by Internet Medical Society


Families affected by a  combination of frontotemporal dementia and the amyotrophic form of motor neuron  disease (MND) have helped scientists to discover a genetic mutation on  chromosome 9 that may account for around 12% of familial frontotemporal  dementia, and as much as 22% of familial MND

The discovery was made  independently by two international groups of researchers and reported inthe  leading international journal Neuron on September 21.


 One study, led by Dr Rosa  Rademakers of the Mayo Clinic, Jacksonville involved  researchers from
University of California, San Francisco  and Los Angeles, and University of British    Columbia.
The discovery emerged from the  identification and analysis of a large kindred stricken by both frontotemporal  dementia and MND. 

 The other study, led by Dr Bryan  Traynor, of the National Institutes of Health, USA, involved a consortium of  researchers from centres across Europe, USA and Canada: UK (Cardiff, Gwent,  London, Manchester), Netherlands (Amsterdam, Rotterdam), Finland (Helsinki,  Kuopio, Oulu), Italy (Cagliari, Rome, Turin), Germany (Wurzburg, USA (Bethesda,  Baltimore, Washington, Miami, Seattle, Los Angeles) and Canada (Toronto). The  findings were based on a study of a large group of Finnish patients with  familial MND, and a family from Gwent, South Wales who had lost many relatives  to early onset MND and frontotemporal dementia.

 Scientists had been searching  chromosome 9 for some years, but until now had not been able to
pinpoint the  gene that causes MND and frontotemporal dementia. The new discovery identifies  the critical gene change as an expanded sequence of 6 DNA (hexanucleotide)  repeats in a gene called C9ORF72. The  genetic change affects a region outside of the normal protein coding portion of  the gene (affecting non-coding RNA).Unaffected people can carry up to 30 DNA  repeats in the gene whereas affected patients with MND or frontotemporal  dementia may carry hundreds of repeats.
It is currently unclear why some people  with the mutation develop frontotemporal dementia, whereas others develop MND  or a combination of both, even within the same family.

 The role of this DNA expansion is  currently unknown, but it probably disrupts multiple mechanisms in motor nerve  cells (motor neurons) and other nerve cells in the brain, leading to their  premature
            failure and cell death.

 The C9ORF72 gene is the most common genetic cause of both frontotemporal  dementia and MND identified to date. The new discovery will lead to new blood  tests for families with a history of this condition, and, potentially, to new  avenues for treating the incurable disease.

 The challenge now will to be to understand  the role of the protein C9orf72 within neurones of the brain and spinal cord,  and to understand how the new mutation causes this function to change. It is  not clear whether the mutation induces a toxic effect in nerve cells or whether  the effects of the mutation operate through a loss of normal cells activity  through a failure to produce or deliver sufficient protein to meet the cell’s  requirements.

 The new findings will spur on a  huge scientific effort over the forthcoming year, and the new
            discoveries will be  eagerly awaited, and undoubtedly receive maximal coverage at FTD2012.

DeJesus-Hernandez M, Mackenzie IR, Boeve  BF et al.  Expanded GGGGCC Hexanucleotide  repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.  Neuron 2011, 72(2): 245-256.
            Renton AE, Majounie E, Waite A et al.  A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome  9p21-linked ALS-FTD. Neuron 2011, 72(2): 257-68.

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