Alternative titles; symbols
SNOMEDCT: 720976009; ORPHA: 79321; DO: 0080556;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q27.1 | Congenital disorder of glycosylation, type Id | 601110 | Autosomal recessive | 3 | ALG3 | 608750 |
A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type Id (CDG Id, CDG1D) is caused by homozygous or compound heterozygous mutation in the ALG3 gene (608750) on chromosome 3q27.
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. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (Leroy, 2006).
CDG1D is a type I CDG that generally presents with severe neurologic involvement associated with dysmorphism and visual impairment. Liver involvement is sometimes present (summary by Marques-da-Silva et al., 2017).
For a discussion of the classification of CDGs, see CDG1A (212065).
Stibler et al. (1995) described 2 unrelated infants with a clinically and biochemically novel form of carbohydrate-deficient glycoprotein syndrome. The first patient was a German boy and the second a Turkish girl born to first-cousin parents. Both children were microcephalic and developed hypsarrhythmia and intractable seizures. The boy had optic atrophy and a coloboma of the iris. Both children had abnormalities of the uvula and high-arched palates. The girl had hypoplasia of the cerebellum, as is seen in CDG Ia (212065). In neither child was there hepatic dysfunction. Serum levels of carbohydrate-deficient transferrin were elevated but not as much as is seen in CDG Ia or CDG IIa (212066). The isoform abnormality suggested a deficiency of 1 or 2 sialic acid residues. In both children there were normal serum levels of albumin, haptoglobin, and thyroid-binding globulin, which are often reduced during infancy in CDG Ia. Korner et al. (1999) reported follow-up of 1 of the patients reported by Stibler et al. (1995) at age 5 years. He had tetraspastic paresis, a severe psychomotor handicap, and multiple dysmorphisms including microcephaly, dysplastic ears, atrophy of the optic nerve, and coloboma of the iris. The epilepsy was reasonably well controlled by valproic acid.
Denecke et al. (2004, 2005) reported a patient with CDG Id. Arthrogryposis multiplex was present at birth, as well as clubfeet and contractures of the hands. He had facial dysmorphism, including epicanthus, strabismus, and broad, flat nasal bridge, and severe visual impairment with reduced amplitude on electroretinography. Laboratory analysis revealed a glycosylation defect of plasma proteins. Analysis of chorion cells of an affected 19-week-old fetus, a sib of the patient, showed the same glycosylation defect in lipid-linked oligosaccharides and some plasma proteins, but normal glycosylation of other proteins, including transferrin. Denecke et al. (2005) suggested that maternal hormonal or placental factors may partially compensate for the glycosylation defect in the fetal stage.
Kranz et al. (2007) reported a brother and sister, aged 9 and 7 years, respectively, with CDG Id, whom the authors claimed were the seventh and eighth patients reported worldwide. Both patients developed intractable seizures shortly after birth. They had microcephaly and progressive cerebral atrophy, and the boy had a hypoplastic corpus callosum. Both were pleasant in demeanor with severe global developmental delay and no speech development. The boy had cortical blindness, and his sister had strabismus. Both showed significant failure to thrive with vomiting, diarrhea, and food intolerance necessitating feeding tubes. Duodenal biopsies showed villous atrophy. Dysmorphic features were variable, but included large ears, bulbous nose, and long fingers. Both had axial hypotonia and hyperreflexia. The boy had pectus excavatum with hypoplastic nipples. Although both patients were severely affected, the girl had more severe digestive issues, while her brother had more neurologic impairment.
From a review of the literature on liver-related symptoms in CDG, Marques-da-Silva et al. (2017) suggested that the finding of 'intrahepatic biliary fibroadenomatosis, including portal fibrosis, and abnormal cystic and branched bile ducts on portal tracts' should prompt testing for mutations in the ALG3 gene.
Paketci et al. (2020) reported 2 sibs with CDG1D. Patient 1 developed seizures after an episode of pneumonia at 40 days of life. Examination showed poor eye contact, axial hypotonia, microcephaly, and retromicrognathia. EEG showed burst suppression pattern. Brain MRI demonstrated mildly increased subarachnoid spaces and cavum septum pellucidum. Ophthalmologic examination demonstrated bilateral albinoid fundi. He also had bilateral conductive hearing loss. Patient 2 had flexor spasms at age 9 weeks, and EEG showed a burst suppression pattern. Brain MRI showed mildly increased subarachnoid spaces. She had hypotonia, microcephaly, low-set ears, and hypotelorism. Both sibs had hemangiomas in the frontal, occipital, and lumbosacral regions.
The transmission pattern of CDG1D in the patient reported by Stibler et al. (1995) (patient 1) and Korner et al. (1999) was consistent with autosomal recessive inheritance.
Korner et al. (1999) found that the defect in 1 of the CDG1D patients reported by Stibler et al. (1995) was in the mannosyltransferase that transfers mannose from dolichyl-phosphate mannose onto the lipid-linked oligosaccharide (LLO) intermediate Man(5)GlcNAc(2)-PP-dolichol. The defect resulted in the accumulation of the LLO intermediate and, due to its leaky nature, a residual formation of full-length LLOs. N-glycosylation was abnormal because of the transfer of truncated oligosaccharides in addition to that of full-length oligosaccharides and because of the incomplete utilization of N-glycosylation sites. The mannosyltransferase is the structural and functional ortholog of the product of the ALG3 gene in Saccharomyces cerevisiae.
Paketci et al. (2020) reported that treatment with a ketogenic diet resulted in control of intractable seizures in 2 sibs with CDG Id.
In a patient with CDG Id reported by Stibler et al. (1995), Korner et al. (1999) identified a homozygous mutation in the ALG3 gene (608750.0001).
In an Italian patient with CDG Id, Denecke et al. (2004) identified homozygosity for a silent mutation in the ALG3 gene, resulting in a 37-bp deletion (608750.0002).
Sun et al. (2005) described a patient with a severe phenotype of CDG Id who carried a homozygous R171Q mutation in ALG3 (608750.0003). The authors noted that the patient had hyperinsulinemic hypoglycemia, which had not previously been reported in CDG Id.
In a brother and sister with CDG Id, Kranz et al. (2007) identified compound heterozygosity for 2 mutations in the ALG3 gene (608750.0004; 608750.0005). Each unaffected parent was heterozygous for 1 of the mutations.
In 2 sibs, born of consanguineous parents, with CDG Id, Paketci et al. (2020) identified homozygosity for a previously reported mutation in the ALG3 gene (608750.0002). The mutation, which was found by whole-exome sequencing, was present in heterozygous state in the parents.
Denecke, J., Kranz, C., Kemming, D., Koch, H.-G., Marquardt, T. An activated 5-prime cryptic splice site in the human ALG3 gene generates a premature termination codon insensitive to nonsense-mediated mRNA decay in a new case of congenital disorder of glycosylation type Id (CDG-Id). Hum. Mutat. 23: 477-486, 2004. [PubMed: 15108280] [Full Text: https://doi.org/10.1002/humu.20026]
Denecke, J., Kranz, C., von Kleist-Retzow, J. C., 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. Pediat. Res. 58: 248-253, 2005. [PubMed: 16006436] [Full Text: https://doi.org/10.1203/01.PDR.0000169963.94378.B6]
Korner, C., Knauer, R., Stephani, U., Marquardt, T., Lehle, L., von Figura, K. Carbohydrate deficient glycoprotein syndrome type IV: deficiency of dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase. EMBO J. 18: 6816-6822, 1999. [PubMed: 10581255] [Full Text: https://doi.org/10.1093/emboj/18.23.6816]
Kranz, C., Sun, L., Eklund, E. A., Krasnewich, D., Casey, J. R., Freeze, H. H. CDG-Id in two siblings with partially different phenotypes. Am. J. Med. Genet. 143A: 1414-1420, 2007. [PubMed: 17551933] [Full Text: https://doi.org/10.1002/ajmg.a.31796]
Leroy, J. G. Congenital disorders of N-glycosylation including diseases associated with O- as well as N-glycosylation defects. Pediat. Res. 60: 643-656, 2006. [PubMed: 17065563] [Full Text: https://doi.org/10.1203/01.pdr.0000246802.57692.ea]
Marques-da-Silva, D., dos Reis Ferreira, V., Monticelli, M., Janeiro, P., Videira, P. A., Witters, P., Jaeken, J., Cassiman, D. Liver involvement in congenital disorders of glycosylation (CDG): a systematic review of the literature. J. Inherit. Metab. Dis. 40: 195-207, 2017. [PubMed: 28108845] [Full Text: https://doi.org/10.1007/s10545-016-0012-4]
Paketci, C., Edem, P., Hiz, S., Sonmezler, E., Soydemir, D., Uzan, G. S., Oktay, Y., O'Heir, E., Beltran, S., Laurie, S., Topf, A., Lochmuller, H., Horvath, R., Yis, U. Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3-CDG. Brain Dev. 42: 539-545, 2020. [PubMed: 32389449] [Full Text: https://doi.org/10.1016/j.braindev.2020.04.008]
Stibler, H., Stephani, U., Kutsch, U. Carbohydrate-deficient glycoprotein syndrome: a fourth type. Neuropediatrics 26: 235-237, 1995. [PubMed: 8552211] [Full Text: https://doi.org/10.1055/s-2007-979762]
Sun, L., Eklund, E. A., Chung, W. K., Wang, C., Cohen, J., Freeze, H. H. Congenital disorder of glycosylation Id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. J. Clin. Endocr. Metab. 90: 4371-4375, 2005. [PubMed: 15840742] [Full Text: https://doi.org/10.1210/jc.2005-0250]