Advances in the Treatment of Fragile X Syndrome

Abstract

The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/ hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties, including primary ovarian insufficiency, neuropathy and the fragile X-associated tremor/ataxia syndrome, in some older premutation carriers. Therefore, multigenerational family involvement is commonly encountered when a proband is identified with a FMR1 mutation. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition. Trials of metabotropic glutamate receptor 5 antagonists are beginning with individuals with fragile X syndrome. Targeted treatments, medical and behavioral interventions, genetic counseling, and family supports are reviewed here. NIH Public Access Author ManuscriptPediatrics. Author manuscript; available in PMC 2010 June 21. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptKeywords fragile X syndrome; autism; behavioral interventions; fragile X mental retardation protein; targeted treatments; fenobam FRAGILE X SYNDROME (FXS) is associated with an array of intellectual and emotional disabilities, ranging from mental retardation (hereafter referred to as intellectual disability) to learning problems, autism, and anxiety. The cause of FXS is decreased or absent levels of fragile X mental retardation protein (FMRP). Decreased levels of FMRP typically are caused by the full mutation (>200 CGG repeats), which usually is methylated, in the proximal regulatory region of FMR1 (fragile X mental retardation 1 gene). 1-3 FXS occasionally occurs because of a point mutation or deletion in FMR1 4,5 or even a smaller expansion in the CGG repeat, which leads to lower levels of FMRP and intellectual disability. 6 Intellectual disability linked to FXS occurs in ~1 per 3600 individuals in the general population, 7,8 whereas milder cognitive and behavioral problems (eg, math and language deficits, social phobia, and attention-deficit/ hyperactivity disorder [ADHD]) associated with FXS may be more common. A more-frequent (1 of 130-250 female individuals and 1 of 250-800 male individuals) but smaller expansion (55-200 CGG repeats) of FMR1 is termed a premutation. [9][10][11][12] In contrast to the full mutation, the premutation usually does not cause decreased FMRP levels but leads to enhanced production of FMR1 mRNA (2-8 times normal levels) 13,14 (Fig 1). The enhanced mRNA production can lead to clinical features in premutation carriers that do not occur in full mutation carriers, including primary ovarian insufficiency and the fragile X-associated tremor/ataxia syndrome (FXTAS).In general terms, the severity of the FXS physical phenotype and intellectual impairment is correlated with the magnitude of the FMRP deficit. 1,2,15 Male individuals with incomplete methylation of a full mutation...

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

“…Around 13-16% of individuals with fragile X develop seizures during their lifetime, 27 which suggests a role for the FMR1 gene in epilepsy. Decreased inhibitory signaling from GABA-A receptors 28 and overactivity of the metabotropic glutamate receptor (mGluR) with resulting altered AMPA receptor activity 29 have been reported as pathogenic mechanisms for increased risk of seizures in fragile X syndrome.…”

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…disorder (Hagerman et al, 2009). FXS patients diagnosed with autism display a more severe social impairment, as well as having lower cognitive and language ability, academic achievement and adaptive behaviour, than seen in FXS individuals without autism (Bailey, Jr. et al, 2001;Hagerman, 2006).…”

“…FXS patients under the age of 5 years old are particularly difficult to treat, as stimulants that are routinely used to treat older patients are not as effective (Hagerman and Hagerman, 2002). The use of clonidine and guanfacine, agonists of the α-andrenergic receptor, are useful in younger children and are without the side effects of stimulants (Hagerman et al, 2009). Clonidine has also been used to treat sleep disturbances, which in some cases have been reported in up to one-third of patients with FXS (Ingrassia and Turk, 2005;Kronk et al, 2010).…”

“…The use anticonvulsants must be carefully evaluated in these patients because many drugs can unintentionally exacerbate other symptoms of FXS. Common anticonvulsants such as phenobarbital and gabapentin are generally avoided, because they tend to increase hyperactivity in individuals with FXS (Hagerman et al, 2009). …”

“…Reduction in intellectual ability ranges from mild to moderate and there is a significant positive correlation between the levels of FMRP and intellectual ability (Loesch et al, 2004). The behavioural phenotype of FXS patients also includes hyperactivity, anxiety, impaired visuo-spatial processing, and developmental delay (Hagerman et al, 2009). Girls with FXS usually suffer from milder cognitive and behavioural deficits than boys primarily due to the fact females still express some FMRP, depending on the ratio of X chromosome inactivation (Freund et al, 1993;Lachiewicz et al, 2006).…”