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

Abstract

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.

Linkage of AD HSP and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates variable expression and low or delayed penetrance

“…Nine categories of intellectual functioning were assessed including verbal IQ, performance IQ, verbal memory, visual memory, information processing speed, fine motor speed, verbal fluency, problemsolving ability and perceptual judgement; detailed descriptions of these tests are provided elsewhere. 21 Failure on more than half of the categories tested was used as a cutoff to identify patients with evidence of cognitive impairment.…”

Dementia in SPG4 hereditary spastic paraplegia

“…3 Although considered a pure form of HSP, some families with SPG4-linked HSP have been reported to have cognitive impairment. [4][5][6][7][8][9][10][11][12] Some have suggested that the cognitive impairment, when it occurs, is mild and subclinical 13,14 ; not all accept the hypothesis that progressive cognitive impairment is an intrinsic feature of SPG-4 linked HSP 9 and further work has been suggested. 15 A neuropathologic study of a patient who developed a late-onset dementing illness, from a family with SPG4-linked HSP due to a missense mutation in exon 10 of the spastin gene, is of relevance.…”

“…15 A neuropathologic study of a patient who developed a late-onset dementing illness, from a family with SPG4-linked HSP due to a missense mutation in exon 10 of the spastin gene, is of relevance. 9 In this article, we describe the neuropathologic features of the dementia of the index case of a large family with SPG4-linked HSP, 4 recently found to have a deletion of exon 17 of the SPG4 gene 16 and some family members were also found to have a deletion in the NIPAI gene (SPG6 locus). We also present longitudinal cognitive assessments in the older patients from the same family in order to characterize the dementia in relation to the deletions in SPG4 and SPG6 genes.…”

“…This family had been identified during an epidemiologic study of HSP in Ireland approximately 12 years ago and had been followed at regular intervals. 4 For the purposes of this study only family members older than 40 years in 2007 were assessed clinically, cognitively, and genetically. All consenting members gave a detailed neurologic history, gave a blood sample for DNA extraction, and were examined by one of 3 neurologists (asymptomatic family members were examined by 2 neurologists).…”

Genetic testing of hereditary spastic paraplegia

“…Urgens vizelési inger szintén a kezdeti, fi gyelemfelkeltő tünetek közé tartozik, ezt egy betegünkben észleltük, akinek tünetei fi atal felnőttkorban kezdődtek és a képhez encopresis és erektilis diszfunkció is társult. Egyes szerzők véleménye szerint [8,20,21,22] különböző mértékű kognitív hanyatlás a HSP4 tünete lehet, ez a tünet beteganyagunkban nem volt megfi gyelhető.…”