquier F, Hennet T, Matthijs G, Dionisi-Vici C. RFT1-CDG: Deafness as a novel feature of congenital disorders of glycosylation. J Inherit Metab Dis. 2009b;32 Suppl 1:S335–8. [PubMed: 19856127]
- Jones MA, Ng BG, Bhide S, Chin E, Rhodenizer D, He P, Losfeld ME, He M, Raymond K, Berry G, Freeze HH, Hegde MR. DDOST mutations identified by whole-exome sequencing are implicated in congenital disorders of glycosylation. Am J Hum Genet. 2012;90:363–8. [PMC free article: PMC3276676] [PubMed: 22305527]
- Kahrizi K, Hu CH, Garshasbi M, Abedini SS, Ghadami S, Kariminejad R, Ullmann R, Chen W, Ropers HH, Kuss AW, Najmabadi H, Tzschach A. Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3. Eur J Hum Genet. 2011;19:115–7. [PMC free article: PMC3039499] [PubMed: 20700148]
- Kodera H, Nakamura K, Osaka H, Maegaki Y, Haginoya K, Mizumoto S, Kato M, Okamoto N, Iai M, Kondo Y, Nishiyama K, Tsurusaki Y, Nakashima M, Miyake N, Hayasaka K, Sugahara K, Yuasa I, Wada Y, Matsumoto N, Saitsu H. De novo mutations in SLC35A2 encoding a UDP-galactose transporter cause early-onset epileptic encephalopathy. Hum Mutat. 2013;34:1708–14. [PubMed: 24115232]
- Koehler K, Malik M, Mahmood S, Gießelmann S, Beetz C, Hennings JC, Huebner AK, Grahn A, Reunert J, Nürnberg G, Thiele H, Altmüller J, Nürnberg P, Mumtaz R, Babovic-Vuksanovic D, Basel-Vanagaite L, Borck G, Brämswig J, Mühlenberg R, Sarda P, Sikiric A, Anyane-Yeboa K, Zeharia A, Ahmad A, Coubes C, Wada Y, Marquardt T, Vanderschaeghe D, Van Schaftingen E, Kurth I, Huebner A, Hübner CA. Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction. Am J Hum Genet. 2013;93:727–34. [PMC free article: PMC3791256] [PubMed: 24035193]
- Kranz C, Basinger AA, Güçsavaş-Calikoğlu M, Sun L, Powell CM, Henderson FW, Aylsworth AS, Freeze HH. Expanding spectrum of congenital disorder of glycosylation Ig (CDG-Ig): sibs with a unique skeletal dysplasia, hypogammaglobulinemia, cardiomyopathy, genital malformations, and early lethality. Am J Med Genet A. 2007a;143A:1371–8. [PubMed: 17506107]
- Kranz C, Denecke J, Lehrman MA, Ray S, Kienz P, Kreissel G, Sagi D, Peter-Katalinic J, Freeze HH, Schmid T, Jackowski-Dohrmann S, Harms E, Marquardt T. A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If). J Clin Invest. 2001;108:1613–9. [PMC free article: PMC200991] [PubMed: 11733556]
- Kranz C, Jungeblut C, Denecke J, Erlekotte A, Sohlbach C, Debus V, Kehl HG, Harms E, Reith A, Reichel S, Grobe H, Hammersen G, Schwarzer U, Marquardt T. A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy. Am J Hum Genet. 2007b;80:433–40. [PMC free article: PMC1821118] [PubMed: 17273964]
- Kranz C, Ng BG, Sun L, Sharma V, Eklund EA, Miura Y, Ungar D, Lupashin V, Winkel RD, Cipollo JF, Costello CE, Loh E, Hong W, Freeze HH. COG8 deficiency causes new congenital disorder of glycosylation type IIh. Hum Mol Genet. 2007c;16:731–41. [PubMed: 17331980]
- Kranz C, Sun L, Eklund EA, Krasnewich D, Casey JR, Freeze HH. CDG-Id in two siblings with partially different phenotypes. Am J Med Genet A. 2007d;143A:1414–20. [PubMed: 17551933]
- Lefeber D, Schonberger J, Morave E, Guillard M, Huyben KM, Verrijp J, Grafakou O, Evangeliou A, Preijers FW, Manta P, Yildiz J, Grunewald S. et al. Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies. Am J Hum Genet. 2009;85:76–86. [PMC free article: PMC2706967] [PubMed: 19576565]
- Losfeld ME, Ng BG, Kircher M, Buckingham KJ, Turner EH, Eroshkin A, Smith JD, Shendure J, Nickerson DA, Bamshad MJ. A new congenital disorder of glycosylation caused by a mutation in SSR4, the signal sequence receptor 4 protein of the TRAP complex. Hum Mol Genet. 2013 [PMC free article: PMC3929095] [PubMed: 24218363]
- Lubbehusen J, Thiel C, Rind N, Ungar D, Prinsen BH, de Koning TJ, van Hasselt PM, Korner C. Fatal outcome due to deficiency of subunit 6 of the conserved oligomeric Golgi complex leading to a new type of congenital disorders of glycosylation. Hum Mol Genet. 2010;19:3623–33. [PubMed: 20605848]
- Marklová E, Albahri Z. Screening and diagnosis of congenital disorders of glycosylation. Clin Chim Acta. 2007;385:6–20. [PubMed: 17716641]
- Marquardt T, Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr. 2003;162:359–79. [PubMed: 12756558]
- Marquardt T, Luhn K, Srikrishna G, Freeze HH, Harms E, Vestweber D. Correction of leukocyte adhesion deficiency type II with oral fucose. Blood. 1999;94:3976–85. [PubMed: 10590041]
- Martin PT, Freeze HH. Glycobiology of neuromuscular disorders. Glycobiology. 2003;13:67R–75R. [PubMed: 12736200]
- Martinez-Duncker I, Dupré T, Piller V, Piller F, Candelier JJ, Trichet C, Tchernia G, Oriol R, Mollicone R. Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter. Blood. 2005;105:2671–6. [PubMed: 15576474]
- Matthijs G, Schollen E, Bjursell C, Erlandson A, Freeze H, Imtiaz F, Kjaergaard S, Martinsson T, Schwartz M, Seta N, Vuillaumier-Barrot S, Westphal V, Winchester B. Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia). Hum Mutat. 2000;16:386–94. [PubMed: 11058895]
- Mention K, Lacaille F, Valayannopoulos V, Romano S, Kuster A, Cretz M, Zaidan H, Galmiche L, Jaubert F, de Keyzer Y, Seta N, de Lonlay P. Development of liver disease despite mannose treatment in two patients with CDG-Ib. Molecular Genetics and Metabolism. 2008;93:40–3. [PubMed: 17945525]
- Molinari F, Foulquier F, Tarpey PS, Morelle W, Boissel S, Teague J, Edkins S, Futreal PA, Stratton MR, Turner G, Matthijs G, Gecz J, Munnich A, Colleaux L. Oligosaccharyltransferase-subunit mutations in nonsyndromic mental retardation. Am. J. Hum. Genet. 2008;82:1150–7. [PMC free article: PMC2427205] [PubMed: 18455129]
- Morava E, Wevers RA, Cantagrel V, Hoefsloot LH, Al-Gazali L, Schoots J, van Rooij A, Huijben K, van Ravenswaaij-Arts CM, Jongmans MC, Sykut-Cegielska J, Hoffmann GF, Bluemel P, Adamowicz M, van Reeuwijk J, Ng BG, Bergman JE, van Bokhoven H, Körner C, Babovic-Vuksanovic D, Willemsen MA, Gleeson JG, Lehle L, de Brouwer AP, Lefeber DJ. A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Brain. 2010;133:3210–20. [PubMed: 20852264]
- Morava E, Zeevaert R, Korsch E, Huijben K, Wopereis S, Matthijs G, Keymolen K, Lefeber DJ, De Meirleir L, Wevers RA. A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia. Eur J Hum Genet. 2007;15:638–45. [PubMed: 17356545]
- Niehues R, Hasilik M, Alton G, Korner C, Schiebe-Sukumar M, Koch HG, Zimmer KP, Wu R, Harms E, Reiter K, von Figura K, Freeze HH, Harms HK, Marquardt T. Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy. J Clin Invest. 1998;101:1414–20. [PMC free article: PMC508719] [PubMed: 9525984]
- Paesold-Burda P, Maag C, Troxler H, Foulquier F, Kleinert P, Schnabel S, Baumgartner M, Hennet T. Deficiency in COG5 causes a moderate form of congenital disorders of glycosylation. Hum Mol Genet. 2009;18:4350–6. [PubMed: 19690088]
- Peters V, Penzien JM, Reiter G, Korner C, Hackler R, Assmann B, Fang J, Schaefer JR, Hoffmann GF, Heidemann PH. Congenital disorder of glycosylation IId (CDG-IId) -- a new entity: clinical presentation with Dandy-Walker malformation and myopathy. Neuropediatrics. 2002;33:27–32. [PubMed: 11930273]
- Rafiq MA, Kuss AW, Puettmann L, Noor A, Ramiah A, Ali G, Hu H, Kerio NA, Xiang Y, Garshasbi M, Khan MA, Ishak GE, Weksberg R, Ullmann R, Tzschach A, Kahrizi K, Mahmood K, Naeem F, Ayub M, Moremen KW, Vincent JB, Ropers HH, Ansar M, Najmabadi H. Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability. Am J Hum Genet. 2011;89:176–82. [PMC free article: PMC3135808] [PubMed: 21763484]
- Rind N, Schmeiser V, Thiel C, Absmanner B, Lübbehusen J, Hocks J, Apeshiotis N, Wilichowski E, Lehle L, Körner C. A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11 leads to congenital disorder of glycosylation-Ip. Hum Mol Genet. 2010;19:1413–24. [PubMed: 20080937]
- Sanz-Nebot V, Balaguer E, Benavente F, Neusub C, Barbosa J. Characterization of transferrin glycoforms in human serum by CE-UV and CE-ESI-MS. Electrophoresis. 2007;28:1949–57. [PubMed: 17523137]
- Schenk B, Imbach T, Frank CG, Grubenmann CE, Raymond GV, Hurvitz H, Korn-Lubetzki I, Revel-Vik S, Raas-Rotschild A, Luder AS, Jaeken J, Berger EG, Matthijs G, Hennet T, Aebi M. MPDU1 mutations underlie a novel human congenital disorder of glycosylation, designated type If. J Clin Invest. 2001;108:1687–95. [PMC free article: PMC200989] [PubMed: 11733564]
- Schollen E, Frank CG, Keldermans L, Reyntjens R, Grubenmann CE, Clayton PT, Winchester BG, Smeitink J, Wevers RA, Aebi M, Hennet T, Matthijs G. Clinical and molecular features of three patients with congenital disorders of glycosylation type Ih (CDG-Ih) (ALG8 deficiency). J Med Genet. 2004a;41:550–6. [PMC free article: PMC1735831] [PubMed: 15235028]
- Schollen E, Kjaergaard S, Martinsson T, Vuillaumier-Barrot S, Dunoe M, Keldermans L, Seta N, Matthijs G. Increased recurrence risk in congenital disorders of glycosylation type Ia (CDG-Ia) due to a transmission ratio distortion. J Med Genet. 2004b;41:877–80. [PMC free article: PMC1735620] [PubMed: 15520415]
- Spaapen LJM, Bakker JA, van der Meer SB, Sijstermans HJ, Steet RA, Wevers RA, Jaeken J. Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder. J Inherit Metab Dis. 2005;28:707–14. [PubMed: 16151902]
- Stibler H, Skovby F. Failure to diagnose carbohydrate-deficient glycoprotein syndrome prenatally. Pediatr Neurol. 1994;11:71. [PubMed: 7527215]
- Stibler H, Stephani U, Kutsch U. Carbohydrate-deficient glycoprotein syndrome--a fourth subtype. Neuropediatrics. 1995;26:235–7. [PubMed: 8552211]
- Stojkovic T, Vissing J, Petit F, Piraud M, Orngreen MC, Andersen G, Claeys KG, Wary C, Hogrel J-Y, Laforet P. Muscle glycogenosis due to phosphoglucomutase 1 deficiency. New Eng J Med. 2009;361:425–7. [PubMed: 19625727]
- Stolting T, Omran H, Erlekotte A, Denecke J, Reunert J, Marquardt T. Novel ALG8 mutations expand the clinical spectrum of congenital disorder of glycosylation type Ih. Mol Genet Metab. 2009;98:305–9. [PubMed: 19648040]
- Sun L, Eklund EA, Van Hove JL, Freeze HH, Thomas JA. Clinical and molecular characterization of the first adult congenital disorder of glycosylation (CDG) type Ic patient. Am J Med Genet A. 2005;137:22–6. [PubMed: 16007612]
- Tamminga RY, Lefeber DJ, Kamps WA, van Spronsen FJ. Recurrent thrombo-embolism in a child with a congenital disorder of glycosylation (CDG) type Ib and treatment with mannose. Pediatr Hematol Oncol. 2008;25:762–8. [PubMed: 19065443]
- Thiel C, Schwarz M, Peng J, Grzmil M, Hasilik M, Braulke T, Kohlschutter A, von Figura K, Lehle L, Korner C. A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis. J Biol Chem. 2003;278:22498–505. [PubMed: 12684507]
- Thiel C, Rind N, Popovici D, Hoffmann GF, Hanson K, Conway RL, Adamski CR, Butler E, Scanlon R, Lambert M, Apeshiotis N, Thiels C, Matthijs G, Korner C. Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip. Hum Mutat. 2012;33:485–7. [PubMed: 22213132]
- Timal S, Hoischen A, Lehle L, Adamowicz M, Huijben K, Sykut-Cegielska J, Paprocka J, Jamroz E, van Spronsen FJ, Korner C, Gilissen C, Rodenburg RJ, Eidhof I, Van den Heuvel L, Thiel C, Wevers RA, Morava E, Veltman J, Lefeber DJ. Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing. Hum Mol Genet. 2012;21:4151–61. [PubMed: 22492991]
- Van Geet C, Jaeken J, Freson K, Lenaerts T, Arnout J, Vermylen J, Hoylaerts MF. Congenital disorders of glycosylation type Ia and IIa are associated with different primary haemostatic complications. J Inherit Metab Dis. 2001;24:477–92. [PubMed: 11596651]
- Varki A. Biological roles of oligosaccharides: all of the theories are correct. Glycobiology. 1993;3:97–130. [PubMed: 8490246]
- Weinstein M, Schollen E, Matthijs G, Neupert C, Hennet T, Grubenmann CE, Frank CG, Aebi M, Clarke JT, Griffiths A, Seargeant L, Poplawski N. CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features. Am J Med Genet A. 2005;136:194–7. [PubMed: 15945070]
- Willer T, Lee H, Lommel M, Yoshida-Moriguchi T, de Bernabe DB, Venzke D, Cirak S, Schachter H, Vajsar J, Voit T, Muntoni F, Loder AS, Dobyns WB, Winder TL, Strahl S, Mathews KD, Nelson SF, Moore SA, Campbell KP. ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nat Genet. 2012;44:575. [PMC free article: PMC3371168] [PubMed: 22522420]
- Wu X, Rush JS, Karaoglu D, Krasnewich D, Lubinsky MS, Waechter CJ, Gilmore R, Freeze HH. Deficiency of UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1 phosphate transferase (DPAGT1) causes a novel congenital disorder of glycosylation type Ij. Hum Mut. 2003;22:144–50. [PubMed: 12872255]
- Wu X, Steet RA, Bohorov O, Bakker J, Newell J, Krieger M, Spaapen L, Kornfeld S, Freeze HH. Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder. Nat Med. 2004;10:518–23. [PubMed: 15107842]
- Wurde AE, Reunert J, Rust S, Hertzber C, Haverkamper S, Nurnberg G, Nurnberg P, Lehle L, Rossi R, Marquardt T. Congenital disorder of glycosylation type Ij (CDG-Ij, DPAGT1-CDG): extending the clinical and molecular spectrum of a rare disease. Mol Genet Metab. 2012;105:634–41. [PubMed: 22304930]
- Zdebska E, Bader-Meunier B, Schischmanoff PO, Dupré T, Seta N, Tchernia G, Kościelak J, Delaunay J. Abnormal glycosylation of red cell membrane band 3 in the congenital disorder of glycosylation Ig. Pediatr Res. 2003;54:224–9. [PubMed: 12736397]
- Jaeken J, Matthijs G, Carchon H, Van Schaftingen E. Defects of N-glycan synthesis. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). 2015. New York, NY: McGraw-Hill. Chap 74.
- Kodera H, Nakamura K, Osaka H, Maegaki Y, Haginoya K, Mizumoto S, Kato M, Okamoto N, Iai M, Kondo Y, Nishiyama K, Tsurusaki Y, Nakashima M, Miyake N, Hayasaka K, Sugahara K, Yuasa I, Wada Y, Matsumoto N, Saitsu H. De novo mutations in SLC35A2 encoding a UDF-galactose transporter cause early-onset epileptic encephalopathy. Hum Mutat. 2013;34:1708. [PubMed: 24115232]
- Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno M, Inazu T, Mitsuhashi H, Takahashi S, Takeuchi M, Herrmann R, Straub V, Talim B, Voit T, Topaloglu H, Toda T, Endo T. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell. 2001;1:717–24. [PubMed: 11709191]
Susan Sparks is a board-certified pediatrician, clinical geneticist, and clinical biochemical geneticist. After completion of her genetics and biochemical genetics fellowship at the National Institutes of Health, she joined the faculty at Children’s National Medical Center in Washington, DC, and is currently on the faculty at Levine Children’s Hospital at Carolinas Medical Center in Charlotte, NC. She received her MD and PhD in molecular biology and pharmacology from the Chicago Medical School in 1997 and 1999, respectively. She has a strong research interest in glycosylation defects including congenital disorders of glycosylation and congenital muscular dystrophies.
Donna Krasnewich is a board-certified clinical biochemical geneticist and pediatrician. She trained at Wayne State University School of Medicine in Detroit, Michigan, and received her MD and PhD in pharmacology in 1986. After completing her fellowship in genetics at the National Institutes of Health (NIH), she joined the faculty of the National Human Genome Research Institutes (NHGRI) at NIH and was the Deputy Clinical Director of NHGRI. She is currently a Program Director at NIH in the National Institute of General Medical Sciences and continues her interest in children with developmental delay and congenital disorders of glycosylation.
- 30 January 2014 (cd) Revision: scope of the overview changed to N-linked glycosylation
- 8 November 2012 (cd) Revision: molecular testing for mutations in TMEM165 and PGM1 available clinically
- 9 August 2012 (cd) Revision: SRD5A3-CDG (CDG-Iq), DDOST-CDG (CDG-Ir), TUSC3-CDG, and congenital disorders of glycosylation multi-gene panels now listed in the GeneTests™ Laboratory Directory; CDG types and associated references added
- 11 August 2011 (cd) Revision: clinical testing available for MAGT1-CDG.
- 21 April 2011 (me) Comprehensive update posted live
- 1 September 2009 (cd) Revision: sequence analysis available clinically for CDG-Io
- 18 December 2008 (cd) Revision: sequence analysis available clinically for CDG-Im, -In, -Ic, -Id, and -If
- 23 June 2008 (me) Comprehensive update posted live
- 15 August 2005 (me) Overview posted to live Web site
- 27 February 2004 (dk) Original submission
Charlotte, North Carolina
Initial Posting: August 15, 2005; Last Revision: January 30, 2014.
University of Washington, Seattle, Seattle (WA)
Sparks SE, Krasnewich DM. Congenital Disorders of N-linked Glycosylation Pathway Overview. 2005 Aug 15 [Updated 2014 Jan 30]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.