Clinical and genetic characteristics of CYP2U1-associated hereditary spastic paraplegia in three children from China

Abstract

Abstract Background and objective Hereditary spastic paraplegia (HSP) type 56 (SPG56), caused by mutations in CYP2U1, is a rare type of HSP with an autosomal recessive (AR) mode of inheritance. The onset of SPG56 usually occurs early and displays complex symptoms. To date, less than 27 variants have been reported from 25 families across different countries and regions worldwide. This study is the first to describe the clinical manifestations, imaging characteristics, and mutated CYP2U1 loci in 3 children from China. Methods CYP2U1 mutations were identified by Trio-WES of the samples obtained from the children clinically diagnosed with HSP. Subsequently, we summarized the clinical presentation, imaging features, and family history and further compared with previously reported cases. Results Five novel mutations, namely, c.1032T>A, c.179C>G, c.570(exon2)delG, c.470(exon1)delC, and c.1526A>C(E5), were identified. Two patients carried compound heterozygous mutations derived from their parents with heterozygous mutations. The third child harbored a homozygous mutation, inherited from his parents. Disease onset was infantile in all the patients. Two patients developed motor regression and one displayed an abnormal gait. The patients exhibited varying degrees of delay in cognitive/language development, active tendon reflexes, positive ankle clonus, and increased muscle tone. Cranial and spinal cord magnetic resonance imaging (MRI) revealed abnormalities in all the patients. Conclusions This study identified five novel variants in the three patients, and expanded the clinical and molecular spectrum of SPG56. The identified mutant loci were relatively conserved across several species, and the findings provide a basis for subsequent functional validation.