NT5C2 – Hereditary Spastic Paraplegia 45

Hereditary spastic paraplegia 45 (SPG45) is a rare autosomal recessive neurodegenerative disorder characterized by early-onset motor delay, dysarthric speech, cerebellar ataxia, nystagmus, strabismus, and progressive lower-limb spasticity. Biallelic variants in NT5C2, encoding cytosolic 5′-nucleotidase II, underlie SPG45 and have been reported in multiple consanguineous families, supporting a loss-of-function mechanism.

Genetic evidence comprises seven affected individuals from three unrelated families. Two sisters aged 8 and 4 years harbor a homozygous c.591_594dup (p.Gln199ValfsTer9) frameshift variant (PMID:39119448), two brothers aged 9 and 3 years carry a homozygous splice donor variant c.1159+1G>T leading to exon 14 skipping (PMID:28327087), and three individuals in an Arab family exhibit a homozygous missense variant c.1379T>C (p.Leu460Pro) (PMID:28884889). All variants segregate recessively in consanguineous pedigrees.

Phenotypic features across cases include delayed motor milestones, brisk deep tendon reflexes, truncal hypotonia, thin corpus callosum on MRI, and, in some individuals, cutaneous discoloration. Variant spectrum encompasses protein-truncating alleles (frameshift, splice-site) and a critical missense substitution within the catalytic domain. No recurrent or founder alleles have been described beyond these private biallelic variants.

Functional assays demonstrate that the c.1159+1G>T splice-site mutation abolishes the canonical transcript and yields markedly unstable protein in vitro (PMID:28327087). The c.591_594dup (p.Gln199ValfsTer9) frameshift is predicted to trigger nonsense-mediated decay. These data support haploinsufficiency as the primary pathogenic mechanism in SPG45.

No conflicting reports have emerged; all patients with biallelic NT5C2 variants exhibit a congruent clinical and molecular phenotype.

Collectively, the evidence fulfills strong clinical validity for NT5C2 in SPG45. Genetic testing for biallelic NT5C2 variants is essential for accurate diagnosis, family counseling, and potential future therapeutic targeting. Key Take-home: Autosomal recessive NT5C2 variants cause SPG45 with a consistent spectrum of spastic paraplegia and cerebellar dysfunction.

References

• Molecular syndromology | 2024 | Two Sibling Cases of Spastic Paraplegia-45 with a Novel Pathogenic Variant in NT5C2 Gene: Concomitant RYR1 Gene in One Sibling. PMID:39119448
• BMC medical genetics | 2017 | NT5C2 novel splicing variant expands the phenotypic spectrum of Spastic Paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup. PMID:28327087
• American journal of medical genetics. Part A | 2017 | Novel homozygous missense mutation in NT5C2 underlying hereditary spastic paraplegia SPG45. PMID:28884889

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