Rett Syndrome

Rett 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 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 DSM-IV criteria include the following disorders as part of the PDDs:

• Virtually always affects girls.
• Initially normal development but some may have been noted as very placid babies.
• Early growth-retardation may be noted in falling off of head circumference from growth curve.
• Neurological disease and problems in other systems.
• Period of developmental stagnation followed by regression.
• Developmental regression may come on acutely over days or more subtly over a few months.
• Often loss of hand motor-skills, stereotypical hand movements, loss of spoken language and gait dyspraxia.
• Other features include breath holding attacks, waking apnoea but normal breathing in sleep, epilepsy, oral-motor dysfunction, gut motility abnormalities, autonomic dysfunction, scoliosis and growth failure.
• Regression period may manifest as screaming epsiodes, sleep disturbance and failure to interact socially.
• After the regression period, things may improve with some hand movements returning, improved spoken language communication and better social interaction; hand and language skills are always likely to be significantly impaired.
• Survival through puberty and into adulthood is the norm.

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 causing PDD. In 1999, the culprit gene, methyl-CpG binding protein-2 (MECP2) was discovered. 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, but 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.¹

Symptoms

The illness has four distinct phases which follow on from an initial period of developmental normality, although some sufferers display overt placidity from birth.

• 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.
  • Can, however, be a more subtle onset and progression in some cases.
  • 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.

Signs

In 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 and hypotonia with handwringing. In 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. Findings emerging in Stage 3 include bruxism, involuntary movements of the tongue, poor weight gain and scoliosis. Stage 4 physical signs include dystonias, rigidity, quadriparesis, muscle wasting, scoliosis/kyphoscoliosis, loss of ability to walk, growth retardation and breathing abnormalities. Hand movements and eye contact tend to improve in Stage 4.

This is largely dependent on the stage of the illness.¹

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. 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.

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 novel 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 ameliorate 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 NG 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. 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 sterotyped hand movements can reduce self-injury and agitation where they are particulalrly severe.

• Cardiac arryhthmias
• 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

Variable as far as 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. Previous life expectancy was probably only to mid twenties but many patients are surviving to much older ages due to improving specialist mangement of the condition.