[Analysis of PI4KA gene variants in a patient with Hereditary spastic paraplegia type 84]

To investigate the clinical and genetic characteristics of a patient with hereditary Spastic paraplegia type 84 (SPG84) due to compound heterozygous variants of the PI4KA gene.

A patient diagnosed at the Affiliated Hospital of Xuzhou Medical University in 2021 was selected as study subject. Clinical and imaging data were retrospectively analyzed. Peripheral blood samples were collected from the patient and his parents for whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing and bioinformatics analysis. Pathogenicity of the variants was assessed based on the guidelines from American College of Medical Genetics and Genomics (ACMG). Quantitative real-time PCR (qPCR) was used to determine the level of PI4KA mRNA in peripheral blood samples, and lipidomics technology was employed to analyze the levels of plasma phosphatidylinositol (PI) and its metabolite phosphatidylinositol 4-phosphate (PI4P). Relevant literature was retrieved from the China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, Chinese Medical Journal Full-Text Database, and PubMed Database. Previous reports of SPG84-associated PI4KA gene variants were summarized. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: XYFY2024-KL644-01).

The patient, a 13-year-old boy, had presented with unsteady gait, spastic paraplegia of lower limbs, increased muscle tone, and cognitive impairment. Diffusion tensor imaging (DTI) revealed absence of right frontoparietal fiber tract and partial interruption of right parietal fiber tract. WES revealed that he has harbored compound heterozygous variants of the PI4KA gene, including a paternally derived c.4076T>G (p.Leu1359Arg) and a maternally derived c.6082C>T (p.Arg2028Trp). Based on the guidelines from ACMG, both were classified as variants of uncertain significance (PM2_Supporting+PP2 PP3). The variants were absent from databases including ClinVar, ExAC, and gnomAD. Conservation analysis indicated high evolutionary conservation of the affected residues, and multiple in silico tools all predicted deleterious effects. Protein structure modeling suggested the variants may disrupt dimer formation and catalytic activity. Functional studies demonstrated significantly reduced PI4KA mRNA expression (P < 0.05) and a decreased plasma PI4P/PI ratio in the patient (P < 0.05). Literature review identified 4 relevant publications involving a total of 6 SPG84 patients with PI4KA variants.

The c.4076T>G and c.6082C>T compound heterozygous variants of the PI4KA gene probably underlay the genetic etiology of SPG84 in this patient. Above finding has expanded the mutational spectrum of the PI4KA gene. Functional analyses has provided preliminary evidence for its pathogenicity, though further validation is still required.