Congenital Disorder Of Glycosylation, Type I/iix

Description

Congenital disorders of glycosylation (CDGs) are divided into 2 main groups: type I CDGs (see, e.g., 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 (see, e.g., 212066) refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. Conventionally, untyped and unclassified cases are labeled 'CDG-x' (Orlean, 2000; Marquardt and Denecke, 2003).

The phenotypes described in this entry most likely do not represent a single disorder, but have been referred by the authors as CDG-x and are included here pending further molecular characterization. In a review of CDGs, Marquardt and Denecke (2003) stated that more than 20% of CDG patients identified still cannot be ascribed to a known enzyme defect and are thus named CDG-x.

Clinical Features

Stibler et al. (1993) described 2 unrelated Swedish and German girls with perinatal hypotonia, mild dystrophic appearance, brisk reflexes, optic atrophy, infantile spasms, and pigmentary skin changes. Brain imaging showed central and cortical atrophy and generalized demyelination. One patient also had Dandy-Walker malformation and hypoplasia of the corpus callosum. Biochemical investigations revealed that serum transferrin showed an equal increase of 4 isoforms with appreciable amounts of normal isoforms and a mild increase in carbohydrate-deficient transferrin. The authors referred to the disorder as 'CDG type III.' Freeze (2000) stated that a patient with similar features had been reported. In a review of CDGs, Marquardt and Denecke (2003) stated that 'CDG type III' belongs to the CDG-x group because the underlying defect is not yet known. In fact, the authors stated that since hardly any proteins were hypoglycosylated in this disorder, it may not even be a primary glycosylation defect.

Acarregui et al. (1998) described 2 Caucasian male sibs who presented in the immediate neonatal period with a severe variant of CDG I, characterized by normal PMM2 (601785) and PMI (154550) activities. Both infants required respiratory support, had significant thrombocytopenia, and died after the withdrawal of respiratory support. Postmortem examination in one of the infants showed cerebellopontine atrophy, hepatosplenomegaly, glomerulonephritis, thymic hypoplasia, and adrenal medullary hemorrhage and necrosis. Presumably the severe phenotype of CDG I in these sibs resulted from deficiency of an enzyme other than PMM2 or PMI.

Huemer et al. (2000) reported a 6-year-old male patient with Budd-Chiari syndrome (600880) and glycoprotein abnormalities associated with CDG Ix. Budd-Chiari syndrome most likely developed after hepatic vein thrombosis caused by coagulation abnormalities resulting from hypoglycosylation and functional impairment of the anticoagulant proteins. There were predominant deficiencies of anticoagulation factors antithrombin III (107300), protein C (612283), and protein S (176880).

De Lonlay et al. (2001) reported the clinical, biologic, and molecular analysis of 26 patients with various forms of CDG type I, including 3 CDG Ix patients detected by Western blotting and isoelectric focusing of serum transferrin. One of the patients with CDG Ix had psychomotor retardation and seizures; the other 2 had severe proximal tubulopathy, bilateral cataract, and white matter abnormalities (1 patient) or multiorgan failure and multiple birth defects (1 patient).

Prietsch et al. (2002) reported the clinical findings and diagnostic workup of a 17-month-old with CDG-x. Predominant clinical signs were psychomotor retardation and truncal hypotonia, stereotyped dystonic hand movements, and ophthalmologic abnormalities such as optic atrophy, nystagmus, and strabismus. Other symptoms that are often found in patients with CDG were absent, including seizures, microcephaly, cerebellar hypoplasia, dysmorphic features, hepatointestinal disease, coagulopathy, or multiorgan involvement. Isoelectric focusing of the patient's serum showed a marked elevation of disialotransferrin, thus confirming an IEF type 1 pattern. A generalized glycosylation defect was confirmed also by IEF of a further glycoprotein (alpha-1-antitrypsin), an increased carbohydrate-deficient transferrin (CDT) serum concentration, and an increased CDT to transferrin ratio. All known types of CDG I, secondary glycosylation abnormalities, and variants of amino acid sequence were excluded.

McKenzie et al. (2007) described 2 sibs with a congenital disorder of glycosylation. The first child died in utero with severe hydrops fetalis and the second died at 3 months of age following preterm delivery, respiratory insufficiency, generalized edema, and protein-losing enteropathy. The sibs shared similar facial features, including hypertelorism, hypoplastic, upturned nose, open mouth, micrognathia, and short neck. Both children had contractures. The patients had a CDG with a type I pattern of serum transferring isoelectric focusing with normal PMM and PMI enzyme levels, thus excluding CDG Ia (212065) and CDG Ib (602579), respectively. Lipid-linked oligosaccharide analysis of fibroblasts did not identify abnormal levels of intermediates associated with other forms of CDG I. McKenzie et al. (2007) concluded that these children represent a previously undescribed form of CDG I or a new disorder secondarily affecting glycosylation.