NT5C2 novel splicing variant expands the phenotypic spectrum of Spastic Paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup

BACKGROUND: Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative diseases. Thin Corpus Callosum (TCC) associated HSP is a distinguished subgroup of complex forms. Purines and pyrimidine, the basic DNA and RNA components, are regulating the cell metabolism, having roles in signal transduction, energy preservation and cellular repair. Genetic defects in nucleotide metabolism related genes have been only recently implicated in brain and neurodegenerative diseases’ pathogenesis. CASE PRESENTATION: We present a consanguineous Qatari family with two brothers, 9 and 3 years, who displayed a characteristic phenotype of early onset and markedly-severe spasticity with tiptoe walking, delayed dysarthric speech, persistent truncal hypotonia, and multiple variable-sized areas of brownish skin discoloration appearing at different places on the body. A clinical diagnosis suggestive of complex hereditary spastic paraplegia (HSP) was set after the family had the second affected child. Whole genome sequencing identified a novel homozygous NT5C2 splice site mutation (NM_012229.4/NM_001134373.2: c.1159 + 1G > T) that recessively segregated in family members. Brain MRI revealed dysgenic and thin corpus callosum (TCC) with peri-trigonal white matter cystic changes in both affected boys, whereas a well-developed corpus callosum with normal white matter was shown in their apparently normal brother, who found to be a carrier for the mutant variant. This mutation led to skipping of exon 14 with removal of 58 amino acid residues at the C-terminal half. The aberrantly spliced NT5C2 showed substantial reduction in expression level in the in-vitro study, indicating marked instability of the mutant NT5C2 protein. CONCLUSION: The present report expands the phenotypic spectrum of SPG45 and confirms NT5C2-SPG45 as a member of the rare TCC SPG-subtypes. Homozygous alteration in NT5C2 seems essential to produce central white matter developmental defects. The study highlights the importance of cytosolic II 5’-nucleotidase (NT5C2) in maintaining the normal balance of purines’ pool in the brain, which seems to play a pivotal role in the normal development of central white matter structures. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12881-017-0395-6) contains supplementary material, which is available to authorized users.