| Rett syndrome | |
|---|---|
| Classification and external resources | |
| ICD-10 | F84.2 |
| ICD-9 | 330.8 |
| OMIM | 312750 |
| DiseasesDB | 29908 |
| eMedicine | med/3202 |
| MeSH | C10.574.500.775 |
Rett syndrome is a neurodevelopmental disorder affecting grey matter.[1] 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 mouthing or wringing are also noted. Girls 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 females 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 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] It is classified as an autism spectrum disorder by the DSM-IV. 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]
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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.
Rett syndrome is usually caused (95% or more) by a de novo mutation in the child, i.e., not inherited from either parent. Parents are generally genotypically normal, without a 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.
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.
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 ceruleus, 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]
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).[14] 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.[15] The incidence of Rett syndrome in males is unknown, partly due to 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.[16][17]
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 (see X-inactivation). 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 (as they only have one X chromosome).
Development is typically normal until 6–18 months, when 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 due 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:
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):
Signs may stabilize for many decades, particularly for interaction and cognitive function such as making choices. Anti-social 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.
Currently there is no cure for Rett syndrome, but studies have shown that restoring MECP2 function may lead to a cure.[18] 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.[19] Such a treatment works because the neuronal cells have not atrophied, but rather are in an immature state.
Treatment of Rett syndrome includes:
There is an association of the disease with brain-derived neurotrophic factor (BDNF).[20]
The recent studies (funded by the International Rett Syndrome Foundation) demonstrating that neurological deficits resulting from loss of MeCP2 can be reversed upon restoration of gene function 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.
The symptoms of RTT severely limit individuals from independently taking part in meaningful activities in their day-to-day lives [22]. As a result, most people with this disorder are very dependent on their caregivers in most areas of their lives [23]. Occupational therapists (OT's) 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 [23]. 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. OT's work together with clients and their families to help clients achieve their unique goals. OT's 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 OT's 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 [23]. The purpose of this therapy is to encourage involvement in this important self-care activity, particularly for individuals with severe cases of RTT [23]. 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 [23].
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 [23]. 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 [23].
Other adaptations to eating include altering the pace of feeding and recommending specific foods and textures that the individual is easily able to swallow [24]. 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 [25]. 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 OT, often in consultation with a nutritionist or dietitian.
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, OT's may adjust and modify tables, chairs, and wheelchairs to promote positive interactions within different social environments [26]. OT's 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 [27]. Finally, occupational therapists work with children and their families to develop skills required to brush their teeth and hair, bathe, and dress [26].
If children with RTT are in school during the day, OT's 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 [27]. 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 [27].
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 [28]. 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. OT's 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 OT's provide in terms of leisure activities, as they work with the child to find activities that he or she finds enjoyable and important [27]. 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 [27].
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 [22]. 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 [22]. 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 [29]. 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. OT's 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 [29]. 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 ACC may be written language, body language, and facial expressions [27].
If individuals with RTT have difficulties using AAC methods, there are further adapted communication techniques that can be used. These strategies include eye-gaze, communication boards, switches, or voice output communication devices. OT's provide education and training on these tools. AAC options are often divided into three levels of technology: no technology, low technology, and higher technology [27]. The simplest way to communicate is through ‘no technology’ methods in which the individuals with RTT points or blinks their eyes to indicate a response. The second type is ‘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 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 [27]. The OT works 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.
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:
A high proportion of deaths are abrupt, but most have no identifiable cause; in some instances death is the result most likely of:
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