The Clinical and Genetic Spectrum of Inherited Glycosylphosphatidylinositol Deficiency Disorders

Pediatrics Neurology Genetics Basic Medical Sciences Medical Imaging Life Sciences Immunology Medicine Cell Biology
Inherited Glycosylphosphatidylinositol Deficiency Multisystem Disorders Neurogenetic Disease Molecular Spectrum Natural History Data

Clinical and Genetic Spectrum Study of Inherited Glycosylphosphatidylinositol Deficiency Disorders (IGDs)

Background Introduction

The glycosylphosphatidylinositol (GPI) anchoring pathway is crucial for post-translational modification of many important proteins in eukaryotes, which are fundamental for cell signaling and early human neurogenesis and neurodevelopment. However, inherited GPI deficiency disorders (IGDs) are a group of rare, phenotypically heterogeneous multisystem diseases mainly caused by mutations in GPI anchoring pathway genes. Although 24 GPI anchoring pathway genes have been associated with human neurogenetic diseases, existing reports are still focused on single genes and lack comprehensive data. Moreover, natural history data for these patients are very limited. Therefore, this study aims to systematically analyze the molecular spectrum, phenotypic characteristics, and natural history of 83 IGD patients from 75 families, providing comprehensive data support.

Paper Source

This study was jointly completed by researchers from multiple institutions, including University College London, Great Ormond Street Hospital for Children NHS Foundation Trust, The Children’s Hospital of Philadelphia, and other institutions. The research was published in the journal “Brain” on March 8, 2024.

Research Methods and Experimental Process

Study Design and Patient Recruitment

This is a multinational retrospective observational study aimed at characterizing the clinical phenotypes, molecular features, and natural history of IGD patients. The study obtained ethical approval from various institutions before commencement and obtained written informed consent from all participating patients. This study recruited 83 patients through international collaboration and the Queen Square Genomics Reference Network, with inclusion criteria including genetically confirmed or clinically diagnosed IGD and sufficient clinical data.

Molecular Detection

Variants in GPI anchoring pathway genes were identified through next-generation whole-exome sequencing, DNA panel sequencing, or whole-genome sequencing. The destructive effects of variants were confirmed by flow cytometry. All variants were based on the GRCh38/hg38 human reference genome and were reinterpreted by independent certified clinical geneticists.

Clinical Characterization

The study collected comprehensive clinical, biochemical, imaging, and genetic data through review of electronic medical records. Core clinical features were defined as those occurring in over 50% of reported patients. For epilepsy patients, classification was based on the International League Against Epilepsy (ILAE) 2017 standards.

Neuroimaging Features

Brain MRI image analysis was performed on all patients using methods such as reverse-trained structured format law (FLAIR), diffusion-weighted imaging (DWI), and magnetic resonance perfusion imaging (DWI).

Statistical Analysis

Kaplan-Meier estimation, Student’s t-test, and chi-square test or Fisher’s exact test were used for data analysis. Exploratory analysis of genotype-phenotype correlations was performed using scaled Euclidean unsupervised hierarchical clustering.

Research Results

Sample Population Information

This study included 83 patients from 75 different families, including 70 newly reported individuals. These patients came from diverse ethnic backgrounds and 21 different countries. The core clinical features identified in the study include developmental delay or intellectual disability (DD/ID, 90.4%), epilepsy (83.1%), hypotonia (72.3%), and movement symptoms (63.9%). 63.9% of patients exhibited dyskinesia or ataxia. Consistent with the baseline data, imaging data showed brain atrophy, pontine atrophy, and corpus callosum abnormalities in most patients.

Genetic Variants and Molecular Spectrum

A total of 93 unique variants were identified, including 22 novel variants. Analysis revealed that variants were widely distributed in the primary structure of genes, and specific genotypes were significantly associated with phenotypes. For example, patients with PIGA and PIGT genotypes tended to have severe epilepsy presentations, while PIGG-type patients exhibited milder clinical phenotypes.

Imaging Features and Clinical Correlations

Imaging analysis revealed that the atrophic regions in the brains of these IGD patients corresponded to the regional expression patterns of GPI-anchored protein genes, suggesting the important role of these genes in the normal development of these regions. Most patients showed brain atrophy, especially in the frontotemporal lobes. Their pontine and cerebellar atrophy tended to have an anteroposterior gradient distribution. Restricted diffusion was particularly prominent in the brainstem and deep gray matter nuclei.

Conclusions and Applications

The study established, for the first time, a large-scale dataset of 83 IGD patients, providing new insights into the disease mechanisms, phenotypic diversity, and natural history of these rare diseases. The study also identified core clinical and imaging features of IGDs, proposing that next-generation sequencing should be performed on patients with specific phenotypes and particular presentations on brain MRI for early diagnosis. The findings have important implications for clinical management, monitoring, and genetic counseling.

Research Highlights

  1. This is the largest reported cohort of IGD patients to date.
  2. Core clinical and imaging features of IGDs were identified.
  3. New genotype-phenotype associations were provided, guiding future management and monitoring.
  4. The phenotypic spectrum of IGDs was expanded, ranging from mild motor disorders with normal cognition to spastic quadriplegia with severe intellectual disability.

Research Significance and Future Prospects

This study provides rich data support for the diagnosis, management, and monitoring of rare genetic diseases. Its findings not only help understand the pathological mechanisms of IGDs but also establish more accurate endpoints for future clinical trials. The multinational collaborative model and large sample size of the study enhance the universality of the research conclusions, giving them broader clinical application value. Through effective genetic counseling for patients and families, we hope the research can improve the quality of life for IGD patients.