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From the Department of Pathology (Drs. Byrne, Fitzgerald, and Parfrey), University College Dublin and St Vincent’s University Hospital; and the Department of Neurology (Drs. Mc Monagle, Webb, and Hutchinson), St Vincent’s University Hospital, Dublin, Ireland.
Address correspondence and reprint requests to Dr. Paula Byrne, Department of Pathology, Biotechnology Centre, University College Dublin, Belfield, Dublin 4, Ireland; e-mail: paula.byrne{at}ucd.ie
OBJECTIVES: To investigate whether cognitive decline is part of the phenotype of SPG4-linked hereditary spastic paraparesis (HSP) and to determine whether cognitive changes are present in haplotype carriers before the onset of paraparesis.
BACKGROUND: The major locus for "pure" autosomal dominant HSP is the SPG4 locus on chromosome 2p. Cognitive impairment linked to this locus has been described in two families.
METHODS: The authors identified 19 families with "pure" autosomal dominant HSP. Five had linkage to the SPG4 locus (maximum lod score for D2S2374: 5.99 at zero recombination in four smaller families and 3.86 at zero recombination in the largest family). Haplotype construction identified a disease haplotype for all families; 41 individuals carried this haplotype (30 affected by HSP, 11 unaffected). All haplotype carriers and 41 matched controls underwent Cambridge Cognitive (CAMCOG) examination. Nonparametric significance tests were used comparing total and subset scores.
RESULTS: Haplotype carriers affected by HSP had lower total CAMCOG scores than control subjects (85.86/107 versus 96.2/107; p < 0.0005). The subsets of orientation, memory, language expression, and comprehension were also significantly lower. Ten individuals had scores 
80/107, indicating mild dementia. Unaffected haplotype carriers had mean total CAMCOG scores lower than control subjects (91.82/107 versus 98.09/107; p = 0.016). In both groups cognitive decline was age-dependent and scores diverged from control subjects from age 40. All SPG4-linked families showed the effect.
CONCLUSION: Mild, age-related cognitive impairment is a feature common to these families. It illustrates variable phenotypic expression at this locus and may be the first manifestation of the disease gene in individuals as yet unaffected by paraparesis.
Key words: Spastic paraparesis—Cognitive impairment—SPG4—Reduced penetrance
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