Neurodegeneration and Early Infantile Epilepsy Associated with ITPA Variants: A Case Series and Review of Literature

Abstract

Background Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency associated with mutations in the ITPA gene is a recently characterized purine pathway defect that presents with early infantile epileptic encephalopathy and lethal course. This disorder is rare, and only 12 cases are reported worldwide.

Methods We report two additional cases of ITPA-associated neurodegeneration and two pathogenic compound heterozygous variants. We also reviewed the previously published cases of ITPA-associated encephalopathy.

Results Both cases presented with progressive infantile-onset encephalopathy, severe developmental delay, microcephaly, facial dysmorphism, and epilepsy. Together with the presented two cases, 14 cases were available for analysis. The mean age of presentation was 16.7 ± 12.4 months (range 3–48 m). The most common clinical features at presentation were developmental delay, seizures, microcephaly, and hypotonia, seen in all 14 (100%) patients. The mean age of seizure onset was 4.75 months (range 2–14 m). Cardiomyopathy was noted in 42% of patients where it was explicitly evaluated (n = 5/12). Consanguinity was reported in 77% of the cases. The cardinal neuroradiological features are T2-signal abnormalities and diffusion restriction in the long tracts, especially the posterior limb of the internal capsule and the optic radiation. The majority of the patients died before 4 years of age (85.7%).

Conclusion ITPA-related encephalopathy presents with infantile-onset neurodegeneration, progressive microcephaly, and epilepsy. Progressive brain atrophy and diffusion restriction in the white matter tracts are important radiological clues.

Keywords

purine - inborn errors of purine metabolism - ITPA gene - infantile encephalopathy - brain atrophy

Publication History

Received: 17 September 2021

Accepted: 19 December 2021

Article published online:
28 January 2022

• References

• 1 Jinnah HA, Sabina RL, Van Den Berghe G. Metabolic disorders of purine metabolism affecting the nervous system. Handb Clin Neurol 2013; 113: 1827-1836
• 2 Banerjee A, Bhatia V, Didwal G, Singh AK, Saini AG. ADSL deficiency—the lesser-known metabolic epilepsy in infancy. Indian J Pediatr 2021; 88 (03) 263-265
• 3 Camici M, Micheli V, Ipata PL, Tozzi MG. Pediatric neurological syndromes and inborn errors of purine metabolism. Neurochem Int 2010; 56 (03) 367-378
• 4 Kevelam SH, Bierau J, Salvarinova R. et al. Recessive ITPA mutations cause an early infantile encephalopathy. Ann Neurol 2015; 78 (04) 649-658
• 5 Sakamoto M, Kouhei D, Haniffa M. et al. A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction. J Hum Genet 2020; 65 (09) 751-757
• 6 Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997; 39 (04) 214-223
• 7 Eliasson AC, Krumlinde-Sundholm L, Rösblad B. et al. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. Dev Med Child Neurol 2006; 48 (07) 549-554
• 8 Alpern GD. Developmental Profile 3. Los Angeles: Western Psychological Services; 2007
• 9 Kaur P, Neethukrishna K, Kumble A, Girisha KM, Shukla A. Identification of a novel homozygous variant confirms ITPA as a developmental and epileptic encephalopathy gene. Am J Med Genet A 2019; 179 (05) 857-861
• 10 Handley MT, Reddy K, Wills J. et al. ITPase deficiency causes a Martsolf-like syndrome with a lethal infantile dilated cardiomyopathy. PLoS Genet 2019; 15 (03) e1007605
• 11 Behmanesh M, Sakumi K, Abolhassani N. et al. ITPase-deficient mice show growth retardation and die before weaning. Cell Death Differ 2009; 16 (10) 1315-1322
• 12 Burgis NE. A disease spectrum for ITPA variation: advances in biochemical and clinical research. J Biomed Sci 2016; 23 (01) 73
• 13 Knaap MSVD, Valk J. Wallerian Degeneration and Myelin Loss Secondary to Neuronal and Axonal Degeneration. In: Magnetic Resonance of Myelination and Myelin Disorders. Berlin, Heidelberg: Springer Berlin Heidelberg; 2005: 832-838 Accessed January 24, 2022 at: https://doi.org/10.1007/3-540-27660-2_105