Congenital disorders of glycosylation

Abstract

Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of >130 diseases caused by defects in various steps along glycan modification pathways. The vast majority of these monogenic diseases are autosomal recessive and have multi-systemic manifestations, mainly growth failure, developmental delay, facial dysmorphisms, and variable coagulation and endocrine abnormalities. Carbohydrate deficient transferrin (CDT) and protein-linked glycan analysis with mass spectrometry can diagnose some subtypes of congenital disorders of glycosylation (CDG), while many currently rely on massively parallel genomic sequencing for diagnosis. Early detection is important, as a few of these disorders are treatable. Molecular and biochemical techniques continue to further our understanding of this rapidly expanding group of clinically and genetically diverse disorders.

Keywords: ALG6-CDG; Congenital disorders of glycosylation; MPI-CDG; N-linked glycosylation; O-linked glycosylation; PMM2-CDG; carbohydrate deficient glycoprotein syndrome; carbohydrate deficient transferrin; congenital disorders of glycosylation (CDG); lipid glycosylation defects.

Figure 1

Ichthyosis, hypotonia, and strabismus in a patient with SRD5A3-CDG. Courtesy of NIH, Lynne Wolfe, CRNP, Donna Krasnewich, MD, PhD.

Figure 2

Clinical portraits of patients with PMM2-CDG from childhood to adulthood (left to right). Esotropia, long philtrum, large, hypoplastic or dysplastic ears, hypotonic facies, and downslanting palpebral fissures are seen (top row). Profile view shows the prominent chin, which is more pronounced with age (bottom row). Courtesy of NIH, Lynne Wolfe, CRNP, Donna Krasnewich, MD, PhD.

Figure 3

Clinical photographs of patients with PMM2-CDG. (A) Happy demeanor. Truncal hypotonia and kyphoscoliosis are often present; (B) MRI showing cerebellar vermis hypoplasia; (C) posterior suprapelvic fat pads present in approximately 25% of patients with PMM2-CDG; (D) suprapubic fat pad seen in infancy, usually disappears by 5 years of age; (E) inverted nipples; (F,G) long thin fingers and atrophied low extremities secondary to demyelinating peripheral neuropathy. Courtesy of NIH, Lynne Wolfe, CRNP, Donna Krasnewich, MD, PhD. MRI, magnetic resonance imaging.