The management of Rett syndrome

Affected babies usually display normal growth and behaviour a time after birth

“Trust the parents who make most of the diagnoses, not the physicians.” (Hajra 1943-2003).

Rett syndrome (RTT) is a complex postnatal neurodevelopmental disorder that is classified as a pervasive development disorder (PDD) by DSM-IV, which is the second most common cause of severe and profound learning disability in girls. Other PPDs include autistic disorder, Heller’s syndrome and Asperger’s syndrome.

With regard to incidence, RTT is noted in 1:10,000 girls (Jan et al 1999), but a French study found RTT in 1:20,000 females aged 12-15 (Amir et al 1999). However, the US population rate is 1:23,000 (Schneider et al 2008). Extremely few boys are affected with RTT.

History
Dr Andreas Rett (1954) and Dr Hagberg (1960) described young females with repetitive ‘hand washing’/wringing movements. Dr Rett (1966) published his findings in German journals and Dr Hagberg (1983) published an article on RTT.

Ruthie Amir (1999) discovered the MECP2 (methyl-CpG binding protein 2) gene near the end of the long arm of the X chromosome at the Xq28 site. When mutated, it causes RTT. This is found in the majority of RTT patients.

It is usually caused (in 95 per cent or more cases) by a de novo mutation in the child (Lewis et al 1992). More than 99 per cent of cases of Rett syndrome are sporadic, with later-age onset having a more severe manifestation.

Characteristics

• According to ICD-10 (F84.2), the characteristics of Rett syndrome are:

1. A condition, so far found only in girls, in which apparently normal early development is followed by partial or complete loss of speech and of skills in locomotion and use of hands, together with deceleration in head growth, usually with an onset between seven and 24 months of age;
2. Loss of purposive hand movements, hand-wringing stereotypes, and hyperventilation are characteristic;
3. Social and play development are arrested but social interest tends to be maintained;
4. Trunk ataxia and apraxia start to develop by age four years and choreoathetoid movements frequently follow;
5. Severe mental retardation in the patient almost invariably results.

• According to DSMIV (299.80), Rett syndrome comprises:

All of the following:
1. Apparently normal prenatal and perinatal development;
2. Apparently normal psychomotor development through the first five months after birth;
3. Normal head circumference at birth;

and it has an onset of all of the following after the period of normal development:
1. Deceleration of head growth between the ages of five and 48 months;
2. Loss of previously acquired purposeful hand skills between five-30 months, with the subsequent development of stereotypical hand movements (e.g. hand-wringing or ‘hand washing’);
3. Loss of social engagement early in the course (although often social interaction develops later);
4. Appearance of poorly co-ordinated gait or trunk movements;
5. Severely impaired expressive and receptive language development with severe psychomotor retardation.

• The features of MeCP2 dysfunction are as follows:

Female: Autism, learning disability, mild mental retardation, seizures, Angelman-like syndrome
Male: Infantile encephalopathy, motor deficits with mental retardation, bipolar disease, tremors, juvenile-onset schizophrenia, psychosis, macro-orchidism, pyramidal signs.

Normal stage
Classically, children with RTT tend to develop normally up to the age of six to 18 months and seemingly achieve normal milestones such as walking and speaking a few words.

Then they go through various stages or phases, such as losing acquired skills and substantial communication and mobility issues. Autistic-like behaviour may be seen. The developmental arrest or stagnant stage is typically from six to 18 months.

There is gross motor developmental delay, loss of eye contact and hypotonia. Handwringing is a very characteristic feature and there is deceleration of head growth, microcephaly, hypotonia, weight loss and weak posture. Short hands and feet are associated.

The rapid developmental deterioration or regression stage is typically from the age of one to four years. It has an acute or subtle onset. Early growth-retardation with head deceleration is seen. There can be signs of autistic behaviour: expressionless face, hypersensitivity to sound, with loss of verbal and non-verbal communication, unresponsive to social clues and social withdrawal.

There are also:

• Abnormalities of midline hand movements: hand-wringing, clapping, flapping, handwashing and ‘mouthing’ of the hands;
• Hyperventilation during wakefulness, breathing anomalies, including breath holding, aerophagia, forced expulsion of air and saliva, apnoea;
• Controlled to intractable epilepsy, ranging from partial complex and tonic clonic type;
• Insomnia, irritability, intermittent strabismus;
• Self-abusive behaviour;
• Mental retardation, motor abnormalities, ataxia, gait apraxia.

The pseudostationary or stationary stage is typically from the ages of two to ten years. There is persisting mental impairment with stereotyped hand movements; generalised rigidity, bruxism (grinding the teeth) and involuntary movements of the tongue; and dystonia, breathing abnormalities (very low in the centile charts). Feeding difficulties and poor weight gain can be seen, due to oral motor dysfunction, and also scoliosis and osteopenia.

The late motor deterioration or postregression stage typically occurs after the age of ten years. Dystonia, hypertonia and Parkinsonism can be seen, along with growth retardation, walking difficulty, quadriparesis, muscle wasting and scoliosis/kyphoscoliosis.

There may be seizures and breathing abnormalities. Behavioural issues include: teeth grinding, night laughing, screaming fits, low mood, anxiety episodes.

Other associated features include: hypotrophic cold blue feet, severe constipation, oropharyngeal dysfunction, tachycardia, long QT interval, sinus bradycardia and Parkinsonian features.

Differential diagnosis
Differential diagnoses include:

Autism – screaming fits; panic attack; inconsolable crying; avoidance of eye contact; lack of social/emotional reciprocity; general lack of interest; markedly impaired use of non-verbal behaviours to regulate social interaction; loss of speech; and balance and co-ordination problems, including losing the ability to walk in many cases.

Cerebral palsy – short stature; hypotonia; delayed or absent ability to walk; gait difficulties; ataxia; microcephaly; spasticity; chorea of hand or facial muscles; dystonia; bruxism.

Angelman syndrome – intellectual and developmental delay; sleep disturbance; epilepsy; hand-flapping; frequent laughter or smiling, and usually a happy demeanour; feeding problems during infancy; delay in sitting and walking; absent or little speech; below-average head size, often with flattening at the back; wide mouth; widely spaced teeth; prominent chin; poor sleeping pattern; strabismus; scoliosis.

Diagnosis
Patients have a normal prenatal and perinatal history. They have normal psychomotor development through the first six months (or this may be delayed from birth) and have normal head circumference at birth. There is postnatal de-celeration of head growth in the majority of patients.

There is also a loss of achieved purposeful hand skill between ages of six to 30 months and there is stereotypical hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms.

Emerging social withdrawal, communication dysfunction, loss of learned words, and cognitive impairment can be seen, along with dyspraxia, breathing problems (hyperventilation, breath-holding, forced expulsion of air or saliva, air swallowing) and bruxism.

Patients may have impaired sleep pattern from early infancy; hypotonia, muscle wasting and dystonia; peripheral vasomotor disturbances (cold, blue hands and feet); scoliosis/kyphosis progressing through childhood; and hypotrophic (small) feet/small, thin hands.

Currently there is no cure for Rett syndrome, although there have been some promising results with gene therapy in mice. It is a multidisciplinary approach in which the paediatrician, psychiatrist, cardiologist, surgeon, neurologist, social worker, psychotherapist, occupational therapist and geneticist play an important roles.

A comprehensive history and neurological examination is necessary, and it is important to examine if there is a family history of muscle disease, RTT, dyslexia, attention deficit hyperactivity disorder, etc.

Neuroimaging of the brain can be helpful in diagnosis. Electroencephalography can see focal, multifocal, generalised epileptiform discharges or slow theta activity (Moser et al 2007). Electrocardiography can help determine whether there is long QT interval (Glaze 2005). Cerebrospinal fluid testing can help determine neurochemical changes (Riikonen 2003, Paterson et al 2005).

Psychoeducation of the patient and the family can be useful, along with behaviour therapy and family therapy to address anxiety and frustration and occupational help and career guidance. Genetic counselling of the family is recommended.

Physiotherapy may be necessary for scoliosis, but scoliosis requires corrective surgery in about 10 per cent of cases. Those who remain ambulatory tend to have less progression of scoliosis. Speech therapy can increase the patient’s communication skills. Pharmacotherapy treatments can help with different aspects of the condition (see table below).

Prognosis
Traditionally, many RTT patients lived only to their mid-twenties, but now many are surviving to much older ages due to improved specialist management. Males with pathogenic MeCP2 mutations usually die within the first two years from severe encephalopathy, but females can live up to 40 years or more. Deaths are abrupt due to spontaneous brainstem dysfunction, cardiac arrest, seizures, abnormally prolonged QT interval and gastric perforation.

Prognosis is variable depending upon developmental difficulties such as maintaining useful hand and communication skills and 60 per cent of patients continue walking throughout adulthood. The remainder never walk or lose the ability as global motor dysfunction sets in.

Neurological deficits can be reversed by restoring gene function and to identify proteins or pathways to suppress MeCP2 dysfunction phenotypes might prove easy therapeutically. RTT patients with severe mutations with milder forms argue that some variant protein might subdue RTT.

• Dr Muhammad Arshad is a Child and Adolescent Psychiatrist at Hawke’s Bay Hospital, New Zealand.
• Prof Michael FitzGerald, is Henry Marsh Professor of Trinity College Dublin.

Psychopharmacology:
Symptom Medications
Infections Antibiotics
Pain Analgesics
Sleep disturbance Melatonin
Osteoporosis Calcium and vitamin D
OCD, depression, anxiety SSRIs
Epilepsy Carbamazepine, valproic acid,
phenytoin
Aggression Antipsychotic in small dose
ADHD Psychostimulants, atomoxetine
Self harming behaviour Antipsychotics
Constipation, reflux Laxatives
Long QT syndrome Beta blockers