Case report and literature review of spastic paraplegia type 5: a patient with two heterozygous CYP7B1 nonsense variants

Background Hereditary spastic paraplegia type 5 (SPG5) is a rare autosomal recessive neurodegenerative disorder associated with biallelic CYP7B1 variants and altered oxysterol metabolism. The relationship between genotype and clinical severity remains uncertain. Case Presentation We describe a 55-year-old woman evaluated at age 55 years for progressive spastic paraplegia. Sequencing identified two heterozygous CYP7B1 nonsense variants, c.1162C>T and c.334C>T, but their allelic phase was not established. An exploratory pooled analysis included 131 patients, of whom 80 had classifiable ambulatory status. In univariable mean bias-reduced cumulative logit regression, the presence of at least one truncating variant was associated with lower odds of worse ambulatory status (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.12–0.78; P = 0.013). The univariable Firth binary sensitivity analysis showed a similar association with wheelchair dependence or no functional ambulation (OR, 0.31; 95% CI, 0.09–0.99; P = 0.048). After adjustment for disease duration, the genotype estimate remained in the same direction but was imprecise (OR, 0.35; 95% CI, 0.12–1.04; P = 0.059), while longer duration was associated with worse ambulatory status (OR per 10 years, 2.22; 95% CI, 1.51–3.26; P < 0.001). Conclusion The clinical findings and two heterozygous CYP7B1 nonsense variants support SPG5 as the leading diagnosis, although their phase and combined functional effect remain unconfirmed. In pooled cross-sectional data, truncating-variant status showed a consistent univariable association with less severe ambulatory impairment, but the adjusted estimate was uncertain. Larger cohorts with standardized outcomes are needed to assess this genotype–phenotype association.