title: Dementia in SPG4 hereditary spastic paraplegia: clinical, genetic, and neuropathologic evidence.
abstract: 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.
  
  
  CONCLUSIONS
  Cognitive decline and dementia is a feature of SPG4-HSP due to a deletion of exon 17 of the spastin gene.
authors: Department of Neurology, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland. mhutchin@iol.ie
authors: S
authors: S
authors: Murphy
authors: G
authors: G
authors: Gorman
authors: C
authors: C
authors: Beetz
authors: P
authors: P
authors: Byrne
authors: M
authors: M
authors: Dytko
authors: P
authors: P
authors: McMonagle
authors: K
authors: K
authors: Kinsella
authors: M
authors: M
authors: Farrell
authors: M
authors: M
authors: Hutchinson
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D004252:DNA Mutational Analysis; D003704:Dementia / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D004185:Disability Evaluation; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D040582:Inheritance Patterns; D008137:Longitudinal Studies; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009483:Neuropsychological Tests; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000150:complications* / Q000235:genetics*; D000074181:Spastin; D025801:Ubiquitin / Q000032:analysis / Q000378:metabolism
chemical_list: D005819:Genetic Markers; D008565:Membrane Proteins; C478824:NIPA1 protein, human; D025801:Ubiquitin; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human