Rett Syndrome (RS)

Introduction

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Stereotypical RS hand wringing

Rett Syndrome is a non-inherited genetic neurodevelopment disease that effects almost exclusively girls (1 in 10,000). In very rare cases, a boy with the mutation can survive. A mutation in the methyl-CpG binding protein 2 gene (MECP2) leads to sever impairments in motor development, language development, loss of purposeful hand movement, stereotopies, ataxia, dystonia, and hypertonicity or hypotonicity. Girls diagnosed with RS also have cognitive impairment, however, the severity of impairment is hard to quantify and test due to the patients lack of speech and inability to use their hands. Girls display abnormalities of breathing, heart rate, peripheral circulation, and emotional hyperexcitability that have to be distinguished from autonomic dysfunction and seizures. [1] Studies using receptor autoradiography demonstrate abnormalities in the density of excitatory glutamate and GABA synaptic receptors in the brains from young female subjects with Rett syndrome. MeCP2, the protein that is abnormal in most female individuals with Rett syndrome, is expressed predominantly in neurons and appears during development at the time of synapse formation.

Symptoms start appearing at 6-8 months of age, girls stop hitting their developmental milestones and start showing symptoms of microcephaly due to decrease in head growth. The hallmark of RS is the intense, sometimes continuous, stereotypic hand wringing, which develop after the loss of purposeful hand movements. [9] Once RS is suspected genetic testing is done to find a mutation of the MECP2 gene on the X chromosome. Atypical Rett syndrome is a milder version of the disease and is caused by mutations in different genes such as CDKL5 or FOXG1. Symptoms vary from child to child, however, typically there are four stages to Rett Syndrome.
Stage 1: At 6 to 18 month the child starts to slow in development. Head growth slows and hand wringing may start. The child may start making less eye contact, showing less interest in toys, and will delay in sitting up and crawling.
Stage 2: During years 1-4 further deterioration occurs either rapid or slow. The child losses any ability to speak, has difficulty initiating movement and gait is unsteady. Breathing irregularities may emerge, such as apnea, hyperventilation, and breath holding. Girls start to exhibit difficulty communicating and symptoms of autism.
Stage 3: This is known as the psuedostationary stage. Between age 2 and 10 girls starts experiencing greater motor deficits, seizures and apraxia. Symptoms of irritability, autistic characteristics and crying seem to decline and girls seem to become more alert and interested in their environment, and attempts at communication increase.
Stage 4: This is the late motor deterioration stage. Characterized by decreased mobility, muscle weakness, spasticity and rigidity. The main mode of communication becomes the eyes.

Studies looking at the brains of girls with Rett syndrome found that there was an alteration of the development of neurotransmitter receptors. Dendritic densities were also significantly reduced. Receptors for GABA and Glutamate are found on the dendrites of the neurons, and not only did the dendrites atrophy but there was an abnormal amount of receptors found on the dendrites. Girls in the study were separated into to two groups, younger and older than 10 years of age. The densities of the neurotransmitter receptors in the basal ganglia were examined. The girls who were younger than 10 years of age displayed a greater amount of GABA and Glutamate receptors than the 10 years and older group. The conclusion from this study was that, "These age-related biphasic changes in synaptic receptors might be connected to the clinical shift from an active phase of psychomotor regression and encephalopathy in younger female individuals with Rett syndrome to a more chronic plateau phase in older female individuals." [5]


Diagnosis is made by clinical observation of signs and symptoms. Girls are monitored for developmental milestones, and their physical and neurological status is closely observed as well. Genetic testing for the MECP2 mutation on the X chromosome is also coupled with clinical findings to diagnose the child.
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Table 1 [9]


Functional Anatomy

Cerebellum

Peduncles
  • Superior Peduncle (Brachium Conjunctivum)
    • Mostly efferent fibers
    • Major output pathway from the cerebellum and input from the anterior spinocerebellar tract
  • Middle Peduncle (Brachium Pontis)
    Anatomical-Lobes-of-the-Cerebellum.jpg
    Lateral view of the cerebellum
    • Exclusively afferent input from the pons
    • Input pathway from cortocopontocerebellar tract. projections from the sensory and motor areas.
  • Inferior Peduncle (Restiform Bodies)
    • Mostly afferent
    • Input pathway for proprioceptive, motor and vestibular information.
Lobes
  • Anterior Lobe
  • Posterior Lobe
  • Flocculonodular Lobe

Regions
cerebellum-11-638.jpg
  • Spinocerebellum (Vermis and intermediate zone)
    • Receives proprioceptive information. Involved in regulating body movements by allowing for error correction. Plays a role in regulation of muscle tone, posture and coordination of movement.
  • Cerebrocerebellum
    • Lateral hemispheres
    • Involved in planning movements and motor learning. Compares the intended movement, information from the cortex and peripheral feedback of how the movement was actually executed. Makes comparison and sends corrections to the motor cortex.
  • Vestibulocerebellum
    • Flocculonodular lobe
    • Involved in controlling balance and ocular reflexes.





Deep nuclei
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  • Dentate
  • interpose (globose and emboliform)
  • Fastigial

Function

The basic function of the cerebellum is maintenance of balance and posture, coordination of voluntary movements, motor learning, and cognitive functions. Most of what is known about the function of the cerebellum comes from studies in which the cerebellum has been damaged either intentionally, as seen in animal trials or humans with cerebellar damage. Animals and humans with cerebellar dysfunction show, above all, problems with motor control, on the side of the body ipsilateral to the damaged cerebellum. They continue to be able to generate motor activity, but it loses precision, prod
ucing erratic, uncoordinated, or incorrectly timed movements. A standard test of cerebellar function is to reach with the tip of the finger for a target at arm's length: A healthy person will move the fingertip in a rapid straight trajectory, whereas a person with cerebellar damage will reach slowly and erratically, with many mid-course corrections. Deficits in non-motor functions are more difficult to detect. Thus, the general conclusion reached decades ago is that the basic function of the cerebellum is not to initiate movements, or to decide which movements to execute, but rather to calibrate the detailed form of a movement. The cerebellum is involved in the timing of movement and in the progression from one movement to the next. It helps control the intensity of muscle contraction and modulates the interplay between agonist and antagonist muscle groups.

Pathways
Afferent pathways
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Efferent Pathways
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Basal Ganglia

Are a group of nuclei located deep in the core of the brain. The are thought to be responsible for the planning and modulation of movement pathways. It is known to allow the initiation of movement and releases the cortex from inhibition.

Nuclei
  • Striatum: Main input nuclei of the basal ganglia
    • Caudate
      • Frontal lobe projects to the head of the caudate. Parietal and occipital lobes project to the body of the caudate. Temporal lobe projects to the tail of the caudate.
    • Putamen
      • Primary motor cortex and sensory areas projects to the putamen.
(Cortical connections to the basal ganglia are glutamatergic - releasing glutamate to excite the striatum )[BG]
  • Globus pallidus (GP)
    • Internus: output from basal ganglia
    • Externus: Internal connections
  • Substantia nigra (SN)
    • Pars compacta: Internal connections
    • Pars reticulata: output from basal ganglia

Direct Pathway
In the direct pathway, striatal cells project directly to GPi. The consequence of this pathway is to increase the excitatory drive of from the thalamus to cortex. The cortical projections to the striatum use the excitatory transmitter glutamate. When they are activated, these cortical projections excite striatal neurons. The striatum has inhibitory output. The cells of the striatum that project to the GPi and SNr release GABA and substance P which has an inhibitory effect. The GPi and SNr are inhibited by the striatum. The neurons in the GPi and SNr project to thalamus ( VA/VL) and also release GABA, and are tonically active in inhibiting the VA/VL. So when the GPi and SNr are inhibited by the striatum, the VA/VL is released from its inhibition from the GPi and SNr. The VA/VL is allowed to fire, excitatory input to the cortex. The direct pathway facilitates movement.
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Indirect Pathway
In the indirect pathway the striatum neurons project to the GPe. The cortical projections to the striatum use the excitatory transmitter glutamate. When they are activated, these cortical projections excite striatal neurons. The striatum has inhibitory output, only in the indirect pathway the striatum inhibits the GPe. To understand the indirect pathway we have to add another nucleus, the subthalamic nucleus. The Neurons in the the GPe project to the subthalamic nucleus (STN). The STN has projections to the GPi. The GPe inhibits the STN tonically with GABA, and so the inhibition of the GPe from the striatum releases the STN from inhibition. The neurons from the STN are excitatory, they release Glutamate, and excite the GPi. The increase in activity in the GPi inhibits the VA/VL more and the VA/VL is unable to excite the cortex. The Indirect pathway inhibits movement.
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GABA and Glutamate










Most inhibitory neurons in the brain and spinal cord use either γ-aminobutyric acid (GABA) or glycine as a neurotransmitter. It is now known that as many as one-third of the synapses in the brain use GABA as their neurotransmitter. The presence of GABA in neurons and terminals is a good initial indication that the cells in question use GABA as a neurotransmitter. GABA is most commonly found in local circuit interneurons, although the Purkinje cells of the cerebellum provide an example of a GABAergic projection neuron.The predominant precursor for GABA synthesis is glucose, which is metabolized to glutamate by the tricarboxylic acidcycle enzymes, although pyruvate and glutamine can also act as precursors. The enzyme glutamic acid decarboxylase (GAD), which is found almost exclusively in GABAergic neurons, catalyzes the conversion of glutamate to GABA. GABA is a neurotransmitter that has an inhibitory effect on the neurons that have GABA receptors. There are three types of GABA receptors. GABAa, GABAb and GABAc receptors. GABAa and c function in a similar manner. When GABA binds to receptor a or c, which are ligand gated chloride channels, they open and allow for the influx of Cl anions. The influx of Cl anions depolarizes the neuron, which causes an inhibitory effect on the neuron. GABAb receptors function a little different. GABAb acts through a G-protein that acts by activating K cation channels, allowing efflux of K cations out of the neuron. This again hyperpolarizes the neuron.

Glutamate is one of the most abundant neurotransmitters found in the nervous
Screen Shot 2017-12-07 at 7.44.25 PM.pngsystem. It is a nonessential amino acid that does not cross the blood brain barrier.
Glutamate is made from glutamine which is released by the glial cells into the presynaptic terminals and is then metabolized by mitochondrial enzyme glutaminase. Glutamate can also be synthesized by transamination of 2-oxoglutarate, and intermediate of the tricarboxylic acid (TCA) cycle Therefore, some of the glucose metabolized by neurons can also be used for glutamate synthesis. Glutamate is removed from the presynaptic terminal by high-affinity glutamate transporters. Several types of ionotropic glutamate receptors have been identified. Three of these are ligand-gated ion channels caleed NMDA receptors, AMPA Receptors and kainate receptors These glutamate receptors are named after the agonists that activate them: N-methyl-d-aspartate, alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate and kainic acid. All of the ionotropic glutamate receptors are nonselective cation channels, allowing the passage of Na and K cations and in some cases Ca cations. The influx of positive ions depolarizes the neuron.







Treatment

At the moment there is no cure for Rett Syndrome. Due to the rare nature of the mutation a lot of what is known about the disease is from studies done one mice. What can be done for the girls is management of symptoms associated with the disease.

Management

Medical management of RS is mostly symptomatic and supportive and varies from patient to patient depending on the specific symptoms displayed. A
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Arm brace typically used with RS
multidisciplinary team approach is advised, aimed at maximizing each patient’s abilities and facilitating any skills that may be emerging. Management should include support groups for families, development of an appropriate education plan, and assessment of available community resources. Pharmacological treatments for RS have included L-carnitine, which may lead to an improvement in patient wellbeing and quality of life, magnesium to reduce the episodes of hyperventilation, and melatonin to improve sleep dysfunction and help the child with sleeping through the night. Decreasing repetitive purposeless hand movements can be achieved by the use of various arm restraints, such as soft elbow splints, and are occasionally helpful in training specific hand skills such as normal eating. These methods are also helpful in decreasing agitation and help to keep the child from hurting herself. Feeding problems are common in RS. Several factors contribute to this, including poor food intake and swallowing difficulties and immature chewing patterns, and the fact the child uses a lot more energy than a normal child when trying to move and creates a caloric imbalance. Some girls have poor weight gain, despite having a normal appetite. This may be because the majority of girls are unable to feed themselves, and very few develop mature chewing patterns. A gastrostomy tube may be used as an alternate to self-feeding to make sure the girl is getting the nutrients she needs.Scoliosis is seen in 65% of girls, some can be fixated with a brace however some may need surgical intervention. Tension at the Achilles tendon is commonly the first sign of rigidity and should be monitored closely. Toe walking is a good indicator of increase tone in the gastrocnemius. Maintaining ortho-braces are used to keep feet aligned with one another, while maintaining active and ambulating often.

Most girls loss any way of expressing themselves verbally, with only a few retaining a few words. The use of boards for communication as well as, technical devices, and switch activated systems. These are used for making choices. Some girls are also able to communicate through eye pointing, gestures, body language, and hand pointing. These abilities need to be recognized and encouraged.[9]




Summary

Rett Syndrome is a rare progressive neurological disorder that occurs in 1 and 10,000 girls. Is a mutation of the MECP2 gene occurs without inheritance and causes developmental changes in a child around 6-8 months. At this point, they lose any skills they had learned up to that point, this is called, developmental regression, such as purposeful hand movements and the ability to communicate. Other deficiencies occur including impaired control of voluntary movements, also known as ataxia, and the development of hand wringing. A lot of girls have slowing of head growth, acquired microcephaly. Affected girls often display autistic-like behaviors, breathing irregularities, feeding and swallowing difficulties, and seizures. Most Rett syndrome cases are caused by identifiable mutations of the MECP2 gene on the X chromosome and can present with a wide range of disability ranging from mild to severe. The course and severity of Rett syndrome is determined by the location, type and severity of the MECP2 mutation and the process of random X-inactivation. So, two girls of the same age with the same mutation can appear significantly different. The mutation is thought to cause changes in the number of receptors on neurons and dendritic atrophy of the nervous system leading to the array of motor and cognitive deficiencies seen in the disorder. There is still lots to be learned about the pathophysiology of the disorder. There is great need for research for further understand to best help girls with RS and research for a cure.



Glossary

  • Gene Mutation: Is a permanent mutation in the DNA sequence that causes a change in a gene and its expression.
  • X Chromosome: The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, (the other is the Y chromosome), and is found in both males and females.
  • MECP2: Protein that is abnormal in most Rett patients. MeCP2 functions as a transcriptional repressor that works in concert with other corepressor molecules.
  • Stereotopies: is a repetitive or ritualistic movement, posture, or utterance. Stereotypies may be simple movements such as body rocking, or complex, such as self-caressing, crossing and uncrossing of legs, and marching in place.
  • Ataxia: describes a lack of muscle control or coordination of voluntary movements, such as walking or picking up objects. A sign of an underlying condition, ataxia can affect various movements, creating difficulties with speech, eye movement and swallowing.
  • Dystonia: Involuntary muscle contractions that cause repetitive and twisting movements.
  • Hypertonicity: Increase of muscular tension, when compared to resting muscle tone.
  • Hypotonicity: Lack of normal muscular tone.
  • Microcephaly: Small head, developmental condition due to the underdevelopment of the brain that causes a child's head to be smaller than normal.
  • Cerebellum: The little brain, functions in the coordination of movement, modulation of tone and posture and plays a role in motor learning. See section on cerebellum.
  • Basal Ganglia: A clustering of nuclei that both facilitate and inhibit movement. It allows for the initiation of movement by releasing the cortex from its inhibition.
  • GABA: Inhibitory neurotransmitter used by the nervous system.
  • Glutamate: Excitatory neurotransmitter used by the nervous system.

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Videos






Suggested Readings


  1. Eye Gaze Technology as a Form of Augmentative and Alternative Communication for Individuals with Rett Syndrome: Experiences of Families in The Netherlands
  2. Teaching Self-Feeding Skills to Patients With Rett Syndrome

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References

[1] Armstrong, D. D. (2005). Neuropathology of Rett Syndrome. Journal Of Child Neurology, 20(9), 747-753.
[2] Armstrong, D. D. (2002). Neuropathology of Rett syndrome. Mental Retardation & Developmental Disabilities Research Reviews, 8(2), 72-76. doi:10.1002/mrdd.10027
[3] Basal Ganglia. (n.d.). Retrieved December 07, 2017, from https://www.kenhub.com/en/library/anatomy/basal-ganglia#_=_
[4] Ducreux, P. D. (n.d.). The Cerebellum . Retrieved December 06, 2017, from http://www.fmritools.com/kdb/grey-matter/cerebellum/cerebellum-3/index.html
[5] Johnston, M. V., Blue, M. E., & Naidu, S. (2005). Rett Syndrome and Neuronal Development. Journal Of Child Neurology, 20(9), 759-763.
[6] Purves, D. (1970, January 01). Glutamate Receptors. Retrieved December 07, 2017, from https://www.ncbi.nlm.nih.gov/books/NBK10802/
[7] Rett syndrome. (n.d.). Retrieved December 07, 2017, from https://www.rettsyndrome.org/about-rett-syndrome
[8] Rett Syndrome NORD. (n.d.). Retrieved December 07, 2017, from https://rarediseases.org/rare-diseases/rett-syndrome/
[9] Weaving, L. S. (2005). Rett syndrome: clinical review and genetic update. //Journal of Medical Genetics,////42//(1), 1-7. doi:10.1136/jmg.2004.027730



Questions

1. Around what age do girls start exhibiting the first symptoms of Rett Syndrome?
a. around their first birthday
b. 4-6 months
c. 6-8 months
d. at birth
2. L-carnitine is used to reduce symptoms of seizures in girls with Rett T/F
3. What macromolecule is the precursor for both GABA and glutamate ?
a. L-dopa
b. 5-HTP
c. tricarboxylic acid
d. glucose
4. Boys that are diagnosed with Rett Syndrome have a MECP2 mutation on the Y chromosome. T/F
5. The GPi is in the indirect pathway and in the direct pathway.
a. excited, inhibited
b. inhibited, excited
c. excited, excited
d. inhibited, inhibited
6. The brachium conjunctivum is the major output pathway to the cerebellum T/F
7. The NMDA and AMPA are both glutamate receptors and kainate is a GABA receptor. T/F
Short answer
8. Explain how the direct pathway facilitates the initiation of movement.
9. List 6 symptoms needed for the diagnosis of Rett syndrome.
10. Parents of a 9 month old baby girl are concerned that their daughter is not not yet crawling and is having difficulty sitting up, something that she used to have no problem doing. They have also caught her holding her breath, at first they thought it was cute, but she seems to be doing it more often and they are starting to get concerned. Would you suspect that the child has Rett syndrome? Why or why not? What further steps should be taken to address the parents concerns?




1. b
2. F
3. d
4. f
5. a
6. T
7. F
8. The cortical projections to the striatum release glutamate and excite the striatum. Striatal projections to the GPi are inhibitory, the inhibition of the GPi releases the Thalamus from its inhibition and it is allowed to send input to the cortex.
9. See main criteria listed on table 1
10. There is suspicion of Rett syndrome or a variation of Rett because the child is showing symptoms associated with Rett. The next steps that need to be taken are more clinical observation of the child, if she does have Rett she in the first stage and should be monitored closely. Once all symptoms are identified, it should be determined whether or not the child has classic Rett or a variation. Genetic should also be done as the child is continually observed. If there is a diagnosis parents should get informed about the disease and join a support group. An education plan should be made for the child to cater learning to her needs, as well as physical and occupational therapy to work on motor skills.