Abstract
Spastic paraplegia type 5 (SPG5/HSP-CYP7B1) is an autosomal recessive hereditary spastic paraplegia (HSP) caused by biallelic variants in the CYP7B1 gene, resulting in dysfunction of the enzyme oxysterol-7-α-hydroxylase. The consequent accumulation of hydroxycholesterols in plasma seems to be pathognomonic for SPG5, and represent a possible target for treatment. We aimed to characterize Norwegian patients with SPG5, including clinical examinations, genetic analyses, measurements of hydroxycholesterols, electrophysiological investigations and brain imaging. Five unrelated patients carried presumed disease-causing variants in CYP7B1, three of the variants were novel. Four patients presented with pure HSP, one with complex HSP. The three tested patients all had markedly increased levels of 25- and 27-hydroxycholesterol in plasma. Our results suggest that the clinical examination is still the best approach to classify disease severity in patients with SPG5. Plasma hydroxycholesterols were elevated, thus presenting as potentially valuable diagnostic biomarkers, in particular in patients where genetic analyses are inconclusive.
Highlights
Spastic paraplegia type 5 (SPG5/HSP-Cytochrome P450 (CYP7B1)) is an autosomal recessive form of hereditary spastic paraplegia (HSP)
Five presumed unrelated patients with SPG5 were identified, repre senting 2.1% of 238 probands with HSP included in the Norwegian research cohort
A summary of the clinical characteristics of the patients is presented in Table 1 and more details are reported in the supplementary material
Summary
Spastic paraplegia type 5 (SPG5/HSP-CYP7B1) is an autosomal recessive form of hereditary spastic paraplegia (HSP). HSP is charac terized by progressive gait problems due to spasticity and weakness in the lower limbs, with or without additional neurological features, and so far ~80 genetic forms have been described. There are no curative or disease-modifying treatment available for HSP and reliable biochemical biomarkers are largely lacking [1]. For SPG5 there is increasing evidence of hydroxycholesterols as reliable biomarkers [2,3,4], there has been performed one preclinical trial investigating treatment targeting the molecular mechanism [5]. SPG5 most often present as a pure form of HSP comprising progressive spasticity and muscle weakness in the lower extremities, which can be accompanied by bladder dysfunction and posterior column sen sory impairment. The clinical features can be heterogeneous, and additional symptoms such as ataxia may occur [2]
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