Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations
Annalisa Vetro1, Tiziana Pisano1, Silvia Chiaro1
1Pediatric Neurology (A.V., T.P., S.C., E. Parrini, D.M., S.V., R.G.), Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence; Metabolic and Muscular Unit (E. Procopio), Meyer Children's Hospital, University of Florence; Department of Medical and Surgical Science (A.G.), University of Modena and Reggio Emilia; Pediatric Immunology (G.M., C.A.), Department of Health Sciences, Meyer Children's Hospital, University of Florence; and IRCCS Stella Maris (R.G.), Pisa, Italy.
Insights
Mutations in the PIGP gene cause a severe early-onset epileptic encephalopathy in children. Reduced expression of CD16 on granulocytes can help diagnose these inherited glycosylphosphatidylinositol deficiencies.
Area of Science:
- Neurogenetics
- Molecular Biology
- Biochemistry
Background:
- Glycosylphosphatidylinositol (GPI) anchor biosynthesis is crucial for cell surface protein localization.
- Defects in GPI anchor biosynthesis can lead to various genetic disorders, including neurodevelopmental abnormalities.
- The phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) gene's role in severe encephalopathies was previously unclear.
Purpose of the Study:
- To investigate the clinical, biochemical, and molecular genetic basis of a severe early-onset epileptic-dyskinetic encephalopathy in an inbred family.
- To identify the genetic cause in 4 children presenting with a severe neurodevelopmental disorder and burst suppression EEG.
- To explore the functional consequences of identified mutations on GPI-anchored protein expression.
Main Methods:
- Clinical evaluation, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) were performed.
- Whole-exome sequencing (WES) was utilized to identify genetic variants.
- Flow cytometry was used to measure the expression of GPI-anchored proteins (GPI-APs) on granulocytes.
Main Results:
- Four affected children presented with severe hypotonia, early dyskinesia, quadriplegia, infantile spasms, and seizures with a burst suppression EEG.
- Homozygous c.384del variant in the PIGP gene was identified in all affected children, predicted to cause a non-functional protein.
- Reduced expression of the GPI-AP CD16 was observed on the granulocytic membrane of affected individuals.
Conclusions:
- PIGP mutations are a cause of severe epileptic-dyskinetic encephalopathy characterized by profound disability and premature death.
- This condition aligns with early infantile epileptic encephalopathy phenotypes.
- Reduced CD16 expression serves as a potential biomarker for diagnosing inherited GPI deficiencies.
Objective:
To describe clinical, biochemical, and molecular genetic findings in a large inbred family in which 4 children with a severe early-onset epileptic-dyskinetic encephalopathy, with suppression burst EEG, harbored homozygous mutations of phosphatidylinositol glycan anchor biosynthesis, class P (PIGP), a member of the large glycosylphosphatidylinositol (GPI) anchor biosynthesis gene family.
Methods:
We studied clinical features, EEG, brain MRI scans, whole-exome sequencing (WES), and measured the expression of a subset of GPI-anchored proteins (GPI-APs) in circulating granulocytes using flow cytometry.
Results:
The 4 affected children exhibited a severe neurodevelopmental disorder featuring severe hypotonia with early dyskinesia progressing to quadriplegia, associated with infantile spasms, focal, tonic, and tonic-clonic seizures and a burst suppression EEG pattern. Two of the children died prematurely between age 2 and 12 years; the remaining 2 children are aged 2 years 7 months and 7 years 4 months. The homozygous c.384del variant of PIGP, present in the 4 patients, introduces a frame shift 6 codons before the expected stop signal and is predicted to result in the synthesis of a protein longer than the wild type, with impaired functionality. We demonstrated a reduced expression of the GPI-AP CD16 in the granulocytic membrane in affected individuals.
Conclusions:
PIGP mutations are consistently associated with an epileptic-dyskinetic encephalopathy with the features of early infantile epileptic encephalopathy with profound disability and premature death. CD16 is a valuable marker to support a genetic diagnosis of inherited GPI deficiencies.
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