Fragile X Syndrome: a complex multigenerational condition

by Colin Reilly, Dr Joyce Senior, School of Education and Lifelong Learning, University College Dublin

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Introduction

Fragile X syndrome is the most common identified inherited form of learning disability (Greco et al. 2002) and it has been identified in every racial/ethnic group that has been studied (Sherman 2002). The vast majority of males affected with Fragile X syndrome have a learning disability (Bennetto and Pennington 2002). For females affected by Fragile X syndrome, 50-70% will have a learning disability and the remainder may have more specific learning difficulties (Riddle et al. 1998). In the USA, the National Fragile X Foundation (2007) is currently quoting a prevalence figure of 1 in 3600-4000 for males and the prevalence rate for females is thought to be approximately half the rate for males.

Inheritance Pattern

It is always from the mother that a child inherits Fragile X syndrome. Female carriers have a 50% chance of having a child with a Fragile X abnormality (i.e. their child may be a carrier or be fully affected by Fragile X syndrome). The daughters of male carriers will always be carriers, but will not be affected by the syndrome. Therefore, in some families male carriers may have grandchildren, but not children, affected with the syndrome. As Fragile X syndrome is a genetic condition, it is relatively common for more than one child in a family to be affected. It is also possible that there may be a number of generations affected in a family. In a recent Irish study involving twenty-two families affected by Fragile X syndrome, nine of the families had more than one child affected (Reilly 2006).

Conditions associated with being a carrier of the gene responsible for Fragile X syndrome As well as being at risk of having children or grandchildren affected by Fragile X syndrome, being a carrier of the gene responsible for Fragile X also places individuals at risk of being affected by either Premature Ovarian Failure (POF), in the case of females, and Fragile X associated Tremor/Ataxia Syndrome (FXTAS) in the case of males. Premature Ovarian Failure (POF) is defined as menopause occurring prior to the age of 40 (National Fragile X Foundation 2007). Sherman (2002) estimated the rate of POF among carrier women to be 21%. Male carriers are at risk of developing Fragile X associated Tremor/Ataxia Syndrome (FXTAS) (Hagerman 2006). FXTAS is a condition that may affect more than onethird of older adult male carriers (Jacquemont et al. 2003).

Some female carriers may also develop FXTAS, although with much lower incidence than males (Hagerman 2006). In addition to the core features of progressive intention tremor and gait ataxia, affected individuals commonly have parkinsonism, autonomic dysfunction, cognitive decline, emotional problems including disinhibition and apathy, and peripheral neuropathy (Jacquemont et al. 2003). FXTAS or POF has only been found in those who are carriers and not in those affected by Fragile X syndrome. A subgroup of male and female carriers may also have also mild cognitive, physical, and/or behavioural problems (Tassone et al. 2000). However, it is thought that these individuals are the exceptions to the typical lack of involvement in the majority of carriers (Hagerman 2002).

Who should be tested for Fragile X syndrome?

The Task Force on Autism (Department of Education and Science 2001) recommends that all those who receive a diagnosis of autism should be tested for Fragile X syndrome. Hagerman (2002) recommends that any child who presents with autism or autistic-like features, and/or learning disability without an identified aetiology, should undergo DNA testing for Fragile X syndrome. McConkie-Rossell et al. (2005) recommend that all individuals with a family history of Fragile X syndrome should be tested, but they caution that Fragile X testing for children less than 18 years of age must be approached carefully, with medical and emotional benefits weighed against potential harm.

Physical and behavioural features of Fragile X syndrome Common physical features which may be found in those (especially males) affected by Fragile X include large and prominent ears, a long narrow face, velvet-like skin, hyper-extensible finger joints, doublejointed thumbs, hypotonia (abnormal muscle slackness), flat feet and a single palmar crease (Hagerman 2002). The physical features of the syndrome may be present in females, but often to a much lesser degree. Individuals with Fragile X syndrome seem to be extra sensitive to sensory stimuli such that they are easily hyperaroused (overexcited) in situations with excess auditory, visual, or tactile stimuli, as in crowded and/or noisy environments (Hagerman 2002). This hyperarousal or over-stimulation in social situations is increasingly being recognised as a key characteristic of those of Fragile X and may be related to the display of challenging and atypical behaviours. Shyness or social anxiety is also a notable feature of children with Fragile X (Sobesky 1996).

Difficulties with sensory integration are common among children with Fragile X (Schopmeyer and Lowe 1992) and these difficulties may need input from professionals with knowledge of sensory integration therapy. The typical communication profile of those who have Fragile X syndrome may involve a combination of delayed early speech and language, attention difficulties, social anxiety and atypical language (Taylor 2004). Atypical language includes tangential language (off-topic questions and responses or comments), perseverative language (the reintroduction of favourite topics over and over), and repetitive speech (repetition of sounds, words or phrases). Approximately 20% of children with Fragile X will also have epilepsy (Musumeci et al. 1999).

Attention deficits, restlessness, hyperactivity and fidgeting have been described as some of the most striking and pervasive of the behaviours associated with Fragile X syndrome (Bregman et al. 1988) and may result in some of the children, especially males, receiving a diagnosis of Attention Deficit/Hyperactivity Disorder (ADHD). Girls with Fragile X and ADHD usually have less hyperactivity, compared to boys with Fragile X, but impulsivity and short attention span can also be a significant problem for girls (Hagerman 2002). Research has shown that autistic-like features, such as hand flapping, perseveration in speech, shyness, and poor eye contact are seen in the majority of individuals with Fragile X syndrome (Turk and Graham 1997). However, the majority of children with Fragile X syndrome do not demonstrate the core social deficits typical of autism (Hagerman 2002). The current view is that up to one-third of children with Fragile X syndrome may meet the diagnostic criteria for autism (The National Fragile X Foundation 2007), while others with autistic-like features may receive a diagnosis of PDD-NOS (Pervasive Developmental Disorder Not Otherwise Specified). The presence of autism with Fragile X syndrome is associated with severe language and social deficits, in addition to lower IQ compared with that of children with Fragile X syndrome without autism (Lewis et al. 2006).

Challenges associated with a diagnosis of Fragile X syndrome

Dykens (1999) asserts that many families with children affected by genetic conditions may be relieved at finding a reason for their child’s difficulties, but many will also receive the genetic diagnosis with a sense of guilt. The potential for self-blame may be particularly great for a condition such as Fragile X syndrome, given that mothers are carriers of the gene responsible for the syndrome. The comment of one mother in Reilly’s (2006) Irish study highlights the potential for self-blame among mothers of children affected by Fragile X:
…there was an awful lot of guilt lying around [at the time of diagnosis]…it is huge when know you are handing your own child a disability…

As well as dealing with a diagnosis of Fragile X, Carmichael (1997) also identifies the burden which falls on the family member who is first in contact with the genetic centre, as this person will often feel responsible for contacting other family members. Some family members may react very badly to the news. They may be angry about being advised to go for testing and may be inclined to ‘shoot the messenger’. Refusal of family members to cooperate with testing may lead to resentment and anger. Some family members may be in denial and refuse to accept the information, or reduce or completely cut off contact with affected family members. The stigma associated with the condition and impact on family functioning was commented on by a number of parents in Reilly’s (2006) study. One mother’s comment highlighted the impact of a diagnosis and its repercussions on family cohesion:
Telling the rest of the family was a nightmare. My parents would not talk to me for a while afterwards. It was all blame and ‘it did not come from me’ sort of thing. It was awful. It is hard to deal with the diagnosis but the aftermath was just as tough.

The time of diagnosis is obviously very challenging for family members and, therefore, it is vital that the professionals involved deal with the issues in a sensitive manner. Asking questions about the family’s history is vital, but yet may cause distress to a family who have recently received a diagnosis of Fragile X. Some parents may be in denial and be reluctant to discuss family history, and may choose not to take up the offer of genetic counselling. Genetic counsellors should be cognisant of the fact that, in general, families are initially overwhelmed, both emotionally and intellectually, by the complexity of the disorder and its implications for other family members (McConkie-Rossell et al, 2005) The genetic counselling process with a condition as complicated as Fragile X should therefore be conceived of as a process involving contact over a period of time (Carmichael 2003). The idea that one grandparent may have passed the genetic mutation to the grandchild is a sensitive issue, and depression, sadness and guilt in grandparents coping with the news that they are carriers are not uncommon (Gane and Cronister 2002). As well as the affected child or children, families affected by Fragile X may have concerns about future children, grandchildren or the possibility of the occurrence of Premature Ovarian Failure (POF) or Fragile X associated Tremor/Ataxia Syndrome (FXTAS).

Summary

Fragile X syndrome is a complex genetic condition that is likely to have far-reaching consequences for affected families. Its impact may be greater than other developmental conditions due to its genetic component, and potential impact on more than one generation in affected families. Families affected by the syndrome are likely to need, and benefit from, formal and informal support. In particular, the provision of genetic counselling and family therapy over an extended period may facilitate coping with, and understanding, the implications of a diagnosis of fragile X.

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