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.

Keywords: ITPA; ITPase; congenital microcephaly; developmental and epileptic encephalopathy 35; heart disease; white matter abnormalities.

Figure 1

Genetic, clinical, and neuroradiological aspects of DEE 35. (a) Structure model of human ITPA protein showing the localization of the residues affected by ITPA missense variants in relation to the ITP‐binding cleft and Mg²⁺ binding site. (b) Bar graph illustrating the distribution of core clinical features of DEE 35, from the most to the less common. Blue bars indicate the number of patients in whom a specific feature is present whereas grey bars indicate the number of subjects in whom that feature was ascertained but it was absent. Ocular involvement includes cataract, visual impairment, optic atrophy, and retinal cone dysplasia. Cardiac involvement consists of dilated cardiomyopathy and rhythm disturbances. Movement disorders include tremors, dystonia, choreoathetoid movements, and dyskinesia. Dysmorphic features were observed in absence of a distinctive facial gestalt. (c) Pie charts illustrating the percent distribution of specific neurological and extra‐neurological manifestations of DEE 35. Rhythm disturbances include tachycardia and long QT syndrome. (d) MRI findings. MRI of P3 at age 6 days (A, B, C). T2‐weighted image (A) shows no atrophy and no signal abnormalities. There is no restricted diffusion (B,C) on diffusion‐weighted imaging (DWI, apparent‐diffusion coefficient maps not shown). MRI of P1 at age 6 months (D, E, F) shows no atrophy, but moderately delayed myelination and T2‐hyperintensity of the posterior limb of the internal capsule (PLIC; D). Restricted diffusion is seen in the optic radiation, PLIC (E), and decussation of the superior cerebellar peduncles (F). Mild diffusion restriction is seen in the globus pallidus (E). MRI of P1 at age 2 years and 8 months (G, H, I) shows seriously deficient myelination and severe cerebral atrophy (G). Restricted diffusion is no longer present (H, I). DEE 35, developmental and epileptic encephalopathy 35; ITP, inosine triphosphate; MRI, magnetic resonance imaging.

Figure 2

Outcome predictors in developmental and epileptic encephalopathy 35. Survival curves according to the Kaplan–Meier method to the presence/absence of congenital microcephaly and cardiac involvement. Congenital microcephaly and cardiac involvement are independent clinical prognostic factors of poor outcome (p = .004)