Fragile X syndrome Flashcards
What is Fragile X syndrome?
FXS is a single gene disorder resulting from an expansion of cytosine-guanine-guanine (CGG) trinucleotide repeats in the 5′ untranslated region of the Fragile-X-Mental-Retardation 1 ( FMR1 ) gene on the Xq27.3 site, at the tip of the long arm of the X chromosome.
What is the significance of the repeats?
The normal CGG segment in the general population repeats 5–40 times. Individuals with more than 200 repeats have the fragile X full mutation and those with 55–200 repeats have the fragile X premutation with repeats of 41–54 known as the intermediate or ‘grey zone’.
How does the repeats cause pathology?
The excessive repeats in the FXS full mutation causes methylation and silencing of the FMR1 gene, halting production of Fragile-X-Mental-Retardation-Protein (FMRP), a protein crucial to the regulation of other proteins and neural synapse development.
What is the prevalence of Fragile x?
A meta-analysis estimated that 1 in 300 females and 1 in 850 males in the total population have the fragile X premutation; while 1 in 11,000 females and 1 in 7,000 males have the full fragile X mutation.
What is the risk of premutations?
Females with fragile X premutation are at risk for Fragile X-associated Primary Ovarian Insufficiency (FXPOI)
Males and females are at risk of developing the neurodegenerative condition, Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).
Approximately 20% of female carriers experience FXPOI, defined as the cessation of menstrual periods before age 40.
The risk of developing FXTAS increases with age and, overall, occurs in 40% of male and 16% of female carriers.
What is the risk of premutation in children?
Increased rates of other conditions have been reported in children with the fragile X premutation including anxiety, attention-deficit-hyperactivity-disorder (ADHD), social deficits and autism spectrum disorder (ASD)
What are the physical characteristics of FRX?
- Prominent ears
- long narrow face
- macroorchidism in males
- flat feet
- high-arched palate
- hyper-flexible joints
- hypotonia.
- Relative macrocephaly (head circumference >50th percentile for age and sex)
- Testicular enlargement not seen usually less than 8 years of life
What are the other physical health problems noted in these patients?
Recurrent otitis media (55%), sleep difficulties (26–32%), epilepsy (10–20%), sleep apnoea (7%), mitral valve prolapse (0.5% in children increasing to 50% in adults), gastroesophagal reflux (11%) and ocular disorders including refractory errors and strabismus (18%).
What is the explanation for some of the behavioural features in FRX?
Hyperarousal is believed to exacerbate many of the behavioural features of FXS such as impulsivity, self-injurious and aggressive behaviour, as individuals may be less able to control their behaviour whilst hyperaroused.
What role does anxiety play a role in FRX?
The majority of people with FXS experience clinical levels of anxiety. Approximately 80% of males with FXS meet clinical cut off for an anxiety disorder with social phobia and specific phobias being the most common. 2 Antecedents of anxiety, such as negative affect, emerge early in young children with FXS. Many people with FXS do not receive a diagnosis of anxiety, which is a barrier to appropriate treatment, monitoring and management.
What are the behavioural markers that may suggest anxiety in these patients?
These include eye gaze aversion, fidgeting/physical discomfort, face-hiding/eye-rubbing, hand-biting, refusals/fleeing situation/avoidance, reduced vocal length/poorer vocal quality, and behavioural distress/negative affect.
How severe is social avoidance in FRX?
The social phenotype of FXS is characterised by avoidant behaviours such as eye gaze aversion, which is almost universal and is unlikely to be accounted for by heightened ASD characteristics alone. Over 80% of males with FXS show social avoidance but this decreases throughout the course of an interaction (a “warm up effect”). Social avoidance generally emerges in early life, from 4 months of age, and increases in severity through childhood and adolescence, stabilising in early adulthood.
What are the differences in the profiles of behaviours between ASD and FRX?
Males with FXS, even those co-diagnosed with ASD, are more socially responsive, less likely to engage in pronoun reversal (a communicative behaviour characteristic of ASD), less likely to display some higher-order repetitive behaviours, and more likely to display language and cognitive impairments than males with idiopathic ASD.
In contrast to individuals with autism, boys with FXS who often exhibit autistic-like features generally take appropriate turns during conversation.
What is the nature of slef-injury and aggression?
Self-injurious behaviour is observed in approximately 50% of males with FXS, with hand-biting being the most common form.
Escaping from interactions, transitions and demands or tasks are common functions of self-injurious behaviour.
Aggressive behaviour also occurs in approximately 50% of males with FXS. The most common forms of aggressive behaviour are hitting and kicking others.
