Fragile X Syndrome Flashcards
What is Fragile X Syndrome?
An X-linked genetic disorder, and the most common inherited cause of intellectual disability.
Two varieties:
Full Mutation
Permutation
Affects between 1/4000 and 1/7000 males, and about 1/2 as many females.
What causes FXS?
Caused by decreased or absent levels of fragile X mental retardation protein.
Due to loss-of-function mutation in the FMR-1 gene.
Typically, we see a massive CGG expansion, which leads to methylation-coupled silencing of the FMR1 gene, and thus absence of FMRP.
> 200 repeats in full mutation. 50-200 repeats in permutation.
Inheritance of FXS does not follow the usual pattern of X-linked dominant inheritance.
Females with full FMR1 mutations may have milder phenotypes than males due to variability in X-inactivation.
DNA Methylation.
DNA Methylation
Turns off gene activity, thus preventing gene transcription.
Occurs on CG repeats (called islands).
Elongation of CGG repeats, seen in FCS patients.
Lower levels of FMRP appear to have major impact on severity of FXS phenotype.
Pathophysiology
FMRP has the highest concentration in the brain and testes.
FMRP functions to bind mRNA and transport it out of the cell nucleus to the synapse (specifically the dendrites).
Brain tissue shows abnormalities in the formation and function of synapses.
Lack of FMRP reduces mRNA suppression.
Impaired neuroplasticity (e.g. learning and memory).
Clinical Presentation of FXS
This varies depending on the degree of methylation (and therefore, FMRP deficit), sex tissue, etc.
Males with full mutation are significantly affected.
Degree of impairment varies widely in females.
Fragile X pre-mutation do not show phenotype.
Males: The degree of impairment correlates with the size of the amplification CGG sites.
Females: The degree of impairment in women appears to correlate with the activation ratio of the Fragile X chromosome, rather than size of amplification.
Physical Features
Long, narrow face with prominent forehead and chin.
Large ears.
Testicular enlargement (in males) with normal testicular function.
Macrocephaly (Latin for big head).
Hypotonia (Latin for low muscle tone).
Cognitive Functions
Macrocephaly is due to increased:
Caudate Nucleus, Fourth Ventricle, and Hippocampal Volume.
Decrease in lateral ventricle volumes.
Increase in Caudate Nucleus volume correlates with the methylation patterns on FMR1 gene.
Both Caudate Nucleus and Lateral Ventricular volumes correlate with IQ. ~50% of females with full-mutation FXS have normal intellect.
Most common cognitive symptoms of FXS are: developmental delays, intellectual disability, and learning disabilities.
Boys with FXS typically have delayed language development and expressive language skills (poor articulation, repetitive language, short and fast utterances, etc.).
Diagnosing FXS
Very important to diagnose it as early as possible, so that appropriate interventions can be initiated.
In the absence of family history, diagnosis is based on cognitive, developmental, and/or behavioural concerns.
A simple genetic test for alterations to the FMR-1 gene can confirm suspicion of FXS in both infants and adults.
After diagnosis, children and ados should undergo multidisciplinary evaluation to determine extent of the disease.
Management of FXS
It’s individualistic. It depends on patients cognitive and behavioural symptoms, strengths, and weaknesses.
Interventions include education plans, speech and language therapy, occupational therapy, behavioural therapy, pharmacotherapy options to treat inattention, hyperactivity, anxiety, mood instability, etc.
Families of individuals with FXS can consult with a genetic counselor to discuss inheritance.
