Rett syndrome

Rett Syndrome
Classification and external resources
ICD-10	F84.2
ICD-9	330.8
OMIM	312750
DiseasesDB	29908
MeSH	C10.574.500.775

Rett syndrome is a neurodevelopmental disorder of the grey matter of the brain^[1] that affects almost exclusively females. The clinical features include small hands and feet and a deceleration of the rate of head growth (including microcephaly in some). Repetitive hand movements, such as wringing and/or repeatedly putting hands into the mouth, are also noted. People with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures.^[2] They typically have no verbal skills, and about 50% of individuals affected are not ambulatory. Scoliosis, growth failure, and constipation are very common and can be problematic.

The signs of this disorder are most easily confused with those of Angelman syndrome, cerebral palsy and autism.

Some argue^{[citation needed]} that it is misclassified as an autism spectrum disorder, just as it would be to include such disorders as fragile X syndrome, tuberous sclerosis, or Down syndrome where one can see autistic features.^[3] However, it has been suggested that it be removed from the DSM-5, because it has a specific etiology.^[4]

It was first described by Austrian pediatrician Andreas Rett in 1966.^[5]

In DSM-IV-TR page 76, Rett's Disorder 299.80 is listed under the broad category of Pervasive Developmental Disorders.

Cause

Genetically Rett syndrome (symbolized RTT) is caused by mutations in the gene MECP2 located on the X chromosome and can arise (1) sporadically or (2) from germline mutations. In less than ten per cent of Rett Syndrome cases, mutations in the genes CDKL5 or FOXG1 have also been found to cause Rett Syndrome. Rett Syndrome is still diagnosed by a clinical observation, and in some very rare cases, no known mutated genes can be found. Genetic blood tests can reveal mutated suspect genes if they exist for confirmation of the observed diagnosis.

Sporadic mutations

In at least ninety five percent of cases, the cause of Rett syndrome is a de novo mutation in the child. That is, it is not inherited from either parent. Parents are generally genotypically normal, without an MECP2 mutation.

In sporadic cases of Rett syndrome, it is thought that the mutated MECP2 is usually derived from the male copy of the X chromosome.^[6] It is not yet known what causes the sperm to mutate, and such mutations are rare.

Germline mutations

It can also be inherited from phenotypically normal mothers who have a germline mutation in the gene encoding methyl-CpG-binding protein-2, MECP2.^[7] MECP2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of Rett syndrome, characterized by infantile spasms or early onset epilepsy, can also be caused by a mutation to the gene encoding cyclin-dependent kinase-like 5 (CDKL5). Rett syndrome affects one in every 12,500 female live births by age 12 years.

Pontine noradrenergic deficits

Brain levels of norepinephrine are lower in people with Rett syndrome^[8] (reviewed in^[9]). The genetic loss of MECP2 changes the properties of cells in the locus coeruleus, the exclusive source of noradrenergic innervation to the cerebral cortex and hippocampus.^[10][11] These changes include hyperexcitability and decreased functioning of its noradrenergic innervation.^[12] Moreover, a reduction of the tyrosine hydroxylase (Th) mRNA level, the rate-limiting enzyme in catecholamine synthesis, was detected in the whole pons of Mecp2-null male as well as in adult heterozygous (Mecp2+/-) female mice.^[13] Using immunoquantitative techniques, a decrease of Th protein staining level, number of locus coeruleus TH-expressing neurons and density of dendritic arborization surrounding the structure was shown in symptomatic Mecp2-deficient mice.^[13] However, locus coeruleus cells are not dying but are more likely losing their fully mature phenotype since no apoptotic neurons in the pons were detected.^[13] Researchers have concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that the locus coeruleus is a critical site at which loss of MECP2 results in CNS dysfunction." The restoration of normal Locus coeruleus function may therefore be of potential therapeutic value in the treatment of Rett syndrome.^[12][13]

Midbrain dopaminergic disturbances

The majority of dopamine in the mammalian brain is synthesized by nuclei located in the mesencephalon. The substantia nigra pars compacta (SNpc), the ventral tegmental area (VTA) and the retrorubral field (RRF) contains dopaminergic neurons expressing tyrosine hydroxylase (Th, i.e. the rate-limiting enzyme in catecholamine synthesis).^[14][15][16]

The nigro-striatal pathway originates from SNpc and irradiate its principal rostral target, the Caudate-Putamen (CPu) through the median forebrain bundle (MFB). This connection is involved in the tight modulation of motor strategies computed by a cortico-basal ganglia- thalamo-cortical loop.^[17]

Indeed, based on the canonical anatomo-functional model of basal ganglia, nigrostriatal dopamine is able to modulate the motor loop by acting on dopaminergic receptors located on striatal GABAergic medium spiny neurons.^[18]

Dysregulation of the nigro-striatal pathway is causative from Parkinson disease (PD) in humans.^[19] Toxic and/or genetic ablation of SNpc neurons produces experimental parkinsonism in mice and primates.^[20] The common features of PD and PD animal models are motor impairments^[21] (hypotonia, bradykinesia, hypokinesia).

RTT pathology, in some aspects overlaps the motor phenotype observed in PD patients.^[22][23][24] Several neuropathological studies on post-mortem brain samples argued for a SNpc alteration evidenced by neuromelanin hypopigmentation, reduction in the structure area, and even controversial, signs of apoptosis. In parallel, an hypometabolism was underlined by a reduction of several catecholamines (dopamine, noradrenaline, adrenaline) and their principal metabolic by-products.^[25] Mouse models of RTT are available and the most studied are constitutively deleted Mecp2 mice developed by Adrian Bird or Rudolph Jaenisch laboratories.^[26][27]

In accordance with the motor spectrum of the RTT phenotype, Mecp2-nulls show motor abnormalities from postnatal day 30 that worsen until death. These models offers a crucial substrate to elucidate the molecular and neuroanatomical correlates of a Mecp2-deficiency.^[28] Recently, it was shown that the conditional deletion of Mecp2 in catecholaminergic neurons (by crossing of Th-Cre mice with loxP-flanked Mecp2 ones) recapitulates a motor symptomatology, it was further documented that brain levels of Th in mice lacking Mecp2 in catecholaminergic neurons only are reduced, participating to the motor phenotype.^[29] However, the most studied model for the evaluation of therapeutics is the Mecp2-null mouse (totally devoid of Mecp2). In this context, a reduction in the number and soma size of Th-expressing neurons is present from 5 weeks of age and is accompanied by a decrease of Th immunoreativity in the caudate-putamen, the principal target of dopaminergic neurons arising from the SNpc.^[30] Moreover, a neurochemical analysis of dopaminergic contents in microdissected midbrain and striatal areas revealed a reduction of dopamine at five and nine weeks of age. It is noteworthy that later on (at nine weeks), the morphological parameters remain altered but not worsen, whereas the phenotype progresses and behavioral deficits are more severe. Interestingly, the amount of fully activated Th (Serine40-phosphorylated isoform) in neurons that remain in the SNpc is mildly affected at 5 weeks but severely impaired by 9 weeks.^[30] Finally, using a chronic and oral L-Dopa treatment on Mecp2-deficient mice authors reported an amelioration of some of the motor deficits previously identified.^[30] Altogether, these results argue for an alteration of the nigrostriatal dopaminergic pathway in Mecp2-deficient animals as a contributor of the neuromotor deficits.

Gender

Male fetuses with the disorder rarely survive to term. Because the disease-causing gene is located on the X chromosome, a female born with a MECP2 mutation on her X chromosome has another X chromosome with an ostensibly normal copy of the same gene, while a male with the mutation on his X chromosome has no other X chromosome, only a Y chromosome; thus, he has no normal gene. Without a normal gene to provide normal proteins in addition to the abnormal proteins caused by a MECP2 mutation, the XY karyotype male fetus is unable to check the development of the disease, hence the failure of many male fetuses with a MECP2 mutation to survive to term. Females with a MECP2 mutation, however, have a non-mutant chromosome that provides them enough normal protein to survive at least to birth. Research shows that males with Rett syndrome almost all have Klinefelter's syndrome as well (in which the male has an XXY karyotype).^[31] Thus, a non-mutant MECP2 gene is necessary for a Rett's-affected embryo to survive in most cases, and the embryo, male or female, must have another X chromosome.

There have, however, been several cases of 46,XY Karyotype males with a MECP2 mutation (associated with classical Rett syndrome in females) carried to term, who were affected by neonatal encephalopathy and died before 2 years of age.^[32] The incidence of Rett syndrome in males is unknown, partly owing to the low survival of male fetuses with the Rett syndrome-associated MECP2 mutations, and partly to differences between signs caused by MECP2 mutations and those caused by Rett's.^[33][34]

The severity of Rett syndrome in females can vary depending on the type and position of the mutation of MECP2 and the pattern of X-chromosome inactivation. It is generally assumed that 50% of a female's cells use the maternal X chromosome while the other 50% uses the paternal X chromosome. However, if most cells in the brain activate the X chromosome with the functional MECP2 allele, the individual will have very mild Rett syndrome; likewise, if most neurons activate the X chromosome with the mutated MECP2 allele, the individual will have very severe Rett syndrome just as males with MECP2 mutations do^{[citation needed]} (as they only have one X chromosome).

Development and signs

Development appears to be normal until 6–18 months. During this time there are subtle developmental deviations and early indicators of Rett syndrome. At around 6-18 months there is a period of developmental stagnation followed by a developmental regression where language and motor milestones regress, purposeful hand use is lost, and acquired deceleration in the rate of head growth (resulting in microcephaly in some) is seen. Hand stereotypes are typical, and breathing irregularities such as hyperventilation, breathholding, or sighing are seen in many. Early on, autistic-like behavior may be seen. The infant with Rett syndrome often avoids detection until 6–18 months, owing to a relatively normal appearance and some developmental progress. However, closer scrutiny reveals disturbance of the normal spontaneous limb and body movements that are thought to be regulated in the brainstem. The brief period of developmental progress is followed by stagnation and regression of previously acquired skills. During regression, some features are similar to those of autism. It is, hence, easy to mistakenly diagnose Rett syndrome for autism.

Signs of Rett syndrome that are similar to autism:

• screaming fits
• inconsolable crying
• avoidance of eye contact
• lack of social/emotional reciprocity
• markedly impaired use of nonverbal behaviors to regulate social interaction
• loss of speech
• sensory problems.

Signs of Rett syndrome that are also present in cerebral palsy (regression of the type seen in Rett syndrome would be unusual in cerebral palsy; this confusion could rarely be made):

• possible short stature, sometimes with unusual body proportions because of difficulty walking or malnutrition caused by difficulty swallowing
• hypotonia
• delayed or absent ability to walk
• gait/movement difficulties
• ataxia
• microcephaly in some - abnormally small head, poor head growth
• gastrointestinal problems
• some forms of spasticity
• chorea - spasmodic movements of hand or facial muscles
• dystonia
• bruxism – grinding of teeth.

Signs may stabilize for many decades, particularly for interaction and cognitive function such as making choices. Asocial behavior may change to highly social behavior. Motor functions may slow as rigidity and dystonia appear. Seizures may be problematic, with a wide range of severity. Scoliosis occurs in most, and may require corrective surgery. Those who remain ambulatory tend to have less progression of scoliosis.

Treatment and prognosis

Currently there is no cure for Rett syndrome, but studies have shown that restoring MECP2 function may lead to a cure.^[35] One area of research is in the use of Insulin-like Growth Factor 1 (IGF-1), which has been shown to partially reverse signs in MeCP2 mutant mice.^[36] Such a treatment works because the neuronal cells have not atrophied, but rather are in an immature state.

Treatment of Rett syndrome includes:

• management of gastrointestinal (reflux, constipation) and nutritional (poor weight gain) issues
• surveillance of scoliosis and long QT syndrome
• increasing the patient's communication skills, especially with augmentative communication strategies
• parental counseling
• modifying social medications
• sleep aids
• selective serotonin reuptake inhibitors (SSRIs)
• anti-psychotics (for self-harming behaviors)
• beta-blockers rarely for long QT syndrome
• occupational therapy, speech therapy and physical therapy (for children with Rett syndrome).

There is an association of the disease with brain-derived neurotrophic factor (BDNF).^[37]

The challenge of developing therapies for MECP2 disorders^[38]

Recent studies, funded by the International Rett Syndrome Foundation, demonstrate that neurological deficits resulting from loss of MECP2 can be reversed upon restoration of gene function. These studies are quite exciting because they show that neurons that have suffered the consequences of loss of MECP2 function are poised to regain functionality once MECP2 is provided gradually and in the correct spatial distribution. This provides hope for restoring neuronal function in patients with RTT. However, the strategy in humans will require providing the critical factors that function downstream of MECP2 because of the challenges in delivering the correct MECP2 dosage only to neurons that lack it, given that the slightest perturbation in MECP2 level is deleterious. Thus, therapeutic strategies necessitate the identification of the molecular mechanisms underlying individual RTT phenotypes and picking out the candidates that can be therapeutically targeted. The next phase of research needs to assess how complete the recovery is. Clearly, lethality, level of activity, and hippocampal plasticity are rescued, but are the animals free of any other RTT signs such as social behavior deficits, anxiety, and cognitive impairments? Since postnatal rescue results in viability, it will be important to evaluate if even the subtler phenotypes of RTT and MECP2 disorders are rescued when protein function is restored postnatally. This is particularly important given emerging data about early neonatal experiences and their long-term effects on behavior in adults.

Occupational therapy and Speech/Language Therapy

The symptoms of RTT severely limit individuals from independently taking part in meaningful activities in their day-to-day lives.^[39] As a result, most people with this disorder are very dependent on their caregivers in most areas of their lives.^[40] Occupational therapists (OTs) try to find ways to encourage these individuals to take part in activities that are meaningful to them, as this has been shown to improve health and well being.^[40] The goals of occupational therapy interventions are to maintain or improve the functional abilities of individuals with this disorder. It is important to remember that services for each individual with RTT can differ greatly. OTs work together with clients and their families to help clients achieve their unique goals. OTs not only provide direct services for the client and families, but they can also connect family members to information and resources outside of occupational therapy. Services provided may include but are not limited to: maintaining motor and daily living skills and maintaining cognitive and communication functioning.

Self-care

Some symptoms such as involuntary stereotypical hand movements can make eating a very difficult self-care task for individuals with RTT. One way OTs address this problem is by educating and encouraging caregivers to practice guided feeding. Guided feeding involves having the individual with RTT grasp the spoon and having the caregiver's hand over top of the child's in order to guide the movement of the individual to eat.^[40] The purpose of this therapy is to encourage involvement in this important self-care activity, particularly for individuals with severe cases of RTT.^[40] Signals such as opening their mouth in preparation for food, rejecting unwanted foods, and spending an increased amount of time watching their helpers, indicates that guided feeding therapy can increase engagement in eating in some cases.^[40]

Another way OTs may increase involvement in eating and hand function in general is by making hand splints. Research suggests that hand splints place the hand in a more functional position and prevent repetitive motion; this leads to better finger and spoon-feeding skills.^[40] Although fully independent feeding is rare for individuals with RTT, hand splints allow them to become more engaged in eating. Alternatively, active participation can be encouraged through the use of elbow splints, which decrease the repetitive stereotyped arm movements characteristic of RTT. As a result, socialization and interaction with the environment during eating may increase.^[40]

Other adaptations to eating include altering the pace of feeding and recommending specific foods and textures that the individual is easily able to swallow.^[41] In addition, OT’s provide adaptive devices such as cuffs and loops (to help the individual hold their utensils), large handled utensils that are easier to grasp, and cups with lids to assist with eating and address proper nutrition. In general, all of these therapeutic methods are aimed at improving the quality of the swallowing response and general eating performance.^[42] Although parental and self-reports indicate good appetite in most of the population, weight loss is an issue that many individuals with RTT face. This suggests the importance of proper nutritional education for both the individual and their caregivers. This education, along with meal management and planning, may be provided by the Speech and language therapist often in consultation with OT, a nutritionist or dietitian.

The Speech and Language Therapist will assess the person for signs respiratory compromise and others symptoms of swallowing difficulty and negotiate management strategies based on balancing maintaining the persons physical safety, psychological well-being and quality of life.

Seating and positioning the individual can also affect how they do daily tasks such as eating, dressing, and grooming. In order for an individual to engage in these tasks, OTs may adjust and modify tables, chairs, and wheelchairs to promote positive interactions within different social environments.^[43] OTs are also involved in educating families on various adaptive devices that can promote comfort, ease of use, and safety for children and their caregivers. Some of the commonly used adaptive devices include bath benches, toilet chairs, and movable shower heads.^[44] Finally, occupational therapists work with children and their families to develop skills required to brush their teeth and hair, bathe, and dress.^[43]

If children with RTT are in school during the day, OTs can play a role in teaching special education assistants (SEA’s) about the self-care needs of the child. This can include education on feeding techniques that are suitable for the child, proper mechanics of lifts and transfers, as well as toileting techniques and routines.

Productivity

Occupational therapists are involved in helping children with RTT function optimally at school. One of their primary concerns is regarding the child’s seating and positioning in the school environment. As RTT highly impacts a child physically, they often require customized seating, whether it is in the form of a wheelchair or customized chair and desk combinations. The OT consults and provides the equipment necessary for children to be stable and comfortable in their seats. This helps children with RTT stay more focused on their learning and classroom activities, instead of expending energy trying to stay seated upright and balanced.^[44] Ultimately, being properly seated may facilitate increased social skills; this is because a child is now able to maintain eye contact with their peers, look around the classroom, and engage with their social environment.^[44]

Additionally, OT’s are very involved with consulting and educating the child’s teachers and SEA’s, to better facilitate the child’s learning and care within the school. The OT may also provide adaptive tools including: communication boards, adaptive school supplies, and the use of eye-gaze and/or switches to activate educational programs on the computer. These tools may facilitate the individual's communication with other people; they may be able to better communicate their needs, preferences, and choices using these devices.

The OT may also suggest certain physical adaptations within the school to better suit the needs of the child. This may include suggestions for classroom setup, adaptations to the washrooms, as well as the installation of ramps, lifts, and/or elevators.

Leisure

Children with RTT need to engage and participate in leisure activities just like typically developing children. Play is the primary activity of childhood and is considered to be both a form of leisure and productivity; it is essential to development as it facilitates cognitive, physical, social, and emotional well-being.^[45] Play is an activity with multiple purposes; it provides opportunities for a child to grow and develop, explore, learn, build relationships, and develop interests. Because play is so central to a child's development, therapists try and find ways that allow these children to play. OTs work with clients and their family to make sure that the interventions focus on play activities that are meaningful to the child, whether it be arts, music, sports, computer games, and/or maintaining social relationships. There is no set list of the services that OTs provide in terms of leisure activities, as they work with the child to find activities that he or she finds enjoyable and important.^[44] Some examples of how OT’s facilitate play include adapting bicycles, providing switches so that the child can turn on music/video players, and connecting the child and her family to resources and programs within the community.^[44]

In addition, some therapeutic activities are regarded as highly enjoyable for children with RTT and can be considered a form of play as well as therapy. One such activity that children with RTT may participate in is aquatic, or swimming therapy. The aims of swimming therapy are to promote relaxation, improve circulation, strengthen muscles, and improve coordination and balance.^[39] Aquatic therapy is an enjoyable and relaxing activity for children with RTT, and in some cases therapy has been associated with a decrease in abnormal hand movements and an increase in goal directed hand movements and feeding skills.^[39] Examples of other activities that are therapeutic and enjoyable include horseback riding therapy and music therapy.

Communication

Individuals with RTT often do not develop, or lose the ability to communicate through speech.^[46] If these individuals cannot communicate with their family and caregivers it makes it very difficult for them to participate in daily activities as they also have severe physical difficulties. OTs plan communication interventions that aim to increase the skills needed for carrying out self-care, productivity, and leisure tasks. Studies suggest that only twenty percent of the people with RTT had the use of words, and most of these words were used out of context and without meaning.^[46] As a result of their lack of language, individuals with RTT can benefit from Augmentative and Alternative Communication (AAC), which are communication methods used in place of speech. Examples of AAC may be written language, body language, and facial expressions.^[44] It is within the scope of practice for speech-language pathologists (not OTs!) to provide a thorough AAC evaluation taking into consideration all factors such as sensory, motor, kinesthetic, speech, and receptive as well as expressive language in its verbal and non-verbal forms. OTs are consulted in this process, to determine motor or sensory skills and deficits, as well as seating and positioning. This evaluation will result in a recommendation of AAC systems, which often include low-technology, mid-technology and high-technology systems. A speech-language pathologist will also provide therapy to help the client with RTT to access and learn the systems once they are procured, through private funds, school districts, or private/public medical insurance.

Some of the AAC systems common to individuals with RTT include eye-gaze boards, communication boards, switches, or voice output communication devices. Speech-Language Pathologists (SLPs), often with specialized AAC training and knowledge, provide education and training to families, educational teams, and other communication partners on these tools. AAC options are often divided into three levels of technology: no technology, low technology, and higher technology (mid-tech or high-tech, consisting of systems requiring the use of a battery or powercord).^[44] The simplest way to communicate is through ‘no technology’ or "unaided" methods in which the individuals with RTT indicates a response (i.e., points, blinks their eyes, raises their eyebrows) to indicate a response. The second type are ‘low technology’ communication systems which often include using pictures, symbols, and/or objects placed on a board. A person then uses eye gaze or finger pointing to show his or her choices. Communication boards can be set up by the SLP and OT in both home and school environments. The third and most complex level of technology is ‘higher technology’. Some of the more commonly used technological devices include voice output systems and computer communication software.^[44] Low-technology, mid-technology, and high-technology systems are considered "aided" systems, as they require the use of an object other than one's own body to communicate. The SLP and OT work with the child, as well as the family, caregivers, and school assistants to encourage the child to communicate as much as possible by using all these different tools.

Variants of Rett syndrome

The clinical signs of Rett syndrome typical form are perfectly identified (e.g. see above). In addition to the classical form of Rett syndrome, several «atypical forms» have been described over the years,^[47] the main groups are:

• Congenital variant (Rolando variant): in this severe subtype of Rett syndrome, the development of the patients and their head circumference are abnormal from birth.^[48] The typical gaze of Rett syndrome patients is usually absent;
• Zappella variant of Rett Syndrome or preserved speech variant: in this subtype of Rett syndrome the patients acquire some manual skills and language is partially recovered around the age of 5 years (that is after the regression phase). Height, weight and head circumference are often in the normal range, and a good gross motor function can be observed.^{[49][50][51][52][53][54]} The Zappella variant is a milder form of Rett syndrome;
• Hanefeld variant or early epilepsy variant. In this form of Rett syndrome, the patients suffer from epilepsy before 5 months of age.^[55]

The definition itself of the Rett syndrome has been refined over the years: as the atypical forms subsist near to the classical form (Hagberg & Gillberg, 1993), the “Rett Complex” terminology has been introduced.^[56][57]

Mortality

Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathy, unless they have an extra X chromosome (often described as Klinefelter syndrome), or have somatic mosaicism.

Females can live up to 40 years or more. Laboratory studies on Rett syndrome may show abnormalities such as:

• EEG abnormalities from 2 years of age
• atypical brain glycolipids
• elevated CSF levels of beta-endorphins and glutamate
• reduction of substance P
• decreased levels of CSF nerve growth factors

A high proportion of deaths are abrupt, but most have no identifiable cause; in some instances death is the result most likely of:

• spontaneous brainstem dysfunction
• cardiac arrest
• seizures
• cardiac conduction abnormalities - abnormally prolonged QT interval on ECG
• gastric perforation

Depiction in popular culture

• The movie Society's Child (2002), starring Jessica Steen and Margot Kidder, is about a mother of a 10-year-old girl with Rett syndrome and a social worker who tries to help her.^[58]
• Jacob Appel's short story, "A Thanatology for Mollusks", features a girl with Rett syndrome whose mother falls in love with her special education instructor.^[59]
• The book Follow the Stars Home (2000) is about a mother of a girl with Rett Syndrome, whose husband abandoned her once he learned the fetus had a disability. The mother ends up falling in love with her ex-husband's brother.
• Silent Angels: the Rett Syndrome Story (2000) is a documentary narrated by Julia Roberts that tells the story of families and genetic researchers as they researched Rett Syndrome.
• Clint Black, a country singing star, was a contestant on the 2009 season of the Celebrity Apprentice and played to win money for the International Rett Syndrome Foundation. His niece had been diagnosed with Rett Syndrome and died at the age of 16.^[60]
• So You Think You Can Dance (Season 4), Jean-Marc Généreux choreographed a Viennese waltz for Kherington Payne and Stephen "Twitch" Boss that he dedicated to daughter Francesca who has Rett syndrome.^[61]
• Angela Martin, a three-time contestant on American Idol has a daughter diagnosed with Rett syndrome. During her first time on the show, the Shriners organization pledged to provide her daughter medical care until she turned 21 years of age.
• The 1991 "Climb for Hope" Mount Everest Expedition documentary (1992), narrated by Leslie Nelson is about Erwin Sniedzins efforts, as a father of his daughter with Rett Syndrome, in organizing this expedition to help raise funds and international awareness and research towards the cause and hopefully a cure of this debilitating disorder. The movie won the Gold award at the 1992 New York International Film Festival. http://www.mkhd.net/ErwinSniedzins.php

References

1. ^ "Rett syndrome" at Dorland's Medical Dictionary
2. ^ "Predictors of Seizure Onset in Rett Syndrome" Le Jian et al
3. ^ Tsai LY (December 1992). "Is Rett's Disorder is a subtype of pervasive developmental disorders?". J Autism Dev Disord 22 (4): 551–61. doi:10.1007/BF01046327. PMID 1483976. 
4. ^ "Proposed Revision | APA DSM-5". http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=95#. Retrieved 2010-05-01. 
5. ^ Rett A (September 1966). "[On a unusual brain atrophy syndrome in hyperammonemia in childhood]" (in German). Wien Med Wochenschr 116 (37): 723–6. PMID 5300597. 
6. ^ Trappe R, Laccone F, Cobilanschi J et al. (May 2001). "MECP2 mutations in sporadic cases of Rett's Disorder are almost exclusively of paternal origin". American journal of human genetics 68 (5): 1093–101. doi:10.1086/320109. PMC 1226090. PMID 11309679. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1226090. 
7. ^ "Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2" Amir, R. et al.
8. ^ Zoghbi HY, Milstien S, Butler IJ et al. (January 1989). "Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome". Ann. Neurol. 25 (1): 56–60. doi:10.1002/ana.410250109. PMID 2913929. 
9. ^ Roux JC and Villard L (2009) Biogenic Amines in Rett Syndrome The usual suspects Behav Genet http://springerlink.com/content/b0j7t62714416536/
10. ^ Hokfelt T,Martensson R,Bjorklund A,Kleinau S,Goldstein M. 1984. Distribution maps of tyrosine-hydroxylase-immunoreactive neurons in the rat brain. In Handbook of Chemical Neuroanatomy, Vol. 2. Classical Transmitters in the CNS, Part I ( A. Bjorklund and T. Hokfelt, eds.) pp. 277-379. Elsevier, New York
11. ^ Berridge CW,Waterhouse BD 2003 The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev 42: 33-84
12. ^ ^{a b} Taneja P, Ogier M, Brooks-Harris G, Schmid DA, Katz DM, Nelson SB (2009). "Pathophysiology of Locus Ceruleus Neurons in a Mouse Model of Rett Syndrome". Journal of Neuroscience 29 (39): 12187–12195. doi:10.1523/JNEUROSCI.3156-09.2009. PMC 2846656. PMID 19793977. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2846656. 
13. ^ ^{a b c d} Roux JC, Panayotis N, Dura E, Villard L. (2009) Progressive Noradrenergic Deficits in the Locus Coeruleus of Mecp2 Deficient Mice J Neurosci Res http://www3.interscience.wiley.com/cgi-bin/fulltext/123208150/HTMLSTART
14. ^ Björklund, A. and Lindvall, O. (1984) Dopamine-containing systems in the CNS. In Handbook of Chemical Neuroanatomy, Vol. 2: Classical Transmitters in the CNS, Part l (Björklund, A. and Hökfelt, T., eds), pp. 55 122, Elsevier, New York
15. ^ Hokfelt, T.,Martensson, R.,Björklund, A.,Kleinau, S.,Goldstein, M. 1984. Distribution maps of tyrosine-hydroxylase-immunoreactive neurons in the rat brain. In Handbook of Chemical Neuroanatomy, Vol. 2. Classical Transmitters in the CNS, Part I (A. Bjorklund and T. Hokfelt, eds.) pp. 277-379. Elsevier, New York
16. ^ Bjorklund A., Dunnett S.B. (2007). "Dopamine neuron systems in the brain: an update". Trends Neurosci 30 (5): 194–202. doi:10.1016/j.tins.2007.03.006. PMID 17408759. 
17. ^ Parent, A., Hazrati, L.N., 1995. Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res. Brain Res. Rev. 20, 91–127.
18. ^ Gerfen, C., 2000. Molecular Effects of dopamine on Striatal-projection pathways. Trends Neurosci. 23, No. 10 (Suppl.).
19. ^ Lees A.J. et al. (2009). ", 2009. Parkinson's disease". Lancet 373 (9680): 2055–2066. doi:10.1016/S0140-6736(09)60492-X. PMID 19524782. 
20. ^ Dauer, W., Przedborski, S., 2003. Parkinson's disease: mechanisms and models. Neuron 881 39, 889–909.
21. ^ Jenner, P., 2008. Functional models of Parkinson's disease: a valuable tool in the development of novel therapies. Ann. Neurol. 64 (Suppl 2), S16–S29.
22. ^ FitzGerald P.M. et al. (1990). ", 1990. "Rett syndrome and associated movement disorders". Mov. Disord 5 (3): 195–202. doi:10.1002/mds.870050303. PMID 2388636. 
23. ^ Neul J.L., Zoghbi H.Y. (2004). "Rett syndrome: a prototypical neurodevelopmental disorder". Neuroscientist 10 (2): 118–128. doi:10.1177/1073858403260995. PMID 15070486. 
24. ^ Segawa, M., 2005. "Early motor disturbances in Rett syndrome and its pathophysiological importance. Brain Dev, 27, S54-S58.
25. ^ Roux J.C., Villard L. (2010). "Biogenic amines in Rett syndrome: the usual suspects". Behav. Genet 40 (1): 59–75. doi:10.1007/s10519-009-9303-y. PMID 19851857. 
26. ^ Guy J. et al. (2001). "A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome". Nat. Genet 27 (3): 322–326. doi:10.1038/85899. PMID 11242117. 
27. ^ Chen R.Z. et al. (2001). "Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice". Nat. Genet 27 (3): 327–331. doi:10.1038/85906. PMID 11242118. 
28. ^ Ricceri, L., et al., 2008. "Mouse models of Rett syndrome: from behavioural phenotyping to preclinical evaluation of new therapeutic approaches. Behav. Pharmacol. 19, 501–517.
29. ^ Samaco R.C. et al. (2009). "Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities". Proc. Natl. Acad. Sci. U. S. A. 106 (51): 21966–21971. doi:10.1073/pnas.0912257106. PMC 2799790. PMID 20007372. http://www.pnas.org/content/106/51/21966.full.pdf. 
30. ^ ^{a b c} Panayotis, N. et al., 2010. "Morphological and functional alterations in the Substantia Nigra pars compacta of the Mecp2-null mouse." Neurobiol. Dis. doi:10.1016/j.nbd.2010.10.006.
31. ^ Schwartzman, J.S., et al. Rett Syndrome in a Boy with 47,XXY Karyotype Confirmed by a Rare Mutation on the MECP2 Gene. 2001. Neuropediatrics 32:162-164
32. ^ Hardwick S.A. et al. (2007). "Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband". European Journal of Human Genetics 15 (12): 1218–29. doi:10.1038/sj.ejhg.5201911. PMID 17712354. 
33. ^ "New Study Reveals Rett Syndrome Can Strike Males" ScienceDaily, August 12, 2006
34. ^ Moog U. et al. (2003). "Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2)". European Journal of Paediatric Neurology 7 (1): 5–12. doi:10.1016/S1090-3798(02)00134-4. PMID 12615169. 
35. ^ "Autism-like disorder 'reversible'", BBC News, 8 February 2007.
36. ^ "Partial reversal of Rett Syndrome-like signs in MeCP2 mutant mice", Proceedings of the National Academy of Sciences, vol 106, no 6, 2029–2034
37. ^ Sun, E.; Wu, H. (Feb 2006). "The Ups and Downs of BDNF in Rett Syndrome". Neuron 49 (3): 321. doi:10.1016/j.neuron.2006.01.014. ISSN 0896-6273. PMID 16446133.  edit
38. ^ "The Story of Rett Syndrome: From Clinic to Neurobiology." Chahrour et al. Neuron, Vol 56, 422-437, 08 November 2007
39. ^ ^{a b c} Bumin G, Uyanik M, Yilmaz I, Kayihar H, Popcu M. Hydrotherapy for Rett Syndrome. Journal of Rehabilitation Medicine; 2003;35:44-45.
40. ^ ^{a b c d e f g} Qvarfordt I, Engerstrom IW, Eliasson AC. Guided eating or feeding: three girls with Rett syndrome. Scand.J.Occup.Ther. 2009 Mar;16(1):33-39.
41. ^ Isaacs JS, Murdock M, Lane J, Percy AK. Eating difficulties in girls with Rett syndrome compared with other developmental disabilities. J.Am.Diet.Assoc 2003 Feb;103(2):224-230.
42. ^ Reilly S, Cass H. Growth and nutrition in Rett syndrome. Disabil.Rehabil. 2001 Feb 15-Mar 10;23(3-4):118-128.
43. ^ ^{a b} Reed KL. Quick reference to occupational therapy. 2nd ed. Gaithersburg (MD): Aspen Publishers; 2001.
44. ^ ^{a b c d e f g h} International Rett Syndrome Foundation [Online]. 2008 February [cited 2010 Apr 2]; Available from: URL:http://www.rettsydrome.org/
45. ^ Ginsburg, K. The importance of play in promoting healthy child development and maintaining strong parent-child bonds. Pediatrics; 2007 Jan; 119(1):182-191.
46. ^ ^{a b} Cass H, Reilly S, Owen L, Wisbeach A, Weekes L, Slonims V, et al. Findings from a multidisciplinary clinical case series of females with Rett Syndrome. Dev Med Child Neurol 2003 Apr;45(5):325-37.
47. ^ Renieri, A; Neul, J; Zappella, M; Kaufmann, WE; Glaze, DG; Christodolou, J; Clarke, AJ; Bahi-Buisson, N et al. (2010). "Rett syndrome: Revised diagnostic criteria and nomenclature". Annals of Neurology 68 (6): 944–50. doi:10.1002/ana.22124. PMC 3058521. PMID 21154482. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3058521. 
48. ^ Renieri, A; Mari, F; Mencarelli, MA; Meloni, I; Ariani, F; Longo, I; Zappella, M; Hayek, G et al. (2008). "FOXG1 Is Responsible for the Congenital Variant of Rett Syndrome". The American Journal of Human Genetics 83 (1): 89–93. doi:10.1016/j.ajhg.2008.05.015. PMID 2443837. 
49. ^ Zappella, M (1992). "The Rett girls with preserved speech". Brain & development 14 (2): 98–101. PMID 1621933. 
50. ^ Skjeldal, OH; Von Tetzchner, S; Jacobsen, K; Smith, L; Heiberg, A (1995). "Rett syndrome--distribution of phenotypes with special attention to the preserved speech variant". Neuropediatrics 26 (2): 87. doi:10.1055/s-2007-979732. PMID 7566462. 
51. ^ Sørensen, E; Viken, B (1995). "Rett syndrome a developmental disorder. Presentation of a variant with preserved speech". Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række 115 (5): 588–90. PMID 7900110. 
52. ^ Zappella, M (1997). "The preserved speech variant of the Rett complex: a report of 8 cases". Eur Child Adolesc Psychiatry 6 (1): 23–5. PMID 9452915. 
53. ^ Renieri, A; Mari, F; Mencarelli, MA; Scala, E; Ariani, F; Longo, I; Meloni, I; Cevenini, G et al. (2009). "Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant)". Brain & development 31 (3): 208–16. doi:10.1016/j.braindev.2008.04.007. PMID 18562141. 
54. ^ Renieri, A; Hayek, G; Zappella, M; Zannolli, R; De Felice, C; De Nicola, A; Guerri, V; Buoni, S et al. (2010). "EEG features and epilepsy in MECP2-mutated patients with the Zappella variant of Rett syndrome". Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 121 (5): 652–657. doi:10.1016/j.clinph.2010.01.003. PMID 20153689. 
55. ^ Huppke, P; Held, M; Laccone, F; Hanefeld, F (2003). "The spectrum of phenotypes in females with Rett Syndrome". Brain & development 25 (5): 346–51. doi:10.1016/S0387-7604(03)00018-4. PMID 12850514. 
56. ^ Gillberg, C (1997). "Communication in Rett syndrome complex". Eur Child Adolesc Psychiatry 6 (1): 21–2. PMID 9452914. 
57. ^ Zappella, M; Gillberg, C; Ehlers, S (1998). "The preserved speech variant: a subgroup of the Rett complex: a clinical report of 30 cases". Journal of autism and developmental disorders 28 (6): 519–26. doi:10.1023/A:1026052128305. PMID 9932238. 
58. ^ http://www.jessicasteen.com/jsp_society.html
59. ^ Flyway, Iowa State University, Volume 5, No. 1-2.
60. ^ http://www.rettsyndrome.org/index.php?option=com_content&task=view&id=487&Itemid=629
61. ^ Parker-Pope, Tara (2008-06-19). "Reality Dance Show Puts Rett Syndrome in the Spotlight". The New York Times. http://well.blogs.nytimes.com/2008/06/19/reality-dance-show-puts-rett-syndrome-in-the-spotlight/. Retrieved 2010-05-22. 

External links

• Rett Syndrome at eMedicine
• Curing Rett Syndrome: How Do We Get There?
• International Rett Syndrome Foundation
• Rett UK
• Rett Syndrome Research Trust
• Rett Syndrome Research Trust UK
• rett at NINDS
• Rett Syndrome Society of Alberta
• Rett Syndrome Magazine
• Rett Syndrome Video Channel
• New Jersey Rett Syndrome Association
• Southeastern Rett Syndrome Alliance
• Rett Girl
• Girl Power 2 Cure
• Ontario Rett Syndrome Association
• Saskatchewan Rett Syndrome Association