Fig. 1 Young girl demonstrating typical wringing of hands associated with RTT
Fig. 1 Young girl demonstrating typical wringing of hands associated with RTT


Overview


Originally described by Austrian pediatrician Andreas Rett in 1966, Rett syndrome (RTT) is a genetic disorder that affects neurological development almost exclusively in females. In the early stages of life, the child exhibits normal development, but between 6-18 months, symptoms of the disorder begin to emerge. RTT is associated with a mutation of MECP2, a gene on the X chromosome. It severely inhibits motor and cognitive functioning, and is characterized by problems with gait, hand control, seizures and aphasia, among other symptoms. Rett syndrome affects between 1/10,000 and 1/23,000 births every year, and is a sporadic disorder, meaning it usually does not occur more than once in a family. It is often misdiagnosed as autism, cerebral palsy, or developmental delay. Motor problems related to Rett syndrome are mediated by the cerebellum and basal ganglia, which are associated with control of movement initiation, coordination of voluntary movements and balance.

Functional Anatomy


Cerebellum

The cerebellum is divided into four functional zones or hemispheres. They are:



Fig. 2 The Cerebellum
Fig. 2 The Cerebellum


  • vermis - the most medial zone;receives input from the spinocerebellar tract which synapes with the fastigial nuclei
  • intermediate zone - lateral to the vermis; receives information from the spinocerebellar tract which synapses with the interposed nuclei
  • lateral zone - outermost zone; receives input from the cerebral cortex via the cerebrocerebellar path which synapses with the dentate nuclei
  • flocculonodular lobe - posterior to the other zones; receives input from the vestibular nuclei and apparatus, which synapses with the vestibular nuclei


Functions of the Cerebellum


  • Maintainence of balance and posture from vestibular and proproceptive input
  • Coordination of voluntary movements by modulating timing and force of the muscle groups
  • Motor learning through adaptation and fine-tuning in solving a motor problem
  • Cognitive function associated with language

Input and output pathways

Fig. 3 Vestibulocerebellar Pathway
Fig. 3 Vestibulocerebellar Pathway

Fig. 4 Spinocerebellar Pathway
Fig. 4 Spinocerebellar Pathway

Fig. 5 Cerebro-cerebellar Pathway
Fig. 5 Cerebro-cerebellar Pathway

The input and output pathways involving the cerebellum include the vestibulo-cerebellar (Fig. 3), spinocerebellar (Fig. 4), and cerebro-cerebellar (Fig. 5) pathways. Each different pathway corresponds to a specific function of the cerebellum.

1. Vestibulocerebellar path - Sensory input from the vestibular apparatus is sent to the flocculonodular lobe of the cerebellum via the inferior peduncle, and then to the medulla, synapsing with the vestibular nuclei there. Signals from the vestibular nuclei descend via the vestibulospinal pathway, activating axial musculature used in balance and posture.

2. Spinocerebellar path - Input from the spinal cord enters the cerebellum through the inferior peduncle and synapses with either the fastigial nuclei in the vermis or interposed nuclei of the intermediate zone. Output signals from the fastigial nuclei are sent to the vestibular nuclei or the reticular formation, while signals from the interposed nuclei are sent to the red nucleus. Fastigial signals descend from the reticular formation via the reticulospinal tract (both pontine and medullary) and is involved in modulating the flexor response. Signals from the red nucleus descend via the rubrospinal tract, the main lateral descending pathway. It causes excitiation of flexor muscles and inhibition of extensors. It is also thought to have a role in movement velocity.

3. Cerebrocerebellar path - Input from the cerebral cortex via the pontine nuceli enters the cerebellum through the middle cerebellar peduncle, and synapses with the dentate nuclei of the lateral hemisphere. Output from the dentate projects to the VL of the thalamus and the red nucleus. Thalamic nuclei then project to the primary motor cortex and descend via the corticospinal tracts (both lateral and ventral). The lateral path controls distal musculature while the ventral tract controls the proximal.


Basal Ganglia

Fig. 6 The Basal Ganglia
Fig. 6 The Basal Ganglia

The basal ganglia is a structure associated with the initiation of movement and also has cognitive functions. It is composed of four major structures, three of which have subparts:

Striatum: made up of the caudate and putamen
Globus Pallidus: has internal (GPi) and external (GPe) components
Substantia Nigra: made up of the pars compacta (SNc) and pars reticula (SNr)
Subthalamic nucleus (STN)

Input and output Pathways
The control of movement by the basal ganglia is the consequence of either the facilitory direct pathway or the inhibitory indirect pathway. In the direct pathway, release of neurotransmitters eventually leads to the disinhibition of the thalamus by the GPi. This disinhibition allows the thalamus to send excitatory signals to the motor cortex to initiate a movement. In the indirect pathway, release of neurotransmitter eventually leads to an increased inhibition of the thalamus by the GPi, decreasing the excitatory response of the thalamus, resulting in movement inhibition. Input to the basal ganglia comes from either the frontal eye field areas of the premotor cortex and association areas, or from the posterior parietal cortex.



Fig. 8 Indirect Pathway of Basal Ganglia
Fig. 8 Indirect Pathway of Basal Ganglia

Fig. 7 Direct Pathway of Basal Ganglia
Fig. 7 Direct Pathway of Basal Ganglia


















Rett Syndrome

Fig. 9 Dr. Andreas Rett at his clinic in Austria
Fig. 9 Dr. Andreas Rett at his clinic in Austria


History

Rett syndrome was first described by Austrian physician Andreas Rett in 1977. He began studying the disorder in 1954 after noticing two young girls in his waiting room exhibiting the same "hand washing" movements. After comparing their medical histories and noting the similarities, Dr. Rett began filming and documenting the two girls along with six of his other young, female patients that displayed similar behaviors. Unsatisfied with studying his own patients, the doctor began traveling through Europe in search of other children with the same symptoms. Although Rett published his findings in 1966, the ideas regarding the pathology of the syndrome remained backwards until later in the 21st century. It was previously thought of as a degenerative disorder that would progressively get worse as the child aged. However, as research continued, and the origin of the disease was linked to mutations of the MECP2 gene on the X-chromosome, it became apparent that Rett syndrome is a neurodevelopmental, rather than degenerative, disorder.

Signs and Symptoms

Signs and symptoms of Rett Syndrome include motor, autonomic nervous and cognitive systems.

Motor System
  • Ataxia
  • Abnormal gait
  • Grinding of teeth
  • Wringing/washing motion of hands
  • Ideomotor apraxia
  • Loss of muscle tone
  • Loss of eye control

Autonomic Nervous System
  • Labored breathing
  • Digestion problems
  • Cardiac function

Cognitive Function
  • Learning impairment
    • loss of interest
  • Speech/language impairment
  • Mood
    • anxious
    • withdrawn


Pathophysiology of the disorder

Fig. 10 Normal binding of MeCP2 protein
Fig. 10 Normal binding of MeCP2 protein

Through much research, the protein Methyl CpG-binding protein 2 (MeCP2) has been defined as the cause of Rett Syndrome. Normally, non-methylated CpG dinucleotides attract MeCP2 proteins, which bind to the dinucleotides shutting off transcription of a gene. MeCP2 is thought to play a key role in assembling certain proteins to turn of transcription. One researcher suggests that the connection between MeCP2 and Rett Syndrome is that a defective MeCP2 gene would cause problems with stopping transcription and expression of inappropriate genes in the brain. Research also suggests that mutated MeCP2 proteins fail to silence imprinted alleles, which leads to a double expression of that gene. In the regulation of the DLX5 gene, the mutation causes misregulation in the production of GABA, a neurotrasmitter involved in many areas of the brain, including the Basal Ganglia. With the mutation of the MeCp2 gene. the production of the DLX5 protein increases through the loss of silent chromatin loops, and activation of neighboring chromatin.

In the basal ganglia, GABA is a neurotransmitter that plays a key role in the initiation of movement. It functions in both the direct and indirect pathways and has an inhibitory effect on its target. With Rett Syndrome, the anatomical implications include a generally smaller sized brain than normal, due to generalized hypoplasia, with reductions in both cerebellar and basal ganglionic regions contributing to much of the motor symptoms. Research has shown that within the cerebellum, the Rett brain has a decreased number of Purkinje cells and astrocytic gliosis in the molecular and granular layers. This hypertrophy of the astrocytes in the cerebellum relates to the release of excitotoxic glutamate, causing death in the nerve cells and severely impairing normal brain function. Glutamate is also involved in the basal ganglionic control of movement, so any irregularities in its concentration will have an effect on both the cerebellum and the basal ganglia, as well as other areas in the brain. Also contributing to the symptoms of RTT is the small dendritic branching of the pyramidal cells in layers III and V of the motor cortex. These pyramidal (Betz) cells are responsible for motor outputs to the via the corticospinal tracts, which control distal and proximal musculature associated with voluntary movements. The loss of these cells corresponds to abnormal gait patterns and problems with balance typical in Rett Syndrome.

Treatment
Currently there is no cure for Rett Syndrome, however, extensive research continues to be done in the hopes that a cure will be found. Treatment for the syndrome is symptom based, meaning the focus is on managing the effects of the disease rather than treating its source. Treatment may include medication (for irregular breathing, seizures or motor difficulties), physical, occupational and hydrotherapy, and special equipment such as braces to prevent scoliosis and assist in locomotion.


Summary


Rett Syndrome (RTT) is a genetic neurodevelopmental disorder that is linked to mutations of the MeCP2 gene that codes for proteins which stop transcription of other genes, namely imprinted alleles of the DLX5 gene. This causes abnormal release of certain neurotransmitters related to cognitive and motor funtions. Through the basal ganglia and the cerebellum, the balance, coordination and initiation of movement are impaired. The person will likely exhibit symptoms of abnormal gait, loss of control of hand and eye movements, loss of speech and learning impairment. There may also be a visible decline in the rate of head growth after the first 12-18 months. Although there is currently no cure for the syndrome, researchers continue to study to MeCP2 gene and its relation to RTT.


Glossary

  • ataxia - lack of muscle coordination during voluntary movement
  • ideomotor apraxia - the inability to translate an idea into motion
  • hypoplasia - incomplete or underdevelopment of an organ or tissue
  • astrocytic gliosis - proliferation or hypertrophy of glial cells (astrocytes)


Quiz

  1. What is the name of the gene that is linked to RTT?
  2. Name three motor symptoms of Rett Syndrome
  3. Diagram the direct pathway of the Basal Ganglia.
  4. Diagram the cerebrocerebellar pathway of the cerebellum.
  5. When do symptoms of RTT begin to occur?
    1. a. at birth
    2. b. 3-6 months
    3. c. 6-18 months
    4. d. after 24 months
  6. What are two neurotransmitters involved in RTT?
    1. a. glutamate, GABA
    2. b. GABA, glucagon
    3. c. glutamate, glucagon
  7. T/F The indirect pathway of the basal ganglia excites the globus pallidus internus, which excites the thalamus.
  8. T/F The spinocerebellar path is a descending pathway associated with control of the axial muscles.
  9. T/F Small dendritic branching of the Betz cells in layer V in the motor cortex is characteristic in RTT.

Further Reading


Longitudinal Hand Function in Rett Syndrome A study of the loss of hand function in Rett patients

Autonomic Responses to Music and Vibroacoustic Therapy in Rett Syndrome A study of the effects of music and vibration therapies on the autonomic nervous system of Rett patients


Resources

IRSF. (2008). What is Rett Syndrome? Retrieved from International Rett Syndrome Foundation: http://www.rettsyndrome.org/index.php?option=com_content&task=blogsection&id=4&Itemid=1000

Jackowski, A., Laureano, M., Del'Aquilla, M., de Moura, L., Assunção, I., Silva, I., & Schwartzman, J. (2011). Update on Clinical Features and Brain Abnormalities in Neurogenetics Syndromes. Journal Of Applied Research In Intellectual Disabilities, 24(3), 217-236. doi:10.1111/j.1468-3148.2010.00603.x

Percy, A. K. (2008). Rett syndrome: from recognition to diagnosis to intervention. Expert Review of Endocrinology & Metabolism, 3(3), 327+. Retrieved from http://go.galegroup.com.proxy2.noblenet.org/ps/i.do?id=GALE%7CA223163511&v=2.1&u=mlin_n_gordon&it=r&p=AONE&sw=w

Richard, G. J., & Hoge, D. R. (1999). Rett Syndrome. In The Source for Syndromes (pp. 98-106). East Moline: Linguisystems, Inc.

Shanon, J. B. (2003). In Movement Disorders Sourcebook (pp. 251-262). Detroit: Omnigraphics.

Thompson, V. , & Block, M. (2010, Spring). Rett Syndrome: implications for physical education and other movement settings. Palaestra, 25(2), 19-27. Retrieved December 20, 2012, from Nursing and Allied Health

University of Texas Health Science Center at Houston. (1997). Motor Corticies; Basal Ganglia; Cerebellum. Retrieved from Neuroscience Online: An Electronic Textbook for the Neurosciences: http://neuroscience.uth.tmc.edu/


Answers to Quiz questions:
1. MeCP2
2. ataxia, ideomotor aphasia, wringing hand motions
3. See basal ganglia anatomy section
4. See cerebellar anatomy section
5. c.
6. a.
7. F
8. F
9. T