Glycosylphosphatidylinositol Biosynthesis Defect 11

A number sign (#) is used with this entry because of evidence that glycosylphosphatidylinositol biosynthesis defect-11 (GPIBD11) is caused by homozygous or compound heterozygous mutation in the PIGW gene (610275) on chromosome 17q12.

Description

GPIBD11 is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, and variable seizures. Some patients may have dysmorphic features or increased serum alkaline phosphatase. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Hogrebe et al., 2016).

For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Clinical Features

Chiyonobu et al. (2014) reported a Japanese male infant, born of unrelated parents, with profoundly delayed development and tonic seizures associated with hypsarrhythmia on EEG, consistent with a clinical diagnosis of West syndrome (see EIEE1, 308350). He also had dysmorphic facial features, including a broad nasal bridge and tented upper lip. Laboratory investigations showed elevated serum alkaline phosphatase (ALP), indicating hyperphosphatasia. Flow cytometry of peripheral blood granulocytes revealed reduced levels of several glycosylphosphatidylinositol-anchored proteins (GPI-APs), including CD59 (107271) and CD14 (158120).

Hogrebe et al. (2016) reported 2 second-degree cousins with hypotonia and delayed psychomotor development apparent from early infancy. One child learned to walk at age 17 months, but was nonverbal and had autistic traits at age 7 years. The other child had not started walking by age 4 years. Both patients developed seizures associated with multifocal spike-wave complexes on EEG. Brain imaging was normal in both patients, and serum alkaline phosphatase was in the high-normal range. GPI-APs were mildly and variably decreased.

Inheritance

The transmission pattern of GPIBD11 in the family reported by Chiyonobu et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a Japanese boy, born of unrelated parents, with hyperphosphatasia with mental retardation syndrome-5, Chiyonobu et al. (2014) identified compound heterozygous missense mutations in the PIGW gene (T71P, 610275.0001; M167V, 610275.0002). In vitro functional expression studies suggested that the mutations reduced PIGW activity. However, Chiyonobu et al. (2014) noted that confirmation of the findings in additional families was warranted.

In 2 second-degree cousins with GPIBD11, Hogrebe et al. (2016) identified a homozygous missense mutation in the PIGW gene (R154G; 610375.0003). The mutation was found by next-generation sequencing and confirmed by Sanger sequencing. Transfection of rat Pigw carrying the R154G mutation into Pigw-deficient CHO cells failed to restore surface expression of certain GPI-anchored proteins, indicating that it is a hypomorphic allele. The patients did not have increased serum alkaline phosphatase, but did have subtle deficiencies in the cellular expression of certain GPI-anchored protein, particularly CD16.