Lecture 5: Fragile X Syndrome

Question 1

What is fragile x syndrome?

Answer 1

• • an X-linked genetic disorder, and the most common inherited cause of intellectual disability
• • There are two types of FXS:
    1) Full mutation FXS
    2) Premutation FXS

Question 2

What causes fragile x syndrome?

Answer 2

• • Caused by decreased or absent levels of fragile X mental retardation (FMR) protein; Due to a loss-of-function mutation in the FMR-1 gene;
• • Typically, we see a massive CGG expansion
• • DNA methylation occurs on CG(G) repeats (called CpG islands) because the methyl group attaches to the cytosine (C)
• • methylation only happens at a CGG repeat
• • DNA methylation turns off gene activity, thus preventing gene transcription
• • Elongation of CGG repeats, as seen in FXS patients, allows hypermethylation (too much methylation) of FMR1 gene which causes decreased or absent levels of FMRP
    1) >200 repeats in full mutation;
    2) 50-200 repeats in premutation.

Question 3

Why is fragile x syndrome different in males and females?

Answer 3

– there are more males than females affected because females have two X chromosomes that can be read from/used. if you have two X chromosomes and one is mutated, you can just check the other X chromosome for the missing/defective genes so you can pull some of that non-mutated information. If you have only one X chromosome, and one Y chromosome, and the X chromosome is defective, there is no other X chromosome to make up for any genetic mutation

Question 4

What is the importance of FMRP?

Answer 4

• • FMRP has the highest concentration in the brain and testes;
• • Appears to be critical for cognitive functioning, reproductive function, etc.

Question 5

What does FMRP do?

Answer 5

• • FMRP functions to bind mRNA and transport it out of the cell nucleus to the synapse (specifically the dendrites).
• • Nucleocytoplasmic (taking it from the nucleus to the cytoplasm) shuttling of mRNA
• • if you don’t have the FMRP then you don’t suppress the mRNA (by taking it out of the nucleus and bringing it to the synapse/cytoplasm). This prevents the mRNA from being translated into a protein. If you don’t have FMRP, then all these mRNA’s will be translated into a protein and the mRNA will not make it to the synapse where they cell wants them to be
• • Your ability to learn something new depends on the synapses changing. If you don’t have the proper proteins at the synapse, then they struggle to change and you can’t learn new things (impaired neuroplasticity)
• • Brain tissue from FXS patients show abnormalities in the formation and function of synapses.

Question 6

How is the clinical presentation for FXS different for males and females?

Answer 6

• • The clinical presentation of FXS varies depending on the degree of methylation (–>FMRP deficit), sex, tissue, etc.
• • Males with full mutation are significantly affected;
• • Females with full FMR1 mutations may have milder phenotypes than males due to variability in X-inactivation
• -50% of females with full-mutation FXS have normal intellect.
• • Degree of impairment varies widely in females;
• • Fragile X pre-mutation do not show phenotype (in females)
• • Males: The degree of impairment correlates with the size of the amplification of CGG sites;
• • Females: The degree of impairment in women appears to correlate with the activation ratio of the fragile X chromosome (how efficient the body is at turning off the genetic information of one X chromosome and turning on and relying the genetic information of the other X chromosome), rather than size of amplification

Question 7

What are the physical clinical features of FXS?

Answer 7

• -Long, narrow face with prominent forehead and chin;
• -Large ears;
• -Testicular enlargement (in males) with normal testicular function;
• -Macrocephaly (L. big head);
• -Hypotonia (L. low muscle tone);

Question 8

What are the neurophysiological features of FXS?

Answer 8

• -Imaging studies have shown that the macrocephaly is due to relatively increased:
  1) Caudate nucleus; volume correlates positively with the methylation patterns on the FMR1 gene
  2) Fourth ventricle;
  3) Hippocampal volume;
• -Decrease in lateral ventricle volumes
• • Both caudate nucleus and lateral ventricular volumes correlate with intelligence quotient (IQ)

Question 9

What are the cognitive features of FXS?

Answer 9

1) Developmental delays (e.g. motor/language milestones);
2) Intellectual disability; mild to severe
3) Learning disabilities;
- - Boys with FXS typically have delayed language development and expressive language skills (poor articulation, repetitive language, short and fast utterances, etc.)
- - Boys with fragile X syndrome will be more delayed compared to girls with fragile X syndrome

Question 10

How do you diagnose FXS?

Answer 10

• -Very important to diagnose FXS 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
• • Following diagnosis, children/adolescents should undergo multidisciplinary evaluation to determine the extent of the disease

Question 11

How can you manage FXS?

Answer 11

• • Management of FXS is individualistic! Dependent on patients cognitive and behavioral symptoms, strengths, and weaknesses.
• • Interventions may include:
    1) Education plans;
    2) Speech and language therapy;
    3) Occupational therapy;
    4) Behavioral therapy;
    5) Pharmacotherapy options to treat inattention, hyperactivity, anxiety, mood instability, etc.
• • Families of individuals with FXS can consult with a genetic counsellor to discuss the inheritance of FMR-1 mutation if thinking about having kids