MECP2 mutation screening for Rett syndrome in India

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). The MECP2 gene provides instructions for making a protein (MeCP2) that is essential for normal brain development. This protein is found to be important for the function of nerve cells in the brain and is present in high levels in mature nerve cells. Various studies suggest that the MeCP2 protein plays a role in forming connections between nerve cells, where cell-to-cell communication occurs. This protein turns off other genes, preventing them from making proteins when they are not needed. It remains uncertain which genes are targeted by the MeCP2 protein, but such genes are probably important for normal brain function. Most cases of classic Rett syndrome are caused by mutations in the MECP2 gene. Males with mutations in the MECP2 gene often die before birth or in infancy. A small number of males with a MECP2 mutation, however, have developed signs and symptoms similar to those of classic Rett syndrome. Some of these boys have an extra X chromosome in many or all of the body's cells. The extra X chromosome contains a normal copy of the MECP2 gene, which produces enough of the MeCP2 protein for the boys to survive. Other males with features of Rett syndrome have mutations in the MECP2 gene that occur after conception and are present in only a fraction of the body's cells. In rare cases, researchers have discovered that the MECP2 gene is abnormally duplicated in boys with intellectual disability and some developmental problems characteristic of Rett syndrome. Although mutations in the MECP2 gene disrupt the normal function of nerve cells, it is unclear how these mutations lead to the signs and symptoms of Rett syndrome. We are providing mutation screening for MECP2 gene for Indian patients affected with Rett syndrome in our tertiary care hospital and research institute at following address. Genetics Unit, Department of Pediatrics, Old O.T block, Room no. 110, First floor, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029 India Ph: 011-26594585 +919999343421 Patients are evaluated using the diagnostic criteria of Rett syndrome used worldwide and then enrolled for screening of MECP2 mutations and polymorphisms. Reference: http://ghr.nlm.nih.gov/gene=mecp2 (Genetics home reference)

Classical and Atypical variant diagnostic criteria for Rett syndrome

Revised Diagnostic Criteria

At our present level of knowledge, the diagnosis of Rett Syndrome is more a clinical one and can not 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, diagnostic criteria for classical and variant Rett Syndrome is essential and 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.

Here is the list of essential and supportive diagnostic criteria for classical and Atypical Rett syndrome.

Essential Diagnostic Criteria for classical Rett syndrome (Patient should fulfill all of these)

• 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
• Impaired or absent locomotion from late infancy

Supportive Criteria for classical Rett syndrome

• Awake disturbances of breathing

• Hyperventilation

• 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 (teeth-grinding)

• Impaired sleep patterns in early infancy

• Profound daytime sleep/ Abnormal sleep cycle

Criteria for Atypical Cases

Inclusion criteria: Patient 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

Exclusion Criteria to rule out the diagnosis of Rett syndrome

• 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