Expanding clinical spectrum of PAICS deficiency: Comprehensive analysis of two sibling cases

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F25%3A10488267" target="_blank" >RIV/00216208:11110/25:10488267 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11310/25:10488267 RIV/00064165:_____/25:10488267

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=c0_QiTFB.o" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=c0_QiTFB.o</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41431-024-01752-2" target="_blank" >10.1038/s41431-024-01752-2</a>

Result language

angličtina

Original language name

Expanding clinical spectrum of PAICS deficiency: Comprehensive analysis of two sibling cases

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30101 - Human genetics

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

European Journal of Human Genetics

ISSN

1018-4813

e-ISSN

1476-5438

Volume of the periodical

33

Issue of the periodical within the volume

7

Country of publishing house

GB - UNITED KINGDOM

Number of pages

8

Pages from-to

870-877

UT code for WoS article

001365198300001

EID of the result in the Scopus database

2-s2.0-85210497017