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NEUROLOGY 2005;64:1578-1585
© 2005 American Academy of Neurology

A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease

J. J. Zarranz, MD, PhD, I. Ferrer, MD, PhD, E. Lezcano, MD, PhD, M. I. Forcadas, MD, PhD, B. Eizaguirre, MD, B. Atarés, MD, B. Puig, PhD, J. C. Gómez-Esteban, MD, C. Fernández-Maiztegui, MD, I. Rouco, MD, T. Pérez-Concha, MD, M. Fernández, MD, O. Rodríguez, MD, A. B. Rodríguez-Martínez, BSc, M. Martínez de Pancorbo, PhD, P. Pastor, MD, PhD and J. Pérez-Tur, PhD

From Neurology Service (Drs. Zarranz, Lezcano, Forcadas, Gómez-Esteban, Fernández-Maiztegui, Rouco, and Pérez-Concha), Department of Neurosciences, and Department of Pathology (Drs. Eizaguirre, Fernández, and Rodríguez), Hospital Cruces, University of the Basque Country, Baracaldo (Vizcaya); Institut of Neuropathology (Drs. Ferrer and Puig), Service of Pathology, Hospital Bellvitge, University of Barcelona, Hospitalet de Llobregat, Barcelona; Service of Pathology (Dr. Atarés), Hospital Txagorritxu, Vitoria (Alava); Department of Z. and Cellular Dynamic School of Pharmacy (Drs. Rodríguez-Martínez and Martínez de Pancorbo), University of the Basque Country, Vitoria (Alava); Neurology Service (Dr. Pastor), Hospital Clinic, University of Barcelona; and Unitat de Genètica Molecular (Dr. Pérez-Tur), Institut de Biomedicina de València-CSIC, Valencia, Spain.

Address correspondence and reprint requests to Professor Juan J. Zarranz, Servicio de Neurología, Hospital de Cruces, 48903 Baracaldo (Vizcaya), Spain; e-mail: jjzarranz{at}hcru.osakidetza.net

Background: Frontotemporal dementia with parkinsonism is often linked to chromosome 17 and is related to mutations in the MAPT gene. In some families the genetic basis is still unknown. The authors report two pedigrees with FTDP-17 harboring a novel mutation (K317M) in exon 11 in the MAPT gene.

Methods: The authors identified two apparently unrelated pedigrees with an autosomal dominant neurodegenerative condition. Thirteen patients were examined and eight autopsies were performed.

Results: Mean age at onset was 48 years. Mean disease duration was 6 years. Dysarthria often heralded the disease. All cases had parkinsonism and pyramidalism and half of them had amyotrophy. Behavioral or personality changes were not a prominent feature. Cognitive decline appeared late in the evolution. Neuropathologically, a massive degeneration of the substantia nigra without Lewy bodies was a constant finding. A variable degree of frontotemporal atrophy was found. Corticospinal tract degeneration and anterior horn neuron loss were present in six of seven autopsies in which the spinal cord was examined. An extensive deposition of abnormal tau protein in a mixed pattern (neuronal, glial) was observed. Pick’s bodies were not seen. Biochemical analysis of tau revealed two bands of 64 and 68 kDa.

Conclusion: Genetic analysis revealed the same novel mutation (K317M) in exon 11 of the MAPT gene in both pedigrees. A common haplotype between members of the two pedigrees suggests that they belong to the same family.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the May 10 issue to find the title link for this article.

Supported in part by grants FIS P1020004 and SAF-2001-4681E, the CIEN network project, and GEN2001–4851-C06–01 from the Spanish Ministerio de Educación y Ciencia and GRUPOS03/015 from the Generalitat Valenciana (to J.P.-T.).

Received September 12, 2003. Accepted in final form January 17, 2005.




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