A case report of PGAP2-related hyperphosphatasia with impaired intellectual development syndrome in a Chinese family and literature review

Abstract

Recently, mutations have been identified in six genes (PIGA, PIGY, PIGO, PGAP2, PIGW and PGAP3) encoding proteins in the Glycosyl phosphatidylinositol(GPI)-anchor-synthesis pathway in individuals with hyperphosphatasia with impaired intellectual development syndrome(HPMRS). Reports involving the rare pathogenic gene, post-GPI attachment to proteins 2 (PGAP2) are quite limited. In this study, we reported two patients with PGAP2 variants related neurodevelopmental disorders from Asian population. The proband, onset of epileptic spasms at 5 months, concurrently with global developmental dalay, facial malformation and elevated alkaline phosphatase. His younger sister, onset of epileptic spasms at 2 months, having similar clinical features as the proband. Their phenotypes are consistent with PGAP2 related diseases. The two missense variants [c.686C>T (p.Ala229Val) and c.677C>T (p.Thr226Ile)] in PGAP2 gene found in this family were segregation with the disease, while c.677C>T (p.Thr226Ile) was a novel variant. All the two patients showed a positive response to ACTH treatment and high-dose pyridoxine. In summary, this study contributes to expanding the pathogenic variant spectrum of PGAP2 related HPMRS, and provides new insights into the treatment.

Keywords: ACTH treatment; PGAP2 variants; epileptic spasms; facial malformation; hyperphosphatasia with impaired intellectual development syndrome; pyridoxine.

Figure 1

Facial features and brain MRI results of the proband and his younger sister. (A) Facial features of the proband at 19 months of age: thick eyebrows, hypertelorism in both eyes, and collapsed nasal bridge. (B) Facial features of the proband's younger sister at 2 months of age: thick eyebrows, collapsed nasal bridge, tented upper lip, and downward-facing corners of the mouth; (C) Large Mongolian patches on the dorsum and rump of the proband's younger sister (D) Proband, 5-month-old cranial MRI: thin corpus callosum, slightly enlarged lateral ventricles, mildly widened extracerebral spaces in bilateral fronto-temporo-parietal lobes, transverse axial T1W, T2W, and sagittal T1W. (E)Proband's younger sister, 2-month-old cranial MRI: hypoplastic corpus callosum, transverse axial T1W, T2W, and sagittal T1W.

Figure 2

VEEG results of the two patients. VEEG of 5 months of age of the proband, (A) Interictal period: hypsarrhythmia with burst suppression; (B) Ictal period:clusters of epileptic spasms. VEEG of 4 months of age of the proband's younger sister, (C) Interictal period: hypsarrhythmia; (D) Ictal period: epileptic spasms.

Figure 3

Two compound heterozygous variants of PGAP2 were identified in this family, and up to now, a total of 17 variants of the PGAP2 gene have been reported to be related to diseases. Variants are scattered throughout the protein without any specific domain. (A) Identification of two compound heterozygous mutations in PGAP2. Pedigree chart and Sanger Validation of the family. Individuals with the compound heterozygous mutations are represented with a full black square, and proven heterozygote carriers are shown by a dot. The proband is indicated with an arrow. (B) Schematic representation of the PGAP2 gene. Exons 1-6 are depicted, truncting variants depicted above, non-truncting variants depicted below. The brown part indicates the transmembrane domain. The mutations of this study is marked in red.