- Loss of purposeful hand movements - replaced by hand wringing and hand flapping
- Loss of language
- Irritability
- Self-abuse
- Autistic features: lack of eye contact, unresponsive to social cues, unresponsive to social cues (though this can improve at around age 5), and hypersensitivity to sound
- Severely underdeveloped cognitive functions


Macalester College

Rett Syndrome is a rare X-linked disorder usually caused by spontaneous (de novo) mutations in the methyl-CpG-binding protein 2 (*MeCP2*) gene. It affects almost exclusively genetic females (1 in 10,000 females). This is because genetic males only have one X chromosome and therefore don’t have dosage compensation occurring, lessening the amount of the mutated gene circulating. Genetic males with the syndrome either die in utero or in infancy due to the severity of the mutation phenotype. For 6 - 18 months persons with Rett Syndrome experience normal development, hitting the usual developmental milestones, until said development suddenly stops and regression begins. There’s usually a mild improvement in some social skills at around age 5, but regression (mental and physical) will continue for the rest of the person’s life.


Rett Syndrome

Sontheimer, H. (2015). Diseases of the Nervous System. Academic Press. 

Diseases of the Nervous System 

Symptoms of Rett Syndrome

- Seizures
- Mobility issues by adolescence
- Autonomic abnormalities: severe constipation, breathing abnormalities
- Reduced life expectancy - most don’t live older than their 60s or 70s 


Comorbidities of Rett Syndrome

There are currently 3 different ways to get a disease phenotype for Rett Syndrome:
through deletion of the entire *MECP2* gene, protein truncation (i.e. permanent modification), or to increase expression of MECP2 by having an extra copy of the *MECP2* gene. All 3 models show various traits of Rett Syndrome:
- Seizures
- Motor dysfunction
- Ataxia
- Tremors
- Hind limb clasping 
- Breathing abnormalities

Mouse Models of Rett Syndrome

*MECP2* mutation can occur in both neurons and glia - and both can contribute to the disease phenotype. Rescuing deficient glial cells is sufficient to reverse the majority of Rett Syndrome symptoms. Select induction of wild-type MECP2 in astrocytes normalized dendritic morphology, increased presynaptic glutamate levels, improved respiratory abnormalities, and there was a decrease in the anxious symptoms. The mice also lived longer - 7 and a half months versus 10 weeks with control animals, which suggests a noncell autonomous function of MeCP2. 


Role of Glia in Rett Syndrome

Microglial cells (which serve as the brain’s immune system) are also affected by the mutation in MECP2:

- Grafting wild-type bone marrow into MECP2 knockout mice essentially erases all disease symptoms, with the added benefit that transplanted mice lived longer (1 year versus 8 weeks with those who were transplanted with mutated marrow)
- Normal MeCP2-expressing microglia can ameliorate disease by contributing to debris clearance (an action which is under the transcriptional control of MeCP2)
- Microglia from MECP2 knockout mice become unsupportive because they release toxic concentrations of glutamate and actively kill neurons (due to glutamate excitotoxicity)

Role of Microglia in Rett Syndrome

- Neuroanatomical abnormalities
- Mutation in MECP2 protein
- High expression of MeCP2 in the brain
- Other gene targets associated with Rett Syndrome

Neurobiology of Rett Syndrome

- Bone marrow ablation and transplant
- Restoring BDNF in the brain
- Activating downstream targets of BDNF
- Statin drugs

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