Rett Syndrome is a rare developmental disorder categorized by the NIMH under the Autism Spectrum Disorders that is marked by severe social and communication impairments as well as repetitive behaviors. Rett Syndrome can be distinguished from the other disorders in the spectrum by a deceleration of head growth between 5 and 48 months, a loss of previously acquired purposeful hand skills with the development of hand-wringing movements or handwashing movements, as well as severe speech impediments; most children with Rett Syndrome can not speak at all. Most if not all language ability gained in first couple of years of life are lost during the Rapidly Destructive Stage detailed below. There is often a loss of social engagement early on in the course of development, though social skills usually improve later on. Those with Rett Syndrome often have poorly coordinated gaits while walking and are severely deficient in language development and psychomotor skills.
Pathology Genes have been identified that are highly linked in causing Rett Syndrome like symptoms, but the mechanisms of development of this disorder are still unknown. There is some evidence of post-natal defiency in synaptic development.
- The disease can be characterized through 4 stages
- 1) Precocious Stagnation between 6-18 months of age. During this stage, there is a stagnation in development and a deceleration of brain perimeter increment, and a tendency towards social isolation.
- 2) Rapidly Destructive between 1-3 years.This stage can last from a couple weeks to many months. During this stage, significant psychomotor regression occurs that may be accompanied by crying spells and irritability. There is a loss of acquired speech and beginning of stereotypic hand movements. Children may also develop breathing irregularities and epilepsy.
- 3) Pseudo-Stationary between 2-10 years.There is an improvement in some of the symptoms, particularly social skills. Motor skills for those with Rett Syndrome may begin to deteriorate. Children with Rett Syndrome will begin to develop ataxia, apraxia, spasticity, scoliosis, and teeth grinding. Episodes of breath loss, aerophagia, and air and saliva forced expulsion occur often.
- 4) Late motor deterioration around 10 years of age. In this stage motor impairments will slowly worsen. Scoliosis and severe cognitive deviance is apparent and choreo-athetosis, dystonia, and peripheral neuromoto disturbances may arise.
- Diagnostic criteria
EEG Those with Rett Syndrome, when given an electroencephalogram test (EEG), will often display sharp waves in the centroparietal regions. At stage 3, spike-wave discharges may occur. These discharages are more easily observed in sleep recordings. By stage 4, there is usually an improvement in electroencephalogram readings, with reduction of epileptiform elements.
Neural Structure Abnormalities Those with Rett Syndrome have significant reductions in the frontal lobe, caudate nucleus, and mesencephalus.
Studies have shown increased CSF glutamate and changes in glutamate receptors depending on the age of the individual in those with Rett Syndrome.1
The development of Rett Syndrome is strongly believed to be caused by mutations in the gene MeCP2, a methylation protein which is responsible for regulation of protein synthesis in the brain. 75%-80% of clinically diagnosed people with Rett Syndrome have MeCP2 mutations. MeCP2 is located on the X chromosome and it is so critical to brain development that there are very few males who are born and survive with an MeCP2 mutation. It is hypothesized that this is why most of those with Rett Syndrome are female and that the variability in symptoms is due to X chromosome deactivation.
Mouse Transgenic mouse models exist with truncated mutations and null mutations in MeCP2. MeCP2 null mice show normal development in the first month after birth, but begin to have increasingly severe neurologic abnormalities and death by approximately 10 weeks.
|Animal Model||Behavorial Phenotype||Animal Life Progression|
|MeCP2 null||hypoactivity, body trembling, gait ataxia, limb clasping. normal in somatic and somatosensory measures, but delays in a few behavioral reflexes||normal development for first month of life, followed by increasingly severe neurological abnormalities and death by ~10 weeks.|
|MeCP2308||Males have normal early development, but by 6 weeks of age begin to show pregressive tremors, hypoactivity, seizure-like responses, stereotyped forelimb movements. Significant signs of motor impairment in a wire suspension task by 8 weeks.||lower penetrance of lethal phenotype than null|
1. Armstrong DD.Neuropathology of Rett syndrome.J Child Neurol. 2005 Sep;20(9):747-53. PMID 16225830
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