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.

Now, because glycosylation is essential to so many cellular functions, PGAP3-CDG generally affects multiple organ systems and causes symptoms from early infancy.

Children with this syndrome typically have moderate to severe intellectual disability, have little to no speech development, and have a delay in reaching childhood milestones, such as sitting, crawling, and walking.

Many individuals have neuromuscular symptoms like low muscle tone and unsteady gait; and develop recurrent seizures in early childhood.

Seizures are usually generalized, which involve muscle rigidity, convulsions, and loss of consciousness and may be difficult to treat.

Autistic behavior and sleep disturbances are also common. Less commonly, there may be cardiac problems, hearing loss, and congenital anomalies affecting the brain and digestive systems.

Diagnosis of PGAP3-CDG is suspected in children with early onset seizures and characteristic facial features, especially if they have increased levels of ALP in the blood.

Diagnosis is confirmed through genetic testing showing a mutation on the PGAP3 gene.There is currently no specific treatment available for the disorder, and treatment focuses on managing the symptoms and preventing complications.

In some cases, seizures can be treated with medications, like pyridoxine or vitamin B6; and surgery may be done to correct cleft palate and other developmental defects.

In addition, physical and occupational therapy and early childhood intervention, which includes support services for children with disabilities, can be helpful to optimize the individual’s life.Alright, as a quick recap, PGAP3-congenital disorder of glycosylation is a rare inherited neurological disorder characterized by intellectual disability and increased levels of alkaline phosphatase in the blood.

Diagnosis is confirmed by genetic testing showing a mutation on the PGAP3 gene. Treatment involves supportive care as there is currently no known cure for the disorder.

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