Abstracts

Rationale: Phosphatidylinositol glycan anchor biosynthesis class A (PIGA) is a key enzyme in Glycosylphosphatidylinositol (GPI) anchor biosynthesis. The are critical to normal early central nervous system development. Germline pathogenic variants have been reported in a wide spectrum of clinical syndrome of PIGA, including XLDD (X- linked intellectual developmental disorder, juvenile hemochromatosis, MCAHS2 (multiple congenital anomalies hypotonia- seizures syndrome 2) and early- onset epileptic encephalopathies. The phenotypic consequences of PIGA variants can be classified into types, severe and less severe, which correlated with the degree of PIGA activity reduction caused by the variants.


Methods: Reporting the medical history and the methods and results of genetic testing of a patient with a novel PIGA mutation..

Results: We report on a male 26 year-old patient with a history of developmental delay and epilepsy with absence and focal to bilateral tonic-clonic seizures since the age of 9 months. Autism was diagnosed at the age of 10 years after the start in infancy of stereotypies, perseverations and lacking spoken communication with other persons. Further investigations revealed excessive iron storage disease, and a heterozygous mutation in the HFE gene (C282Y) was found. Cardiopathy required the implantation of a cardioverter defibrillator. In 2019, he suffered from a cardioembolic left hemispheric stroke with subsequent right-sided spastic hemiparesis and focal motor seizures. Since the pharmacoresistant seizures (despite treatment with brivaracetam, cenobamate, clobazam, and perampanel) were extremely sensitive to fever, a comprehensive genetic examination was performed, particularly in order to look after a mutation in the sodium channel 1A or 2A gene.

A de novo novel pathogenic variant c.242G >A in PIGA was identified through exome sequencing in our patient. The single- nucleotide substitution (NC_000023.10:g.15349811C >T(chrX/hg19)) is located in exon 3. The variant was not detected in the healthy parents. We present a male patient with a novel germline PIGA pathogenic variant and his related phenotype, which consist of features belonging to both subtypes. We compare the described pathogenic variant with the variants and clinical aspects in the literature.


Conclusions: In cases of complex epilepsy syndromes with seemingly unrelated additional disorders, it is increasingly justified to perform extensive genetic testing in the hope to detect a unifying diagnosis and pathophysiology. This may become even more important when, based on personalized medicine,specific treatments for such complex syndromes or disorders will become available in the (near?) future.

Funding: none