ECON 546 Lecture Notes - Lecture 12: Metabotropic Glutamate Receptor 5, Design Patterns, Mmp9
27 Jun 2018
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Lecture 12: Fragile X Syndrome Wednesday, February 14, 2018
Dr. Tak Pan Wong
Intellectual Disability
Causes of Mental Retardation
- May be caused by infection during gestation
- Environment: nutritional deprivation
- Deprivation can cause not only physical, but also mental retardation
oIf the children are rescued from deprivation, the symptoms may be reversible
Genetics and Mental Retardation
- Down’s syndrome is associated with mental retardation, dementia
- Not usually inheritable
- Fertility of DS patients is low, only in exceptional circumstances do they have children
and pass on the trisomy 21
- Phenylketonuria is more heritable, mutation is passed down
FXS Introduction
- Males are more commonly affected
- Affect all ethnicities equally
Fragile Sites on X Chromosomes
- Many different types of FXS, classification is growing in complexity
- FRAXA: most common form
oRelated to gene FMR1
oMacro-orchidism: bigger balls
- FRAXE: consists of 1% of FXS cases
oRelated to FMR2
FXS Symptoms
- People with FXS don’t necessarily have all these features
- Low muscle tone = get tired quite easily from physical exertion
- Cardiac issues as a result of connective tissue abnormalities
- Comorbidity with mental illness (ASD, ADHD)
oShown to be one of the most known causes of autism
- Seizures are fairly common, usually the most common neurological problem
oMust be treated, can cause brain damage
- Significant spine morphology changes fewer mushroom spines in FXS, thinner and
longer (immature spines more common) = could be related to changes in synaptic
functions in the brain and formation of seizures
X Linked Disease
- Female offspring will have a 50% chance
- Male offspring will have a 100% chance (the X has to come from the mother)
find more resources at oneclass.com
find more resources at oneclass.com
Sherman Paradox
- Some male individuals will have the disease, and some will be carriers mutation is
insufficient to show phenotypes
- Paradox: in subsequent generations, there will be higher incidence of FXS (why??)
Answer: Trinucleotide repeat expansion
- Number of repeats will estimate the severity of the disease
FMR1 Gene
- Loss of function mutation because of methylation of CGG repeats – less production
- Gene is non-functional, FMRP (fragile X mental retardation protein) translation is
reduced, or even no expression leads to mental retardation
- More repeats = more methylation = fewer repeats
Male Premutation Carrier
- Female will get the X chromosome, male will be fine (affected X chromosome not
transmitted)
Male Full Mutation Carrier
- For males with full mutation: something during spermatogenesis removes trinucleotide
repeats
- Full mutation will not be transmitted to female offspring
Female Full Mutation Carrier
- Female symptoms are usually less severe than male because of other X chromosome
compensation = relatively normal expression of FMRP
- Full mutations will be transmitted from a mother to her offspring
Female Premutation Carrier
- Premutations will also be transmitted to the offspring
- There will be an increase in the repeats during oogenesis explains anticipation and
why there is an increase in prevalence
- Premutation mothers can have offspring with full mutations
- In females there is a large trinucleotide expansion
Amplification of CGG in FXS
- For full mutations, fathers can have children with no mutations of premutations because
of the correction
Huntington’s Disease
- Another trinucleotide disease
- Cannot be corrected with spermatogenesis
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
May be caused by infection during gestation. Deprivation can cause not only physical, but also mental retardation. Environment: nutritional deprivation: if the children are rescued from deprivation, the symptoms may be reversible. Down"s syndrome is associated with mental retardation, dementia. Fertility of ds patients is low, only in exceptional circumstances do they have children and pass on the trisomy 21. Phenylketonuria is more heritable, mutation is passed down. Many different types of fxs, classification is growing in complexity. Fraxa: most common form: related to gene fmr1, macro-orchidism: bigger balls. Fraxe: consists of 1% of fxs cases: related to fmr2. People with fxs don"t necessarily have all these features. Low muscle tone = get tired quite easily from physical exertion. Cardiac issues as a result of connective tissue abnormalities. Comorbidity with mental illness (asd, adhd: shown to be one of the most known causes of autism.
