Rett Syndrome

Pervasive developmental disorders

The DSM-IV criteria include the following disorders as part of the PDDs (see our specific records):

• Autistic disorder (Autism)
• Rett 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.^1,2 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 CNS development.

It appears to arise as a sporadic mutation or chromosomal abnormality affecting the X chromosome:

• There is a small sub-group 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 syndrome-like illness that often includes seizures or infantile spasms can be caused by mutation in the CDKL5 (cyclin-dependent kinase-like 5) gene.²

It is a moderately rare condition, but a relatively common cause of PDD:

• A recent French survey found a prevalence of about 1 case per 20,000 females aged 4–15.³
• 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.
• US prevalence is approximately 1 per 23,000 population.⁴

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 (ASD).
The characteristic features of Rett syndrome are:⁴

• Virtually always affects girls
• 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
  • Handwringing is noted and is a very characteristic feature
  • Symptoms can be vague and the only abnormality may be unusual placidity when compared to 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-retardation 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 patient is awake, with 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 non-verbal communication may be exploited
  • There is persisting mental 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 age 10
  • 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

Stage 1

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 handwringing

Stage 2

• 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

Stage 3

• Bruxism (grinding the teeth)
• Involuntary movements of the tongue
• Poor weight gain
• Scoliosis

Stage 4

• Dystonias
• Rigidity
• Quadriparesis
• Muscle wasting
• Scoliosis/kyphoscoliosis
• Growth retardation
• Breathing abnormalities

NB: Hand movements and eye contact tend to improve

This is largely dependent on the stage of the illness.⁴

To definitively make the diagnosis, sequencing of the MECP2 gene is performed through specialist labs.

• 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 syndrome is a possibility, chromosomal analysis may be performed.
• Neuroimaging may be used to exclude other causes of the neurological manifestations.
• ECG and possibly 24-hour ECG may be needed as there is an association with cardiac arrythmias.
• Gastrointestinal motility problems may be investigated by barium swallow, endoscopy, manometry and pH studies.
• 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 MECP2 gene that may cause disease in boys.^2,5 There is a variant of the illness where speech is preserved.
• Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene may cause a severe Rett-like early-onset syndrome.
• Some patients have long QT syndrome and are prone to cardiac arrhythmias.⁶

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 anti-epileptic drugs such as carbamazepine and sodium valproate have been used with success.
  • Other therapeutic avenues include newer anti-epileptic 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 non-verbal 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.⁷
  • Families need empathic 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 mental impairment
• Loss of ability to walk
• Gastrointestinal complaints
• Epilepsy
• Cachexia
• 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

• Previous life expectancy was probably only to mid-twenties, but 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.