Alternative titles; symbols
SNOMEDCT: 277894008, 724142005; ORPHA: 79329; DO: 0070253;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q21.3 | Congenital disorder of glycosylation, type IIa | 212066 | Autosomal recessive | 3 | MGAT2 | 602616 |
A number sign (#) is used with this entry because congenital disorder of glycosylation type IIa (CDG IIa, CDG2A) is caused by homozygous or compound heterozygous mutation in the gene encoding GlcNAc-T II (MGAT2; 602616) on chromosome 14q21.
Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. These glycoconjugates play critical roles in metabolism, cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity, among others. CDGs are divided into 2 main groups: type I CDGs (see, e.g., CDG1A, 212065) comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein, whereas type II CDGs refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. The biochemical changes of CDGs are most readily observed in serum transferrin (TF; 190000), and the diagnosis is usually made by isoelectric focusing of this glycoprotein (reviews by Marquardt and Denecke, 2003; Grunewald et al., 2002).
Genetic Heterogeneity of Congenital Disorder of Glycosylation Type II
Multiple forms of CDG type II have been identified; see CDG2B (606056) through CDG2Z (620201), and CDG2AA (620454) to CDG2BB (620546).
Ramaekers et al. (1991) reported an Iranian child with a form of CDG different from CDG1A, and Jaeken et al. (1993) investigated a Belgian boy, aged 9 years, with remarkably similar findings. In contrast to classic CDG1A, both patients had more severe psychomotor retardation, no peripheral neuropathy, and normal cerebellum on MRI. Biochemical differences from classic CDG were the absence of proteinuria, no increase in serum glutamic-pyruvic transaminase activity, normal serum albumin level, deficiency of clotting factors IX and XII, normal activity in serum of arylsulfatase A, and decreased activity of beta-glucuronidase. Both children also had increased serum carbohydrate-deficient transferrin.
Cormier-Daire et al. (2000) described a child with CDG IIa who had severe mental retardation, chronic feeding problems with severe diarrhea, growth retardation, distinctive dysmorphic features including a beaked nose, long philtrum, thin vermilion border of the upper lip, large ears, gum hypertrophy, and thoracic deformity. This child also had an abnormal ERG with both cones and rods affected.
De Cock and Jaeken (2009) reported a boy with CDG2A who died at age 18 years. Multiple dysmorphic features were noted at birth. He had thin lips, gum hypertrophy, large and posteriorly rotated ears, hook nose, large mouth, retrognathia, short neck, and distal limb anomalies. He also showed severe developmental delay. He later developed gastrointestinal problems, such as gastroesophageal reflux and volvulus, recurrent respiratory infections, and seizures. Kyphoscoliosis was also present. In general, he showed poor growth with muscle atrophy and lack of pubertal development. A coagulopathy developed at age 9 years, which led to the correct diagnosis of CDG2A.
Alkuraya (2010) reported a consanguineous Saudi family in which 9 individuals had severe mental retardation associated with a distinct facial appearance. Affected individuals had small head circumference, retrognathia, long eyelashes, thick eyebrows, prominent columella, prominent nasal bridge, thin upper lip, everted lower lip, diastema, and an open mouth due to the combination of retrognathia and an abnormally obtuse lower incisor mandibular plane angle. Other features included mild to moderate bilateral sensorineural hearing loss, early hypotonia and late hypertonia, short terminal phalanges, and poor general growth with postnatal short stature. Microarray studies did not detect chromosomal abnormalities, and the authors postulated that it represented a novel autosomal recessive disorder.
Jaeken et al. (1994) showed that fibroblast extracts from 2 patients with CDG IIa had over 98% reduced activity of UDP-GlcNAc:alpha-6-D-mannoside beta-1,2-N-acetylglucosaminyltransferase II (GlcNAc-T II), an enzyme localized to the Golgi apparatus.
Charuk et al. (1995) showed that mononuclear cell extracts from a patient with CDG IIa had no detectable activity of GlcNAc-T II and that similar extracts from 12 blood relatives of the patient, including the father, mother, and a brother, had enzyme levels 32 to 67% of normal (average 50.1% +/- 10.7% SD), consistent with autosomal recessive inheritance. The structure of erythrocyte membrane glycoproteins bands 3 and 4.5 were shown to be altered in the CDG patient. Similar to patients with hereditary erythroblastic multinuclearity with a positive acidified-serum lysis test (HEMPAS; 224100), erythrocyte membrane glycoproteins in the CDG patient had increased reactivities with concanavalin A, demonstrating the presence of hybrid or oligomannose carbohydrate structures. However, CDG IIa patients had a totally different clinical presentation, and their erythrocytes did not show the serology typical of HEMPAS, suggesting that those 2 disorders are different. Schachter and Jaeken (1999) reviewed both disorders.
Patients with CDG Ia have a thrombotic tendency, whereas a patient with CDG IIa, described by Van Geet et al. (2001), had an increased bleeding tendency. Van Geet et al. (2001) observed abnormal glycosylation of platelet glycoproteins in CDG Ia causing enhanced onset of platelet interactions, leading to thrombotic tendency. Reduced GP Ib (231200)-mediated platelet reactivity with vessel wall components in the CDG IIa patient under flow conditions provided a basis for his bleeding tendency.
The transmission pattern of CDG2A in the families reported by Jaeken et al. (1994) and Tan et al. (1996) was consistent with autosomal recessive inheritance.
In the Iranian and Belgian patients with CDG2A reported by Jaeken et al. (1994), Tan et al. (1996) identified 2 different homozygous mutations in the MGAT2 gene (602616.0001; 602616.0002), respectively.
In a patient with CDG IIa, Cormier-Daire et al. (2000) identified compound heterozygosity for 2 point mutations in the MGAT2 gene (602616.0003, 602616.0004).
By homozygosity mapping followed by whole-exome sequencing, Alazami et al. (2012) determined that the family reported by Alkuraya (2010) actually had CDG2A caused by a homozygous mutation in the MGAT2 gene (K237N; 602616.0005). The diagnosis was confirmed by isoelectric focusing of serum transferrin, which showed an increase of disialotransferrin and a decrease of longer sialotransferrins. Alazami et al. (2012) emphasized the striking dysmorphic features in this metabolic disorder.
CDGs were formerly referred to as 'carbohydrate-deficient glycoprotein syndromes' (Marquardt and Denecke, 2003; Grunewald et al., 2002). Conventionally, untyped and unclassified cases of CDG are labeled CDG-x (see 212067) until they are characterized at the molecular level. Orlean (2000) discussed the revised nomenclature for CDGs proposed by the participants at the First International Workshop on CDGs in Leuven, Belgium, in November 1999.
Alazami, A. M., Monies, D., Meyer, B. F., Alzahrani, F., Hashem, M., Salih, M. A., Alkuraya, F. S. Congenital disorder of glycosylation IIa: the trouble with diagnosing a dysmorphic inborn error of metabolism. (Letter) Am. J. Med. Genet. 158A: 245-246, 2012. [PubMed: 22105986] [Full Text: https://doi.org/10.1002/ajmg.a.34347]
Alkuraya, F. S. Mental retardation, growth retardation, unusual nose, and open mouth: an autosomal recessive entity. Am. J. Med. Genet. 152A: 2160-2163, 2010. [PubMed: 20684000] [Full Text: https://doi.org/10.1002/ajmg.a.33575]
Charuk, J. H. M., Tan, J., Bernardini, M., Haddad, S., Reithmeier, R. A. F., Jaeken, J., Schachter, H. Carbohydrate-deficient glycoprotein syndrome type II: an autosomal recessive N-acetylglucosaminyltransferase II deficiency different from typical hereditary erythroblastic multinuclearity, with a positive acidified-serum lysis test (HEMPAS). Europ. J. Biochem. 230: 797-805, 1995. [PubMed: 7607254] [Full Text: https://doi.org/10.1111/j.1432-1033.1995.0797h.x]
Cormier-Daire, V., Amiel, J., Vuillaumier-Barrot, S., Tan, J., Durand, G., Munnich, A., Le Merrer, M., Seta, N. Congenital disorders of glycosylation IIa cause growth retardation, mental retardation, and facial dysmorphism. J. Med. Genet. 37: 875-877, 2000. [PubMed: 11228641] [Full Text: https://doi.org/10.1136/jmg.37.11.875]
de Cock, P., Jaeken, J. MGAT2 deficiency (CDG-IIa): the life of J. Biochim. Biophys. Acta 1792: 844-846, 2009. [PubMed: 19419693] [Full Text: https://doi.org/10.1016/j.bbadis.2009.02.001]
Grunewald, S., Matthijs, G., Jaeken, J. Congenital disorders of glycosylation: a review. Pediat. Res. 52: 618-624, 2002. [PubMed: 12409504] [Full Text: https://doi.org/10.1203/00006450-200211000-00003]
Jaeken, J., Carchon, H., Stibler, H. The carbohydrate-deficient glycoprotein syndromes: pre-Golgi and Golgi disorders? Glycobiology 3: 423-428, 1993. [PubMed: 8286854] [Full Text: https://doi.org/10.1093/glycob/3.5.423]
Jaeken, J., De Cock, P., Stibler, H., Van Geet, C., Kint, J., Ramaekers, V., Carchon, H. Carbohydrate-deficient glycoprotein syndrome type II. J. Inherit. Metab. Dis. 16: 1041 only, 1993. [PubMed: 8127054] [Full Text: https://doi.org/10.1007/BF00711522]
Jaeken, J., Schachter, H., Carchon, H., De Cock, P., Coddeville, B., Spik, G. Carbohydrate deficient glycoprotein syndrome type II: a deficiency in Golgi localised N-acetyl-glucosaminyltransferase II. Arch. Dis. Child. 71: 123-127, 1994. [PubMed: 7944531] [Full Text: https://doi.org/10.1136/adc.71.2.123]
Marquardt, T., Denecke, J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Europ. J. Pediat. 162: 359-379, 2003. [PubMed: 12756558] [Full Text: https://doi.org/10.1007/s00431-002-1136-0]
Orlean, P. Congenital disorders of glycosylation caused by defects in mannose addition during N-linked oligosaccharide assembly. J. Clin. Invest. 105: 131-132, 2000. [PubMed: 10642590] [Full Text: https://doi.org/10.1172/JCI9157]
Ramaekers, V. T., Stibler, H., Kint, J., Jaeken, J. A new variant of the carbohydrate deficient glycoproteins syndrome. J. Inherit. Metab. Dis. 14: 385-388, 1991. [PubMed: 1770799] [Full Text: https://doi.org/10.1007/BF01811710]
Schachter, H., Jaeken, J. Carbohydrate-deficient glycoprotein syndrome type II. Biochim. Biophys. Acta 1455: 179-192, 1999. [PubMed: 10571011] [Full Text: https://doi.org/10.1016/s0925-4439(99)00054-x]
Tan, J., Dunn, J., Jaeken, J., Schachter, H. Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development. Am. J. Hum. Genet. 59: 810-817, 1996. [PubMed: 8808595]
Van Geet, C., Jaeken, J., Freson, K., Lenaerts, T., Arnout, J., Vermylen, J., Hoylaerts, M. F. Congenital disorders of glycosylation type Ia and IIa are associated with different primary haemostatic complications. J. Inherit. Metab. Dis. 24: 477-492, 2001. [PubMed: 11596651] [Full Text: https://doi.org/10.1023/a:1010581613821]