ITPA – Inosine Triphosphatase Deficiency

Inosine triphosphate pyrophosphohydrolase (ITPA) deficiency is an autosomal recessive metabolic disorder characterized by accumulation of inosine triphosphate (ITP) in erythrocytes and early infantile neurodegeneration. Biallelic ITPA variants impair the sanitization of nucleotide pools, leading to toxic nucleotide accumulation and multisystem involvement.

Genetic evidence supporting the ITPA–inosine triphosphatase deficiency association includes 14 unrelated probands presenting with infantile-onset encephalopathy, developmental delay, seizures, microcephaly, hypotonia, cardiomyopathy, and facial dysmorphism ([PMID:35098521]). Consanguinity was reported in 77% of affected families ([PMID:35098521]), consistent with autosomal recessive inheritance and homozygous or compound heterozygous variant segregation.

The variant spectrum is dominated by two recurrent alleles: c.94C>A (p.Pro32Thr) and c.124+21A>C. Homozygotes for c.94C>A have undetectable erythrocyte ITPase activity, whereas heterozygotes retain ~22.5% of mean control activity; c.124+21A>C homozygotes retain ~60% activity ([PMID:12384777]). Compound heterozygotes for these two variants show ~10% residual activity, correlating with severe clinical phenotypes.

Functional studies demonstrate that c.94C>A disrupts exonic splicing regulatory elements, leading to misspliced transcripts and reduced enzyme stability, with P32T mutant melting temperature reduced by 5 °C and diminished protein levels in patient fibroblasts ([PMID:19631656]). Enzyme kinetics and complementation assays in bacterial and yeast models confirm loss-of-function, while mRNA splicing assays implicate the IVS2+21A>C allele in exon 3 missplicing ([PMID:17113761]).

Mechanistically, ITPA deficiency operates via loss-of-function/haploinsufficiency: destabilized transcripts and proteins fail to hydrolyze noncanonical nucleotides, resulting in neurotoxicity and cell death. Concordance across clinical, biochemical, and model organism data supports a strong gene–disease relationship.

Key Take-home: Biallelic ITPA variants reliably predict inosine triphosphatase deficiency, enabling molecular diagnosis, carrier screening, and informing management of drug-related toxicity.

References

• Human genetics • 2002 • Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency PMID:12384777
• Neuropediatrics • 2022 • Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants: A Case Series and Review of Literature PMID:35098521
• Journal of molecular biology • 2009 • Functional study of the P32T ITPA variant associated with drug sensitivity in humans PMID:19631656
• Biochimica et biophysica acta • 2007 • The ITPA c.94C>A and g.IVS2+21A>C sequence variants contribute to missplicing of the ITPA gene PMID:17113761

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