A novel NT5C2 Variant in a Family with Spastic Paraplegia and Intellectual Disability

Introduction

Hereditary spastic paraplegia (HSP) is a genetic neurodegenerative disorder that can be categorized into two main types, uncomplicated and complicated, based on clinical manifestations. The disease has various inheritance patterns, including autosomal recessive (AR), autosomal dominant (AD), and X-linked forms (Hedera P et al., GeneReviews(R), Seattle (WA); 1993). It is characterized by motor neuron degeneration affecting the corticospinal tract. Complicated HSP is associated with additional symptoms such as seizures, intellectual disability, dementia, extrapyramidal disturbances, peripheral neuropathy, and muscle atrophy (Hedera P et al., GeneReviews(R), Seattle (WA); 1993).

HSP exhibits genetic and clinical heterogeneity and is linked to over 80 loci or genes (Murala S et al., Neurol Sci 2021; 42: 883–894). There are 76 documented spastic gait disease-loci (SPG) ranging from SPG1 to SPG76, with over 50 corresponding genes (Damiani D et al., Int J Mol Sci 2024; 25). Despite the fact that many distinct genes have been discovered, it is now understood that they produce proteins involved in just a small number of cellular functions, such as intracellular trafficking, organelle shaping, myelination, development, metabolism (lipid and nucloside metabolism), recycling/degradation, cytoskeleton dynamics, mitochondrial functions, and signaling pathways (Elsayed LEO et al., Front Mol Biosci 2021; 8: 690899). The 5′ nucleotidase cytosolic II (NT5C2) enzyme plays a crucial role in nucleotide metabolism and maintaining purine pools in the brain and spinal cord (Dieck CL et al., Cancer Cell 2018; 34: 136–147.e136 and Camici M et al., Neurochem Int 2010; 56: 367–378).

It contributes to the dephosphorylation of adenosine monophosphate and inosine monophosphate, leading to the production of adenosine which regulates neuronal transmission and has neuroprotective properties (Camici M et al., Neurochem Int 2010; 56: 367–378 and Straussberg R et al., Am J Med Genet A 2017; 173: 3109–3113).

Loss-of-function (LoF) variants in NT5C2 result in HSP, while somatic gain-of-function (GoF) variants are associated with treatment-resistant leukemia (Dieck CL et al., Cancer Cell 2018; 34: 136–147.e136 and Novarino G et al., Science 2014; 343: 506–511). SPG45 was first identified in 2009 by Dursun et al. due to a homozygous truncating variant in the NT5C2 gene and is associated with AR-HSP with intellectual disability (Dursun U et al., Neurogenetics 2009; 10: 325–331). To date, seven articles have reported 25 patients with NT5C2 LoF variants from 11 different families (Straussberg R et al., Am J Med Genet A 2017; 173: 3109–3113, Novarino G et al., Science 2014; 343: 506–511, Dursun U et al., Neurogenetics 2009; 10: 325–331, Elsaid MF et al., BMC Med Genet 2017; 18: 33, Darvish H et al., NPJ Genom Med 2017; 2, Naseer MI et al., Front Genet 2020; 11: 14, Ipek R et al., Mol Syndromol 2024; 15: 297–302).

In this article, we present the clinical, radiological, and genetic findings of two siblings of the Turkish origin who have SPG45 due to a novel likely pathogenic variant in the NT5C2 gene.

Publication History

Received: 12 March 2025

Accepted after revision: 20 November 2025

Article published online:
09 December 2025