Neurodevelopmental Disorders Fragile X Syndrome

Question 1

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: - Full mutation FXS;
- Premutation FXS.
In Canada, FXS affects between 1/4000 and 1/7000 males, and about 1⁄2 as many females.

Question 2

What causes FXS?

Answer 2

FXS is an X-linked disorder
The 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.
- There appears to be variability in the expressivity and penetrance of the X chromosome in FXS.

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, which leads to methylation-coupled silencing of the FMR1 gene, and thus absence of FMRP.
1. >200 repeats in full mutation; 2. 50-200 repeats in premutation.

Question 3

DNA Methylation

Answer 3

DNA methylation turns off gene activity, thus preventing gene transcription.
DNA methylation occurs on CG(G) repeats (called CpG islands).
Elongation of CGG repeats, as seen in FXS patients, allows hypermethylation of FMR1 gene.
Lower levels of FMRP appear to have major impact on severity of FXS phenotype.

Question 4

Pathophysiology

Answer 4

FMRP has the highest concentration in the brain and testes;
- Appears to be critical for cognitive functioning, reproductive function, etc.
FMRP functions to bind mRNA and transport it out of the cell nucleus to the synapse (specifically the dendrites).
- Nucleocytoplasmic shuttling of mRNA
Brain tissue from FXS patients show abnormalities in the formation and function of synapses.
- Lack of FMRP reduces mRNA suppression;
- Impaired neuroplasticity (e.g. learning and memory);

Question 5

Clinical Presentation of FXS

Answer 5

The clinical presentation of FXS varies depending on the degree of methylation (à 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 (in females)

Question 6

Clinical Presentation of FXS in Males and females

Answer 6

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, rather than size of amplification.

Question 7

Clinical Presentation of FXS: Physical Features

Answer 7

Physical features of FXS may include:
- 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

Clinical Presentation of FXS: Cognitive Functions

Answer 8

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

Intellectual disability ranges from mild to severe
- ~50%offemaleswithfull- mutation FXS have normal intellect.

Question 9

The most common cognitive symptoms of FXS:

Answer 9

1. Developmental delays (e.g. motor/language milestones);
2. Intellectual disability;
3. Learning disabilities;

Boys with FXS typically have delayed language development and expressive language skills (poor articulation, repetitive language, short and fast utterances, etc.).

Question 10

Diagnosing 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 behavioral concerns.
A simple genetic test for alterations to the FMR-1 gene can confirm suspicion of FXS in both infants and adults.

Question 11

Management of FXS

Answer 11

Management of FXS is individualistic!
- Dependent on patients cognitive and behavioral symptoms, strengths, and weaknesses.
Interventions may include:
- Education plans;
- Speech and language therapy;
- Occupational therapy;
- Behavioral therapy;
- Pharmacotherapy options to treat inattention, hyperactivity, anxiety, mood instability, etc.