2. Academic Validation
  3. Expanding clinical spectrum of PAICS deficiency: Comprehensive analysis of two sibling cases

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

  • Eur J Hum Genet. 2024 Nov 27. doi: 10.1038/s41431-024-01752-2.
Wen-Chin Weng # 1 2,  Vaclava Skopova # 3,  Veronika Baresova 3,  Yao-Lin Liu 4,  Hsueh-Wen Hsueh 5,  Yin-Hsiu Chien 1 2 6,  Wuh-Liang Hwu 1 2 6,  Olga Souckova 3 7,  Ales Hnizda 3,  Stanislav Kmoch 3,  Ni-Chung Lee 8 9 10,  Marie Zikanova 11
Affiliations

Affiliations

  • 1 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
  • 2 Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan.
  • 3 Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
  • 4 Department of Ophthalmology, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
  • 5 Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
  • 6 Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
  • 7 OMICS Mass Spectrometry Core Facility, Biology Departments, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic.
  • 8 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan. ncleentu@ntu.edu.tw.
  • 9 Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan. ncleentu@ntu.edu.tw.
  • 10 Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan. ncleentu@ntu.edu.tw.
  • 11 Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. marie.zikanova@lf1.cuni.cz.
  • # Contributed equally.
PMID: 39604553 DOI: 10.1038/s41431-024-01752-2
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.

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