Rett Syndrome Factsheet

Clinical features
Classic Rett syndrome is a progressive neurodevelopmental disorder that predominately affects females. Development is typically normal in early childhood with onset of developmental stagnation appearing by 18 months, followed by developmental regression from 1 to 4 years. Repetitive hand movements (such as flapping, wringing) replace purposeful hand movements and are characteristic of Rett syndrome. Other common clinical features include acquired microcephaly, intellectual disability, autistic-like features, apraxia, tremors, gait ataxia, and seizures. Individuals with Rett syndrome may have arrhythmia secondary to a prolonged QT interval. Atypical or variant Rett syndrome describes both more severe, earlier onset Rett as well as later onset and sometimes less severe presentations. Some individuals with variant Rett do not develop all the characteristic features such as stereotypical hand movements and/or loss of speech. Individuals with Rett syndrome typically live into adulthood.

Diagnosis
Diagnosis can be made through clinical findings or detecting a MECP2 mutation or deletion through genetic testing. The clinical criteria for both classic and variant Rett syndrome requires a period of developmental regression followed by stagnation or recovery. Exclusion criteria for classic Rett are (1) neurologic disease secondary to perinatal brain injury, infection or metabolic disease, and (2) psychomotor developmental delay in the first six months of life. Individuals with classic Rett must also have: Loss of acquired, purposeful hand movements Loss of acquire speech Gait abnormalities Stereotypic hand movements

Individuals with atypical Rett may have two or more of the above main criteria, and five or more of supportive criteria. Supportive criteria include breathing disturbances and bruxism when awake, abnormal sleep pattern, abnormal muscle tone, peripheral vasomotor disturbances, scoliosis or kyphosis, growth retardation, small cold hands and feet, inappropriate laughing or screaming, diminished pain response, and deliberate eye communication.

Genetics
Rett syndrome is caused by a mutation or deletion in the MECP2 gene, located on the X chromosome.

Inheritance & Genetic Counseling

Rett syndrome is inherited in an X-linked dominant inheritance pattern. Males with mutations in MECP2 have severe neonatal encephalopathy and are unlikely to survive. MECP2 mutations are typically do novo or sporadic occurrences. Occasionally, (<1% of cases) Rett can be inherited from a parent with germline mosaicism for a MECP2 mutation, or an asymptotic or mildly affected mother with a MECP2 mutation with skewed Xinactivation. For this reason, to determine recurrence risks, it is appropriate to offer targeted mutation testing to the patients mother. If she has the mutation, she has a 50% recurrence risk with each pregnancy. If the mother is negative for the mutation, gonadal mosaicism is either parent still possible, so the recurrence risk is very low, but is not zero.

Published December 2013 NCHPEG All rights reserved

Clinical testing
Testing for Rett syndrome begins with gene sequencing with reflex to deletion/duplication analysis if sequencing is normal. Mutations in the MECP2 gene are found in approximately 80% of individuals who meet criteria for classic Rett syndrome; 8% of these individuals have partial or whole gene deletions. MECP2 mutations are found in 40% of individuals with atypical Rett presentations; 3% have partial or whole gene deletions. Not all patients with a clinical diagnosis of Rett will have an identified molecular cause.

Management
There is no cure for Rett syndrome. Treatments are available to manage the symptoms of the disease and include regular surveillance for growth, nutrition, dentition, gastrointestinal function, mobility, communication skills, hand function, scoliosis, cardiac arrhythmia, and seizures and other neurologic complications. Individuals with Rett syndrome often benefit from augmented communication devices. There are guidelines for the management of scoliosis in Rett syndrome (Downs et al. 2009). Because of the risk of cardiac arrhythmia, drugs that prolong the QT interval should be avoided.

References
GeneReviews: MECP2-Related Disorders at http://www.ncbi.nlm.nih.gov/books/NBK1497/ Downs et al. 2009. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine 34(17):E607-17. Genetic Home Reference: Rett Syndrome at http://ghr.nlm.nih.gov/condition/rett-syndrome International Rett Syndrome Foundation at http://www.rettsyndrome.org/ National Institute of Neurological Disorders and Stroke: Rett Syndrome Fact Sheet at http://www.ninds.nih.gov/disorders/rett/detail_rett.htm. Rett Syndrome Research Trust at http://www.rsrt.org/

Published October 2013 NCHPEG All rights reserved