Congenital Disorder Of Glycosylation, Type Iil

A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type IIl (CDG2L) is caused by homozygous or compound heterozygous mutation in the COG6 gene (606977) on chromosome 13q14.

Homozygous mutation in the COG6 gene can also cause Shaheen syndrome (SHNS; 615328), which shows overlapping clinical features.

Description

CDG2L is an autosomal recessive multisystem disorder apparent from birth or early infancy. It is characterized by poor growth, gastrointestinal and liver abnormalities, delayed psychomotor development, hypotonia, recurrent infections, hematologic abnormalities, increased bleeding tendency, and hyperhidrosis or hyperkeratosis. More variable features include nonspecific dysmorphic facial features and cardiac septal defects. The disorder often results in death in infancy or the first years of life (summary by Rymen et al., 2015).

For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066).

Clinical Features

Lubbehusen et al. (2010) reported a female infant, born of nonconsanguineous Turkish parents, with a severe neurologic disorder resulting in death at 5 weeks of age. At birth, she showed intractable focal seizures, vomiting, and loss of consciousness due to intracranial bleeding resulting in part from a vitamin K deficiency. Laboratory studies showed mildly increased lactate, aspartate aminotransferase, and creatine kinase. Family history revealed 2 other children who died in the perinatal period with signs of an increased bleeding tendency.

Huybrechts et al. (2012) reported a 27-month-old girl, born of consanguineous Moroccan parents, with CDG2L. At birth, she was noted to have dysmorphic features, including microcephaly, postaxial polydactyly, broad palpebral fissures, retrognathia, and anal anteposition. During the first months of life, she had recurrent infections, diarrhea, and failure to thrive, and was found to have a primary combined immunodeficiency with hypogammaglobulinemia and defective cellular immunity without lymphopenia. Granulocyte function was also abnormal. She later developed multisystem abnormalities, including hepatomegaly, abnormal liver enzymes, micronodular cirrhosis, macrovesicular steatosis, axial hypotonia, mild neurodevelopmental delay, proximal tubulopathy, and inflammatory bowel disease. Serum transferrin isoelectric focusing was abnormal, showing a type II pattern. Rymen et al. (2015) reported follow-up of this patient. She continued to have recurrent infections, chronic gastrointestinal inflammation and malabsorption, failure to thrive, hepatomegaly with elevated liver enzymes, and renal tubulopathy, all of which contributed to death at age 6 years.

Rymen et al. (2015) reported 7 additional patients with CDG2L, including the sister and 2 sib cousins of the patient reported by Lubbehusen et al. (2010). The sib cousins (P4.1 and P4.2) were said to be born of parents from Morocco; 3 patients were Turkish and 1 was from Bulgaria. Some of the pregnancies showed decreased fetal movements and were complicated by oligo- or polyhydramnios. The patients presented in the first months of life with neonatal hypotonia, failure to thrive, severely delayed psychomotor development, and nonspecific dysmorphic features. Other common features included liver involvement with hepatosplenomegaly, cholestasis, elevated liver enzymes, hyperbilirubinemia, and fibrosis or cirrhosis, as well as chronic diarrhea, enteropathy, microcephaly, cardiac septal defects, recurrent infections, hypohidrosis, and hyperkeratosis. One patient had arthrogryposis, clubfeet, and hip dysplasia, and another had postaxial polydactyly. Brain imaging was abnormal in some patients, showing hypoplasia of the corpus callosum, cortical atrophy, enlarged ventricles, and cerebellar atrophy. One patient had abnormal gyration. Several patients had thrombocytopenia, anemia, pancytopenia, and/or coagulation defects with bleeding episodes. Two patients had intractable seizures. Five of the 7 patients died in the first days or weeks of life. Two patients were still alive at ages 21 and 12 years. The 12-year-old girl learned to sit without support, but was never able to walk. She developed stereotypic movements of the hands and self-aggressive behavior and had recurrent infections. A sister was born with similar clinical features; she died at age 15 months. All patients studied showed a type 2 CDG pattern on serum transferrin analysis.

Biochemical Features

Isoelectric focusing of serum transferrin from the patient reported by Lubbehusen et al. (2010) showed transferrin molecules with 4, 3, 2, 1, or no sialic acid residues, consistent with CDG type II. Partial loss of sugar residues of N-glycans was demonstrated by Western blot analysis of serum transferrin, and further analysis of the transferrin-linked N-glycans showed complete or partial loss of galactose and neuraminic acid residues. Isoelectric focusing of alpha-1-antitrypsin and apolipoprotein CIII indicated a combined defect of N- and O-glycosylation. Western blot analysis of COG subunits showed decreased COG5 (55%), COG6 (21%), and COG7 (62%).

Inheritance

Congenital disorder of glycosylation in the family reported by Lubbehusen et al. (2010) was transmitted in an autosomal recessive manner.

Molecular Genetics

In a patient with fatal congenital disorder of glycosylation type IIl, Lubbehusen et al. (2010) identified a homozygous mutation in the COG6 gene (G549V; 606977.0001). Northern blot analysis showed reduced COG6 mRNA (15% of controls), indicating instability of the mutant transcript. Retroviral gene transfer of wildtype COG6 corrected COG complex defects in patient fibroblasts.

Huybrechts et al. (2012) found homozygosity for the G549V mutation in the COG6 gene in a 27-month-old girl, born of consanguineous Moroccan parents, with CDG2L.

In 6 patients, including 2 sibs, with CDG2L, Rymen et al. (2015) identified homozygous or compound heterozygous mutations in the COG6 gene (see, e.g., 606977.0001; 606977.0003-606977.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing and/or by targeted sequencing of CDG gene panels. Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to result in a loss of function. DNA from a seventh patient was not available.