Disorder Definitions
What is Rett syndrome (RTT)?

Rett syndrome (RTT) is an X-linked dominant disorder predominantly affecting females, associated in 96% of affected individuals with mutations in the gene, methyl-CpG-binding protein 2 (MECP2) and characterized by apparently normal early development followed by a regression with loss of fine motor skills and effective communication, stereotypic movements, and apraxia or complete absence of gait. Additional features include abnormal postnatal deceleration in the rate of head growth, periodic breathing, gastrointestinal dysfunction, epilepsy, and scoliosis. Average survival to age 50 is expected.

What is MECP2 Duplication disorder?

MECP2 Duplication disorder is a neurodevelopmental disorder associated with duplication of the MECP2 gene including other gene duplications of variable size, making this a rather heterogeneous disorder in terms of clinical involvement. Clinical features include absence spoken language, poor or shuffling gait, and significant epilepsy. Some males have significant upper respiratory infections or sinusitis that is believed to be due to other duplicated genes. It is predominantly noted in males although a significant number of mothers of these males also have the same duplication, but due to favorable skewing of X-chromosome inactivation (XCI) are minimally affected in most instances.

  1. "Some males have significant upper respiratory infections or sinusitis that is believed to be due to other duplicated genes." Suggested: Most affected individuals have increased susceptibility to respiratory infections. [Reason: Most have this problem to a greater or lesser extent, it is the leading cause of death in this group, and a Zoghbi study in Science Translational Medicine demonstrated that partial immunodeficiency is directly related to duplication of MECP2.]
  2. "Associated with duplication of the MECP2" Suggested "duplication or triplication" [Reason: A good number of those affected actually have triplications.]
  3. "It is predominantly noted in males although a significant number of mothers of these males also have the same duplication, but due to favorable skewing of X-chromosome inactivation (XCI) are minimally affected in most instances." Suggested: The disorder is predominantly noted in males although about 10% of currently diagnosed individuals are females. Most females with duplications are asymptomatic carriers or have minimal symptoms due to favorable skewing of X-chromosome inactivation (XCI). More severe symptoms occur in females when less favorable skewing is present or the duplication is translocated to another chromosome. [Reason: in many cases, the extra copies of the Xq28 genes are translocated to another chromosome. Skewing does not play a role in these cases and males and females are equally affected.]
  4. "Poor or shuffling gait" Suggested: Limited ambulation, wide and shuffling gate.
  5. Consider adding. Regression of cognitive and motor skills often accompanies onset of seizures.
What are Rett-related disorders?

Rett-related disorders are due to a variety of genetic abnormalities. Individuals with MECP2 mutations but failing to meet the clinical criteria for RTT may include males with a significant neonatal encephalopathy or developmental delay with significant motor impairments, or females who may be normal or have mild learning disability or may have more significant psychotic or autistic-like manifestations due either to favorable skewing of XCI or to specific MECP2 mutations that may yield less significant neurodevelopmental abnormalities. Individuals with mutations in CDKL5 (X-linked) and FOXG1 (autosomal recessive) may have features consistent with atypical RTT again consisting of significant neurodevelopmental delays, epilepsy, and abnormal motor function.

CDKL5 Disorder
CDKL5 Disorder is a rare neurological disorder that affects both girls and boys within the first few months of life. CDKL5 is a gene on the X chromosome that creates the CDKL5 protein, which is essential for normal brain development. CDKL5 stands for Cyclin Dependent Kinase-Like 5. Females and males are affected, males typically being more severely involved due to a single X-chromosome. CDKL5 is a loss of function disorder that causes early-onset, refractory epilepsy leading to an epileptic encephalopathy, severe neuro-developmental impairment and multi-organ involvement. Children diagnosed with CDKL5 disorder often cannot walk or talk. Many suffer from scoliosis, cortical visual impairment and severe gastrointestinal symptoms. Communication is difficult for children with CDKL5, which can be isolating and frustrating. It is believed that children with CDKL5 disorder have stronger receptive skills and understand what is going on around them, but are unable to express themselves.

FOXG1 Disorder
FOXG1 disorder, previously known as the congenital RTT variant, is characterized by postnatal microcephaly often associated with corpus callosum abnormalities, and marked dyskinetic movements.11,12 Mutations in the FOXG1 on chromosome 14 are responsible for this autosomal dominant disorder, affecting both females and males. Thus, while shared features exist between these disorders, the unique features indicate each should be considered as distinct entities: a critcally important concept as the therapeutic approach to each is likely to be equally distinct.

No direct comparison between all of these disorders has been performed. Since 2014, a National Institutes of Health sponsored Natural History Study has been following individuals with these disorders. A direct comparison of these four related disorders using cross-sectional data collected at the baseline study visit on overall clinical severity, regression, and seizures is currently available. This information is critical to the development of future clinical trials and could potentially help with earlier diagnosis, assessment, and treatment of these disorders.

Frequently Asked Questions
This is a study of the clinical features of a specific disorder over time to understand the typical progression of symptoms and signs across the age spectrum. If the disorder is related to a specific gene, the variation in clinical features is measured against the different mutations in the specific gene responsible for the disorder. This is called the phenotype-genotype correlation.
A natural history study does not include a treatment trial, but is an essential initial study in establishing a clinical trial through developing a clear understanding of the natural history of that disorder as well as the phenotype-genotype correlation.
The study is funded through the NIH Office of Rare Diseases Research, the National Institute of Child Health and Human Development, and the National Institute of Neurological Disorders and Stroke. Rettsyndrome.org is cost sharing in the Natural History Study for the training component which is a necessary part of the Natural History Study. Costs of travel to the specific site are not covered by this study.
Specific sites are listed on the Participating Clinical Centers page. You will find contact information for the various sites including the one closest to you as well as all other sites. You may also find this information at www.rettsyndrome.org.