Autosomal dominant hereditary spastic paraparesis with cognitive loss linked to chromosome 2p

A family initially considered to have 'pure' autosomal dominant hereditary spastic paraparesis (HSP), was found on neuropsychological testing to have evidence of late onset cognitive impairment. This family showed genetic linkage to the SPG4 locus on chromosome 2p previously reported for pure HSP. Of 56 living members, 44 were examined, 30 of whom were > 30 years of age and 12 members were found to be affected with HSP including four asymptomatic cases. One other family member (III-5), aged 62 years, died prior to this study of a 4-year dementing illness. Neuropsychological assessment of 11 affected members and 11 matched, unaffected, family controls showed no significant differences between the two groups. However, the neuropsychological test profile in four of 11 affected members tested (mean age 47.2 years) and one of 11 family controls (mean age 41.5 years) showed global cognitive impairment. The pattern of cognitive dysfunction was the same for all five family members identified and was similar to that found in subcortical dementia. The presence of cognitive impairment appeared to be related to age and not the severity of the paraplegia. Both the severity of the paraplegia and the age of onset (21-60 years) varied considerably in this family.