Glycosylphosphatidylinositol Biosynthesis Defect 1

A number sign (#) is used with this entry because of evidence that GPI biosynthesis defect-1 (GPIBD1) is caused by homozygous mutation in the PIGM gene (610273) on chromosome 1q23.

Description

Glycosylphosphatidylinositol is a glycolipid that anchors more than 150 proteins to the cell surface, and these proteins, termed GPI-anchored proteins (GPI-APs), perform a variety of functions as enzymes, adhesion molecules, complement regulators, and coreceptors in signal transduction pathways. Reduced surface levels of GPI-APs or abnormal GPI-AP structure can therefore result in variable manifestations. Glycosylphosphatidylinositol biosynthesis defect-1 (GPIBD1) is characterized predominantly by portal hypertension due to portal vein thrombosis. Most patients have absence seizures, cerebral thrombosis, and macrocephaly. Some patients have mildly to moderately impaired intellectual development (summary by Makrythanasis et al., 2016; Pode-Shakked et al., 2019).

Genetic Heterogeneity of Glycosylphosphatidylinositol Biosynthesis Defects

Also see GPIBD2 (239300), caused by mutation in the PIGV gene (610274); GPIBD3 (614080), caused by mutation in the PIGN gene (606097); GPIBD4 (300868), caused by mutation in the PIGA gene (311770); GPIBD5 (280000), caused by mutation in the PIGL gene (605947); GPIBD6 (614749), caused by mutation in the PIGO gene (614730); GPIBD7 (615398), caused by mutation in the PIGT gene (610272); GPIBD8 (614207), caused by mutation in the PGAP2 gene (615187); GPIBD9 (615802), caused by mutation in the PGAP1 gene (611655); GPIBD10 (615716), caused by mutation in the PGAP3 gene (611801); GPIBD11 (616025), caused by mutation in the PIGW gene (610275); GPIBD12 (616809), caused by mutation in the PIGY gene (610662); GPIBD13 (616917), caused by mutation in the PIGG gene (616918); GPIBD14 (617599), caused by mutation in the PIGP gene (605938); GPIBD15 (617810), caused by mutation in the GPAA1 gene (603048); GPIBD16 (617816), caused by mutation in the PIGC gene (601730); GPIBD17 (618010), caused by mutation in the PIGH gene (600154); GPIBD18 (618143), caused by mutation in the PIGS gene (610271); GPIBD19 (618548), caused by mutation in the PIGQ gene (605754); GPIBD20 (618580), caused by mutation in the PIGB gene (604122); and GPIBD21 (618590), caused by mutation in the PIGU gene (608528).

Clinical Features

Almeida et al. (2006) reported 3 affected children from 2 unrelated consanguineous families, of Middle Eastern and Turkish origin, respectively, with a newly described inherited deficiency of GPI. The probands from each family developed portal vein thrombosis and portal hypertension by age 2 years. One developed absence seizures at age 4 years, and the other developed atonic seizures at age 3 years. The younger sib in the Turkish family was treated with prophylactic oral anticoagulants and did not develop thrombosis, but still developed absence seizures at age 5 years. None of the patients had central venous thrombosis or vascular anomalies and none showed hemolysis or bone marrow failure. Detailed laboratory studies showed variably decreased expression of GPI-linked proteins, including CD59 (107271) and CD24 (600074), on hematopoietic cells. Almeida et al. (2006) noted that paroxysmal nocturnal hemoglobinuria (PNH; 300818), an acquired clonal disorder caused by mutation in the PIGA gene (311770), is also characterized by a GPI defect.

Pode-Shakked et al. (2019) reported 4 patients from 2 unrelated Arab families with glycosylphosphatidylinositol deficiency and mutations in the PIGM gene. Three sibs in family A had cerebral and portal vein thrombosis, macrocephaly, prominent superfical facial/abdominal veins, and hepato- or splenomegaly. The 2 oldest sibs, a brother and sister, had persistent atypical absence seizures beginning at age 3 to 4 years. The brother died at age 7 due to complications of cirrhosis. Another sister, who was diagnosed prenatally, had portal and cerebral vein thromboses beginning at age 7 months. She had an acute episode of left-sided hemiplegia at age 16 months, with residual left-sided hemiplegia and inability to speak. Both sisters had mildly to moderately impaired intellectual development. The 4-year-old boy in family B had cerebral and portal vein thrombosis, macrocephaly, dilated superficial facial and abdominal veins, and hepatosplenomegaly.

Molecular Genetics

Almeida et al. (2006) identified a homozygous mutation in the promoter region of the PIGM gene (610273.0001) in 3 patients from 2 unrelated consanguineous families with glycosylphosphatidylinositol deficiency. The mutation occurred in a conserved region in the promoter region of the gene and disrupted binding of the transcription factor SP1 (189906). PIGM mRNA levels were severely reduced. The findings confirmed that the disorder is caused by a defect in the biosynthetic pathway crucial for anchoring proteins to the cell surface.

In 4 affected members from 2 unrelated Arab families with GPIBD1, Pode-Shakked et al. (2019) identified homozygosity for the same promoter mutation in the PIGM gene that had been identified by Almeida et al. (2006). The mutation segregated with the disorder in both families.

Clinical Management

Almeida et al. (2007) reported follow-up of 1 of the patients with GPI deficiency reported by Almeida et al. (2006). This 14-year-old girl had severe refractory seizures occurring several times a day, which resulted in her being wheelchair-bound, poorly responsive, and unable to feed herself. Treatment with sodium phenylbutyrate, a histone deacetylase inhibitor, resulted in significant clinical improvement and remission of seizures. In vitro studies of patient cells showed no evidence of histone acetylation at the mutated PIGM promoter, suggesting that the SP1-binding site is crucial for histone acetylation. PIGM transcription and mRNA levels were increased in the presence of sodium butyrate even in the presence of the mutation. Patient cells in vitro and in vivo showed restoration of GPI biosynthesis and expression after treatment.

Three patients in the families with GPIBD1 reported by Pode-Shakked et al. (2019) were treated with sodium phenylbutyrate. The 2 sisters in family A had modest clinical improvement, but the authors noted difficulty with treatment adherence in the family. The boy in family B began treatment at age 15 months; at follow-up at age 4 years, he remained clinically neurologically intact and without seizures. In both families, no significant changes were demonstrated using serial measurements of GPI surface markers (CD59, CD24, FLAER) after initiation of treatment.