#ShareForRare: Rett syndrome
What is Rett syndrome?
Rett syndrome (RTT) is a rare neurodevelopmental disorder that occurs almost exclusively in females. This X-linked genetic condition typically becomes apparent after 6–18 months of age and involves a slowing of development, distinctive hand movements, loss of speech, decelerated brain and head growth, gait anomalies, seizures, and intellectual disability. It is also associated with gastrointestinal and respiratory issues, scoliosis, and behavioral disorders.
The classic form of the condition is caused by mutations in the methyl CpG-binding protein 2 gene (MECP2), located in chromosome Xq28, which has been proven to be essential for embryonic development and is subject to X inactivation. It encodes for the MeCP2 chromatin-associated protein which binds methylated CpGs. It can both activate and repress transcription, regulating the activity of several genes, including ones involved in the brain’s development and function. This protein likely plays a role in the maturation of neurons and maintaining synapses between them. In less than 5% of cases, which were historically diagnosed as atypical or congenital Rett syndrome, mutations in other genes such as CDKL5 (the Hanefeld variant) and FOXG1 (the Rolando or congenital variant) can cause overlapping signs and symptoms that clinically resemble RTT.
Being an X-linked dominant condition, XY individuals typically suffer from severe neonatal encephalopathy that is usually lethal in infancy if they are born with a MECP2 mutation, with most male fetuses rarely making it to term. However, many females with Rett syndrome continue to live into middle age and beyond, with studies showing that 70% of individuals with typical Rett syndrome survived to at least 50 years of age.
It is commonly stated that Rett syndrome affects about 1 in 10,000 females. A recently published meta-study estimated that the global prevalence of the disease was 7.1 per 100,000 females using a sample of over 9.5 million women.
Molecular aspects of Rett syndrome
Pathogenic variants in the X-linked gene MECP2 are found in most cases of classic Rett syndrome (RTT). The most frequent mutation is a cytosine to thymine change at CpG dinucleotides; however, the spectrum of mutation types includes missense, nonsense, and frameshift mutations, with over 300 unique pathogenic nucleotide changes described, as well as deletions encompassing whole exons.
The specific type of mutation in MECP2 is thought to affect disease severity and progression. For example, in a study comparing 29 cases of the Zapella (or “preserved speech”) variant, a milder version of RTT, with 129 classic Rett patients, it was revealed that the majority of patients showing progress in manual and verbal abilities carried either missense mutations, especially p.R133C, or late truncating variants in the MECP2 gene.
In the vast majority of cases, sporadic mutations in this gene occur spontaneously during embryonic development, meaning they occur randomly for no known reason. While Rett syndrome is typically not inherited, rare familial cases do occur, but this accounts for less than 1% of cases.
As of March 2023, over 900 pathogenic variants in the MECP2 gene have been identified as RTT-causing, including almost 600 unique point mutations. According to Franklin, out of the 599 pathogenic SNPs reported, 447 (74.6%) are loss-of-function mutations, 127 are missense changes and 23 are non-coding.
Clinical features and diagnostics
Typical RTT progression is divided into 4 stages, with different phenotypic presentations corresponding to each one:
Stage I: Called early-onset, it typically begins between 6 and 18 months of age. Children with Rett do not show any symptoms at birth. The first complications usually appear between 6 to 18 months of life and are often subtle at their onset, and consequently, they might be overlooked. Some infants may show delays or even regression in gross motor skills, such as crawling or sitting, and reduced eye contact. Hand-wringing and decreasing head growth may occur, but not enough to draw attention. This stage usually lasts for a few months but can continue for more than a year.
Stage II: The rapid destructive stage usually begins between ages 1 and 4 and may last weeks or months. Its onset may be rapid or gradual as the child loses purposeful hand skills and spoken language. Stereotypic, or repetitive, hand movements and breathing irregularities also may occur at this stage. The characteristic hand movements continue while the child is awake but disappear during sleep. Irritability, autistic-like symptoms, walking difficulties, and slowed head growth are other possible symptoms in this age range.
Stage III: During the plateau or pseudo-stationary stage, the disease usually reaches a steady state. This phase, between ages 2 and 10, is marked by frequent seizures, apraxia, and motor problems. Irritability and autistic-like symptoms such as loss of communication may ease, with possible improvements in behavior, alertness, and communication skills. Many girls remain in this stage for most of their lives.
Stage IV: The last stage of the disease, which can last for years or decades, is characterized by muscle weakness, scoliosis, and reduced mobility. Girls who were previously able to walk may stop walking. Cognition, communication, or hand skills generally do not decline in stage IV. Repetitive hand movements may even decrease and eye gaze usually improves.
Affected individuals can present with a range of clinical severity from classic Rett syndrome to milder variants. The reasons for these differences are not fully understood, however, studies show that it is likely related to X-chromosome inactivation and the nature of the exact mutation present. A complete list of associated phenotypes, together with their occasionality, can be found here.
Rett syndrome diagnosis involves close observation of the child’s growth and development to detect any abnormalities regarding developmental milestones. The clinical diagnosis of RTT requires fulfillment of the current diagnostic criteria, and the exclusion of other conditions with similar symptoms, such as brain injuries and diseases with gross developmental anomalies in the first 6 months of life. Apart from the display of a period of regression followed by recovery or stabilization, the four main criteria that are absolutely required for the diagnosis of typical RTT are:
- Partial or complete loss of acquired purposeful hand skills
- Partial or complete loss of acquired spoken language
- Gait abnormalities
- Stereotypic hand movements
Nevertheless, atypical forms of RTT can be diagnosed after the identification of 2 out of the 4 main criteria, providing the period of regression followed by recovery or stabilization is present, and 5 other supporting criteria are displayed, including:
- Breathing disturbances when awake
- Bruxism when awake
- Impaired sleep pattern
- Abnormal muscle tone
- Peripheral vasomotor disturbances
- Scoliosis/kyphosis
- Growth retardation
- Small cold hands and feet
- Inappropriate laughing/screaming spells
- Diminished response to pain
- Intense eye communication — use of eye pointing
Genetic testing identifies variants in MECP2 in 95–97% of individuals with typical RTT, but is currently not mandatory for diagnosis. However, it has become increasingly common for clinicians to recommend these types of tests, not only to confirm the diagnosis, but also to get information about the specific molecular change, and clarify eligibility for clinical trials and other studies.
Treatments and clinical trials
Although there is currently no cure for Rett syndrome, there are treatments that can help manage symptoms and provide support. A holistic team approach is typically used to treat the person throughout life. This multidisciplinary team may include a primary care physician or pediatrician, physical therapist, occupational therapist, speech-language pathologist, nutritionist, and support services in academic and occupational settings.
Some girls may require special equipment such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs to help them maintain adequate weight. In addition, pharmacological approaches are usually aimed at improving sleep disturbances, breathing disturbances, seizures, stereotypic movements, and general well-being, as well as the cardiac risk associated with prolonged QT interval.
Very recently, in March 2023, the FDA approved the first disease-specific treatment for Rett Syndrome. The oral drug, commercialized as Daybue (trofinetide), can be prescribed to girls over 2 years old and women with RTT. This analog of the neuropeptide (1–3) IGF-1, which is obtained by enzymatic cleavage of the growth factor IGF-1 within the brain, has anti-inflammatory properties, and it’s been shown to improve core symptoms of RTT in a phase 3 study. The pharmaceutical company behind Daybue stated that it will be available by the end of April 2023.
To date, there are 73 clinical trials reported to study therapeutic strategies for Rett syndrome, with 10 actively recruiting or enrolling by invitation. One clinical trial is even investigating a potential gene therapy for RTT using CRISPR/Cas9 technology.
Resources
There are interesting resources for patients and caregivers, such as the NIH’s Genomic and Rare Disease (GARD) and MedlinePlus. Furthermore, Rett Syndrome News, a digital platform created for the RTT community, provides news and information on the disease, as well as first-hand community perspectives from patient and caregiver columnists.
For doctors and other help professionals, the website Orphanet and the NIH’s Genetic Testing Registry offer information to help with diagnosis and testing.
Regarding advocacy, Several NGOs are especially dedicated for the connect families affected by the disease, such as the International Rett Syndrome Foundation. In addition, the NORD (National Organization for Rare Disorders) offers programs of education, advocacy, research, and patient services for many rare diseases, and has resources for patients, caregivers, clinicians, and researchers.
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