Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI)
Miles D Thompson1, Alexej Knaus2
1Krembil Brain Institute, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada.
Insights
Mabry syndrome, a developmental disability, is now understood as a glycophosphatidylinositol (GPI) biosynthesis disorder (GPIBD). Genetic sequencing identified PGAP2 gene variants in early cases, highlighting the need for new treatments for these rare genetic disorders.
Area of Science:
- Genetics
- Biochemistry
- Developmental Biology
Background:
- Mabry syndrome, characterized by developmental disability and seizures, was initially described in 1970.
- Advances in massively parallel sequencing have enabled the identification of underlying genetic causes for developmental disabilities.
- Glycophosphatidylinositol (GPI) biosynthesis disorders (GPIBDs) are a group of congenital disorders of glycosylation (CDG).
Purpose of the Study:
- To re-evaluate the original Mabry syndrome cases using modern genetic techniques.
- To identify the specific genetic variants responsible for the phenotype observed in the index patients.
- To discuss the implications of these findings for understanding GPIBDs and patient care.
Main Methods:
- Utilized improved laboratory diagnostics and molecular techniques.
- Performed exome and genome sequencing on patients originally described by Mabry et al.
- Analyzed genetic variants in genes involved in GPI biosynthesis and post-attachment modification.
Main Results:
- Identified biallelic variants in the PGAP2 gene in the first reported Mabry syndrome patients.
- Confirmed that Mabry syndrome is a GPI biosynthesis disorder (GPIBD), specifically HPMRS3.
- Discussed the longevity of index patients and the potential benefit of pyridoxine treatment for seizures.
Conclusions:
- The original Mabry syndrome cases are linked to PGAP2 gene variants, classifying it as HPMRS3.
- Genetic sequencing has been crucial in defining GPIBDs and their associated phenotypes.
- There is a clear need for innovative treatments to improve outcomes for patients with developmental disabilities like Mabry syndrome.
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.
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