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728 http://neurology.thelancet.com Vol 5 September 2006

New frontotemporal-dementia gene identifi ed

Mutations in PGRN, the gene that encodes the growth factor progranulin, cause up to 20% of cases of familial frontotemporal dementia (FTD), more than twice the number of cases caused by mutations in MAPT, the only other gene known to cause FTD. Both PGRN and MAPT are found in the same 2 Mbp region of chromosome 17; this extraordinary coincidence solves the 10-year-old mystery of what causes tau-negative, chromosome-17 associated FTD.

FTD is the second most common dementing disorder in people under age 65 years, and 35–50% of patients have a family history of the disease. Mutations in the gene encoding microtubule associated protein tau were fi rst shown to be associated with tau-positive FTD in 1998; however, since then investigators

have indentifi ed several families with FTD linked to the same region on chromosome 17 as MAPT that lack the neurofi brillary tangles of hyper-phosphorylated tau characteristic of MAPT disorder. Instead, patients in several aff ected families have ubiquitin-immunoreactive, lentiform inclusions.

With families with tau-negative FTD linked to chromosome 17q21 iden tifi ed in North America, the UK, and Belgium, researchers began to search for mutations in other genes in the MAPT linkage region. After investigating the coding sequences of over 80 of the 165 or so genes in 17q21, a mutation in PGRN was found in a Canadian lineage with ubiquitin-associated FTD. At the tenth International Conference on Alzheimer’s Disease (Madrid, July 16–20), Stuart Pickering-Brown described his excitement at receiving a late-night phonecall from Mike Hutton, a colleague based in the USA, confi rming that they had found the mutation in another gene in the MAPT region. Subsequently, Pickering-Brown and colleagues in the UK, Belgium, Canada, and the USA identifi ed mutations in PGRN in nine families with clinical and pathological features consistent with tau-negative FTD (Nature 2006; published online July 16. DOI:10.1038/nature05016). In each of the families, the mutations lead to loss of function in one allele of PGRN which encodes a growth factor involved in development, wound repair,

and infl ammation. PGRN has also been linked with tumorigenesis and other neurodegenerative disorders, including Alzheimer’s disease.

Researcher Ian Mackenzie (University of British Columbia, Canada) says that a key fi nding of the study is “the genetic basis of FTD in these families and particularly the unique pathogenesis that it suggests: haploinsuffi ciency of a gene encoding a growth factor leading to neurodegeneration through lack of growth support”. Mackenzie suggests that replacement of the missing protein is a potential therapeutic goal.

A total of eight mutations in PGRN were identifi ed in the nine families. “The clinical presentation is quite variable, both between families and even within a single family”, explains Mackenzie. “We do not expect these diff erences to be related to the specifi c mutation since all the mutations we have identifi ed thus far cause haploinsuffi ciency (functional loss of one allele), rather than toxic gain of function. The clinical variation may be due to some other genetic or environmental factor.”

Lars Gustafson (University Hospital, Lund, Sweden) sees the discovery as extremely good news. “FTD is strongly underdiagnosed and mistreated and we need tools to improve clinical diagnosis and develop new ideas on aetiopathogenesis of this genetically and pathologically heterogeneous group of dementias.”

Peter Hayward

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Are men more likely to pass on multiple sclerosis?Men with multiple sclerosis (MS) may be up to 2·2 times more likely than women to pass the disease on to their children, a new report suggests (Neurology 2006; 67: 305–10).

Although environmental factors are almost certainly involved in the development of MS, complex

genetic factors also seem to be at work—eg, some 15% of MS patients have a family member within one generation who also has the disease, although no single gene seems to be responsible. Furthermore, in the general population women are twice as likely as men to have MS, perhaps

revealing that men need a greater or more powerful genetic load of susceptibility genes for the disease to develop—genes they can pass on to their off spring.

“Men appear to be more resistant to MS than women”, explains Orhun Kantarci (Mayo Clinic Colleges of

Other FTD-associated genes lurk elsewhere in the human genome

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Medicine, Rochester, Maine, USA), “so they may need more susceptibility genes or perhaps more powerful allelic versions of them before they become clinically aff ected. However, while such a protection mechanism, would be advantageous to them, it would leave them with a greater chance of passing those genes on and having a child that develops the disease, a phenomenon known as the Carter eff ect.”

Earlier studies have provided confl icting results regarding the Carter eff ect in MS. The strength of this new work lies in the size of the study population: 45 children with medically confi rmed MS, all the off spring of an aff ected father or mother selected from 3598 individuals.

“The families of these children had the same sex distribution for MS as normally seen”, explains Kantarci, “and the sex of the aff ected parent did not distort the sex ratio of the unaff ected children. However, the results showed that men with MS transmitted the disease to their children, independent of the child’s sex, more often than did aff ected women.”

This new information is unlikely, however, to lead to any immediate clinical advances. “Unfortunately we still need to identify the genes involved in MS susceptibility, determine the involvement of possible epigenetic factors, and learn the reasons for male overtransmission—or female undertransmission. Currently there is

no intervention that could prevent it”, explains Kantarci. “This study should not change how we counsel our patients; however, we hope it will facilitate further research in understanding the genetic contributions to MS risk.”

“Families with an aff ected parent are already known to have a 20-fold greater chance of having a child with MS”, remarks Begoña Ezquieta (Gregorio Marañón Hospital, Madrid, Spain), “so this eff ect of the father is already taken into account in the advice counsellors currently give. Additionally, environmental factors appear more important in this disease than any genetic component.”

Adrian Burton

Memory, sense of smell, and alcoholOlfactory defi cits in alcoholics are associated with prefrontal cognitive dysfunction, and research has shown that olfactory impairments are common in those with alcohol dependence. In a new study, Claudia Rupp and colleagues (Innsbruck Medical University, Innsbruck, Austria) report that olfactory dysfunction is associated with impairment of executive function in alcoholics.

Olfactory defi cits are common in ageing adults and patients with disorders of the CNS, including alcohol abuse disorders. The basis of olfactory defi cits in alcoholism is presently unknown. However, Rupp and colleagues’ new study investigated the role of neurocognitive functioning in the areas of the brain where the olfactory region is located. Olfactory discrimination ability was positively associated with executive function performance (Alcohol Clin Exp Res 2006; 30: 1355–63).

In their study, Rupp and colleagues recruited 32 alcoholics (18 men, 14 women) and 30 healthy controls matched for age, sex, education, general global cognitive measures, and smoking status. All participants

were assessed for olfactory function (detection threshold, quality discrim-ination, identifi cation), executive function (with the Wisconsin card-sorting test), and memory (with the German version of the California-verbal-learning test). Compared with controls, those who were alcohol dependent were impaired in all three domains.

“The prefrontal cortex and its subcortical connections represent the primary neural substrate that subserves executive functions”, Rupp explained to The Lancet Neurology. “Thus, our fi ndings suggest that in alcohol dependence olfactory discrimination defi cits may be associated with defi cits in brain systems involving the prefrontal lobe. Frontal lobe dysfunction may play a signifi cant role in alcoholism and other drug addictions.”

Michael Cowen (Howard Florey Institute, University of Melbourne, Australia) points out that previous research has shown that the Wisconsin card-sorting test is a very sensitive measure of cognitive fl exibility and that olfactory and visual cues can be powerful motivators to relapse

drug-seeking behaviour. “If olfactory function is impaired in alcoholics, perhaps we are getting into the level of formed habit. What would really make this study explosive was if, in a cohort study, they found the olfactory discrimination defi cits preceded the development of alcoholism.”

Nayanah Siva

Olfactory dysfunction in alcoholics is associated with prefrontal cognitive defi cits