Rett Syndrome
Rett Syndrome is a severe neurodevelopmental disorder that primarily affects females and is characterized by a period of apparently normal early growth followed by a loss of acquired skills, particularly purposeful hand use and spoken language, and the emergence of distinctive hand stereotypies and gait abnormalities. The syndrome was first described by Dr. Andreas Rett in 1966 and is now recognized as a genetic disorder most commonly caused by mutations in the MECP2 gene located on the X chromosome. This gene encodes methyl-CpG-binding protein 2, which is critical for normal brain development and function through its role in transcriptional regulation and chromatin remodeling. Pathogenesis involves disrupted synaptic development and neuronal maturation, leading to widespread deficits in cognitive, motor, and autonomic function. The health impacts of Rett Syndrome are profound, encompassing severe intellectual disability, motor dysfunction, epilepsy, breathing irregularities, scoliosis, growth failure, and gastrointestinal disturbances. The disorder follows a progressive course with an initial period of stagnation followed by rapid regression and subsequent stabilization, but individuals often require lifelong care and support.
Classic Rett Syndrome is the most common and prototypical form of the disease, characterized by normal early development followed by a rapid regression between 6 and 18 months of age. Affected individuals lose purposeful hand skills and spoken language and develop repetitive hand movements such as wringing or clapping. Additional features include gait ataxia, loss of social engagement, seizures, breathing irregularities, and growth retardation. This type is almost exclusively seen in females and is typically associated with pathogenic variants in the MECP2 gene.
Atypical Rett Syndrome encompasses variants of the disorder that do not meet the full diagnostic criteria for classic Rett Syndrome. These include the early-onset seizure variant, characterized by prominent seizures before the onset of regression, and the congenital variant, in which developmental abnormalities are evident from birth. Atypical forms may be associated with mutations in genes other than MECP2, such as CDKL5 or FOXG1, and often present with a broader spectrum of severity and clinical features.
The preserved speech variant, also known as the Zappella variant, is a milder subtype of Rett Syndrome in which affected individuals retain some degree of speech and hand function. Regression is less severe, and motor impairment is typically less pronounced. This form is usually associated with specific MECP2 mutations and demonstrates a more favorable prognosis with better cognitive and functional outcomes.
Although Rett Syndrome predominantly affects females, rare cases in males have been reported, often presenting with more severe symptoms due to the presence of only one X chromosome. Male Rett Syndrome may result from somatic mosaicism, Klinefelter syndrome (47,XXY), or de novo mutations. The clinical course is typically more rapidly progressive and may include early-onset encephalopathy, severe intellectual disability, and early mortality.
Rett Syndrome is a rare disorder with an estimated prevalence of 1 in 10,000 to 15,000 live female births worldwide. The condition primarily affects females, with a male-to-female ratio of approximately 1:100, reflecting the X-linked dominant inheritance and the lethality of MECP2 mutations in most hemizygous males. The majority of cases are sporadic, resulting from de novo mutations in the MECP2 gene, although familial cases have been documented. The disorder has been identified across diverse ethnic and geographic populations. The median age of symptom onset is between 6 and 18 months, corresponding to the period of developmental regression. Advances in genetic testing have improved diagnostic accuracy and contributed to a more precise understanding of the epidemiological features of Rett Syndrome.
The diagnosis of Rett Syndrome is based on a combination of clinical assessment and molecular genetic testing. Diagnostic criteria, as outlined by the RettSearch Consortium, require the presence of a period of regression followed by recovery or stabilization, loss of purposeful hand skills, loss of spoken language, gait abnormalities, and the development of stereotypic hand movements. Supportive criteria include breathing disturbances, bruxism, impaired sleep, abnormal muscle tone, peripheral vasomotor disturbances, and growth retardation. Atypical forms may fulfill only some of these criteria. Molecular confirmation is achieved through sequencing of the MECP2 gene to identify pathogenic mutations, which are present in over 95% of classic cases. In cases where MECP2 mutations are absent, analysis of CDKL5 and FOXG1 genes may be indicated, particularly in atypical presentations. Differential diagnosis includes other neurodevelopmental disorders such as autism spectrum disorder, cerebral palsy, and childhood disintegrative disorder. Ancillary investigations, such as electroencephalography (EEG), brain MRI, and metabolic studies, are used to exclude other conditions and assess comorbidities but are not diagnostic for Rett Syndrome.
Trofinetide is an approved therapeutic agent for the treatment of Rett Syndrome, offering a novel approach to symptom management by targeting underlying neurobiological mechanisms. This drug has demonstrated efficacy in improving core symptoms of the disorder, such as communication abilities and motor function, as well as reducing behavioral and physical impairments associated with Rett Syndrome. Trofinetide is administered orally and has been evaluated in clinical trials, showing favorable outcomes in terms of safety and tolerability. Its use represents a significant advancement in the management of Rett Syndrome, providing a targeted pharmacological option for affected individuals.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | trofinetide (Rec INN; USAN) | 853400-76-7 | C13 H21 N3 O6 | 315.322 |
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