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Rett's Syndrome is a pervasive developmental disorder (PDD).
PDDs are a spectrum of diseases that impair or arrest a child's development, or cause its regression.
The condition was first reported in 1966 by Dr Andreas Rett (an Austrian paediatric neurologist) but has only recently become widely recognised as a discrete disease entity.
The Diagnostic and Statistical Manual Fourth Edition (DSM-IV) criteria include the following disorders as part of the PDDs (see separate articles):
- Autistic disorder (autism).
- Rett's syndrome.
- Childhood disintegrative disorder (Heller's syndrome).
- Asperger's syndrome.
- PDD not otherwise specified (PDDNOS).
The culprit gene, methyl-CpG binding protein-2 (MECP2) was discovered in 1999. This gene encodes for a protein that is involved in the methylation and regulation of other genes' activities. Although the target genes that are affected are unknown, they obviously play a crucial role in central nervous system (CNS) development.
It appears to arise as a sporadic mutation or chromosomal abnormality affecting the X chromosome:
- There is a small subgroup of affected sufferers who have a preserved-speech variant of the illness.
- Variable X-chromosome inactivation (lyonisation) may account for its non-pedigree pattern inheritance, variable phenotypic expression and rare presence in boys.
- A severe early-onset Rett's syndrome-like illness that often includes seizures or infantile spasms can be caused by mutation in the cyclin-dependent kinase-like 5 (CDKL5) gene.
Symptom reversal has been shown in mice.
It is a moderately rare condition, but a relatively common cause of pervasive developmental disorder (PDD):
- A French survey found a prevalence of about 1 case per 20,000 females aged 4-15 years.
- There is international variation with rates as high as 1 in 10,000 live female births in some series, but no obvious racial preponderance in studies of racially heterogeneous American patients.
- USA prevalence is approximately 1 per 23,000 population.
The conditions often cause sufferers to display autism-like behaviours, but differ from classical autism in that there is usually a history of an initial period of normal development. They may also be known as autistic spectrum disorders (ASDs). Rett's syndrome nearly always affects girls. The characteristic features are:
- Stage 1 - developmental arrest:
- Typically from 6-18 months.
- Tends to be gross motor developmental delay, loss of eye contact and a waning interest in play.
- Hypotonia may be present.
- Hand-wringing is noted and is a very characteristic feature.
- Symptoms can be vague and the only abnormality may be unusual placidity when compared with a normal child.
- Stage 2 - rapid developmental deterioration or regression:
- Typically age 1-4 years.
- May be a sudden onset of deterioration with an identifiable day when things changed; however it may be a more subtle onset and progression in some cases.
- Early growth restriction may be noted in falling off of head circumference from growth curve.
- There are autism-like behaviours with loss of verbal and other communication, hand use and social interaction.
- There are abnormalities of hand movements when the patient is awake, with the hands usually held in midline; there may be hand-wringing, clapping, handwashing or movements from hand to mouth.
- There may be episodes of hyperventilation or breath-holding.
- There can be vacant spells (that may resemble some forms of partial seizure) and actual fits.
- Sleep can be disturbed.
- Intermittent strabismus may be noted.
- The child may present with irritability.
- Stage 3 - stationary or pseudostationary phase:
- Typically aged 2-10 years.
- There may be an improvement in behaviour, use of the hands and communication skills.
- Eye contact returns and nonverbal communication may be exploited.
- There is persisting intellectual impairment with stereotyped hand movements.
- Generalised rigidity, bruxism and movements of the tongue may occur.
- Motor dysfunction or dystonia may be present.
- Breathing abnormalities can persist.
- Children may eat well, but put on little weight and are very low in the centile charts.
- Feeding may start to present difficulties due to oral motor dysfunction.
- Stage 4 - late motor deterioration:
- Typically occurs after the age of 10 years.
- Cognitive, communication and hand skills usually remain stable.
- Generalised motor dysfunction such as dystonia, hypertonia and Parkinsonism can present.
- Walking may cease.
- If there are fits, they tend to be less frequent in this stage.
Developmental assessment will reveal:
- Gross motor developmental delay.
- Loss of eye contact.
- Growth deceleration as revealed by weight, height and head circumference charts.
- Hypotonia with hand-wringing.
- Autism-like behaviour begins to emerge - particularly, poor social interaction, poor communication and loss of language.
- The abnormal, stereotyped midline hand movements will be evident.
- Episodes of hyperventilation or breath-holding may be witnessed, along with vacant episodes or seizures.
- Muscle wasting
- Growth restrictionmental
- Breathing abnormalities
NB: hand movements and eye contact tend to improve.
These vary with the stage of the illness.
|Differential diagnosis of Rett's syndrome according to stage of illness|
|Stage 1||Stage 2||Stage 3||Stage 4|
|A variety of (usually rare) neurodegenerative conditions that may affect children in their second decade.|
To make the diagnosis definitively, sequencing of the methyl-CpG binding protein-2 (MECP2) gene is performed through specialist laboratories.
- If this test is negative then a battery of investigations to reveal metabolic disturbance and look for organic acidoses will be needed.
- This will include measuring a variety of blood and urine organic acids and carrying out liquid-gas chromatography of the urine.
- Where Angelman's syndrome is a possibility, chromosomal analysis may be performed.
- Neuroimaging may be used to exclude other causes of the neurological manifestations.
- Electrocardiography (ECG_ and possibly 24-hour ECG may be needed as there is an association with cardiac arrhythmias.
- Gastrointestinal motility problems may be investigated by barium swallow, endoscopy, manometry and pH studies.
- Electroencephalography (EEG) may be used to investigate seizures, along with video-EEG recording. Polysomnography and investigations of respiratory pattern and function may be needed to assess those with sleep disturbance or breathing abnormalities.
- There are rare mutations of the methyl-CpG binding protein-2 (MECP2) gene that may cause disease in boys. There is a variant of the illness where speech is preserved.
- Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene may cause a severe Rett's syndrome-like early-onset syndrome.
- Some patients have long QT syndrome and are prone to cardiac arrhythmias.
A co-ordinated multidisciplinary specialist team approach, preferably with close involvement of the primary care team is the best model for care of this complex illness.
- Epilepsy should be investigated, with consideration of EEG-video recording, particularly to assess nocturnal disturbance:
- Vacant spells are not always due to epilepsy, so should not necessarily be treated unless there is good evidence that symptoms are connected to EEG disturbances.
- Conventional antiepileptic drugs such as carbamazepine and sodium valproate have been used with success.
- Other therapeutic avenues include newer antiepileptic drugs such as topiramate and lamotrigine, ketogenic diets and vagal nerve stimulator medications or implants.
- Long QT syndrome should be checked for and managed according to specialist advice, to lessen the risk of fatal cardiac arrhythmias.
- Feeding is usually a problem to some degree, as is maintaining weight, so a high-calorie, relatively high-fat content diet helps, and is also of help to some patients with epilepsy through its ketogenic effect:
- Assessment of oral motor function with use of correct positioning and other practical aids to ingestion and swallowing should be explored.
- Supplemental feeding by nasogastric or gastrostomy routes may be used.
- If medical therapy for gastro-oesophageal reflux is ineffective, then surgical procedures such as fundoplication may be useful.
- Constipation can be a problem and should be monitored and managed carefully.
- Scoliosis doesn't usually do well with orthotic treatments alone and patients with severe or function-limiting spinal curvature may benefit from surgical intervention.
- Osteoporosis is common and should be treated with calcium and vitamin D supplementation.
- Communication may be difficult, but nonverbal means should be assessed, explored and enhanced as much as possible:
- The use of picture boards and other visual aids to communication can be very helpful.
- Holistic therapy is thought to help some patients and appears to be popular with them and their families:
- Hydrotherapy, massage and horse riding have been used to help patients and their families cope with this condition.
- Families need empathetic social and sometimes psychological support; advice and advocacy for interactions with educational authorities can be beneficial. Screaming and nocturnal disturbance are often troublesome issues.
- Expert input may be helpful to exclude an organic cause that cannot be communicated, or to come up with practical solutions.
- The patient's home may need adaptations and aids to improve mobility and safety.
- Mobility aids such as hinged ankle-foot orthoses to overcome hypertonia, may help maintain independent walking:
- Hand splints that prevent the stereotyped hand movements, can reduce self-injury and agitation where they are particularly severe.
- Cardiac arrhythmias.
- Severe intellectual impairment.
- Loss of ability to walk.
- Gastrointestinal complaints.
- Screaming episodes.
- Nocturnal disturbance and poor sleep with alertness for up to 18 hours per day in many cases.
- Difficulties in coping with the condition for families/carers.
- Previously, life expectancy was only to mid-twenties; however, many patients are surviving to much older ages due to improved specialist management of the condition.
- Prognosis is variable where the developmental difficulties are concerned:
- Achievement and maintenance of some useful hand and communication skills is the norm for some patients.
- About 60% of patients can continue to walk throughout adulthood.
- The remainder never walk or lose the ability as global motor dysfunction sets in.
Further reading & references
- Chiu S; Pervasive Developmental Disorder, eMedicine, Apr 2010; Good overview of the range of conditions that cause PDD
- International Rett Syndrome Association; Resources for patients, their families, carers and healthcare professionals; Home page
- Percy AK; Rett syndrome: recent research progress. J Child Neurol. 2008 May;23(5):543-9. Epub 2007 Dec 3.
- 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 Oct;23(2):185-8.
- Rett Syndrome, Online Mendelian Inheritance in Man (OMIM)
- Guy J, Gan J, Selfridge J, et al; Reversal of neurological defects in a mouse model of Rett syndrome. Science. 2007 Feb 23;315(5815):1143-7. Epub 2007 Feb 8.
- Bienvenu T, Philippe C, De Roux N, et al; The incidence of Rett syndrome in France. Pediatr Neurol. 2006 May;34(5):372-5.
- Bernstein BE et al; Rett's Syndrome, eMedicine, Apr 2010
- Moog U, Smeets EE, van Roozendaal KE, et al; Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). Eur J Paediatr Neurol. 2003;7(1):5-12.
- Ellaway CJ, Sholler G, Leonard H, et al; Prolonged QT interval in Rett syndrome. Arch Dis Child. 1999 May;80(5):470-2.
- Lotan M; Management of Rett syndrome in the controlled multisensory (Snoezelen) environment. A review with three case stories. ScientificWorldJournal. 2006 Jul 8;6:791-807.
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.
Dr Sean Kavanagh
Dr Hayley Willacy