Rett Syndrome
From Iusmgenetics
Revision as of 23:05, 18 October 2011 by 134.68.138.157 (Talk)
Contents |
[edit] Rett syndrome
[edit] General background information
[edit] Mode of inheritance
- X-linked dominant
- A sex-dependent phenotype: affects mainly girls
- Prevalence is 1 / 10k-15k girls
- Demonstrates heterogeneity and variable expression
- There are "classical" and "variant" types
- 99% of cases are caused by a sporadic mutation
- 70% of these cases are mutations of the paternal X
- Rarely seen in males
- Why?
- Because girls are twice as likely to get an affected X (they have two).
- Some mutant X chromosomes may be in-utero lethal for males
- Since most cases come from sperm and since fathers only pass the diseased chromosome (X) to daughters, more girls will get the disease.
- May get diseased males when he is 47,XXY
- Why?
- Occurs in all racial and ethnic groups
- Often misdiagnosed as autism or cerebral palsy
- Is a form of X-linked cognitive impairment
- Rett syndrome in males:
- Can have MeCP2 mutations
- Most die before birth or infancy
- No X-inactivation
- Mosaics
- Small number of males have extra X chromosome
- Allows them to survive
[edit] Single important gene
- MeCP2: methyl CpG binding protein 2
- MeCP2 normally serves to bind methylated CpG dinucleotides, recruit other factors, and thus prevent HDAC
- Recall that CpG dinucleotides are often found in regulatory sequences of genes
- Recall that methylated promotors result in non-transcription
[edit] Etiology
- Mutant MeCP2 products fail to methylate CpG dinucleotides and thus fail to turn off genes
- This is a loss of function
- In general, aberrant gene activation leads to dedifferentiation
- This is particularly important in the brain in Rett syndrome--thus the neurological defects
- Most (70-80%) MeCP2 mutations are in the coding regions.
- Some disease-causing MeCP2 mutations are deletions (20-30%).
- Protein MeCP2 is essential for brain development
- Strongly expressed in CNS
- Plays a role in forming synapses
- Silences other genes by binding to methylated CpG dinucleotides adjacent to A/T sequences
- Has a TRD (transcription repression domain) and a MBD (methyl binding domain)
- Epigenetic regulation; recruits histone acetylases to close up chromatin.
- Most widely known target is BDNF
- It can also act as a transcriptional activator but is usually thought of as an inhibitor.
- Alternative splicing
- Critical for communication between nerve cells
- There is poor genotype-phenotype correlation other than that deletions cause a more severe disease state.
[edit] Pathogenesis
- Pts present as normal at birth and have normal development, initially.
- Onset is 6-18 months (though some can onset even at neonate)
- Neurodevelopmental regression
- More then 200 mutations identified (allelic heterogeneity).
- The "amount" of mutation correlates to the severity of the phenotype.
[edit] Stage I = Early Onset phenotypes
- Stage I
- Early onset
- Disease manifests between 6-18 months
- Often overlooked
- Delays in gross motor skills
- sitting & crawling
- Duration: a few months
[edit] Stage II = Rapid Destructive Stage
- Stage II
- Rapid destructive stage
- Between 1 & 4 years
- Loss of purposeful hand skills (wringing or washing movements), spoken language, breathing difficulties while awake (though not while sleeping), autistic-like behaviors (loss of social interaction, high irritability), slowed head growth which correlates with small brain size.
- Duration: weeks to months
[edit] Plateau Stage with Apraxia and Seizures
- Stage III
- Plateau stage
- Between ages 2-10
- Apraxia and seizures are predominant
- Apraxia: the "inability to make purposeful movements" per wordnet
- Apraxia is the most severely disabling feature
- Interfering with every body movement, speech, & eye gaze
- Improvement in behavior, non-spoken communication skills (that is, autistic behaviors go away)
- Many females remain in stage III for most of their lives
[edit] Late Motor Deterioration
- Stage IV
- Late motor deterioration stage
- Reduced mobility, scoliosis, rigidity
- Therefore they are often wheelchair bound for most of their lives.
- Cognition, communication, and hand skills do not decline in this stage.
- Wheelchair bound
- Duration: up to decades
[edit] Phenotypic information
- RTT is a progressive disease that has four stages.
- Characterized by disabilities in mobility, speech, uncontrolled, repetitive hand movements, breathing difficulties, severe cognitive impairment
- Head growth decelerates at onset
- Achieved, purposeful hand skills are lost
- Psychomotor regression occurs, including:
- Social withdrawal
- Communication dysfunction
- Loss of learned words
- Cognitive impairment
- "Stereotypic" movements (hand movements) develop: hand washing, wringing, squeezing, hand clapping, tapping, rubbing, hand mouthing
- Gait dysfunction develops
- Increased incidence of sudden death
[edit] Diagnosis
- Clinical diagnosis
- Confirmed by DNA testing
- Prenatal detection of mutation
- If family has a history: amniocentesis, CVS, and genetic testing.
- Primarily diagnosis occurs by the signs and symptoms seen during early growth and development
- Essential and supportive criteria: phenotypes that most patients have but are not required to make the diagnosis (difficulty breathing, scoliosis, in this case).
- Simple blood test to confirm MeCP2 mutation is merely a complement to the clinical observation diagnosis.
- Mutation alone does not mean RTT
- Can be seen in other diseases
- MLPA can be used
[edit] Treatment
- No curative treatment
- No cure but it is thought that Rett is reversible once we find the right therapies.
- Treatment is symptomatic requiring multiple disciplines
- Medication for breathing and motor difficulties, anticonvulsants, occupational therapy, physical and hydrotherapy, aid in scoliosis
- Possibly IGF-1 by Intravenous injection
[edit] Recent research
[edit] 5 important facts
- Mutation alone can not diagnose, need full clinical diagnosis
- MeCP2 gene encodes MeCP2 protein which is essential for normal brain development
- Most symptoms do not appear until 6-18 months
- Most common symptoms are: disabilities in mobility, speech, uncontrolled, repetitive hand movements, breathing difficulties, severe cognitive impairment
- IGF-1 systemic treatment may be a potential therapy to partially reverse the symptoms of RTT
[edit] Not to be confused with
- Two other genes produce similar disorders: CDKL5 and Netrin G1
- Atypical RTT Caused by CDKL5 Mutation
- Atypical form is called "early onset seizure variant"
- Occurs because of mutation of CDKL5 gene at Xp22
- Opposite end of the chromosome.
- Have all of the normal Rett syndrome phenotypes but also have seizures.
- This is an example of locus heterogeneity.
- Not well understood
- Atypical form is called "early onset seizure variant"
[edit] Questions and answers
- If a child is only tested for a MeCP2 deletion with no clinical evaluation, does the child have Rett Syndrome? Why or why not?
- If a child comes in to the doctor’s office who is believed to have RTT, what are the most common symptoms?
