In a narrow sense, inherited GPI deficiency (IGD) is a recessive hereditary disease caused by the decreased surface expression of GPI-anchored proteins (GPI-APs) or the expression of structurally abnormal GPI-APs because of mutations of genes involved in the biosynthesis and modification of GPI-APs.
In a broad sense, IGD includes hereditary diseases caused by the decreased surface expression of GPI-APs or the disturbed transport of GPI-APs because of mutations of genes other than GPI pathway genes that affect gene expression, splicing, or protein transport.

1. 1) Clinical symptoms
   Intellectual disability and motor developmental delay, often accompanied by epilepsy (sometimes familial), without any perinatal difficulties.
   Other symptoms that are sometimes seen:
   • Early-onset epileptic encephalopathy (Ohtahara syndrome, West syndrome, etc.)
   • Characteristic facial features (hypertelorism, broad nasal bridge, tented upper lip, cleft palate)
   • Abnormalities in fingers and toes (brachytelephalangy, hypoplastic nails)
   • Multiple organ anomalies (an aganglionic megacolon, kidney or anorectal anomalies)
   • Hearing loss or visual impairment
   • Skin abnormalities (ichthyosis, etc.)
   • Hypotonia
2. 2) Abnormal findings from clinical inspections that are sometimes seen:
   1. ① Hyperphosphatasia
   2. ② Hypophosphatasia with bone dysplasia
   3. ③ Brachytelephalangy by X-ray
   4. ④ Abnormal ABR
   5. ⑤ Abnormal MRI
      High signal intensity at the brain stem and midbrain in diffused or T2-weighted images
      Cerebellar atrophy and brain leukodystrophy
3. 3) Definitive diagnosis
   • Detect the decreased surface expression of CD16 on granulocytes (not always present).
   • Find the responsible gene by targeted exome sequencing or whole exome sequencing.
   • Perform functional analysis to confirm that the mutation is responsible for the disease.
4. 4) Classification of IGD types
   (1) IGD with decreased expression of GPI-APs
   • • High serum ALP
     (PIGW, PIGV, PIGO, and PGAP2 deficiencies)
   • • Normal serum ALP
     (PIGA, PIGQ, PIGY, PIGL, PIGM, and PIGN deficiencies; note that mild elevation of serum ALP is often seen in PIGA deficiency and high serum ALP was associated with a case with PIGL deficiency)
   • • Lower than normal serum ALP
     (PIGT deficiency)
   (2) IGD with normal expression of GPI-APs
   • • High serum ALP
     (PGAP3 deficiency; note that a mild reduction of GPI-APs was seen in PGAP3 deficiency)
   • • Normal serum ALP
     (PIGG and PGAP1 deficiencies)

1. 1) Caused by mutations in GPI biosynthesis and attachment genes:
   PIG gene deficiencies (PIGA, PIGQ, PIGY, PIGL, PIGW, PIGM, PIGV, PIGN, PIGO, PIGG, PIGT deficiencies)
2. 2) Caused by mutations in genes involved in the modification of GPI-APs:
   PGAP gene deficiencies (PGAP1, PGAP3, PGAP2 deficiencies)
3. 3) Caused by genes other than GPI pathway genes

Decreased expression of certain GPI-APs and associated symptoms

• Decreased expression of ALP and seizures
  Tissue non-specific ALP (an isozyme of ALP) is expressed on neurons and dephosphorylates pyridoxal phosphate (PLP) into pyridoxal (PL) to be taken up into neurons passively, which is again phosphorylated inside the cells and acts as a coenzyme for γ-aminobutyric acid (GABA) synthetase. As GABA is an inhibitory neurotransmitter, a defect in PLP in neurons that decreases the synthesis of GABA leads to seizures.

• Hyperphosphatasia
• Hypophosphatasia with bone dysplasia
• Brachytelephalangy by X-ray
• Abnormal ABR
• Abnormal MRI
  ・ High signal intensity at the brain stem and midbrain in diffused or T2-weighted images
  ・ Cerebellar atrophy and brain leukodystrophy
• Flow cytometric analysis
• Decreased expression of CD16 on granulocytes

A clinical trial of pyridoxine (vitamin B6) treatment for IGD is on going in Japan.