Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1

Abstract

Background and ObjectivesTo expand the clinical knowledge of GPAA1-related glycosylphosphatidylinositol (GPI) deficiency.MethodsAn international case series of 7 patients with biallelic GPAA1 variants were identified. Clinical, biochemical, and neuroimaging data were collected for comparison. Where possible, GPI-anchored proteins were assessed using flow cytometry.ResultsTen novel variants were identified in 7 patients. Flow cytometry samples of 3 available patients confirmed deficiency of several GPI-anchored proteins on leukocytes. Extensive phenotypic information was available for each patient. The majority experienced developmental delay, seizures, and hypotonia. Neuroimaging revealed cerebellar anomalies in the majority of the patients. Alkaline phosphatase was within the normal range in 5 individuals and low in 1 individual, as has been noted in other transamidase defects. We notably describe individuals either less affected or older than the ones published previously.DiscussionClinical features of the cases reported broaden the spectrum of the known phenotype of GPAA1-related GPI deficiency, while outlining the importance of using functional studies such as flow cytometry to aid in variant classification.

Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis

“…Genetic defects of GPI-T subunits cause severe NEDHCAS (neurodevelopmental disorders with hypotonia and cerebellar atrophy, with or without seizures) [17][18][19][20][21] , while abnormal amplification of GPI-T subunits are linked to cancers 22,23 . Recent structural studies have provided insights into the mechanisms underlying these defects 24,25 , apart from revealing the overall assembly of the GPI-T complex and the GPIbinding cavity.…”

A Novel Homozygous GPAA1 Variant in a Patient with a Glycosylphosphatidylinositol Biosynthesis Defect

“…Transamidase complex disorders related to GPAA1 defects are very rare. To our knowledge, seventeen patients have been reported at the moment [6,7]. Our patient shares with them the main clinical features, including a severe developmental delay, hypotonia, epilepsy, and nystagmus (Table 1).…”

“…A significant clinical variability has been observed in several features, including the degree of intellectual disability (usually moderate to severe, but mild disability has been reported) and the pattern of the seizures. The facial phenotype is quite aspecific, although some features seem to be recurrent, such as a prominent forehead, a broad nose, and a tented upper lip [7].…”