The development of Rett syndrome happens in 4 stages . The ages at which each stage occurs and the presentations for the stage are detailed below:
This is known as developmental arrest and is seen in patients aged 6-18 month. Symptoms include:
- Delay in gross motor development
- Lack of interest in playing
- Inability to maintain eye contact
- Wringing of the hands (the main sign of the disease)
- Calm and dull appearance that is not seen in healthy infants of same age
- Hyperventilation and holding of breath
This is the rapid deterioration or regression stage and it is seen in children aged 1-4 years.
- Behaviour consistent with autism is most dominant at this stage and so the child loses ability to speak and is unable to use the finger and hands naturally.
- During wakefulness, hand-to-mouth movements, clapping, wringing etc. are noticeable.
This is the pseudostationary stage and is seen in children aged 2-10 years.
- Feeding is often difficult at this stage.
- Rigidity and involuntary movement of the tongue is also common.
This is the Late motor deterioration stage and it is seen in children aged 10 years and above (>10 years).
Entire Body System
- Developmental Disorder
Today Rett syndrome is classified as a pervasive developmental disorder, a group of conditions that includes the autism spectrum disorders and childhood disintegrative disorder. [britannica.com]
Keywords External Validity Independent Study Developmental Disorder Pervasive Developmental Disorder Rett Syndrome These keywords were added by machine and not by the authors. [doi.org]
[…] of written expression F81.89 Other developmental disorders of scholastic skills F81.9 Developmental disorder of scholastic skills, unspecified F82 Specific developmental disorder of motor function F84 Pervasive developmental disorders F84.0 Autistic [icd10data.com]
Rett syndrome, one of the leading causes of mental retardation and developmental regression in girls, is the first pervasive developmental disorder with a known genetic cause. [ncbi.nlm.nih.gov]
Definition Rett syndrome is a rare childhood neurological and developmental disorder that almost exclusively affects females. [ninds.nih.gov]
Irritability and crying. Children with Rett syndrome may become increasingly agitated and irritable as they get older. Periods of crying or screaming may begin suddenly, for no apparent reason, and last for hours. [mayoclinic.org]
They are likely to have panic attacks and fits of screaming or long bouts of crying though there is plenty of laughing as well. [rettsyndromesouthafrica.com]
Irritability, crying and restlessness may be seen. In some cases, development may continue but at a delayed rate. For example, an infant may learn to sit upright, but not to crawl. [rarediseases.org]
Some children have long periods of screaming, crying, and irritability that can last hours. [girlpower2cure.org]
It is therefore likely that there are individuals falling between these two extreme phenotypes. OBJECTIVE: To describe three patients showing only minor symptoms of Rett syndrome. [ncbi.nlm.nih.gov]
There may be difficulty falling to sleep or frequent awakenings during the middle of the night Intermittent strabismus may be noted. The child may present with irritability. [patient.info]
She stopped crawling and pulling herself up on her feet, and when she sat up she would fall over. Mrs Beckett took her back for testing, and six weeks later doctors confirmed Maika had Rett syndrome. [dailymail.co.uk]
- Feeding Difficulties
He presented the association of postnatal microcephaly, severe axial dystonia with severe feeding difficulties with protruding tongue movements during the first year of life that subsequently evolved into dyskinetic movement disorders with hand stereotypies [ncbi.nlm.nih.gov]
Breathing irregularity is also associated with feeding difficulties, notably because of dysfunctional coordination between breathing and swallowing. [neurolixis.com]
This is likely to contribute to feeding difficulties, breathing problems and delay in reaching motor milestones. Feeding difficulties Feeding difficulties are typical in newborn babies. [purasyndrome.org]
Some girls do not achieve walking, and those that do walk tend to have a broad-based gait. there is a tendency to develop scoliosis other problems include feeding difficulties, periodic agitation and breathing problems most girls are non-verbal epilepsy [cafamily.org.uk]
Related Problems Some common problems common in people with Rett syndrome include: Sleep problems  Seizures (occur in as many as 80% of patients)  Increase risk of fractures  Scoliosis  Feeding difficulties  Clinical Trials A list of ongoing [web.archive.org]
- Short Stature
A striking deceleration of growth has been found across all measurements in most girls with Rett syndrome who end up with short stature and microcephaly. The mortality (death) rate among children with Rett syndrome is increased (1.2% per year). [medicinenet.com]
Rett syndrome patients with short stature, females (000s) Table 10. Rett syndrome patients with skeletal problems, females (000s) Table 11. Rett syndrome patients with seizures, females (000s) Table 12. [giikorea.co.kr]
Short stature, renal dysfunction, and polydactyly are some signs of Bardet-Biedl syndrome or Laurence-Moon syndrome when associated with pigmentary retinopathy. [patient.info]
She also had short stature, was underweight, and had microcephaly. Her EEG showed bilateral occipital dominant high-voltage slow spike and wave complexes. Her brain CT and MRI were normal. [dx.doi.org]
An 8-month-old male was admitted to the pediatric department due to an initial seizure event following aspiration pneumonia and was referred to our clinic for the evaluation of unexplained neuroregression. [ncbi.nlm.nih.gov]
Death may be sudden and is often followed by secondary pneumonia. Some of the risk factors commonly seen are difficulty with swallowing, loss of mobility and seizures. [symptoma.com]
Death is often related to seizure, aspiration pneumonia, malnutrition, and accidents. [nlm.nih.gov]
For example, swallowing problems or breathing issues can lead to a risk of aspiration pneumonia. This type of pneumonia occurs when food, saliva or other liquids go into the lungs instead of the stomach. [my.clevelandclinic.org]
Death, when it comes, is usually caused by pneumonia and other conditions exacerbated by Rett. Many patients live into their 40s and beyond. How to help For more information about Rett syndrome and how to help, visit rettsyndrome.org. [eu.floridatoday.com]
The altered production of short chain fatty acids associated with this microbiota might reinforce the constipation status of RTT subjects and contribute to RTT gastrointestinal physiopathology. [ncbi.nlm.nih.gov]
Ongoing, severe constipation and gastroesophageal reflux (GERD ). Poor circulation that can lead to cold and bluish arms and legs. Severe language development problems. [nlm.nih.gov]
Growth failure, scoliosis and constipation are also common and they prove the most problematic amongst all symptoms. Individuals with this condition are prone to gastrointestinal disorders and as much as 80% of affected people have seizures. [symptoma.com]
Ongoing, severe constipation and gastroesophageal reflux (GERD). Poor circulation that can lead to cold and bluish arms and legs. Severe language development problems. [medlineplus.gov]
Supplements may be tried for constipation, alertness, or rigid muscles. Stem cell therapy, alone or in combination with gene therapy, is another hopeful treatment. [ufhealth.org]
CONCLUSIONS: Dysphagia was primarily limited to oral preparatory phases, while the pharyngeal phase was normal in most patients. The high percentage of dysphagia suggests the need to accurately monitor the feeding capability of RS children. [ncbi.nlm.nih.gov]
[…] transient inability to move (“freezing” episodes), muscle rigidity (dystonia), spasticity and/or joint contractures, or poor balance abnormal sleep patterns and night waking gastrointestinal motility problems (reflux, constipation, poor nutrient absorption) dysphagia [cheo.on.ca]
The 38.9 % of the individuals did not present dysphagia, 46.3 % presented dysphagia for solid foods but not for liquid ones, while only the 14.7 % presented dysphagia for both. [ojrd.biomedcentral.com]
Abraham, Ben Taragin and Alesandra Djukic, Co-occurrence of Dystonic and Dyskinetic Tongue Movements with Oral Apraxia in Post-regression Dysphagia in Classical Rett Syndrome Years of Life 1 Through 5, Dysphagia, 30, 2, (128), (2015). [doi.org]
- Failure to Thrive
Specialists are available to evaluate problems such as: Scoliosis Chewing/swallowing dysfunction Failure to thrive Gastroesophageal reflux Motor dysfunction A child with Rett syndrome may receive referrals to be evaluated by additional specialists from [texaschildrens.org]
He weighed 2810 g and subsequently spent 3 weeks in a special care nursery due to poor feeding, failure to thrive and apnoea. [doi.org]
Jaw & Teeth
- Stereotyped Behavior
The patient had severe intellectual disability, hypotonia, and a stereotypic behavior, “hand gripping,” described as being typical of RTT, bruxism, and exhibited no purposeful hand skills, was unable to walk independently, and could not articulate any [dx.doi.org]
Heightened anxiety and repetitive stereotyped behavior are commonly observed in RTT ( 43 ), and a large body of evidence supports the notion that 5HT modulates both of these behaviors ( 4, 5 ). [doi.org]
Background Autism is a condition that manifests in early childhood and is characterized by qualitative abnormalities in social interactions, markedly aberrant communication skills, and restricted repetitive and stereotyped behaviors. [emedicine.com]
Mutations in the P/Q type calcium channel CACNA1A have been implicated in epileptic encephalopathy, familial hemiplegic migraine, episodic ataxia 2, and spinocerebellar ataxia 6, but not Rett syndrome. [ncbi.nlm.nih.gov]
Cerebroatrophic hyperammonemia, dementia, ataxia, and loss of purposeful hand use, Rett disorder, Rett's disorder, Rett's syndrome, RTT, RTS Prevention - Rett syndrome There's no known way to prevent Rett syndrome. [checkorphan.org]
Additional findings include autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures (60-80%), and acquired microcephaly. [orpha.net]
- Loss of Speech
Within 1 to 2 years, this deterioration progresses to loss of speech, severe dementia, behavior reminiscent of autism, stereotypic hand-wringing movements, loss of purposeful use of the hands, jerky ataxia (wobbliness) of the trunk, intermittent hyperventilation [medicinenet.com]
Symptoms include Loss of speech Loss of hand movements such as grasping Compulsive movements such as hand wringing Balance problems Breathing problems Behavior problems Learning problems or intellectual disability Rett syndrome has no cure. [medlineplus.gov]
Disease definition A rare genetic neurological disorder almost exclusively affecting females, characterized by rapid developmental regression in infancy with loss of purposeful hand movements, loss of speech, gait abnormalities, and repetitive stereotypic [orpha.net]
- Involuntary Movements
An 8-year-old boy with the congenital variant of RTT who showed severe psychomotor deterioration, epilepsy, acquired microcephaly, and involuntary movements including jerky movements of the upper limbs and tongue protrusion. [ncbi.nlm.nih.gov]
Rigidity and involuntary movement of the tongue is also common. Stage IV This is the Late motor deterioration stage and it is seen in children aged 10 years and above (>10 years). [symptoma.com]
Abnormal or involuntary movements, such as jerking movements of the arms and legs and repeated hand motions, are common, and most affected children do not learn to sit or walk without assistance. [ghr.nlm.nih.gov]
They may also experience increasing muscle weakness, joint contractures, and spasticity, a condition characterize by involuntary muscles spasms that result in slow, stiff movements of the legs. [rarediseases.org]
- Abnormal Gait
Rett syndrome is a neurodevelopmental genetic disorder, characterized by developmental delay, hand stereotypies, abnormal gait, and acquired microcephaly. Epilepsy is very common in Rett syndrome and can be medically intractable. [ncbi.nlm.nih.gov]
[…] breathing difficulty ambulating seizures Physical exam apraxia abnormal gait scoliosis decreased head circumference usually starts to become evident at 5-6 months poor circulation indicated by cold, blue extremities Imaging Radiographs recommended views [orthobullets.com]
These gait patterns are among the most common gait abnormalities in children with cerebral palsy. [en.wikipedia.org]
Mecp2 -null male mice acquire neurological phenotypes reminiscent of RTT at ∼6 weeks after birth, including hypoactivity, abnormal gait, cognitive defects and breathing problems, leading to death at ∼6–12 weeks of age ( 14, 15 ). [doi.org]
Females that present any of the clinical presentations above are subjected to genetic testing to properly establish the presence of the condition   . In patients where MECP2 mutation is not found, it is important to undergo other diagnostic tests that are aimed at finding out the possible causes of the signs and symptoms being experienced.
Furthermore, RTT subjects suffer from an intestinal dysbiosis characterized by an abnormal expansion of the Candida population, a known factor responsible for the hyper-activation of pro-inflammatory immune responses. [ncbi.nlm.nih.gov]
[…] microbial taxa belonging to Bifidobacterium, several Clostridia (among which Anaerostipes, Clostridium XIVa, Clostridium XIVb ) as well as Erysipelotrichaceae, Actinomyces, Lactobacillus, Enterococcus, Eggerthella, Escherichia/Shigella and the fungal genus Candida [angsa.it]
At present, there is no cure for the Rett syndrome. However, studies have demonstrated that restoration of the functions of the MECP2 may bring about a cure . The treatment of the condition focuses on management. This includes the following:
- Management of gastrointestinal issues like reflux and constipation and nutritional poor weight gain issues
- Surveillance of scoliosis
- Surveillance of long QT syndrome by annual ECG
- Increasing the patient's communication skills, especially with augmentative communication strategies
- Parental counselling
- Modifying social medications
- Provision of sleep aids
It is not easy to predict the developmental potential for patients with the Rett syndrome. Some individuals with this syndrome are able to maintain and achieve some functional skills . Around 60% of RS patients are able to retain their abilities to ambulate. Others lose ambulation and due to scoliosis, dystonia, or atrophy, they may never walk.
The survival rate is poor in individuals that are 10 years or older and the 35-year survival rate is placed at 70%. Death may be sudden and is often followed by secondary pneumonia. Some of the risk factors commonly seen are difficulty with swallowing, loss of mobility and seizures. It is however, important to note that life expectancy is better in patients with Rett syndrome in comparison to patients with profound intellectual disability. The 35-year survival rate for the latter is only 27%.
Rett syndrome is caused genetically by mutations that occur in the MECP2 gene that is found on the X chromosome . It can arise sporadically or from germline mutations. Rett syndrome was first described via clinical observations but the diagnosis becomes definitive only when the defect in the MECP2 gene becomes definitive. However, there have been some rare cases of the condition where the MECP2 remains unaffected.
Approximately, the incidence of Rett syndrome occurs is 1 case per 23,000 live female births. In some countries, wide variations have been reported with some of them posting figures showing 1 case per 10,000 live female births . Figures in Japan suggest 1 case per 45,000 females aged 6 to 14. Variations in incidence may be due to the inclusion of atypical and/or variant forms of this condition. The atypical forms include congenital RS, preserved speech variants, as well as milder forms with later onset of regression.
The syndrome becomes evident clinically by 2 to 4 years of age, however the neurodevelopmental malfunction in children begin when they are 6 to 18 months or younger.
The patients identified are often female because the disease is X-linked. Most of the males that have the syndrome are believed to die in utero.
Studies have shown no racial variations of the syndrome as well.
The severity and symptom of the RS condition is dependent on both the percentage of defective genes that are activated as well as the type of mutation responsible for the condition . Varying mutation types have been seen in the 3 coding regions of the MECP2 gene and most of these cause truncations and missense proteins.
The mutations in the MECP2 gene bring about a loss of function of this protein with an unregulated expression of the genes that are normally affected. Some of these are crucial in the development of the nervous system past the early stages. The nervous system is the primary site of the condition but the specific target genes remain unknown. Due to the dysfunction of the MECP2 gene, astrocyte function is abnormal in Rett syndrome patients.
Rett syndrome cannot be prevented.
Formerly known as cerebroatrophic hyperammonemia, Rett syndrome (RS) is a genetic and neurologic disorder that affects the grey matter of the brain . It is a very rare condition that is seen predominantly in females with occasional occurrence in males.
The common clinical features are deceleration in head growth and small hands and feet. Other common symptoms are repetitive hand movements such as continuously putting hand in mouth and hand wringing. Growth failure, scoliosis and constipation are also common and they prove the most problematic amongst all symptoms. Individuals with this condition are prone to gastrointestinal disorders and as much as 80% of affected people have seizures. They generally do not have any verbal skills and more than 50% of those affected do not walk.
Rett syndrome is a genetic disorder that has been classified as rare. It affects the way the brain develops and is seen almost entirely in girls.
Babies that have this condition develop normally at first but the symptoms become visible by the time they are 6 months old. As time passes, children with the condition show increasing difficulty with movement, communication and coordination. This often affects their ability to use their hands, walk and communicate.
Presently, there is no known cure for the condition but potential treatments are being considered. Treat for now is focused on improving movement and communication and also providing care and support for the affected children and their families.
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- Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat Genet. Oct 1999;23(2):185-8.
- Dayer AG, Bottani A, Bouchardy I, Fluss J, Antonarakis SE, Haenggeli CA, et al. MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain Dev. Jan 2007;29(1):47-50.
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- Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23:185.
- Allen RC, Zoghbi HY, Moseley AB, et al. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992; 51:1229.
- Cheadle JP, Gill H, Fleming N, et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet 2000; 9:1119.