PIGO mutations in intractable epilepsy and severe developmental delay with mild elevation of alkaline phosphatase levels

Abstract

Summary Aberrations in the glycosylphosphatidylinositol (GPI)–anchor biosynthesis pathway constitute a subclass of congenital disorders of glycosylation, and mutations in seven genes involved in this pathway have been identified. Among them, mutations in PIGV and PIGO, which are involved in the late stages of GPI‐anchor synthesis, and PGAP2, which is involved in fatty‐acid GPI‐anchor remodeling, are all causative for hyperphosphatasia with mental retardation syndrome (HPMRS). Using whole exome sequencing, we identified novel compound heterozygous PIGO mutations (c.389C>A [p.Thr130Asn] and c.1288C>T [p.Gln430*]) in two siblings, one of them having epileptic encephalopathy. GPI‐anchored proteins (CD16 and CD24) on blood granulocytes were slightly decreased compared with a control and his mother. Our patients lacked the characteristic features of HPMRS, such as facial dysmorphology (showing only a tented mouth) and hypoplasia of distal phalanges, and had only a mild elevation of serum alkaline phosphatase (ALP). Our findings therefore expand the clinical spectrum of GPI‐anchor deficiencies involving PIGO mutations to include epileptic encephalopathy with mild elevation of ALP.

Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders

“…Although seizures were not reported (at 2 years of age), in other respects such as the cupid's-bow-shaped upper lip, intermittently elevated alkaline phosphatase, hypoplasia of distal phalanges, postnatal microcephaly and hearing loss, the phenotype for 263039 appears to be similar to published cases. 34, 44, 45 …”

Characterization of Glycosylphosphatidylinositol Biosynthesis Defects by Clinical Features, Flow Cytometry, and Automated Image Analysis

“…Psychomotor delay, ID and variable AP elevation are the only consistent features of all individuals with pathogenic mutations in PIGV [9, 27-33], PIGO [7, 16, 17, 30, 34-36], PGAP2 [4, 8, 18, 37], PGAP3 [5, 19, 38-40], PIGW [3, 41], and PIGY [6]. Speech development, especially expressive language, is more severely affected than motor skills in the majority of the affected individuals (Table S1).…”

“…This practice is now challenged by a growing number of exceptions. The expressivity of most features is variable and even the AP seems to be a biomarker with some variability: Some individuals with mutations in PIGA also show elevated AP levels [10, 13-15], and some individuals with mutations in PIGO, PGAP2 and PGAP3 show AP levels that are only borderline high [16-19]. Recently, deleterious mutations were identified in PIGC, PIGP and PIGG in individuals with intellectual disability (ID), seizures and muscular hypotonia, but other features were missing that were considered to be a prerequisite for MCAHS or HPMRS [20-22].…”

Molecular analysis of glycosylphosphatidylinositol anchor deficient aerolysin resistant isolates in gulf war i veterans exposed to depleted uranium

“…Also, rare GPIa negative cells are found in the blood and bone marrow of healthy individuals (Nafa et al, 1998;Hu et al, 2005). Germinal mutations in all but seven of the 26 GPIa pathway genes have been demonstrated to be the cause a number of genetic diseases from severe forms with multiple malformations to milder forms with intellectual disability (Kim et al, 2000;Kranz et al, 2001;Schenk et al, 2001;Garcia-Silva et al, 2004;Almeida et al, 2006;Lefeber et al, 2009;Krawitz et al, 2010Krawitz et al, , 2012Maydan et al, 2011;Barone et al, 2012;Ng et al, 2012;Thompson et al, 2012;Kvarnung et al, 2013;Chiyonobu et al, 2014;Martin et al, 2014;Nakamura et al, 2014;Nakashima et al, 2014;Ohba et al, 2014;Fujiwara et al, 2015;Ilkovski et al, 2015;Lam et al, 2015;Fleming et al, 2016;Hogrebe et al, 2016;Khayat et al, 2016;Makrythanasis et al, 2016;Edvardson et al, 2017;Johnstone et al, 2017;Nguyen et al, 2017Nguyen et al, , 2018Pagnamenta et al, 2018).…”