PHENOTYPE

Three patients have been reported with this severe mental retardation dysmorphy syndrome (MIM 212066, 602616) (27, 74, 75, 128). They had epilepsy and a striking stereotypic behavior. Laboratory investigations revealed lowered serum values of a number of glycoproteins, similar to those with PMM deficiency. There was an increase of serum glutamic-oxaloacetic, but not of glutamic-pyruvic transaminase. Isoelectrofocusing of serum transferrin showed a type 2 pattern (see PMM Deficiency) but with nearly absent tetrasialotransferrin. Contrary to the defects in the CDG-I group, liver biopsy showed no lysosomal inclusions. Fine structure analysis of the glycans on serum transferrin revealed that some of the normal, disialo-biantennary N-glycans are replaced by truncated, monosialo-monoantennary N-glycans and pinpointed the defect to the GlcNAc-transferase II (GnT II) in the Golgi [for details, see (74)]. GnT II activity was reduced by over 98% in fibroblasts and mononuclear blood cells from patients (75).

GENOTYPE

The human UDP-N-acetylglucosamine:alpha-6-D-mannoside-beta-1,2-N-acetylglucosaminyltransferase II gene (MGAT2) is located on chromosome 14q21. The coding region contains only one exon, with an open reading frame of 1341 bp that encodes a protein of 447 amino acids (147). Mutation analysis of the GnT II coding sequence (MGAT2 gene) in the two patients revealed that they were homozygous for the S290F and H262R mutations, respectively (148). Both mutations occur in the C-terminal catalytic domain, locations that are conserved between rat and human GnT II and inactivate the enzyme (148). Since the original description and molecular characterization of CDG-IIa, only one other case has been identified (33). This patient was compound heterozygous for a missense (N318D) and a nonsense (C339X) mutation. One probable explanation for the paucity of diagnosed cases is that the GnT II deficiency is a very severe disorder. This is illustrated by the knockout mouse model. Homozygous knockout (Mgat2-/-) mice survive to term, but they are born stunted with various congenital abnormalities and die early in the neonatal phase (23).

PHENOTYPE

A defect in the first step of the N-glycan processing was reported in a neonate with dysmorphic features and generalized hypotonia (38) (MIM 601336). The clinical course was characterized by hypoventilation, seizures, feeding problems, hepatomegaly, and fatal outcome at 2.5 months. Interestingly, isoelectrofocusing of serum transferrin was normal, whereas that of serum hexosaminidase showed a slight cathodal shift. Thin layer chromatography of oligosaccharides in urine revealed an abnormal band that was identified as the tetrasaccharide Glc(1-2)Glc(1-3)Glc(1-3)Man. Electronmicroscopy showed lamellar inclusions in lysosomes of liver parenchymal cells and macrophages as well as numerous empty, membrane-bound vacuoles in neurons of the frontal and occcipital brain lobes. Severe glucosidase I deficiency was found in the liver and cultured skin fibroblasts (<3% residual activity). This observation shows that, in neonates with a possible diagnosis of a glycosylation defect, analysis of oligosaccharides in the urine might be a worthwhile test.

GENOTYPE

The full-length human GCS1 cDNA contains 2881 bp and encodes a protein of 834 amino acids, which corresponds to a molecular mass of 92 kDa (80). GCS1 is located on chromosome 2p12-p13 (81). The only known patient, described above, is compound heterozygous for two missense mutations in the GCS1 gene, R486T and F652L (38).

fenotype

Peters et al. described the first patient with CDG-IId. The boy presented with macrocephaly caused by a Dandy Walker malformation, progressive hydrocephaly, muscular hypotonia with elevated creatine kinase indicating myopathy, transient cholestatic syndrome and extensive coagulation abnormalities including a prolonged aPTT, reduced Protein S, ATIII, factor XI and factor VIII. Other laboratory findings showed elevated AST and reduced IGF-I and IGF binding protein 3 (17).

genotype

Deficiency in beta-1,4-galactosyltransferase 1 (B4GALT1) causes CDG-IId. The only described patient has a homozygous insertion 1021InsC leading to a premature stop codon and a loss of 50 amino acids at the C-terminus (17).

(17) Congenital disorder of glycosylation IId (CDG-IId) - a new entity: clinical presentation with Dandy-Walker malformation and myopathy. Peters V, Penzien JM, Reiter G, Körner C, Hackler R, Assman B, Fang J, Schaefer JR, Hoffman GF, Heidemann PH. Neuropediatrics 2002; 33: 27-32

fenotype

The first patient with CDG-IIf has been described by Willig et al. in 2001(18). The four month old boy presented with a new syndrome including macrothrombocytopenia, neutropenia and complete lack of the sialyl-LewisX antigen or CD15s. The initial presentation was a spontaneous and massive bleeding of the posterior chamber of the right eye and cutaneous hemorrhages. Due to a sever thrombocytopenia, more sever hemorrhages developed together with respiratory stress syndrome and opportunistic infections. Steroid treatment and transfusions ameliorated his condition only temporary. At the age of 34 months a bone marrow transplantation was performed, but complications including GVHD, pulmonary viral infection, massive pulmonary hemorrhage with refractory respiratory failure led to death at the age of 37 months.

Peripheral blood smears revealed hypogranular gaint platelets. Megakaryocyte hyperplasia was observed in bone marrow aspirates. Megakaryocytes showed morphological abnormalities like small mononuclear megakaryocytes, hyposegmentation, vacuolation and  abnormal fragmentation into large platelet masses. CD15s was lacking on PMN cells, but no other abnormalities in chemotaxis or generation of reactive oxygen species were detected.   

genotype

The human CMP-sialic acid transporter consists of 337 amino acids. In this patient with CDG-IIf due to a defect in the CMP-sialic acid transporter a splice mutation (partial skipping of exon6)

on one allele inducing a 130 bp deletion and a premature stop codon at position 684 together with two microdeletions which generate a frameshift in position 277 and a premature stop codon at possition 327 on the other allele were identified. The splice mutation is probably caused by a four basepair insertion in intron 6 found in the mother of the patient.