PIGA – West syndrome

PIGA encodes the phosphatidylinositol glycan anchor biosynthesis class A protein, a key enzyme in the first step of glycosylphosphatidylinositol (GPI) anchor synthesis. West syndrome is an infantile-onset epileptic encephalopathy characterized by epileptic spasms and hypsarrhythmia. Germline variants in PIGA have been implicated in early-onset epileptic encephalopathies, including West syndrome, through disrupted GPI-anchor biosynthesis leading to neuronal hyperexcitability.

A cohort study of 172 patients with early-onset epileptic encephalopathies identified four hemizygous PIGA mutations in probands presenting with West syndrome or related phenotypes, demonstrating X-linked recessive inheritance (PMID:24706016). A separate family with X-linked early-onset epileptic encephalopathy harbored the private variant c.427A>G (p.Lys143Glu), segregating with disease and showing reduced GPI-anchored protein expression in proband granulocytes (PMID:26923721).

PIGA deficiency follows an X-linked recessive mode; affected males are hemizygous for pathogenic alleles, while carrier females may show partial GPI-anchor reduction without overt seizures. The variant spectrum includes missense and truncating changes; one representative allele is c.356G>A (p.Arg119Gln).

Functional assays in patient blood granulocytes demonstrate markedly reduced GPI-anchored CD16 and other surface proteins ([PMID:24706016]). Complementation studies in PIGA-deficient JY5 cells reveal variable restoration of GPI anchoring by mutant constructs, correlating residual enzyme activity with clinical severity. In vitro reduction of CD16 on patient cells further confirms a loss-of-function mechanism ([PMID:26923721]).

Collectively, genetic and experimental data support a haploinsufficiency mechanism for PIGA in West syndrome. X-linked hemizygous variants leading to impaired GPI-anchor biosynthesis culminate in epileptic spasms and developmental arrest. This association has been replicated in independent families and is concordant with functional evidence.

Key take‐home: Testing for PIGA variants and assessing GPI-anchored protein levels in male infants with West syndrome can guide diagnosis, genetic counseling, and potential targeted interventions.

References

• Neurology | 2014 | PIGA mutations cause early-onset epileptic encephalopathies and distinctive features PMID:24706016
• Brain & development | 2016 | A novel PIGA mutation in a family with X-linked, early-onset epileptic encephalopathy PMID:26923721

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