CYP7B1 – Hereditary Spastic Paraplegia Type 5A

Hereditary Spastic Paraplegia Type 5A (SPG5A) is a rare autosomal recessive neurodegenerative disorder marked by progressive spastic paraparesis and corticospinal tract degeneration. SPG5A patients typically present with lower limb spasticity, proprioceptive impairment, white matter hyperintensities on brain MRI, and variable age at onset in childhood or adulthood. CYP7B1 encodes oxysterol 7α-hydroxylase, a key enzyme in neurosteroid and bile acid metabolism. Biallelic loss-of-function or missense variants in CYP7B1 disrupt oxysterol clearance, leading to neuroaxonal injury.

In a cohort of nineteen SPG5A patients from seventeen Taiwanese families, targeted resequencing of CYP7B1 identified six distinct pathogenic variants, including three novel alleles (p.Asn131IlefsTer4, p.Ala295Val, p.Leu439Arg) (PMID:32202070). These patients exhibited classic spastic paraparesis with proprioceptive deficits and spinal cord atrophy on MRI. Segregation analysis confirmed autosomal recessive inheritance in all pedigrees.

The recurrent nonsense variant c.334C>T (p.Arg112Ter) was detected in fourteen of sixteen allelic backgrounds, consistent with a founder effect in Han Chinese (PMID:32202070). Other variant classes include frameshift, missense, and in-frame duplications, collectively supporting a loss-of-function mechanism. No alternative phenotypes have been attributed to CYP7B1 variants in this context.

Biochemical assays demonstrate that CYP7B1 deficiency impairs conversion of 25-hydroxycholesterol to bile acid intermediates, resulting in accumulation of neurotoxic oxysterols. Oxysterol profiling in Cyp7b1–/– mice revealed elevated 25-HC and 26-HC in brain and plasma, mirroring patient biochemistry (PMID:22111624; PMID:31013940). These findings corroborate haploinsufficiency of CYP7B1 as the pathogenic mechanism.

Mouse knockout models exhibit altered sterol homeostasis without overt motor deficits, suggesting species differences but validating the metabolic pathway disruption seen in SPG5A. The concordance between human genetic data and murine oxysterol accumulation strengthens the causal link.

Collectively, the evidence fulfills ClinGen criteria for a Definitive gene–disease association: multiple unrelated probands (n = 19), multi-family segregation, founder variant, and concordant functional studies. SPG5A genetic testing is clinically actionable for diagnosis, family screening, and potential future enzyme-based therapies.

References

• Annals of Clinical and Translational Neurology • 2020 • Clinical characteristics of Taiwanese patients with Hereditary spastic paraplegia type 5. PMID:32202070
• The FEBS Journal • 2012 • Cytochrome P450s in the synthesis of cholesterol and bile acids--from mouse models to human diseases. PMID:22111624
• Biomolecules • 2019 • Mining for Oxysterols in Cyp7b1-/- Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5. PMID:31013940

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