What is Rett Syndrome?

Rett syndrome is a unique neurodevelopmental disorder that is first noticed in infancy and primarily affects girls, but can be rarely seen in boys. Rett syndrome has been most often misdiagnosed as autism, cerebral palsy, or global developmental delay. Rett syndrome is found in all ethnic and racial groups and occurs worldwide in 1 of every 10,000 to 15,000 female births.

Rett syndrome was discovered by Dr. Andreas Rett in 1966 when he published his finding in German medical journal but Rett syndrome got the attention of scientific community only after 1983 when Dr. Hagberg published his similar findings on Rett syndrome in an English-language journal and named the disease as Rett syndrome after the name of Dr. Andreas Rett.

Symptoms of Rett syndrome appear after an early period of apparently normal or near normal development until six to eighteen months of life, when there is a slowing down or stagnation of skills. A period of regression then follows when the girl loses communication skills and purposeful use of her hands. Soon, repetitive hand movements such as hand washing, hand clenching, clapping, hand mouthing, wringing and tapping start appearing along with walking problems, and slowing of the normal rate of head growth. Other problems may include seizures, bruxism, scoliosis, digestion problems and breathing problems while she is awake. In the early years, there may be a period of isolation or withdrawal when she is irritable and cries inconsolably. Over time, motor problems may increase, but in general, irritability lessens and eye contact and communication improve.

A major discovery in 1999 by Ruthie Amir showed that MECP2 gene (present on X chromosome) mutations causes Rett syndrome. This discovery proved that Rett syndrome is an X-linked disorder. Rett is X-linked dominant disorder as only one of the two X chromosomes need to have the mutation in order for it to cause the disorder and that is why it is usually found only in girls.

There are more than 300 different mutations found on the MECP2 gene. Most of these mutations are found in eight different “hot spots.” MeCP2 protein helps in brain development and mutations in MECP2 gene causes abnormal functioning of brain that are responsible for cognitive, sensory, emotional, motor and autonomic function. These can include learning, speech, sensory sensations, mood, movement, breathing, cardiac function, and even chewing, swallowing, and digestion.

Rett syndrome can present with a wide range of disability ranging from mild to severe. The course and severity of Rett syndrome is determined by the location, type and severity of mutation and X-inactivation. Therefore, two girls of the same age with the same mutation can appear quite different.

Currently there are no effective treatments for Rett Syndrome. Most girls survive into adulthood and require total, 24-hour-a-day care.

In 2007 the journal Science published the work of Dr. Adrian Bird,  demonstrating the reversal of Rett Syndrome in mature mouse models with late stage disease. Only days away from death, these animals recovered normal function and became indistinguishable from healthy mice in a matter of weeks.

This remarkable success has projected the Rett syndrome research to a new area of possibility and positions Rett Syndrome to be the first curable childhood neurological disorder. The future of children and adults with Rett Syndrome depends on research. Without it, they will be completely dependent and locked in for the rest of their lives.

Rett syndrome presents many challenges, but with love, therapy, help and support, those with the syndrome can learn from school and community activities well into middle age and beyond. They show a full range of emotions and their engaging personalities as they take part in social, educational, and other activities at home and in the society.

Words of Dr. Andreas Rett about Rett Girls and their Families:
"They feel all the love given to them. They have a great sensitivity for love. I am sure of this. There are many mysteries, and one of them is the girls’ eyes. I tell all the parents to look at their eyes. The eyes are talking to them. I am sure the girls understand everything, but they can do nothing with the information."

"It is the parents who make most of the diagnoses, not the doctors, who often tell mothers that they are hysterical. Such doctors are very wrong - they know nothing, but say something."

Diagnosis and Testing of Rett Syndrome:

Rett syndrome is most often misdiagnosed as autism, cerebral palsy, or non-specific developmental delay. In the past, making the correct diagnosis called not only for a long list of diagnostic tests and procedures to rule out other disorders, but it also took from months to years waiting to confirm the diagnosis as new symptoms appeared over time. Today, we have a simple blood test to confirm the diagnosis. However, since we know that the MECP2 mutation is also seen in other disorders, the presence of the MECP2 mutation in itself is not enough for the diagnosis of Rett syndrome. Diagnosis requires either the presence of the mutation (a molecular diagnosis) or fulfilment of the diagnostic criteria (a clinical diagnosis, based on signs and symptoms that you can observe) or both.

MECP2 mutation screening for Rett syndrome in India
Mutation screening for MECP2 gene for Indian patients affected with Rett syndrome is provided by the following Laboratory. Patients are first evaluated by a team of doctors using the diagnostic criteria of Rett syndrome used worldwide and then enrolled for screening of MECP2 mutations and polymorphisms.

MECP2 Testing in AIIMS

Dr.Rajni Khajuria(Research Associates)

C/o Madhulika Kabra (Professor and office-in-charge)
Genetics Unit, Dept. Of Pediatrics,
Molecular Genetics Laboratory
Old O.T Block, Room No. 110, First floor,
All India Institute of Medical Sciences,
Ansari Nagar, New Delhi-110029
Phone no# 011-26594585, 09999343421
E-mail: madhulikakabra@hotmail.com
                 rajni.aiims@gmail.com

Diagnostic Criteria of Classical Rett Syndrome(Hagberg et al.,2002)

At our present level of knowledge, the diagnosis of Rett Syndrome s more a clinical one and cannot be ruled out on the basis of MECP2 mutations presence or absence, that means Rett Syndrome can occurs with or without mutations in MECP2, the mutations in MECP2 have also been found in those who does not have any clinical features of either classic or variant Rett Syndrome. Therefore, a diagnostic criterion for classical and variant Rett Syndrome is essential and these should be noted very carefully while clinical examination of the patient. Moreover a patient can be examined two or more times by different team of clinicians to confirm the diagnostic criteria.

Necessary criteria (must be present for the diagnosis)
  1. Apparently normal prenatal and perinatal history
  2. Psychomotor development largely normal through the first six months or may be delayed from birth
  3. Normal head circumference at birth
  4. Postnatal deceleration of head growth in the majority of patients
  5. Loss of achieved purposeful hand skill between ages six months and 2.5 years
  6. Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing etc.
  7. Emerging social withdrawal, communication dysfunction, loss of learned words, and cognitive impairment
  8. Impaired (dyspraxic) or failing locomotion
Supportive criteria of Classical Rett syndrome (may or may not be seen)
  1. Awake disturbances of breathing (hyperventilation, breath-holding, forced Expulsion of air or saliva, air swallowing)
  2. Teeth grinding (bruxism)
  3. Impaired sleep pattern from early infancy
  4. Abnormal muscle tone successively associated with muscle wasting and dystonia
  5. Peripheral vasomotor disturbances (cold, blue hands and feet)
  6. Scoliosis/kyphosis progressing through childhood
  7. Growth retardation
  8. Hypotrophic (small) feet; small, thin hands
Exclusion criteria (rule out the diagnosis)
  1. Enlarged organs or other signs of storage disease
  2. Retinopathy, optic atrophy, or cataract
  3. Evidence of brain damage before or after birth
  4. Existence of identifiable metabolic or other progressive neurological disorder
  5. Acquired neurological disorder resulting from severe infection or head trauma

Diagnostic Criteria for Atypical/Variant Rett Syndrome(Hagberg et al.,2002)
Inclusion Criteria
  1. meet at least three of six main criteria
  2. meet at least five of eleven supportive criteria
Six main criteria (must meet three out of six):
  1. Absence or reduction of hand skills
  2. Reduction or loss of babble speech
  3. Monotonous pattern to hand stereotypies
  4. Reduction or loss of communication skills
  5. Deceleraton of head growth from first years of life
  6. A regression stage followed by a recovery of interaction contrasting with slow neuromotor regression
Eleven supportive criteria (must meet at least five out of eleven):
  1. Breathing irregularities
  2. Bloating/air swallowing
  3. Teeth grinding, harsh sounding type
  4. Abnormal locomotion
  5. Scoliosis/kyphosis
  6. Lower limb muscle atrophy
  7. Cold, purplish feet, usually growth impaired
  8. Sleep problems including night screaming outbursts
  9. Laughing/screaming spells
  10. Diminished response to pain
  11. Intense eye contact/eye pointing

Revised Diagnostic Criteria of Rett Syndrome(Neul et al.,2010)

Consider diagnosis when postnatal deceleration of head growth observed Required for typical or classic RS
  1. A period of regression followed by recovery or stabilization Breathing irregularities
  2. All main criteria and all exclusion criteria
  3. Supportive Criteria are not required,although often present in typical RS
Required for atypical or variant RTT
  1. A period of regression followed by recovery or stabilization Breathing irregularities
  2. At least 2 out of the 4 main criteria
  3. 5 out of 11 supportive criteria
Main criteria:
  1. Partial or complete loss of acquired purposeful hand skills
  2. Partial or complete loss of acquired spoken language
  3. Gait abnormalities: Impaired (dyspraxic) or absence of ability
  4. Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms
Exclusion criteria for classical/typical RS
  1. Brain injury secondary to trauma (peri- or postnatally), neurometabolic disease, or severe infection that causes neurological problems
  2. Grossly abnormal psychomotor development in first 6 months of life
Supportive criteria:
  1. Breathing disturbances when awake
  2. Bruxism when awake
  3. Impaired sleep pattern
  4. Abnormal muscle tone
  5. Peripheral vasomotor disturbances
  6. Scoliosis/kyphosis
  7. Growth retardation
  8. Small cold hands and feet
  9. Inappropriate laughing/screaming spells
  10. Diminished response to pain
  11. Intense eye communication-"eye pointing"
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