Alternative titles; symbols
SNOMEDCT: 720977000; ORPHA: 79325; DO: 0080560;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
11q14.1 | Congenital disorder of glycosylation, type Ih | 608104 | Autosomal recessive | 3 | ALG8 | 608103 |
A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type Ih (CDG Ih; CDG1H) is caused by compound heterozygous mutation in the gene encoding dolichyl-P-glucose:Glc-1-Man-9-GlcNAc-2-PP-dolichyl-alpha-3-glucosyltransferase (ALG8; 608103) on chromosome 11q14.
CDGs, previously called carbohydrate-deficient glycoprotein syndromes, grew from hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans. For a general discussion of CDGs, see CDG1A (212065).
CDG1H is a severe form of CDG. The majority of patients have brain involvement, liver pathology, gastrointestinal symptoms, dysmorphism (including brachydactyly), eye involvement (especially cataract), and skin symptoms. Most patients die within the first year of life (summary by Marques-da-Silva et al., 2017).
Chantret et al. (2003) described a novel subtype of CDG I, which they designated CDG Ih, in a female child of unrelated healthy parents. The patient was referred at 4 months of age for edematoascitic syndrome related to severe hypoalbuminemia resulting from protein-losing enteropathy. She had no dysmorphic manifestations and normal psychomotor development, but she had severe diarrhea and moderate hepatomegaly. Routine blood tests showed that factor XI (164900), protein C (176800), and antithrombin III (107300) were 12%, 21%, and 17% of normal, respectively. The combination of coagulation factor anomalies and protein-losing enteropathy suggested CDG. The electrophoretic profile of transferrin derived from the patient's serum revealed 3 distinct components whose migration positions coincided with transferrin species observed in patients with CDG I.
Schollen et al. (2004) described 3 patients from 2 families with CDG Ih associated with a severe clinical phenotype and early infant death. A brother and sister displayed antenatal symptoms, including intrauterine growth retardation and reduced fetal movements. Postnatally, the boy was lethargic and difficult to feed, and subsequently developed diarrhea, vomiting, and massive ascites, and died at 3 months of age. His sister became edematous with electrolyte disturbances within hours of birth and died 3 days later. The third patient had dysmorphic features including an asymmetric skull, large fontanel, hypertelorism, low-set and abnormally positioned ears, long philtrum, short neck, cryptorchidism, camptodactyly, and clubfeet. He also had bilateral thoracic and pulmonary hypoplasia, perimembranous and trabecular ventricular septal defects and a patent ductus, multiple cystic intra- and extrahepatic bile ducts, cholestasis, and diffuse renal microcysts. Laboratory examination revealed anemia, severe thrombocytopenia, and primary hypothyroidism. He had no vomiting or diarrhea, but developed progressive ascites complicated by tachypnea and dyspnea and died at 3 months of age. None of the 3 patients had any apparent CNS abnormalities.
Hock et al. (2015) summarized the clinical features in 15 patients with CDH1H, 12 of whom had previously been reported. Six of 12 patients had prenatal abnormalities, including 3 with intrauterine growth retardation, 5 with oligohydramnios, and 3 with hydrops fetalis. Seven patients were born prematurely. Nine patients had gastrointestinal symptoms, including diarrhea, vomiting, feeding problems with failure to thrive, and/or protein-losing enteropathy. Nervous system features included hypotonia, developmental delay, seizures, and structural brain abnormalities. Laboratory findings included thrombocytopenia in 9 patients, elevated serum transaminases in 8, and abnormal clotting factors in 8. Eye abnormalities included cataracts in 5 patients, retinopathy in 1, and optic atrophy in 1. Eight patients had integumentary involvement, including fat pads, wrinkly skin, cutis laxa, and inverted nipples. Nine patients died within the first year of life.
Chantret et al. (2003) found that the pattern of accumulation of dolichyl-linked oligosaccharides in fibroblasts from the patient they reported with CDG Ih suggested a defect in the addition of the second glucose residue onto lipid-linked oligosaccharides. Northern blot analysis revealed that cells from the patient possessed only 10 to 20% normal amounts of ALG8 mRNA, which encodes the enzyme that catalyzes this reaction.
The transmission pattern of CDH Ih in the family reported by Chantret et al. (2003) was consistent with autosomal recessive inheritance.
In a patient with CDG Ih, Chantret et al. (2003) identified compound heterozygosity for a 1-bp deletion and a 1-bp insertion in the ALG8 gene (608103.0001 and 608103.0002). Cells from the patient were successfully complemented with wildtype ALG8 cDNA, indicating that these mutations were the underlying cause of CDG Ih.
Schollen et al. (2004) described 3 patients from 2 families with CDG Ih. In each family they identified compound heterozygosity for a splice site mutation and a missense mutation (see 608103.0003-608103.0006) in the ALG8 gene.
Hock et al. (2015) identified compound heterozygous mutations in the ALG8 gene (608103.0004; 608103.0007; 608103.0010) in 2 unrelated patients (patients 2 and 5) with CDG Ih. The mutations were identified by sequencing of the ALG8 gene. Patient 2 had a similarly affected deceased sib who did not undergo gene sequencing. All 3 patients had a type 1 pattern on plasma transferrin isoelectric focusing.
Chantret, I., Dancourt, J., Dupre, T., Delenda, C., Bucher, S., Vuillaumier-Barrot, S., de Baulny, H. O., Peletan, C., Danos, O., Seta, N., Durand, G., Oriol, R., Codogno, P., Moore, S. E. H. A deficiency in dolichyl-P-glucose:Glc-1-Man-9-GlcNAc2-PP-dolichyl alpha-3-glucosyltransferase defines a new subtype of congenital disorders of glycosylation. J. Biol. Chem. 278: 9962-9971, 2003. [PubMed: 12480927] [Full Text: https://doi.org/10.1074/jbc.M211950200]
Hock, M., Wegleiter, K., Raiser, E., Kiechl-Kohlendorfer, U., Scholl-Burgi, S., Fauth, C., Steichen, E., Pichler, K., Lefeber, D. J., Matthjis, G., Keldermans, L., Mauer, K., Zschocke, J., Karall, D. ALG8-CDG: novel patient and review of the literature. Orphanet J. Rare Dis. 10: 73, 2015. [PubMed: 26066342] [Full Text: https://doi.org/10.1186/s13023-015-0289-7]
Jaeken, J., Vanderschueren-Lodeweyckx, M., Casaer, P., Snoeck, L., Corbeel, L., Eggermont, E., Eeckels, R. Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG-deficiency, increased serum arylsulphatase A and increased CSF protein: a new syndrome? (Abstract) Pediat. Res. (suppl.) 14: 179 only, 1980.
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]
Schollen, E., Frank, C. G., Keldermans, L., Reyntjens, R., Grubenmann, C. E., Clayton, P. T., Winchester, B. G., Smeitink, J., Wevers, R. A., Aebi, M., Hennet, T., Matthijs, G. Clinical and molecular features of three patients with congenital disorders of glycosylation type Ih (CDG-Ih) (ALG8 deficiency). (Letter) J. Med. Genet. 41: 550-556, 2004. [PubMed: 15235028] [Full Text: https://doi.org/10.1136/jmg.2003.016923]