In the human body, every tissue—such as the brain, heart, muscle, fat, and skin—is made up of tissue-specific cells. In these cells, more than 20,000 types of proteins are produced from genes via RNA. Proteins are distributed in the nucleus (which contains genes), organelles such as mitochondria, the cytoplasm, and the cell membrane, where they perform essential functions. Among the proteins present on the cell membrane, there is a group of proteins that share a common structure called GPI-anchored proteins. More than 150 GPI-anchored proteins have been identified, including enzymes such as alkaline phosphatase (ALP), and they play important roles. A GPI anchor is a glycolipid used to attach these proteins to the cell membrane. Within the cell, the anchor part and the protein part are synthesized separately, then linked together and function on the cell surface. It is known that 30 genes are required for the synthesis and remodeling of the GPI anchor. If GPI anchors are completely absent due to abnormalities in these genes, more than 150 GPI-anchored proteins cannot be expressed on the cell surface (or are expressed with an abnormal structure), and complete deficiency is lethal in utero. Inherited GPI deficiency (IGD) develops when a variant in one of these 30 genes reduces enzyme activity, resulting in decreased amounts of GPI-anchored proteins on the cell surface or abnormal GPI-anchor structures. As of 2026, inherited GPI deficiency due to variants in 24 genes has been reported.

The main symptoms are epilepsy and psychomotor developmental delay. Patients may also show characteristic facial features, elevated serum alkaline phosphatase (ALP), hypoplasia of distal phalanges and/or nails, hearing loss, and various congenital anomalies such as Hirschsprung disease and renal hypoplasia. Depending on the gene involved, epilepsy may not occur. Clinical manifestations vary according to which gene is affected and how severely the variant impacts gene function.

Since PIGM deficiency—the first inherited GPI deficiency (IGD) reported worldwide—was described in 2006, cases have been identified one after another since 2010. As of 2026, approximately 70 patients have been identified in Japan, and approximately 800 patients worldwide. This is a newly recognized disorder, and we expect that more patients will be identified as our research group develops diagnostic guidelines and expands screening efforts.

This is a genetic disorder caused by variants in any one of the 30 genes involved in GPI-anchor biosynthesis and remodeling. As of 2026, inherited GPI deficiency (IGD) due to variants in 24 genes has been reported. Among these genes, only PIGA is located on the X chromosome; the others are on autosomes. Therefore, PIGA deficiency affects only boys, and in many cases the PIGA variant is inherited from the mother. Deficiencies of the other genes are typically inherited when a child receives one altered gene from each parent.

If a child has unexplained congenital epilepsy or developmental delay, the condition can be diagnosed by drawing blood and measuring the levels of GPI-anchored proteins on the surface of white blood cells using flow cytometry. Elevated ALP in routine laboratory testing further raises suspicion. To identify which of the 30 genes carries a variant, genetic testing is performed using DNA extracted from blood to analyze the gene sequence and detect abnormalities. For some genes, a decrease may not be observed; therefore, if the clinical features strongly suggest IGD, genetic testing may be performed even when flow cytometry does not show a clear reduction.
In Japan, our research group has accepted and analyzed blood samples from general medical institutions; however, flow cytometry is now available under insurance coverage as the “granulocyte CD16” test, and genetic testing is also more readily available under insurance as an IGD gene panel test. Please consult your primary physician.

This is a recently discovered disorder and is caused by gene variants; therefore, there is currently no established curative treatment. However, it has become clear that reduced levels of one GPI-anchored protein, alkaline phosphatase, can lead to inadequate uptake of vitamin B6, which may contribute to seizure attacks. Accordingly, vitamin B6 (pyridoxine) administration is remarkably effective for seizure control in some cases. We aim to clarify disease mechanisms further and, in addition to various supplementation therapies, to develop disease-modifying treatments. Although this is a congenital disorder, symptoms can progress after birth; thus, we believe that early diagnosis and early initiation of treatment may help alleviate symptoms. We are also developing gene replacement therapy using adeno-associated virus (AAV) to supplement the normal gene, and efficacy has been confirmed in experiments using model mice. Although clinical application in humans will still take time, we are continuing development toward practical use.