Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin. For a general discussion of CDGs, see CDG Ia (212065) and CDG Ib (602579).

Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Acquired forms of the disorder can be caused by intestinal malabsorption of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome. The pathomechanism is based on a reduced hepatic gamma-carboxylation of glutamic acid residues of all vitamin K-dependent blood coagulation factors, as well as the anticoagulant factors protein C (612283) and protein S (176880). Posttranslational gamma-carboxylation of proteins enables the calcium-dependent attachment of the proteins to the phospholipid bilayer of membranes, an essential prerequisite for blood coagulation. Vitamin K1 acts as a cofactor for the vitamin K-dependent carboxylase in liver microsomes, GGCX. Genetic Heterogeneity of Combined Deficiency of Vitamin K-Dependent Clotting Factors Combined deficiency of vitamin K-dependent clotting factors-2 (VKFCD2; 607473) is caused by mutation in the gene encoding vitamin K epoxide reductase (VKORC1; 608547) on chromosome 16p11.

Syndrome with characteristics of severe psychomotor retardation, failure to thrive and intolerance to wheat and dairy products. So far, only two cases have been described. The disease is caused by mutations in the COG8 gene, which encodes a subunit of the COG complex. This complex is involved vesicle transport in the Golgi apparatus.

Heterozygous protein S deficiency, like protein C deficiency (176860), is characterized by recurrent venous thrombosis. Bertina (1990) classified protein S deficiency into 3 clinical subtypes based on laboratory findings. Type I refers to deficiency of both free and total protein S as well as decreased protein S activity; type II shows normal plasma values, but decreased protein S activity; and type III shows decreased free protein S levels and activity, but normal total protein S levels. Approximately 40% of protein S circulates as a free active form, whereas the remaining 60% circulates as an inactive form bound to C4BPA (120830). Zoller et al. (1995) observed coexistence of type I and type III PROS1-deficient phenotypes within a single family and determined that the subtypes are allelic. Under normal conditions, the concentration of protein S exceeds that of C4BPA by approximately 30 to 40%. Thus, free protein S is the molar surplus of protein S over C4BPA. Mild protein S deficiency will thus present with selective deficiency of free protein S, whereas more pronounced protein S deficiency will also decrease the complexed protein S and consequently the total protein S level. These findings explained why assays for free protein S have a higher predictive value for protein S deficiency. See also autosomal recessive thrombophilia due to protein S deficiency (THPH6; 614514), which is a more severe disorder.

Autosomal recessive thrombophilia due to protein S deficiency is a very rare and severe hematologic disorder resulting in thrombosis and secondary hemorrhage usually beginning in early infancy. Some affected individuals develop neonatal purpura fulminans, multifocal thrombosis, or intracranial hemorrhage (Pung-amritt et al., 1999; Fischer et al., 2010), whereas others have recurrent thromboses later in childhood (Comp et al., 1984). See also autosomal dominant thrombophilia due to protein S deficiency (THPH5; 612336), a less severe disorder caused by heterozygous mutation in the PROS1 gene.