Rett syndrome
Encyclopedia
Rett syndrome is a neurodevelopmental disorder of the grey matter
of the brain that almost exclusively affects 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. 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 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. However, it has been suggested that it be removed from the DSM-5
, because it has a specific etiology.
It was first described by Austrian pediatrician Andreas Rett
in 1966.
In DSM-IV-TR page 76, Rett's Disorder 299.80 is listed under the broad category of Pervasive Developmental Disorders.
located on the X chromosome and can arise (1) sporadically or (2) from germline mutations. In less than ten percent 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.
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. It is not yet known what causes the sperm to mutate, and such mutations are rare.
mutation in the gene encoding methyl-CpG-binding protein-2, MECP2
. 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.
are lower in people with Rett syndrome (reviewed in). 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
. These changes include hyperexcitability and decreased functioning of its noradrenergic innervation. 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. 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. 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. 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.
. 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).
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.
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.
Dysregulation of the nigro-striatal pathway is causative from Parkinson disease (PD) in humans. Toxic and/or genetic ablation of SNpc neurons produces experimental parkinsonism in mice and primates. The common features of PD and PD animal models are motor impairments (hypotonia, bradykinesia, hypokinesia).
RTT pathology, in some aspects overlaps the motor phenotype observed in PD patients. 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. Mouse models of RTT are available and the most studied are constitutively deleted Mecp2 mice developed by Adrian Bird or Rudolph Jaenisch laboratories.
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. 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.
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. 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. 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. Altogether, these results argue for an alteration of the nigrostriatal dopaminergic pathway in Mecp2-deficient animals as a contributor of the neuromotor deficits.
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). 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. 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.
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 (as they only have one X chromosome).
.
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. 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 of Rett syndrome includes:
There is an association of the disease with brain-derived neurotrophic factor
(BDNF).
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.
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. The purpose of this therapy is to encourage involvement in this important self-care activity, particularly for individuals with severe cases of RTT. 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.
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. 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.
Other adaptations to eating include altering the pace of feeding and recommending specific foods and textures that the individual is easily able to swallow. 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. 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. 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. Finally, occupational therapists work with children and their families to develop skills required to brush their teeth and hair, bathe, and dress.
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. 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.
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. 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. 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.
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. 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. 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. 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. 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. 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). 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. 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.
In addition to the classical form of Rett syndrome, several «atypical forms» have been described over the years, the main groups are:
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.
, 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:
Grey matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil , glial cells and capillaries. Grey matter contains neural cell bodies, in contrast to white matter, which does not and mostly contains myelinated axon tracts...
of the brain that almost exclusively affects females. The clinical features include small hands and feet and a deceleration of the rate of head growth (including microcephaly
Microcephaly
Microcephaly is a neurodevelopmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex. Microcephaly may be congenital or it may develop in the first few years of life...
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. They typically have no verbal skills, and about 50% of individuals affected are not ambulatory. Scoliosis
Scoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
, 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
Angelman syndrome
Angelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements , frequent laughter or smiling, and usually a happy demeanor....
, cerebral palsy
Cerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
and autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
.
Some argue that it is misclassified as an autism spectrum disorder, just as it would be to include such disorders as fragile X syndrome
Fragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
, tuberous sclerosis
Tuberous sclerosis
Tuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral...
, or Down syndrome
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
where one can see autistic features. However, it has been suggested that it be removed from the DSM-5
DSM-5
The next edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders , commonly called DSM-5 , is currently in consultation, planning and preparation...
, because it has a specific etiology.
It was first described by Austrian pediatrician Andreas Rett
Andreas Rett
Andreas Rett was an Austrian neurologist and author. Rett received many awards, including the Grand Medal for Special Earnings from the Republic of Austria.-Biography:...
in 1966.
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 MECP2MECP2
MECP2 is a gene that provides instructions for making its protein product, MECP2, also referred to as MeCP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in high levels...
located on the X chromosome and can arise (1) sporadically or (2) from germline mutations. In less than ten percent of Rett Syndrome cases, mutations in the genes CDKL5
CDKL5
CDKL5 is a gene that provides instructions for making a protein called cyclin-dependent kinase-like 5 also known as serine/threonine kinase 9 that is essential for normal brain development. Although little is known about the protein's function, it may play a role in regulating the activity of...
or FOXG1
FOXG1
Forkhead box protein G1 is a protein that in humans is encoded by the FOXG1 gene....
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 mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
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. 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 germlineGermline
In biology and genetics, the germline of a mature or developing individual is the line of germ cells that have genetic material that may be passed to a child.For example, gametes such as the sperm or the egg, are part of the germline...
mutation in the gene encoding methyl-CpG-binding protein-2, MECP2
MECP2
MECP2 is a gene that provides instructions for making its protein product, MECP2, also referred to as MeCP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in high levels...
. 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
CDKL5
CDKL5 is a gene that provides instructions for making a protein called cyclin-dependent kinase-like 5 also known as serine/threonine kinase 9 that is essential for normal brain development. Although little is known about the protein's function, it may play a role in regulating the activity of...
). Rett syndrome affects one in every 12,500 female live births by age 12 years.
Pontine noradrenergic deficits
Brain levels of norepinephrineNorepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
are lower in people with Rett syndrome (reviewed in). The genetic loss of MECP2 changes the properties of cells in the locus coeruleus, the exclusive source of noradrenergic innervation to the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
and hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
. These changes include hyperexcitability and decreased functioning of its noradrenergic innervation. Moreover, a reduction of the tyrosine hydroxylase (Th) mRNA level, the rate-limiting enzyme in catecholamine synthesis, was detected in the whole pons
Pons
The pons is a structure located on the brain stem, named after the Latin word for "bridge" or the 16th-century Italian anatomist and surgeon Costanzo Varolio . It is superior to the medulla oblongata, inferior to the midbrain, and ventral to the cerebellum. In humans and other bipeds this means it...
of Mecp2-null male as well as in adult heterozygous (Mecp2+/-) female mice. 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. 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. 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.
Midbrain dopaminergic disturbances
The majority of dopamine in the mammalian brain is synthesized by nuclei located in the mesencephalonMesencephalon
The midbrain or mesencephalon is a portion of the central nervous system associated with vision, hearing, motor control, sleep/wake, arousal , and temperature regulation....
. The substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
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).
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.
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.
Dysregulation of the nigro-striatal pathway is causative from Parkinson disease (PD) in humans. Toxic and/or genetic ablation of SNpc neurons produces experimental parkinsonism in mice and primates. The common features of PD and PD animal models are motor impairments (hypotonia, bradykinesia, hypokinesia).
RTT pathology, in some aspects overlaps the motor phenotype observed in PD patients. 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. Mouse models of RTT are available and the most studied are constitutively deleted Mecp2 mice developed by Adrian Bird or Rudolph Jaenisch laboratories.
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. 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.
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. 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. 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. 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 chromosomeChromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
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
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
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
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
to survive at least to birth. Research shows that males with Rett syndrome almost all have Klinefelter's syndrome
Klinefelter's syndrome
Klinefelter syndrome, 46/47, XXY, or XXY syndrome is a condition in which human males have an extra X chromosome. While females have an XX chromosomal makeup, and males an XY, affected individuals have at least two X chromosomes and at least one Y chromosome...
as well (in which the male has an XXY karyotype). 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. 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.
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 (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 autismAutism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
.
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
Cerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
(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 malnutritionMalnutritionMalnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....
caused by difficulty swallowingDysphagiaDysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia.... - hypotoniaHypotoniaHypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
- delayed or absent ability to walk
- gait/movement difficulties
- ataxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
- microcephalyMicrocephalyMicrocephaly is a neurodevelopmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex. Microcephaly may be congenital or it may develop in the first few years of life...
in some - abnormally small head, poor head growth - gastrointestinal problems
- some forms of spasticitySpasticitySpasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
- choreaChorea (disease)Choreia is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term choreia is derived from the Greek word χορεία , see choreia , as the quick movements of the feet or hands are vaguely comparable to dancing or piano playing.The term...
- spasmodic movements of hand or facial muscles - dystoniaDystoniaDystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
- bruxismBruxismBruxism is characterized by the grinding of the teeth and typically includes the clenching of the jaw. It is an oral parafunctional activity that occurs in most humans at some time in their lives. In most people, bruxism is mild enough not to be a health problem...
– 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
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
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. 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. 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, constipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
) and nutritional (poor weight gain) issues - surveillance of scoliosisScoliosisScoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
and long QT syndromeLong QT syndromeThe long QT syndrome is a rare inborn heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsade de pointes . These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation... - increasing the patient's communication skills, especially with augmentative communication strategies
- parental counseling
- modifying social medications
- sleep aids
- selective serotonin reuptake inhibitorSelective serotonin reuptake inhibitorSelective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s (SSRIs) - anti-psychotics (for self-harming behaviors)
- beta-blockers rarely for long QT syndromeLong QT syndromeThe long QT syndrome is a rare inborn heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsade de pointes . These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation...
- occupational therapyOccupational therapyOccupational therapy is a discipline that aims to promote health by enabling people to perform meaningful and purposeful activities. Occupational therapists work with individuals who suffer from a mentally, physically, developmentally, and/or emotionally disabling condition by utilizing treatments...
, speech therapy and physical therapyPhysical therapyPhysical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...
(for children with Rett syndrome).
There is an association of the disease with brain-derived neurotrophic factor
Brain-derived neurotrophic factor
Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF...
(BDNF).
The challenge of developing therapies for MECP2 disorders
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. As a result, most people with this disorder are very dependent on their caregivers in most areas of their lives. 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. 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. The purpose of this therapy is to encourage involvement in this important self-care activity, particularly for individuals with severe cases of RTT. 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.
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. 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.
Other adaptations to eating include altering the pace of feeding and recommending specific foods and textures that the individual is easily able to swallow. 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. 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. 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. Finally, occupational therapists work with children and their families to develop skills required to brush their teeth and hair, bathe, and dress.
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. 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.
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. 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. 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.
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. 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. 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. 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. 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. 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). 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. 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, 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. The typical gaze of Rett syndrome patients is usually absent;
- ZappellaMichele ZappellaMichele Zappella is an Italian psychiatrist and scholar of Child Neuropsychiatry. He is a native of Viareggio, Italy.- Professional background :...
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. 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.
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.
Mortality
Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathyEncephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
, unless they have an extra X chromosome (often described as Klinefelter syndrome), or have somatic mosaicism
Mosaic (genetics)
In genetic medicine, a mosaic or mosaicism denotes the presence of two populations of cells with different genotypes in one individual who has developed from a single fertilized egg...
.
Females can live up to 40 years or more. Laboratory studies on Rett syndrome may show abnormalities such as:
- EEGElectroencephalographyElectroencephalography is the recording of electrical activity along the scalp. EEG measures voltage fluctuations resulting from ionic current flows within the neurons of the brain...
abnormalities from 2 years of age - atypical brain glycolipidGlycolipidGlycolipids are lipids with a carbohydrate attached. Their role is to provide energy and also serve as markers for cellular recognition.-Metabolism:...
s - elevated CSF levels of beta-endorphinBeta-endorphinβ-endorphin is an endogenous opioid peptide neurotransmitter found in the neurons of both the central and peripheral nervous system.The amino acid sequence is:...
s and glutamate - reduction of substance PSubstance PIn the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
- 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 arrestCardiac arrestCardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
- seizures
- cardiac conduction abnormalities - abnormally prolonged QT interval on ECG
- gastric perforation
Depiction in popular culture
- The movie Society's Child (2002), starring Jessica SteenJessica SteenJessica Steen is a film and television actress, noted for her roles in Captain Power and the Soldiers of the Future, Homefront, Earth 2, Armageddon, Left Behind: World at War, NCIS, and Flashpoint....
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. - 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.
- 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 BlackClint BlackClint Patrick Black is an American country music singer-songwriter, record producer, multi-instrumentalist and occasional actor. Signed to RCA Records in 1989, Black made his debut with his Killin' Time album, which produced four straight Number One singles on the U.S. Billboard Hot Country...
, 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. - So You Think You Can Dance (Season 4), Jean-Marc GénéreuxJean-Marc Genereux-Biography:Généreux met his partner and wife, France Mousseau, while ballroom dancing in Quebec, Canada. They competed successfully as amateurs starting in 1977, and then professionally in 1986, in the Latin and 10-dance dancesport divisions, and retired in 1998....
choreographed a Viennese waltz for Kherington PayneKherington PayneKherington Taylor Payne is an American dancer and actress who came to prominence as a Top 10 Finalist in Season 4 of the hit reality-dance show So You Think You Can Dance and in a role in the 2009 reinvention of the movie Fame. She's been a principal dancer for Katy Perry, and is also a lead cast...
and Stephen "Twitch" Boss that he dedicated to daughter Francesca who has Rett syndrome. - 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
External links
- Rett Syndrome at eMedicineEMedicineeMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely, two medical doctors. The website is searchable by keyword and consists of approximately 6,800 articles, each of which is associated with one of 62 clinical subspecialty textbooks...
- Curing Rett Syndrome: How Do We Get There?
- International Rett Syndrome Foundation
- Rett UK
- Rett Syndrome Research Trust
- Rett Syndrome Research Trust UK
- 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