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RETT syndrome
Scientists generally describe four stages of Rett syndrome. Stage I, called early onset,
typically begins between 6 and 18 months of age. This stage is often overlooked
because symptoms of the disorder may be somewhat vague, and parents and doctors
may not notice the subtle slowing of development at first. The infant may begin to show
less eye contact and have reduced interest in toys. There may be delays in gross motor
skills such as sitting or crawling. Hand-wringing and decreasing head growth may occur,
but not enough to draw attention. This stage usually lasts for a few months but can
continue for more than a year.
Stage II, or the rapid destructive stage, usually begins between ages 1 and 4 and may
last for weeks or months. Its onset may be rapid or gradual as the child loses purposeful
hand skills and spoken language. Characteristic hand movements such as wringing,
washing, clapping, or tapping, as well as repeatedly moving the hands to the mouth
often begin during this stage. The child may hold the hands clasped behind the back or
held at the sides, with random touching, grasping, and releasing. The movements
continue while the child is awake but disappear during sleep. Breathing irregularities
such as episodes of apnea and hyperventilation may occur, although breathing usually
improves during sleep. Some girls also display autistic-like symptoms such as loss of
social interaction and communication. Walking may be unsteady and initiating motor
movements can be difficult. Slowed head growth is usually noticed during this stage.
Stage III, or the plateau or pseudo-stationary stage, usually begins between ages 2 and
10 and can last for years. Apraxia, motor problems, and seizures are prominent during
this stage. However, there may be improvement in behavior, with less irritability, crying,
and autistic-like features. A girl in stage III may show more interest in her surroundings
and her alertness, attention span, and communication skills may improve. Many girls
remain in this stage for most of their lives.
Stage IV, or the late motor deterioration stage, can last for years or decades. Prominent
features include reduced mobility, curvature of the spine (scoliosis) and muscle
weakness, rigidity, spasticity, and increased muscle tone with abnormal posturing of an
arm, leg, or top part of the body. Girls who were previously able to walk may stop
walking. Cognition, communication, or hand skills generally do not decline in stage IV.
Repetitive hand movements may decrease and eye gaze usually improves.
insufficient amounts or structurally abnormal forms of the protein are produced and can
cause other genes to be abnormally expressed.
Not everyone who has an MECP2 mutation has Rett syndrome. Scientists have
identified mutations in the CDKL5 andFOXG1 genes in individuals who have atypical or
congenital Rett syndrome, but they are still learning how those mutations cause the
disorder. Scientists believe the remaining cases may be caused by partial gene
deletions, mutations in other parts of the MECP2 gene, or additional genes that have
not yet been identified, and they continue to look for other causes.
Is Rett syndrome inherited?
Although Rett syndrome is a genetic disorder, less than 1 percent of recorded cases are
inherited or passed from one generation to the next. Most cases are spontaneous,
which means the mutation occurs randomly. However, in some families of individuals
affected by Rett syndrome, there are other female family members who have a mutation
of theirMECP2 gene but do not show clinical symptoms. These females are known as
asymptomatic female carriers.
Who gets Rett syndrome?
Rett syndrome is estimated to affect one in every 10,000 to 15,000 live female births
and in all racial and ethnic groups worldwide. Prenatal testing is available for families
with an affected daughter who has an identified MECP2 mutation. Since the disorder
occurs spontaneously in most affected individuals, however, the risk of a family having a
second child with the disorder is less than 1 percent.
Genetic testing is also available for sisters of girls with Rett syndrome who have an
identified MECP2 mutation to determine if they are asymptomatic carriers of the
disorder, which is an extremely rare possibility.
The MECP2 gene is found on a persons X chromosome, one of the two sex
chromosomes. Girls have two X chromosomes, but only one is active in any given cell.
This means that in a girl with Rett syndrome only a portion of the cells in the nervous
system will use the defective gene. Some of the child's brain cells use the healthy gene
and express normal amounts of the protein.
The severity of Rett syndrome in girls is in part a function of the percentage of their cells
that express a normal copy of the MECP2 gene. If the active X chromosome that is
carrying the defective gene is turned off in a large proportion of cells, the symptoms will
be mild, but if a larger percentage of cells have the X chromosome with the
normal MECP2gene turned off, onset of the disorder may occur earlier and the
symptoms may be more severe.
The story is different for boys who have a MECP2 mutation known to cause Rett
syndrome in girls. Because boys have only one X chromosome (and one Y
chromosome) they lack a back-up copy that could compensate for the defective one,
and they have no protection from the harmful effects of the disorder. Boys with such a
defect frequently do not show clinical features of Rett syndrome but experience severe
problems when they are first born and die shortly after birth. A very small number of
boys may have a different mutation in the MECP2 gene or a sporadic mutation after
conception that can cause some degree of intellectual disability and developmental
problems.
Is treatment available?
There is no cure for Rett syndrome. Treatment for the disorder is symptomatic
focusing on the management of symptoms and supportive, requiring a
multidisciplinary approach. Medication may be needed for breathing irregularities and
motor difficulties, and anticonvulsant drugs may be used to control seizures. There
should be regular monitoring for scoliosis and possible heart abnormalities.
Occupational therapy can help children develop skills needed for performing selfdirected activities (such as dressing, feeding, and practicing arts and crafts), while
physical therapy and hydrotherapy may prolong mobility. Some children may require
special equipment and aids such as braces to arrest scoliosis, splints to modify hand
movements, and nutritional programs to help them maintain adequate weight. Special
academic, social, vocational, and support services may be required in some cases.
What is the outlook for those with Rett syndrome?
Despite the difficulties with symptoms, many individuals with Rett syndrome continue to
live well into middle age and beyond. Because the disorder is rare, very little is known
about long-term prognosis and life expectancy. While there are women in their 40s and
50s with the disorder, currently it is not possible to make reliable estimates about life
expectancy beyond age 40.
What research is being done?
Within the Federal government, the National Institute of Neurological Disorders and
Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and
Human Development (NICHD), the National Institute of Mental Health (NIMH), and the
Office of Rare Diseases Research (ORDR) support clinical and basic research on Rett
syndrome.
Understanding the cause of this disorder is necessary for developing new therapies to
manage specific symptoms, as well as for providing better methods of diagnosis. The
discovery of the main Rett syndrome gene (MECP2) in 1999 provides a basis for further
genetic studies and enables the use of recently developed animal models such as
transgenic mice which are deficient in MECP2. These mice have neurologic
abnormalities that can be reversed by activating theMECP2 gene later in life. (For
information about the September 2011 workshop on optimizing animal models in Rett
syndrome
preclinical
research,
visit
http://www.ninds.nih.gov/news_and_events/proceedings/Rett-Syndrome-MouseModels.htm.)
One NINDS-supported study looks for mutations in the MECP2 gene of individuals with
Rett syndrome to learn about MeCP2 protein function and dysfunction. Information
from this study will increase understanding of the disorder and may lead to new
therapies. Other research aims at identifying molecular pathways that are affected by
the dysfunction, developing animal models of the disorder, and early-stage therapy
development.
Some researchers suggest that the specific type of mutation in the MECP2 gene affects
the severity of symptoms of Rett syndrome. Studies are now underway to understand
each mutation that may cause the features of Rett syndrome, and how these mutations
might change the features of the syndrome. One NIH-funded study of the natural
history of Rett syndrome should also provide new information about these topics.
Scientists know that lack of a properly functioning MeCP2 protein disturbs the function
of mature brain cells but they do not know the exact mechanisms by which this
happens. Investigators are trying to find other genetic switches that operate in a similar
way to the MeCP2 protein. Once they discover how the protein works and locate similar
switches, they may devise therapies that can substitute for the malfunctioning switch.
Another outcome might involve manipulating other biochemical pathways to
compensate for the malfunctioning MECP2 gene, thereby preventing progression of the
disorder. Gene therapy to achieve regulated expression of a normal MECP2 gene is
also under study in animal models.
Researchers are also trying to find other genes that may be involved in Rett syndrome.
Some studies have helped to narrow the search for these genes, but much is still
unknown about how these genes may cause or contribute to Rett syndrome.
What are the different types of Rett syndrome?
Ewen Callaway
18 March 2012
Rett Syndrome, an autism spectrum disorder, causes problems with communication,
coordination and movement.
A bone-marrow transplant can treat a mouse version of Rett syndrome, a severe autism spectrum
disorder that affects roughly 1 in 10,00020,000 girls born worldwide (boys with the disease
typically die within a few weeks of birth).
The findings, published today in Nature1, suggest that brain-dwelling immune cells called
microglia are defective in Rett syndrome. The authors say their findings also raise the possibility
that bone-marrow transplants or other means of boosting the brains immune cells could help to
treat the disease.
If we show the immune system is playing a very important role in Rett patients and we could
replace it in a safe way, we may develop some feasible therapies in the future, says Jonathan
Kipnis speculates that microglia from Rett mice have trouble clearing cellular rubbish in the
brain, making it more difficult for their neurons to work properly. If this can be established with
additional research, clinical trials of bone-marrow transplants may be worth trying, Kipnis says.
With the Rett Syndrome Research Trust, based in Trumbull, Connecticut, he has begun
approaching bone-marrow transplant centres with this possibility. "This is very, very
preliminary," he cautions. "It works fantastically in mice, but we can cure almost anything in
mice."
Less drastically, Kipnis thinks that the disease could also be treated with drugs that improve
microglia function. Girls with Rett syndrome have one working copy of MECP2, so half of their
microglia may work.
Frauke Zipp, a neuro-immunologist at the Johannes Gutenberg University Mainz in Germany,
agrees that a clinical trial of cell transplantation to treat Rett syndrome is far afield, but not
inconceivable if additional research pins down their role in disease.
These findings contribute to the idea that Rett syndrome is a very complicated disorder
involving multiple cell types and systems, adds Gail Mandel, a neuroscientist at Oregon Health
Sciences University near Portland. Some form of gene therapy may be a way of fixing all these
different problems, she says.
References: http://www.ninds.nih.gov/disorders/rett/detail_rett.htm
http://www.childrenshospital.org/health-topics/conditions/rett-syndrome
http://www.nature.com/news/bone-marrow-transplant-reverses-rett-syndrome-in-mice1.10243
for childhood disintegrative disorder are Heller's syndrome, dementia infantilis, and
disintegrative psychosis.
Description
Thomas Heller, an Austrian educator, first described childhood disintegrative disorder
in 1908. It is a complex disorder that affects many different areas of the child's
development. It is grouped with the pervasive developmental disorders (PDDs)
and is related to the better known and more common disorder of autism.
Initially CDD was considered strictly a medical disorder and was believed to have
identifiable medical causes. After researchers reviewed the reported cases of CDD,
however, no specific medical or neurological cause was found to account for all
occurrences of the disorder. For that reason, CDD was included in the fourth edition of
the Diagnostic and Statistical Manual of Mental Disorders , or DSM-IV , in
1994. The Diagnostic and Statistical Manual is the standard reference work consulted by
mental health professionals in the United States and Canada.
Symptoms
Children with CDD have at least two years of normal development in all areaslanguage
understanding, speech, skill in the use of large and small muscles, and social
development. After this period of normal growth, the child begins to lose the skills he or
she has acquired. This loss usually takes place between ages three and four, but it can
happen any time up to age ten.
The loss of skills may be gradual, but more often occurs rapidly over a period of six to
nine months. The transition may begin with unexplained changes in behavior, such as
anxiety, unprovoked anger, or agitation. Behavioral changes are followed by loss of
communication, social, and motor skills. Children may stop speaking or revert to single
words. They often lose bowel or bladder control and withdraw into themselves, rejecting
social interaction with adults or other children. They may perform repetitious activities
and often have trouble moving from one activity to the next.
In this way CDD resembles autism. In autism, however, previously acquired skills are
not usually lost. According to the Handbook of Autism and Pervasive Developmental
Disorders , virtually all children with CDD lose speech and social skills. About 90%
lose self-help skills (the ability to feed, wash, and toilet themselves); and about the same
number develop non-specific overactivity. After a time, the regression stops, but the
child does not usually regain the skills that were lost.
Demographics
CDD is a rare disease, much less common than autism. About 1 in 100,000 children are
thought to have CDD. It is possible, however, that the disorder is under-diagnosed. For a
long time, it was thought that CDD occurred equally among boys and girls. Newer
research suggests that it is about four times more common in boys, and that many girls
who were diagnosed with CDD actually had Rett's disorder , a disorder that shares
many of the symptoms of CDD but occurs almost always in girls.
Diagnosis
CDD is most commonly diagnosed when the parents of the affected child consult the
pediatrician about the child'sloss of previously acquired skills. The doctor will first give
the child a medical examination to rule out epilepsy or other medical conditions. The
child'shead may also be x rayed to rule out head trauma or a brain tumor. Following the
medical examinations and tests, the child will be referred to a psychiatrist who
specializes in treating children and adolescents. The psychiatrist will then make the
differential diagnosis of CDD.
To be diagnosed with CDD, a child must show loss or regression in at least two of the
areas listed below. Usually regression occurs in more than two areas. These are:
motor skills
Children with CDD are unable to start conversations with other people and often do not
communicate with nonverbal signals (smiles, gestures, nodding the head, etc.) either.
They also lose interest in playing games and in relationships with other people. They
may engage in strange repetitive behavior, such as bobbing the head up and down, or
other repeated movements. These changes must not be caused by a general medical
condition or another diagnosed mental disorder.
CDD must be differentiated from autism and such other specific pervasive
developmental disorders as Rett's disease. It also must be differentiated
from schizophrenia . One of the differences between CDD and other PDDs is that to
be diagnosed with CDD, a child must develop normally for at least two years before loss
of skills occurs, and the loss must occur before age ten. Parents' reports of the child's
development, records in baby books, medical records kept by the child's pediatrician,
and home movies are often used to document normal development through the first two
years of life.
Treatments
Treatment for CDD is very similar to treatment for autism. The emphasis falls on early
and intense educational interventions. Most treatment is behavior-based and highly
structured. Educating the parents so that they can support the child'streatments at
home is usually part of the overall treatment plan. Speech and language therapy,
occupational therapy, social skills development, and sensory integration therapy may all
be used according to the needs of the individual child
Families with a child who has CDD often find themselves highly stressed. Practical
demands on caregivers are high, and CDD takes an emotional toll on family members.
Finding appropriate providers with experience delivering services for a child with CDD
is sometimes difficult, especially outside large cities. Support groups for families can
help reduce their isolation and frustration. Because CDD is rare, autism support groups
and organizations include families of children with CDD in their services.
Prognosis
The prognosis for children with CDD is very poor; it is worse than the prognosis for
children with autism. Once skills are lost, they are not usually regained. Only about 20%
of children diagnosed with the disorder reacquire the ability to speak in sentences. Most
adults with CDD remain dependent on full-time caregivers or are institutionalized.
Prevention
Since the causes of CDD are unknown, there are no known ways to prevent this
disorder.
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References: http://www.minddisorders.com/Br-Del/Childhood-disintegrative-disorder.html