Rett Syndrome, which is named after Dr. Andreas Rett who identified the syndrome in 1966, is a debilitating neurological disorder.  Rett Syndrome is believed to affect 1 in 10,000 females.  It is very rare, but is possible, for males to have this disorder.  

     Girls with RS will usually develop normally until 6-18 months of age.  They then enter a period of regression, losing hand skills and speech that they had acquired.  Other problems may include seizures and irregular breathing patterns and motor control problems.  Barring complications or illness the girls can live into adulthood, but usually many never regain speech or the ability to use their hands.

    Diagnostic Criteria

• Period of apparent normal development until 6 - 18 months of age.  Although some girls have an earlier onset of RS symptoms and therefore have no apparently normal period of development.

• Normal head circumference at birth followed by slowing of the rate of head growth (3 months - 4 years).

• Loss of or severely impaired verbal language and loss of purposeful hand skills, which combine to make assessment of receptive language and intelligence difficult.

• Purposeful hand use is replaced by stereotypical hand movements including one or more of the following: washing, wringing, clapping, tapping, mouthing, clasping, and finger manipulation, which can become almost constant while awake.

• If able to walk the gait is usually wide-based and stiff legged.

• Shakiness of the torso, which may also involve the limbs, especially when upset or agitated.

Supportive Criteria

• Breathing pattern irregularities which include hyperventilation, breath holding, apnea and air swallowing which may result in abdominal bloating and distention.
• EEG abnormalities
• Seizures
• Scoliosis
• Teeth Grinding
• Gastrointestinal issues which may include reflux, constipation and poor nutrient absorption
• Growth retardation and decreased body fat and muscle mass
• Biting, chewing, and swallowing problems/difficulties
• Poor circulation to legs and feet
• Decreased mobility with age
• Muscle rigidity/spasticity/joint contractures
• Small feet
• Abnormal sleep patterns
• Irritability and agitation

Revised Diagnostic Criteria

Commentary

     It is important to emphasize that at our present level of knowledge, the diagnosis of RS remains a clinical one and is not made solely on the basis of MECP2 mutations.  This means that RS occurs with and without mutations in MECP2, and, additionally, mutations in MECP2 have been identified in individuals who lack the clinical features of either classic or variant RS.  Therefore, consensus on the diagnostic criteria for classic and variant forms of RS is essential and these criteria must be applied consistently for the accuracy of phenotype/ genotype correlation studies.

Rett Syndrome and MECP2 Mutations

• Rett syndrome is a clinical diagnosis

• Rett syndrome is not synonymous with MECP2 mutations

• Rett syndrome may be seen with MECP2 mutations

• Rett syndrome may be seen without MECP2 variations

• MECP2 may be seen without Rett syndrome

Female Phenotypes with MECP2 Mutations

• Rett syndrome

• Preserved Speech Variant

• Delayed Onset Varient

• Mild Learning Disability

• Angelman Syndrome

• Normal Carriers

Male Phenotypes with MECP2 Mutations

• Fatal Encephalopathy
• Rett/ Klinefelter Syndrome (extra X chromosome)
• Angelman Syndrome
• X-Linked Mental Retardation/ Progressive Spasticity
• Somatic Mosaicism / -Neurodevelopmental Delay
• Rett Syndrome and MECP2 Mutations

Revised Rett Syndrome Diagnostic Criteria (necessary for diagnosis)

• Apparently normal prenatal and perinatal period
• Psychomotor development may appear normal through the first six months or may be delayed from birth 
• Normal head circumference at birth 
• Postnatal deceleration of head growth in most children
• Decrease of  purposeful hand skills between ages 6 and 30 months
• Communication dysfunction and social withdrawal in early childhood
• Severely impaired expressive and receptive language and psychomotor impairment
• Stereotypic hand movements such as hand wringing/ squeezing, clapping/ tapping, mouthing and washing/ rubbing automatisms
• Impaired or absent locomotion from late infancy

Supportive Criteria (may also be seen)

• Awake disturbances of breathing

• Hyperventalation

• Breath-holding

• Forced expulsion of air or saliva

• EEG abnormalities

• Slow waking background and intermittent rhythmical slowing (3-5 htz)

• Epileptiform discharges, with or without clinical seizures

• Seizures

• Abnormal muscle tone associated with muscle wasting and dystonia

• Peripheral vasomotor disturbances (cold, blue feet and hands)

• Scoliosis/ kyphosis

• Growth retardation

• Hypotrophic small feet

• Bruxism (tooth-grinding)

• Impaired sleep patterns in early infancy

• Profound daytime sleep/ Abnormal sleep cycle

Exclusion Criteria (rules out the diagnosis of RS)

• Organomegaly or other signs of storage disease

• Retinopathy or optic atrophy

• Evidence or perinatal or postnatal brain damage

• Existence of identifiable metabolic or other progressive neurological disorder

• Acquired neurological disorders resulting from severe infections or head trauma

Criteria for Atypical Cases

Inclusion criteria: Must meet at least three of six main criteria and at least five of eleven supportive criteria

Six Main Criteria

• Absence or reduction of finger skills

• Loss of babble speech

• Loss of communication skills

• Deceleration of head growth

• Hand stereotypies 

• RS disease profile: a regression stage followed by a recovery of interaction, contrasting with slow neuromotor regression

Eleven Supportive Criteria

• Breathing irregularities 

• Teeth grinding

• Scoliosis/ kyphosis

• Lower limb muscle atrophy

• Cold, purplish feet

• Bloating

• Abnormal locomotion

• Sleep disturbances

• RS eye pointing

• Pain indifference

• Laughing/ screaming spells