PGAP2-Related Hyperphosphatasia-Mental Retardation Syndrome: Report of a Novel Patient, Toward a Broadening of Phenotypic Spectrum and Therapeutic Perspectives

Abstract

PGAP2 gene has been known to be the cause of “hyperphosphatasia, mental retardation syndrome-3” (HPMRS3). To date, 14 pathogenic variants in PGAP2 have been identified as the cause of this syndrome in 24 patients described in single-case reports or small clinical series with pan-ethnic distribution. We aim to present a pediatric PGAP2-mutated case, intending to further expand the clinical phenotype of the syndrome and to report our experience on a therapeutic approach to drug-resistant epilepsy.

We present the clinical, neuroradiological, and genetic characterization of a Caucasian pediatric subject with biallelic pathogenic variants in the PGAP2 gene revealed by next generation sequencing analysis.

We identified a subject who presented with global developmental delay and visual impairment. Brain magnetic resonance imaging showed mild hypoplasia of the inferior cerebellar vermis and corpus callosum and mild white matter reduction. Laboratory investigations detected an increase in alkaline phosphatase. At the age of 13 months, he began to present epileptic focal seizures with impaired awareness, which did not respond to various antiseizure medications. Electroencephalogram (EEG) showed progressive background activity disorganization and multifocal epileptic abnormalities. Treatment with high-dose pyridoxine showed partial benefit, but the persistence of seizures and the lack of EEG amelioration prompted us to introduce ketogenic diet treatment.

Our case provides a further phenotypical expansion of HPMRS3 to include developmental and epileptic encephalopathy. Due to the limited number of patients reported so far, the full delineation of the clinical spectrum of HPMRS3 and indications for precision medicine would benefit from the description of new cases and their follow-up evaluations.

Keywords

developmental and epileptic encephalopathy - glycosylphosphatidylinositol (GPI)-anchor biosynthesis - pyridoxine - ketogenic diet

Ethics Committee Approval

Ethics committee approval is not required because genetic analyses are only for clinical diagnosis.

Consent for Publication

Consent from patients and parents was obtained to publish detailed medical histories of patients.

Author Contributions

A.S., M.T., C.V., and S.O. were responsible for the conception and design of the paper; A.S., M.T., C.V., and S.O. wrote the original draft of the paper; S.G., M.P., E.R., G.P., and V.D.G. analyzed data.

All authors contributed to the writing of the final manuscript.

Declaration of Competing Interest

V.D.G. received research fundings and speaker fees from Eisai srl, GW Pharmaceuticals, Neu-raxpharm, Nutricia, Kanso, and Nestlè. V.D.G., S.G., A.P., M.P., E.R., C.V., and S.O. received financial support from the Italian Ministry of Health (RC 2022-2024) for the IRCCS Mondino Foundation in Pavia, Italy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

^* Drs Saracino and Totaro equally contributed to this investigation (co-first authors)

Publication History

Received: 29 September 2023

Accepted: 02 January 2024

Article published online:
16 February 2024

• References

• 1 Hansen L, Tawamie H, Murakami Y. et al. Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability. Am J Hum Genet 2013; 92 (04) 575-583
• 2 Thompson MD, Knaus AA, Barshop BA. 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 2020; 63 (04) 103822
• 3 Krawitz PM, Murakami Y, Rieß A. et al. PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome. Am J Hum Genet 2013; 92 (04) 584-589
• 4 Jezela-Stanek A, Ciara E, Piekutowska-Abramczuk D. et al. Congenital disorder of glycosylphosphatidylinositol (GPI)-anchor biosynthesis—the phenotype of two patients with novel mutations in the PIGN and PGAP2 genes. Eur J Paediatr Neurol 2016; 20 (03) 462-473
• 5 Naseer MI, Rasool M, Jan MM. et al. A novel mutation in PGAP2 gene causes developmental delay, intellectual disability, epilepsy and microcephaly in consanguineous Saudi family. J Neurol Sci 2016; 371: 121-125
• 6 A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers—PubMed [Internet]. [cited 2023 Dec 26]. Accessed January 11, 2024: https://pubmed-ncbi-nlm-nih-gov.bibliosan.idm.oclc.org/29119105/
• 7 Froukh T, Nafie O, Al Hait SAS. et al. Genetic basis of neurodevelopmental disorders in 103 Jordanian families. Clin Genet 2020; 97 (04) 621-627
• 8 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 9 Thompson MD, Killoran A, Percy ME, Nezarati M, Cole DEC, Hwang PA. Hyperphosphatasia with neurologic deficit: a pyridoxine-responsive seizure disorder?. Pediatr Neurol 2006; 34 (04) 303-307
• 10 Tanigawa J, Nabatame S, Tominaga K. et al. High-dose pyridoxine treatment for inherited glycosylphosphatidylinositol deficiency. Brain Dev 2021; 43 (06) 680-687
• 11 Specchio N, Curatolo P. Developmental and epileptic encephalopathies: what we do and do not know. Brain 2021; 144 (01) 32-43
• 12 Thompson MD, Li X, Spencer-Manzon M. et al. Excluding digenic inheritance of PGAP2 and PGAP3 variants in Mabry syndrome (OMIM 239300) patient: phenotypic spectrum associated with PGAP2 gene variants in hyperphosphatasia with mental retardation syndrome-3 (HPMRS3). Genes (Basel) 2023; 14 (02) 359
• 13 Dakshinamurti K, Sharma SK, Geiger JD. Neuroprotective actions of pyridoxine. Biochim Biophys Acta 2003; 1647 (1-2): 225-229
• 14 Messina M, Manea E, Cullup T, Tuschl K, Batzios S. Hyperphosphatasia with mental retardation syndrome 3: Cerebrospinal fluid abnormalities and correction with pyridoxine and Folinic acid. JIMD Rep 2022; 64 (01) 42-52