P1‐288: Is the Arg5His MAPT variant pathogenic for dementia and motor neuron disease?

Résumé fourni par la source

Most pathogenic mutations in MAPT occur in and around exon 10. Hayashi et al (2002) reported a single case of FTD/Parkinsonism with the exon 1 Arg5His variant and Poorkaj et al (2002) reported a single case of PSP having the R5L variant. The pathogenicity of mutations in exon 1 remains unclear. An unusual family was identified during a screening program searching for mutations in PS1, PS2, APP, GRN and MAPT in families with late onset dementia. We found a two generation family in which three persons with dementia including one with ALS have the Arg5His variant in MAPT. Two persons with the Arg5His variant had dementia and came to autopsy. One with dementia (onset 86 years) had mild neuritic plaques and Braak stage 3/6 that did not meet criteria for AD, but did meet criteria for diffuse Lewy body disease. The other case had dementia (onset 72 years) and classic ALS with motor neuron degeneration including TDP-43 inclusions but also did not meet criteria for AD nor DLB. One 89 year old with MCI and an 86 year old man with dementia both have the Arg5His variant. However, the Arg5His variant did not segregate with disease in this family because two elderly persons with dementia do not have the variant and one normal woman at age 78 does have the variant. Interestingly the case of Hayashi et al was Japanese and our family is Japanese-American. None of 53 (106 chromosomes) Japanese controls in our study nor 54 (108 chromosomes) controls in the Hayashi study have the Arg5His variant. Thus this variant is not a common polymorphism in the Japanese population. In conclusion, there is evidence for and against the pathogenicity of the Arg5His variant in MAPT and additional families and studies are required to resolve this question. Of interest, the exon 10+14 mutation in MAPT is sometimes associated with motor neuron disease. The Arg5His variant may represent a risk factor for non-AD dementia and/or motor neuron disease with decreased penetrance.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.