ITPA – Developmental and epileptic encephalopathy 35

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe autosomal recessive neurodevelopmental disorder caused by biallelic loss-of-function variants in ITPA, which encodes inosine triphosphate pyrophosphatase, a key purine metabolism “house-cleaning” enzyme (MONDO:0014719). A recent cohort study of 28 newly described and 12 previously reported patients (40 total) delineated the full genotypic and phenotypic spectrum of DEE 35 (PMID:34989426).

Inheritance is strictly autosomal recessive, with no reported heterozygous phenotypes. To date, 40 affected probands have been identified carrying 18 distinct pathogenic ITPA variants, including 6 predicted loss-of-function alleles (nonsense, frameshift, exon deletions) and 12 missense or splice-site changes (PMID:34989426). Parental testing in multiple families confirmed trans configuration without phenotypic effects in carriers. Segregation data are limited beyond proband identification.

The variant spectrum includes canonical splice-site disruptions (e.g., c.264-2A>G, c.124+2T>C), missense substitutions such as c.545T>C (p.Leu182Pro), and multi-exon deletions. No recurrent or founder alleles have emerged. All reported variants are exceedingly rare or private to affected families. Enzyme-disrupting alleles cluster within the active-site and fold-stability regions of ITPA.

Clinically, all individuals exhibit profound developmental delay, congenital microcephaly (HP:0000252), refractory early-onset epilepsy, and neurodevelopmental regression. Brain MRI reveals consistent delayed myelination and restricted diffusion in early-myelinating structures. Congenital microcephaly and cardiac involvement predict poorer survival by Kaplan–Meier analysis (PMID:34989426).

Functional studies demonstrate that pathogenic variants disrupt ITPase activity via distinct mechanisms. The R178C mutant abolishes active-site hydrogen bonding and reduces catalytic efficiency to near zero, confirming position 178 as essential (PMID:37506994). Earlier work on the common P32T polymorphism revealed impaired subunit stability and ∼10–20% residual activity in erythrocytes (PMID:12384777). These findings concord with the loss-of-function model.

In summary, biallelic ITPA variants meet strong ClinGen criteria for pathogenicity in DEE 35, with robust genetic and experimental concordance. Molecular diagnosis enables definitive counseling, prognostication, and potential future enzyme-replacement or gene-targeted therapies. Key take-home: Autosomal recessive ITPA deficiency causes DEE 35, supporting routine ITPA sequencing in unexplained congenital microcephaly with refractory epilepsy.

References

• • • Developmental and epileptic encephalopathy 35 is a severe neurological condition caused by biallelic ITPA variants. PMID:34989426
• Archives of biochemistry and biophysics • 2023 • Arginine-178 is an essential residue for ITPA function. PMID:37506994
• Human genetics • 2002 • Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. PMID:12384777

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