PGAP3-congenital disorder of glycosylation: Year of the Zebra

PGAP3-congenital disorder of glycosylation, or PGAP3-CDG for short, also known as Mabry syndrome and previously known as hyperphosphatasia with impaired intellectual development syndrome 4, is a rare inherited neurological disorder caused by defects in one of the pathways of glycosylation.

Glycosylation is a biological process where a series of enzymes work sequentially to attach sugar chains, called glycans, to proteins and fatty molecules, forming glycoproteins and glycolipids, respectively. When there is a defect in glycosylation, one of the steps leading to the attachment of glycans does not take place correctly, which affects the final structure of multiple glycoproteins.

In PGAP3-CDG, there is a defect in the enzyme involved in stabilizing and anchoring these glycoproteins to a cell’s surface, which can have effects on multiple biological processes, such as helping cells recognize, adhere, or communicate with one another. Alkaline phosphatase, or ALP, is an example of a glycoprotein that is normally bound to the cell membrane but when the anchor is defective, ALP is unable to bind properly and is instead released into the bloodstream.

Like most other disorders of glycosylation, PGAP3-CDG is an autosomal recessive disorder, meaning an individual must inherit two copies of the mutated PGAP3 gene, one from each parent, to develop the disorder.

Affected individuals can have distinctive facial features that include a broad and short nose, wide-set eyes, a thin upper lip, large ears, and full cheeks; though these features may not be apparent in infancy. In addition, some individuals are born with a small head circumference and cleft palate, which is when the roof of the mouth doesn’t fuse completely.