19 September 2008
Two US medical centres have announced that they will launch the first systematic newborn screening programmes for the inherited disorder fragile X syndrome using a new blood spot test. Fragile X results from the expansion of a CGG repeat sequence on the X chromosome FMR1 gene; normally under 55 repeats, expansion to 55-200 repeats is classed as a pre-mutation (PM) and above 200 repeats is classed as a full mutation (FM). Of individuals with a full mutation, all males and around half of females have the disease, which causes learning disability and behavioural problems, with around 1 in 4000 males and 1 in 8000 female affected in the general population. Males typically show more severe learning disability than females, and Fragile X is the most common inherited form of learning disability.
Individuals with pre-mutations do not show any form of mental retardation, but female PM carriers are at risk of having children with full mutations, and also have an increased incidence of premature ovarian failure. Male carriers are not at increased risk of transmitting a full mutation to their children, but may develop a neurodegenerative disorder called fragile X–associated tremor/ataxia syndrome (FXTAS) in later life (see previous news); this can more rarely affect female PM carriers too.
Studies have suggested that cascade testing in affected families or universal prenatal screening may be appropriate for Fragile X (see previous news), but there is no screening programme in the UK (see National Screening Committee policy statement); this decision will be reviewed in 2009/10. It has been proposed that newborn screening for the condition, since it would result in identification of PM or FM children who may never, in fact, be affected by the disease, could potentially result in some serious harms for the child and family (see previous news). Even prenatal screening has raised concerns (see previous news).
The new test has been developed by researchers at University of California, Davis M.I.N.D. Institute and the Rush University Medical Center with National Institutes of Health (NIH) funding, and will be used in a pilot study from autumn 2008 on all newborns at the two centres, estimated to reach a total of 30,000 in the coming five years. The test uses a polymerase chain reaction (PCR) based technique to amplify the FMR1 gene expansion region and allows detection of expanded repeat regions. This means that the test will identify pre-mutation carriers as well as those with the full mutation. Senior researcher Dr Randi Hagerman said: “While the newborn screening study is not specifically designed to offer treatment, the diagnosis will open the door to new therapies for infants…Once we have identified affected infants, we will propose treatment options for them.”(see press release).
Comment: There is no cure for Fragile X Syndrome, although drugs may alleviate some of the symptoms, so the prospects of treating affected children are currently very limited. Despite this there are arguable benefits of early diagnosis, paticularly in allowing prompt access to supportive treatment to address behavioural problems, and special educational help. It may also allow the diagnosis of FM or PM status in family members, who may have associated health problems or mild learning disability. However, many would question the ethics of identifying PM or FM infants, since PM status is not associated with any significant health impacts until maturity, whilst FM status does not necessarily mean that an individual will ever show any symptoms of Fragile X; moreover, none of the infants would be capable of giving informed consent for the decision to test.