To report a novel change in the HSPD1 gene associated with hereditary spastic paraplegia (HSP) with leukoencephalopathy and cognitive decline.

We describe a Finnish family with three individuals in two generations presenting with features compatible with HSP.

In the three affected patients, the progressive spastic paraplegia was complicated by leukoencephalopathy and cognitive dysfunction. The onset of  paraplegia symptoms was between 12 to 19 years. All three patients developed some degree of progressive cognitive dysfunction, with clinical onset between 24 to 45 years. Brain MR imaging of patients I-1 (at age 46), II-1 (at ages 20 and 30), and II-2 (at ages 16, 18, and 24) revealed symmetric T2 subcortical and periventricular white matter hyperintesities in all three patients. DNA samples were available from patients II-1 and II-2. Testing for mutations in the SPG4 gene and for spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7, 10, 12, and 17, and for mitochondrial DNA point mutations 3243A>G, 8344A>G, and 8993T>C/G were negative. In whole exome analysis, both patients harboured a heterozygous change c.130G>A (p.Val44Ile) in the HSPD1 gene. No other pathogenic changes were detected. The detected change was not a reported polymorphism, and in silico prediction analyses suggested pathogenicity.

We suggest that the c.130G>A (p.Val44Ile) change in HSPD1 is pathogenic and results in complicated HSP with leukoencephalopathy and progressive cognitive dysfunction in addition to spastic paraplegia. The phenotype may be interpreted as intermediate between the previously described pure HSP and the severe, early onset neurodegenerative phenotype associated with HSPD1 mutations.