Scientific Background
Glycosylphosphatidylinositol anchors (GPI anchors) are protein complexes of the plasma membrane that anchor glycoproteins to the cell surface. Defects of the GPI anchor and resulting disorders of the GPI-anchored proteins represent a special subgroup of glycosylation disorders (congenital disorders of glycosylation or CDG syndrome).
Some of the first diseases in which defects in GPI anchor associated genes were identified belong to the group of "hyperphosphatasia with mental retardation", for example the disease originally called Mabry syndrome, with symptoms of a severe developmental disorder with muscular hypotonia as well as epilepsy, facial dysmorphia such as midface hypoplasia and hypertelorism, hypoplastic distal phalanges of fingers and toes, and the leading symptom of persistent isolated hyperphosphatasia. In this group of GPI anchor defects, specific changes in the GPI anchor cause, among other things, alkaline phosphatase (AP), which is normally anchored to the plasma membrane at GPI anchors, to occur freely in the blood in large quantities, thus leading to the altered serum parameter of "elevated" alkaline phosphatase, i.e., "hyperphosphatasia". This hyperphosphatasia is one of the leading symptoms of this group of severe developmental disorders. Depending on the type and location of the various GPI anchor defects, such pathological changes in serum parameters may be present, but if the underlying disturbance of the GPI anchor synthesis or function is in other locations, these signs of a defect in the GPI anchors may be completely absent, making diagnosis more difficult in these cases. Typical symptoms of many GPI anchor defects are severe developmental disorders, epilepsy, partly congenital organ malformations and facial dysmorphia. In recent years, various genes have been identified which lead to a disruption of the mechanism of GPI anchor synthesis or function. Most GPI anchor defects follow an autosomal recessive inheritance pattern.
Using Next Generation Sequencing (NGS), it is now possible, in the event of clinical suspicion, to make a diagnosis in individual cases by means of extended diagnostics (gene panel analysis) and thus to make more precise statements on the prognosis and the risk of recurrence.
References
Knaus et al. 2018, Genome Med 10:3 / Makrythanasis et al. 2016, Am J Hum Genet 98:615-26 / Murakami et al. 2012, J Biol Chem 287:6318-25 / Krawitz et al. 2010, Nat Genet 42:827-829