Mabry C, Bautista A, Kirk RFH, Dublilier LD, Braunstein H, Koepke JA. J Pediatr 1970;77:74-85. Mabry et al reported the first 4 patients with hyperphosphatasia with mental retardation syndrome (HPMRS) to present with generalized seizures and facial dysmorphism. The syndrome can be distinguished from other developmental disabilities by the stable elevation of alkaline phosphatase without bone disease.1Thompson M.D. Nezarati M.M. Gillessen-Kaesbach G. Meinecke P. Mendoza-Londono R. Mornet E. et al.Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: five new patients with Mabry syndrome.Am J Med Genet A. 2010; 152A: 1661-1669Crossref PubMed Scopus (36) Google Scholar Few published reports of the syndrome appeared before we identified a patient whose seizures responded to pyridoxine.2Cole D.E. Thompson M.D. Neurogenic aspects of Mabry syndrome.Subcell Biochem. 2015; 76: 343-361Crossref PubMed Scopus (12) Google Scholar Improved syndromology1Thompson M.D. Nezarati M.M. Gillessen-Kaesbach G. Meinecke P. Mendoza-Londono R. Mornet E. et al.Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: five new patients with Mabry syndrome.Am J Med Genet A. 2010; 152A: 1661-1669Crossref PubMed Scopus (36) Google Scholar made it possible to use next-generation sequencing to identify the recessive mutations that cause what became known as Mabry syndrome (OMIM 239300).2Cole D.E. Thompson M.D. Neurogenic aspects of Mabry syndrome.Subcell Biochem. 2015; 76: 343-361Crossref PubMed Scopus (12) Google Scholar There are at least 6 phenotypes. HPMRS 1, 2, 5, and 6 result from disruption of 4 genes encoding phosphatidylinositol glycan (PIG) anchor biosynthesis enzymes that act in the endoplasmic reticulum: type V (PIGV) type O (PIGO), type W (PIGW), and type Y (PIGY). HPMRS 4 and 3 result from disruption of 2 genes encoding postattachment to proteins (PGAP) enzymes that stabilize glycosylphosphatidylinositol attachment to proteins in the golgi: PGAP3 and PGAP2.3Carmody L. Blau H. Danis D. Gourdine J.-P. Vasilevsky N. Krawitz P. et al.Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphosphatidylinositol (GPI)-anchor biosynthesis genes.Orphanet J Rare Dis. 2020; 15: 40Crossref PubMed Scopus (13) Google Scholar The report by Mabry et al describes the first of at least 21 inherited glycosylphosphatidylinositol biosynthesis defects (GPIBDs) that together compose approximately 0.15% of all developmental disabilities.4Pagnamenta A.T. Murakami Y. Taylor J.M. Anzilotti C. Howard M.F. Miller V. et al.Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.Eur J Hum Genet. 2017; 25: 669-679Crossref PubMed Scopus (48) Google Scholar The HPMRS3 (GPIBD8 [MIM: 614207]) phenotype presented by Mabry et al, resulting from biallelic inheritance of PGAP2 mutations, is the prototypical HPMRS phenotype among GPIBDs.5Thompson M.D. Knaus A.A. Barshop B.A. Caliebe A. Muhle H. Nguyen T.T.M. et al.A post glycosylphosphatidylinositol (GPI) attachment to proteins, type 2 (PGAP2) variant identified in Mabry syndrome index cases: Molecular genetics of the prototypical inherited GPI disorder.Eur J Med Genet. 2019; (https://www.ncbi.nlm.nih.gov/pubmed/31805394. Accessed May 15, 2020)PubMed Google Scholar This work demonstrates the value of case studies to basic science, clinical innovation, and patient follow-up.