Clinico‐radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Abstract

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects.Exome sequencing was performed to identify underlying ITPA pathogenic variants.Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Detailed genetic and clinical analysis of a novel de novo variant in HPRT1: Case report of a female patient from Saudi Arabia with Lesch–Nyhan syndrome

“…Genomic DNA (gDNA) was isolated from blood using a Gentra ® Puregene DNA Purification Kit (Gentra Systems, Inc. Minneapolis, MN, US), according to the manufacturer’s instructions. Whole-exome sequencing (WES) was performed on the patient’s DNA, as described previously ( Aldhalaan et al, 2021 ; Scala et al, 2022 ). To confirm the result, gDNA samples were amplified by PCR using HPRT1-specific primers (forward GTG​AAA​AGG​ACC​CCA​CGA​AG and reverse CAA​ATT​ATG​AGG​TGC​TGG​AAG​GA).…”

Inosine triphosphate pyrophosphatase: A guardian of the cellular nucleotide pool and potential mediator of RNA function

“…Identified variants include microdeletions, essential splice site variants, frameshift, nonsense and missense variants (Figure 3). Identified deletions include a homozygous deletion of ITPA Exons 1-5 in one individual likely to produce complete loss-of-function (Scala et al, 2022). Similarly, the essential splice site variants and the frameshift or nonsense variants introducing premature stop codons upstream of the last exon of the gene are likely to completely abrogate gene expression.…”

“…All described individuals with severe ITPase deficiency have epilepsy, and this is frequently refractory to treatment (Scala et al, 2022). Age at seizure-onset ranges from 2 days to 7 months, with median age-at-onset of 4 months.…”

“…Polymorphisms in ITPA leading to partial loss of function have been reported since the late 1960s as causing a mild condition with accumulation of ITP in erythrocytes (Vanderheiden, 1965). More recently, biallelic loss‐of‐function ITPA variants leading to severe or complete loss of ITPase activity have been reported to cause a fatal infantile neurodevelopmental disorder characterized by epilepsy, hypotonia, microcephaly, and often, dilated cardiomyopathy (Alcon‐Grases et al, 2020; Garg et al, 2022; Handley et al, 2019; Kaur et al, 2019; Kevelam et al, 2015; Muthusamy et al, 2021; Sakamoto et al, 2020; Scala et al, 2022; Sharma et al, 2022). These recent studies have added to the ongoing interest in better understanding the cellular roles of ITPase and in elucidating the mechanisms underlying pathogenesis in its absence.…”

Inosine Triphosphate Pyrophosphatase (ITPase): Functions, Mutations, Polymorphisms and Its Impact on Cancer Therapies

“…Missense mutations are responsible for the change in the primary structure of the amino acid. In such cases, it is observed that Arg-178 is replaced with cysteine [11,21]. Moreover, a study also showed that ITPase deficiency may lead to refractory epilepsy, microcephaly, and neurodevelopmental disease [22].…”