PGAP3
Name of disorder PGAP3-congenital disorder of glycosylation (PGAP3-CDG), also known as Post-GPI Attachment to Proteins Phospholipase 3 deficiency or Hyperphosphatasia with mental retardation syndrome 4
Symptoms

PGAP3-CDG is a rare genetic disease grouped with other disorders disrupting Glycosylphosphatidylinositol (GPI-) anchor synthesis. It is characterized by intellectual disability and increased levels of an enzyme called alkaline phosphatase (AP) in the blood (hyperphosphatasia). Most patients with PGAP3-CDG show signs and symptoms at birth or in the first years of life. The typical symptoms are often neurological and include weak muscle tone (hypotonia), a lack of muscle control and coordination with an unsteady gait (ataxia), severe developmental delay, intellectual disability, and epilepsy (with seizure onset between the first days of life to a few years of age). In some patients, seizures are treatable with antiepileptic medication, but in many, epilepsy is difficult to treat. Autistic behavior and sleep disturbances are very common in PGAP3-CDG.

Many patients show distinct facial features (facial dysmorphism), including a broad nasal bridge and tip, a short nose, long palpebral fissures, an increased distance between the eyes (hypertelorism), a long philtrum, a thin and wide upper lip, large earlobes, and full cheeks. Around half of the patients have been born with a cleft palate. A small head circumference (microcephaly) can, but does not have to be, part of the symptoms. Brain imaging may show structural abnormalities of the brain. Typically, patients show an elevation of alkaline phosphatase in the blood (hyperphosphatasia).

There are more than 30 PGAP3-CDG patients published in the medical literature as of 2021.

Diagnosis

PGAP3-CDG is inherited in an autosomal recessive manner, which means that individuals with PGAP3-CDG have two faulty copies of the PGAP3 gene. It is usually diagnosed through genetic blood tests, either as part of an epilepsy panel or through whole exome sequencing (WES). PGAP3-CDG can also be identified by testing for the presence of GPI-anchored proteins on the surface of granulocytes (a subset of white blood cells), which can be tested by a method called flow cytometry in the patient’s blood, but genetic testing is needed to confirm the diagnosis.

Treatment and prognosis

To date, there are no known specific treatment options for PGAP3-CDG. Treatment is aimed at the management of symptoms and the prevention of complications. Most diagnosed PGAP3-CDG patients are still young, which makes long-term prognosis difficult. The oldest PGAP3-CDG patient, to our knowledge, is 23 years old.