Expanding clinical spectrum of PAICS deficiency: Comprehensive analysis of two sibling cases
Journal
European journal of human genetics : EJHG
Journal Volume
33
Journal Issue
7
Start Page
870
End Page
877
ISSN
1018-4813
Date Issued
2025-07
Author(s)
Skopova, Vaclava
Baresova, Veronika
Souckova, Olga
Hnizda, Ales
Kmoch, Stanislav
Zikanova, Marie
Abstract
De novo synthesis of purines (DNPS) is a biochemical pathway that provides the purine bases for synthesis of essential biomolecules such as nucleic acids, energy transfer molecules, signaling molecules and various cofactors. Inborn errors of DNPS enzymes present with a wide spectrum of neurodevelopmental and neuromuscular abnormalities and accumulation of characteristic metabolic intermediates of the DNPS in body fluids and tissues. In this study, we present the second case of PAICS deficiency due to bi-allelic variants of PAICS gene encoding for a missense p.Ser179Pro and truncated p.Arg403Ter forms of the PAICS proteins. Two affected individuals were born at term after an uncomplicated pregnancy and delivery and presented later in life with progressive cerebral atrophy, epileptic encephalopathy, psychomotor retardation, and retinopathy. Plasma and urinary concentrations of dephosphorylated substrates of PAICS, AIr and CAIr were elevated, though they remained undetectable in skin fibroblasts. Both variants affect structural domains in SAICARs catalytic site and the oligomerization interface. In silico modeling predicted negative effects on PAICS oligomerization, enzyme stability and enzymatic activity. Consistent with these findings, affected skin fibroblasts were devoid of PAICS protein and enzyme activity. This was accompanied by alterations in contents of other DNPS proteins, which had co-localized in granular structures that are characteristic of purinosome formation. Our observation expands the clinical spectrum of PAICS deficiency from recurrent abortions and fatal neonatal form to later onset neurodevelopmental disorders. The rarity of this condition may be based on poor clinical recognition and limited access to specialized laboratory tests diagnostic for PAICS deficiency.
SDGs
Type
journal article