Rett Syndrome

From Iusmgenetics

(Difference between revisions)
134.68.138.157 (Talk)
(Created page with '==Rett syndrome== ===General background information=== ===Mode of inheritance=== *'''X-linked dominant''' *A '''sex-dependent''' phenotype: affects mainly girls *Prevalence is …')
Newer edit →

Revision as of 01:23, 14 October 2011

Contents

Rett syndrome

General background information

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 girls, more girls will get the disease.
    • May get diseased males when he is 47,XXY


  • 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
  • XchromInactivation.gif

Single important gene

  • MeCP2: methyl CpG binding protein 2
  • MeCP2 normally serves to bind methylated CpG dinucleotides and prevent HDAC
    • Recall that CpG dinucleotides are often found in regulatory sequences of genes
    • Recall that methylated promotors result in non-transcription

Etiology

  • Mutant MeCP2 products fail to methylate CpG dinucleotides and thus fail to turn off genes
  • 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
  • MeCP2_regulation.jpg


  • There is poor genotype-phenotype correlation other than that deletions cause a more severe disease state.

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.
  • nrg1878-f1.jpg


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

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
  • tabitha2.JPG

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

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
  • 070614100445.jpg


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

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

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
  • image-1542-orig.jpg

Recent research

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

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

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?
Retrieved from "http://editthis.info/iusmgenetics/Rett_Syndrome"
Personal tools