Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI) Disorders

Abstract

The case report by Mabry et al. (1970) of a family with four children with elevated tissue non-specific alkaline phosphatase, seizures and profound developmental disability, became the basis for phenotyping children with the features that became known as Mabry syndrome. Aside from improvements in the services available to patients and families, however, the diagnosis and treatment of this, and many other developmental disabilities, did not change significantly until the advent of massively parallel sequencing. As more patients with features of the Mabry syndrome were identified, exome and genome sequencing were used to identify the glycophosphatidylinositol (GPI) biosynthesis disorders (GPIBDs) as a group of congenital disorders of glycosylation (CDG). Biallelic variants of the phosphatidylinositol glycan (PIG) biosynthesis, type V (PIGV) gene identified in Mabry syndrome became evidence of the first in a phenotypic series that is numbered HPMRS1-6 in the order of discovery. HPMRS1 [MIM: 239300] is the phenotype resulting from inheritance of biallelic PIGV variants. Similarly, HPMRS2 (MIM 614749), HPMRS5 (MIM 616025) and HPMRS6 (MIM 616809) result from disruption of the PIGO, PIGW and PIGY genes expressed in the endoplasmic reticulum. By contrast, HPMRS3 (MIM 614207) and HPMRS4 (MIM 615716) result from disruption of post attachment to proteins PGAP2 (HPMRS3) and PGAP3 (HPMRS4). The GPI biosynthesis disorders (GPIBDs) are currently numbered GPIBD1-21. Working with Dr. Mabry, in 2020, we were able to use improved laboratory diagnostics to complete the molecular diagnosis of patients he had originally described in 1970. We identified biallelic variants of the PGAP2 gene in the first reported HPMRS patients. We discuss the longevity of the Mabry syndrome index patients in the context of the utility of pyridoxine treatment of seizures and evidence for putative glycolipid storage in patients with HPMRS3. From the perspective of the laboratory innovations made that enabled the identification of the HPMRS phenotype in Dr. Mabry's patients, the need for treatment innovations that will benefit patients and families affected by developmental disabilities is clear.

Keywords: Mabry syndrome; case study; glycophosphatidylinositol (GPI) biosynthesis disorder (GPIBD); human phenotype ontology (HPO) analysis; hyperphosphatasia with neurologic deficit (HPMRS); identity by descent filtering; whole exon sequencing; whole genome sequencing.

Figure 1

C. Carleton Mabry (1930–2021). Reproduced with permission from David Mabry.

Figure 2

The original Mabry syndrome index cases, front row, from left: VI-7 (born. 02/17/57; died 05/31/71), VI-16 (born 06/27/58), and VI-6 (born 10/30/55; died 10/19/85); back row: VI-4 (born 03/29/52) and normal mother (V-2) of VI-4, -6 and -7. Patient VI-4 and patient VI-16, photographed in Lexingon, Kentucky, were both homozygous for thec.881C > T, p.T294M PGAP2 variants. Adapted from Thompson et al., 2020 [30].

Figure 3

Dr. Mabry working with a patient. Reproduced with permission from David Mabry.

Figure 4

Glycosylphosphatidylinositol biosynthesis, transamidase and remodeling pathways. (A) Biosynthesis of mammalian GPI. The complete GPI precursor competent for attachment to proteins is synthesized in the ER from PI by stepwise reactions (1)–(11). Man4 side chain is attached in the ER to some GPI (step (12)). The preassembled GPI is en bloc transferred to proteins (step (13)). Genes involved in these reaction steps are shown. (B) Maturation of mammalian GPI-APs during ER–plasma membrane (PM) transport. Nascent GPI-APs generated by the transfer of GPIs to proteins (step 12) undergo two reactions, inositol-deacylation (step 14) and removal of the EtNP side chain from Man2 (step 15) in the ER. The ER–Golgi transport of GPI-APs is mediated by COPII-coated vehicles (step 16). In the Golgi apparatus, GPI-APs undergo fatty acid remodeling (steps 17 and 18). Some GPI anchors have a modified GalNAc side chain (steps 19–21). The mature GPI APs are transported to the PM where they are associated with raft microdomains. Genes involved in these reaction steps are shown below step numbers. Adapted from [29]. Reproduced with permission from Kinoshita, T., Open Biology; published by Elsevier, 2020.

Figure 5

Vitamin B6 metabolism and alkaline phosphatase. Different forms of pyridoxine (P) are absorbed from the gastrointestinal tract (GI). Pyridoxine 5′phosphate (P5′P) is converted to pyridoxal (PL) in the blood, which can be transported across the blood brain barrier, where neuronal alkaline phosphatase acts to reform the metabolically active P5′P form in the CNS. Adapted from Thompson et al. [65].

Figure 6

Electron micrograph of macrophages showing evidence of stored material. (A) Mabry syndrome index case (HPMRS3), m, mitochondria; er, endoplasmic reticulum; n, nucleus, c. stored material. Reproduced with permission from Mabry et al., J. Pediatrics; published by Elsevier, 1970. (B) HPMRS4 case, n, nucleus, * stored material. Adapted from Thompson et al. [28].