Genetic, clinical and neuroimaging profiles of sporadic and autosomal recessive hereditary spastic paraplegia cases in Chinese

Spastic paraplegias (SPGs) are a group of clinically and genetically heterogeneous neurodegenerative diseases. Mutations in 78 genes have been identified in autosomal dominant hereditary SPG (AD-HSP) and autosomal recessive hereditary SPG (AR-HSP). Compared to familial HSP, much less is known about the genetic and clinical profiles of sporadic SPGs. In this study, we have screened mutations for 18 sporadic SPGs or AR-HSP patients (mainly Northern Chinese) by whole-exome sequencing. We identified 12 mutations in five genes in 9 (50%) patients, including 9 novel ones: SPG5A/CYP7B1 (c.851C > A; c.122 + 2 T > G), SPG11/KIAA1840 (c.1735 + 3_ 1735 + 6del AAGT); SPG7/SPG7 (c.1454G > A; c.1892_ 1906dup GAGGACGGGCCTCGG); SPG39/PNPLA6 (c.1591G > A; c. 2990C > T); SPG15/ ZFYVE26 (c. 4804C > T; c. 4278 G > A). Among all the mutations, 7 were detected in the SPG5A and SPG11. Age at onset was significantly younger in cases with mutations (15.45 ± 6.78 years) than those without mutations (25.56 ± 10.90 years) (P = 0.03). Except for two cases with the SPG5A mutations, all cases presented with complicated SPGs. Three cases carrying mutations in SPG7, SPG15, SPG39 showed symptoms and signs of ataxia. One case carrying the homozygous c.259 + 2 T > C mutation in CYP7B1 showed serum parameters indicating liver impairment. Magnetic resonance imaging showed significantly thinned corpus callosum in cases with SPG11 and SPG15, but not in those with SPG5A, SPG7 or SPG39. In contrast, cerebellar atrophy was prominent in the SPG7 and SPG39 cases. These findings expand the spectrum of genetic, clinical and imaging features of sporadic SPG and AR-HSP, and have important implications in genetic counselling, molecular mechanisms and precise diagnosis of the disease.