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

Alison M R Castle; Smrithi Salian; Haim Bassan; Efrat Sofrin-Drucker; Raffaella Cusmai; Kristin C Herman; Delphine Heron; Boris Keren; Devon L Johnstone; Wendy Mears; Susanne Morlot; Thi Tuyet Mai Nguyen; Rachel Rock; Elliot Stolerman; Julia Russo; William Boyce Burns; Julie R Jones; Valentina Serpieri; Hannah Wallaschek; Ginevra Zanni; David A Dyment; Philippe M Campeau

doi:10.1212/NXG.0000000000000631

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

Neurol Genet. 2021 Oct 21;7(6):e631. doi: 10.1212/NXG.0000000000000631. eCollection 2021 Dec.

Authors

Alison M R Castle¹, Smrithi Salian¹, Haim Bassan¹, Efrat Sofrin-Drucker¹, Raffaella Cusmai¹, Kristin C Herman¹, Delphine Heron¹, Boris Keren¹, Devon L Johnstone¹, Wendy Mears¹, Susanne Morlot¹, Thi Tuyet Mai Nguyen¹, Rachel Rock¹, Elliot Stolerman¹, Julia Russo¹, William Boyce Burns¹, Julie R Jones¹, Valentina Serpieri¹, Hannah Wallaschek¹, Ginevra Zanni¹, David A Dyment¹, Philippe M Campeau¹

Affiliation

¹ Department of Genetics (A.M.R.C., D.A.D.), Children's Hospital of Eastern Ontario, Ottawa; CHU Sainte Justine Research Centre (S.S., T.T.M.N., P.M.C.), Université de Montréal, Quebec, Canada; Pediatric Neurology & Development Center (H.B.), Shamir (Assaf Harofeh) Medical Center, Zerifin, Tel Aviv University; Pediatric Genetics Clinic (E.S.-D.), Schneider Children's Medical Centre, Petach Tikya, Tel Aviv University, Israel; Unit of Neurophysiology, Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy; Section of Medical Genomics (K.C.H.), Medical Investigation of Neurodevelopmental Disorders Institute, University of California, Davis, Sacramento; APHP (B.K.), Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France; APHP Sorbonne-Université (D.H.), UF Génétique Médicale, Hôpitaux Pitié-Salpêtrière et Trousseau, Centre de Référence "déficiences intellectuelles de causes rares", Paris, France; Children's Hospital of Eastern Ontario Research Institute (D.L.J., W. M., D.A.D.), Ottawa, Canada; Department of Human Genetics (S.M., H.W.), Hannover Medical School, Germany; Biochemical Diseases (R.R.), BC Children's Hospital, Vancouver, British Columbia, Canada; Greenwood Genetic Center (E.S., J.R., W.B.B., J.R.J.), SC; Department of Molecular Medicine (V.S.), University of Pavia; Neurogenetics Research Center (V.S.), IRCCS Mondino Foundation, Pavia; Unit of Neuromuscular and Neurodegenerative Disorders (G.Z.), Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy; and Medical Genetics Division (P.M.C.), Department of Pediatrics, Sainte-Justine University Hospital Centre, Montreal, Quebec, Canada.

Abstract

Background and objectives: To expand the clinical knowledge of GPAA1-related glycosylphosphatidylinositol (GPI) deficiency.

Methods: An 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.

Results: Ten 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.

Discussion: Clinical 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.