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Dementia in SPG4 hereditary spastic paraplegia

Clinical, genetic, and neuropathologic evidence

From the Department of Neurology (S.M., G.G., P.McM., K.K., M.H.), St. Vincent’s University Hospital, University College Dublin, Ireland; Institut für Klinische Chemie und Laboratoriumsdiagnostik (C.B.), Universitätsklinikum Jena, Germany; School of Medicine and Medical Science (P.B., M.D.), University College Dublin; and Department of Neuropathology (M.F.), Beaumont Hospital, Dublin, Ireland.

Address correspondence and reprint requests to Professor Michael Hutchinson, Department of Neurology, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland mhutchin{at}iol.ie

Background: Cognitive impairment and dementia has been reported in autosomal dominant hereditary spastic paraparesis (HSP) linked to the SPG4 locus. There has only been one postmortem examination described; not all accept that progressive cognitive decline is a feature of this disorder.

Objective: A family with SPG4-HSP known to have a deletion of exon 17 in the spastin gene (SPG4delEx17) was cognitively assessed over a 7-year period. The index family member died and a postmortem examination was performed.

Methods: Thirteen family members older than 40 years were clinically and cognitively assessed using the Cambridge Cognitive Assessment over a 7-year period. The presence of SPG4delEx17 was assessed; a neuropathologic examination of the brain of the index family member was performed.

Results: Cognitive decline occurred in 6 of the 13 family members and in all 4 older than 60 years. Two genetic deletions were identified: SPG4delEx17 in 12 of the 13 family members and a deletion of SPG6 (SPG6del) in 5. Eight individuals had the SPG4delEx17 deletion only; 4 had evidence of progressive cognitive impairment. Four family members had both SPG4delEx17 and SPG6del; 2 of these had cognitive impairment. One family member with the SPG6del alone had neither HSP nor cognitive impairment. The index case with both deletions died with dementia; the brain showed widespread ubiquitin positivity within the neocortex and white matter.

Conclusion: Cognitive decline and dementia is a feature of SPG4-HSP due to a deletion of exon 17 of the spastin gene.

Abbreviations: ALS = amyotrophic lateral sclerosis; CAMCOG = Cambridge Cognitive Examination; CAMDEX = Cambridge Mental Disorders of Elderly Examination; FTD = frontotemporal dementia; HSP = hereditary spastic paraparesis; MLPA = multiplex ligation-dependent probe amplification; MMSE = Mini-Mental State Examination.

Disclosure: Author disclosures are provided at the end of the article.

Received January 15, 2009. Accepted in final form April 22, 2009.