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December 2021; 7 (6) ArticleOpen Access

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
First published October 21, 2021, DOI: https://doi.org/10.1212/NXG.0000000000000631
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Figures

  • Figure 1
    Figure 1 Sagittal T1 Images From Patients With GPAA1-Related Glycosylphosphatidylinositol Deficiency

    (A) Neuroimaging from patient I, taken at age 21 years. Note the cerebellar atrophy with prominent folia. (B) Sagittal T1 MRIs from patient II, in whom biallelic GPAA1 variants were found incidentally on exome sequencing. The cerebellum is normal in this patient. (C) Neuroimaging from patient III from 2018. Although her initial MRI did not report cerebellar hypoplasia/atrophy, subsequent cerebellar atrophy was noted on this follow-up imaging (shown) performed at age 2 years. Slightly delayed myelination and mild thinning of the corpus callosum was also identified. (D) Sagittal T1 MRI images from patient V, showing severe vermian hypoplasia/atrophy and thinning of the superior cerebellar peduncle and bilateral cerebellar hemisphere atrophy. The corpus callosum was also noted to be hypoplastic.

  • Figure 2
    Figure 2 Variant Localization and Residue Conservation

    (A) Schematic representation of missense and frameshift GPAA1 variants, with previously reported variants indicated in blue, and novel variants indicated in red. (B) Amino acid conservation in vertebrates. (C) Three-dimensional modeling of the luminal domain of GPAA1, which spans residues 66–348.35 Shown in red are 2 missense variants within this domain.

  • Figure 3
    Figure 3 Flow Cytometry Analysis of CD16 on Granulocytes in patients II, III, and VII Compared With a Healthy Control

    The histograms are representatives of at least 2 separate experiments using 3 different controls. There was a 47%, 37%, and 12% decrease in the CD16 level on the granulocytes of patients II, III, and VII, respectively, compared with controls. In addition, there was no significant reduction in glycosylphosphatidylinositol-anchored protein levels in the father of patient VII, who carries a frameshift variant. PE-A = phycoerythrin area.

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