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Deciphering the premature mortality in PIGA-CDG - An untold story
Allan Bayat1, Marius Kløvgaard2, Katrine M Johannesen1
1Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark; Department for Regional Health Services, University of Southern Denmark, Odense, Denmark.
Insights
Congenital disorder of glycosylation (PIGA-CDG) significantly increases mortality risk, with 30% of patients dying before age 20. Respiratory failure is a common cause of death in these severe developmental and epileptic encephalopathy cases.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Congenital disorder of glycosylation (CDG) due to defective PIGA protein causes severe X-linked developmental and epileptic encephalopathy.
- Patients often experience treatment-refractory seizures, intellectual disability, and global developmental delay.
- Previous reports suggest a high risk of premature mortality in PIGA-CDG.
Purpose of the Study:
- To evaluate the observed high mortality rate in PIGA-CDG patients.
- To determine the primary causes of death in individuals with PIGA-CDG.
Main Methods:
- Comprehensive literature review.
- Collection of unpublished patient data via an international network.
Main Results:
- Reviewed data from 88 patients; 30 (34%) deceased before age 20, yielding a 30% overall mortality.
- Median age at death was 2 years; 50% died from respiratory failure, 10% from possible SUDEP.
- Other causes included cardiomyopathy, liver failure, and gastrointestinal bleeding; 30% had unclassified causes of death.
Conclusions:
- PIGA-CDG is associated with a significantly increased risk of premature death compared to most monogenic developmental and epileptic encephalopathies.
- Respiratory failure is a leading cause of mortality, highlighting the need for targeted interventions.
- Further investigation into causes of death is warranted due to frequent unclassified outcomes and rare autopsies.
Objective:
Congenital disorder of glycosylation (CDG) due to a defective phosphatidylinositol glycan anchor biosynthesis class A protein (PIGA) is a severe X-linked developmental and epileptic encephalopathy. Seizures are often treatment refractory, and patients have intellectual disability and global developmental delay. Previous reports have suggested that patients with PIGA-CDG have a high risk of premature mortality. This study aimed to evaluate the observed high mortality and the causes of death in PIGA-CDG patients.
Methods:
We reviewed the literature and collected additional unpublished patients through an international network.
Results:
In total, we reviewed the data of 88 patients of whom 30 patients born alive were deceased, and the overall mortality before the age of 20 years was 30 % (26/88). Age at death ranged from 15 days to 48 years of life. The median age at death was two years and more than half of the patients deceased in early childhood. The PIGA-specific mortality rate/1000 person-years was 44.9/1000 person-years (95 %, CI 31.4-64.3). There were no cases of definite or probable sudden unexpected death in epilepsy (SUDEP) and half of the patients died due to respiratory failure (15/30, 50 %) or possible SUDEP (3/30, 10 %). Three patients (10 %) died from severe cardiomyopathy, liver failure and gastrointestinal bleeding, respectively. The cause of death was unclassified in nine patients (30 %). Autopsies were rarely performed and the true cause of death remains unknown for the majority of patients.
Significance:
Our data indicate an increased risk of premature death in patients with PIGA-CDG when compared to most monogenic developmental and epileptic encephalopathies.
