Bulletin

Issue: May 2005

Research in Action

Two facets of fragile X – New neurological disorder detected

A collaborative research team from La Trobe University and the University of California has identified and characterised a new progressive neurological disorder in older men.

The disorder which presents as tremor, walking and balance problems (ataxia), and intellectual decline, has been provisionally named FXTAS.

A La Trobe group led by Dr Danuta Loesch, and another from UC at Davis led by Professor Randi Hagerman, identified the disorder while investigating families with fragile X syndrome, the most common cause of inherited severe developmental delay.

Their findings were recently published in The Journal of American Medical Association and Clinical Genetics.

The newly-identified disorder affects older men who are carriers of a small change, known as a ‘premutation’, in the same (FMR1) gene that also causes fragile X syndrome.

Dr Loesch, a Senior Research Fellow in La Trobe’s Department of Psychological Science, said that at least one in 800 men in the general population carried the premutation in the FMR1 gene.

‘Our collaborative research showed that, both in Australia and the USA, as many as 30 to 40 per cent of these carriers may develop progressive tremor/ataxia symptoms after the age of 50,’ Dr Loesch said.

‘This indicates that at least one in 3000 older men in the general population will develop fragile X-associated tremor ataxia, which has serious implications for the community at large, as well as medical professionals.

‘The underlying cause of this disorder, premutation in the FMR1 gene, is generated by small expansion of a particular gene segment, which is repeated too many times.

‘This repetition is called “CGG repeat”, because it contains the same trio of DNA building blocks (cytosine, guanine, guanine) in the same repetitive order. The average normal number is 30 such trios, and the expansion between 55 and 200 CGG repeats has been defined as “premutation”, which leads to neurological disorder later in life.

‘These expansions tend to increase further in successive generations, leading to a “full mutation” corresponding to less than 200 CGG repeats, which causes fragile X syndrome.

‘Although fragile X syndrome occurs by a completely separate mechanism and affects different individuals to late-onset neurological disorder, both these conditions are related to the same gene and may occur in one and the same family.

‘Because the size of CGG repeat tends to increase in following generations, young children affected with fragile X syndrome seen in paediatric or genetic clinics often led us to their grandfathers affected with neurological disorder.

‘However, neurologists or other medical professionals who see older people with tremor/ataxia, are rarely aware that they need to look for a family history of fragile X in their grandchildren.

‘But not all individuals affected with balance problems and tremor caused by fragile X premutation may have grandchildren or other relatives affected with fragile X.

‘Because this premutation may be, according to our results, the fairly common cause of neurological problems in elderly population, these individuals themselves should be tested for the presence of this premutation.

‘Screening for the premutation in older men who have tremor and balance problems is important regardless of their family history, especially if they have been diagnosed with Parkinson’s disease or various forms of ataxia of unknown cause,’ Dr Loesch said.

A new NHMRC funded study from 2005 to 2007 led by Dr Loesch will determine what proportion of males affected with late-onset tremor/ataxia/atypical Parkinson’s syndromes of unknown cause, are also the carriers of premutation in the FMR1 gene.

This study will be conducted at La Trobe’s School of Psychological Science, in collaboration with Monash and Melbourne university neurology clinics and institutes.

Dr Loesch said that the results of the screening will impact on future diagnostic procedures in neurological practice and allow neurologists to tailor more effectively treatment of neurological conditions associated with fragile X premutation.

‘Another important clinical application of our study is that the carriers identified will be informed of genetic risks for future generations who may inherit fragile X syndrome,’ she said.

‘The way premutation causes a progressive neurological disorder is unknown, but the results of our study will help to understand how a serious neurological disorder occurring late in life in otherwise normal people, is caused by the same gene known to cause mental retardation in early childhood.

‘This will be accomplished by conducting comprehensive neuropsychological and neurological investigations, including magnetic resonance imaging, in patients identified as premutation carriers by our initial screening.

‘The clinical findings will be then compared with the molecular changes in the FMR1 gene, including the number of CGG repeats, and the level of this gene’s transcript, mRNA (messenger RNA).

‘Recent studies have found consistently elevated FMR1 mRNA levels in premutation carriers, which led to a hypothesis that overactivity of the gene, the mechanism termed “RNA toxic gain-of-function”, may be involved in causing progressive degeneration of brain tissue and neurological disorder.

‘We hope that these fascinating developments will soon attract even wider collaborations, and both La Trobe University internal, and external support, to study this new genetic mechanism in more depth using both human data and animal models,’ Dr Loesch said.

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