Rett Syndrome
Disease Details
Family Health Simplified
- Description
- Rett syndrome is a rare genetic neurological disorder that predominantly affects girls and leads to severe cognitive and physical impairments, including loss of purposeful hand use and speech abilities.
- Type
- Rett syndrome is a genetic neurodevelopmental disorder. The type of genetic transmission is typically X-linked dominant. It is usually caused by mutations in the MECP2 gene on the X chromosome.
- Signs And Symptoms
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Signs and symptoms of Rett syndrome include:
1. **Slowed Growth**: Slow growth of the head, hands, and feet.
2. **Loss of Movement and Coordination**: Loss of purposeful hand skills (e.g., grasping) and the development of repetitive hand movements (e.g., hand-wringing).
3. **Loss of Communication Abilities**: Reduced or complete loss of ability to speak and communicate.
4. **Gait Abnormalities**: Unsteady or awkward walking; some children may lose the ability to walk.
5. **Breathing Problems**: Problems like hyperventilation, apnea, and breath-holding spells.
6. **Seizures**: Many children with Rett syndrome experience seizures.
7. **Cognitive Impairments**: Severe intellectual disability and developmental delays.
8. **Scoliosis**: Abnormal curvature of the spine.
9. **Sleep Disturbances**: Problems with sleep patterns and duration.
10. **Irritability and Agitation**: Periods of irritability and distress, especially in early childhood.
These symptoms typically emerge after a period of normal development that may last 6 to 18 months. - Prognosis
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Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathy, unless they have one or more extra X chromosomes, or have somatic mosaicism.
Male fetuses with the disorder rarely survive to term. Because the disease-causing gene is located on the X chromosome, a female born with an MECP2 mutation on her X chromosome has another X chromosome with an ostensibly normal copy of the same gene, while a male with the mutation on his X chromosome has no other X chromosome, only a Y chromosome; thus, he has no normal gene. Without a normal gene to provide normal proteins in addition to the abnormal proteins caused by a MECP2 mutation, the XY karyotype male fetus is unable to slow the development of the disease, hence the failure of many male fetuses with a MECP2 mutation to survive to term.
Females with a MECP2 mutation, however, have a non-mutant chromosome that provides them enough normal protein to survive longer. Research shows that males with Rett syndrome may result from Klinefelter's syndrome, in which the male has an XXY karyotype. Thus, a non-mutant MECP2 gene is necessary for a Rett's-affected embryo to survive in most cases, and the embryo, male or female, must have another X chromosome.
There have, however, been several cases of 46,XY karyotype males with a MECP2 mutation (associated with classical Rett syndrome in females) carried to term, who were affected by neonatal encephalopathy and died before 2 years of age. The incidence of Rett syndrome in males is unknown, partly owing to the low survival of male fetuses with the Rett syndrome-associated MECP2 mutations, and partly to differences between signs caused by MECP2 mutations and those caused by Rett's.Females can live up to 40 years or more. Laboratory studies on Rett syndrome may show abnormalities such as:
EEG abnormalities from 2 years of age
atypical brain glycolipids
elevated CSF levels of beta-endorphin and glutamate
reduction of substance P
decreased levels of CSF nerve growth factorsA high proportion of deaths are abrupt, but most have no identifiable cause; in some instances death is the result most likely of:
spontaneous brainstem dysfunction
cardiac arrest, likely due to long QT syndrome, ventricular tachycardia or other arrhythmias
seizures
gastric perforation - Onset
- Rett syndrome typically manifests in early childhood, most commonly between 6 to 18 months of age, after a period of seemingly normal development.
- Prevalence
- Rett syndrome has a prevalence of approximately 1 in 10,000 to 15,000 live female births.
- Epidemiology
- Rett syndrome is a rare genetic neurological disorder that primarily affects females, with an estimated prevalence of 1 in 10,000 to 15,000 live female births. The disorder is caused by mutations in the MECP2 gene, which is located on the X chromosome. This condition is seldom seen in males due to the mutation's impact on the X chromosome, which typically results in more severe outcomes. Although Rett syndrome occurs worldwide, its prevalence can vary slightly among different populations and regions.
- Intractability
- Yes, Rett syndrome is generally considered intractable. It is a severe neurological disorder that primarily affects females and leads to significant impairments in cognitive, sensory, emotional, motor, and autonomic function. Although there are treatments available to manage symptoms and improve quality of life, there is currently no cure for Rett syndrome, making it intractable.
- Disease Severity
- Rett syndrome is a severe neurological disorder that predominantly affects females. It leads to a progressive loss of motor and communication skills, severe cognitive impairment, seizures, and other medical complications. The severity can vary, but it typically results in significant disability requiring lifelong care. The term "nan" does not correspond to any known aspect of Rett syndrome.
- Healthcare Professionals
- Disease Ontology ID - DOID:1206
- Pathophysiology
- Rett syndrome is a neurodevelopmental disorder primarily affecting females, caused by mutations in the MECP2 gene on the X chromosome. The MECP2 gene is responsible for producing a protein essential for brain development and function. These mutations lead to the loss of proper MECP2 protein function, affecting the regulation of other genes crucial for normal neurological development. This disruption results in the characteristic features of Rett syndrome, including severe cognitive impairment, loss of motor skills (such as hand use and coordination), and difficulties with communication and breathing.
- Carrier Status
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Rett syndrome is a rare genetic neurological disorder that primarily affects females. It is usually caused by mutations in the MECP2 gene located on the X chromosome. Females typically have two X chromosomes, so one intact MECP2 gene can partially compensate for the defective one, leading to the characteristic symptoms of Rett syndrome. Males, with only one X chromosome, are generally more severely affected and often do not survive infancy.
Carrier status for Rett syndrome is uncommon because the condition typically arises from new mutations rather than being inherited from a carrier parent. Mothers of affected children are usually not carriers of the MECP2 mutation, although there are rare cases where a mother can be a carrier of a germline mutation. Genetic testing can determine carrier status if there's a family history of Rett syndrome or if a mutation in the MECP2 gene has been identified in an affected family member. - Mechanism
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Rett syndrome is a neurodevelopmental disorder primarily affecting females and is typically caused by mutations in the MECP2 gene located on the X chromosome.
**Mechanism:**
The primary mechanism involves mutations in the MECP2 gene, which encodes the MECP2 protein. The MECP2 protein is crucial for brain development and function, as it regulates the expression of other genes by binding to methylated DNA and modifying chromatin structure.
**Molecular Mechanisms:**
1. **MECP2 Dysfunction:** Mutations in MECP2 lead to a dysfunctional or absent MECP2 protein, disrupting its ability to regulate gene expression. This results in abnormal neuronal development and synaptic function.
2. **Altered Chromatin Structure:** MECP2 plays a key role in chromatin remodeling. Its dysfunction can lead to inappropriate opening or closing of chromatin, affecting the availability of various genes for transcription.
3. **Gene Expression Regulation:** MECP2 mutations cause dysregulation of multiple target genes, proteins, and signaling pathways that are essential for normal neuronal function. This includes genes involved in synaptic plasticity, neural connectivity, and neurotrophic support.
4. **Impact on Neurons and Synapses:** The defective MECP2 protein affects the maturation and maintenance of neurons and synapses, leading to widespread neurological deficits characteristic of Rett syndrome, such as loss of motor skills, communication abilities, and cognitive function. - Treatment
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Currently there is no cure for Rett syndrome. Treatment is directed towards improving function and addressing symptoms. A multi-disciplinary team approach is typically used to treat the person throughout life. This team may include a primary care physician, physical therapist, occupational therapist, speech-language pathologist, nutritionist, and support services in academic and occupational settings. Some children may require special equipment and aids such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs to help them maintain adequate weight.Because of the increased risk of sudden cardiac death, when long QT syndrome is found on an annual screening EKG it is treated with an anti-arrhythmic such as a beta-blocker. There is some evidence that phenytoin may be more effective than a beta-blocker.While medicinal interventions to mitigate breathing challenges in children with Rett Syndrome (RTT) are still being developed, children with RTT may be prescribed rebreathing techniques (e.g., rebreathing masks), oxygen delivery, or non-invasive ventilation as preventative or rescue breathing treatments. High oxidative stress levels in individuals with RTT have exacerbated effects on their cardiorespiratory health and functionality, dramatically increasing the risk for sudden cardiac death—an anomaly that has an associated 300x increased occurrence risk in children with Rett Syndrome. Due to this, it is vital to closely monitor atypical breathing behaviors in children with RTT, making sure to effectively use lifesaving respiratory improvement devices and strategies as prescribed.
Prescribed treatment methods may vary depending on the breathing characteristic phenotype expressed by the child. Physicians have identified three major RTT breathing phenotypes; forceful breathers, feeble breathers, and apneustic breathers. For forceful breathers, for example, rebreathing masks may be used while the child is awake.In Dec 2021, Australian company Neuren Pharmaceuticals reported positive results in a phase 3 trial of trofinetide for the treatment of Rett syndrome. In September 2022, the FDA accepted a new drug application for trofinetide and granted it priority review. In March 2023 the drug received FDA approval for treatment of Rett Syndrome. - Compassionate Use Treatment
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Rett syndrome is a rare neurodevelopmental disorder primarily affecting females, caused by mutations in the MECP2 gene. Currently, there is no cure, but several compassionate use and experimental treatments are being explored:
1. **Trofinetide**: This synthetic analog of glypromate (a neurotrophic factor) has shown promise in clinical trials to improve symptoms related to Rett syndrome.
2. **Gene therapy**: Research is ongoing into gene replacement and editing strategies to correct the MECP2 mutation.
3. **NNZ-2566**: An experimental drug that mimics the action of the naturally occurring protein insulin-like growth factor 1 (IGF-1), aiming to improve neurological symptoms.
4. **Ketamine**: Low-dose ketamine has been investigated for its potential neuroprotective and symptom-relief properties.
5. **Bone marrow transplantation**: Though still in very preliminary stages, some studies suggest that bone marrow transplants may induce improvements by delivering healthy cells that can impact brain function.
Consultation with a healthcare provider specializing in Rett syndrome is essential to evaluate the suitability and availability of these treatments. - Lifestyle Recommendations
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For individuals with Rett syndrome, lifestyle recommendations typically focus on maximizing quality of life and developmental potential. Key considerations include:
1. **Therapies and Interventions**: Early and ongoing interventions such as physical therapy, occupational therapy, and speech therapy can help manage symptoms and improve abilities.
2. **Regular Medical Care**: Routine check-ups with healthcare providers familiar with Rett syndrome to monitor and manage various health issues, including breathing irregularities, seizures, and scoliosis.
3. **Nutritional Support**: A well-balanced diet and, in some cases, nutritional supplements tailored to the individual's needs to ensure proper growth and health.
4. **Medication**: May be prescribed to manage symptoms like seizures, constipation, or mood issues.
5. **Assistive Devices**: Use of adaptive equipment, such as communication devices, braces, or wheelchairs, to aid mobility and communication.
6. **Educational Support**: Individualized education plans (IEPs) that cater to the child's specific needs and strengths.
7. **Social Interaction**: Encouragement of social interactions and recreational activities to enhance emotional well-being.
8. **Family Support**: Counseling and support groups to help families cope with the challenges of caring for a person with Rett syndrome.
9. **Environmental Adaptations**: Creating a safe and stimulating home environment that accommodates the individual's needs and promotes independence.
Close collaboration with a multidisciplinary team of health professionals is essential to tailor these recommendations to each individual's needs. - Medication
- Currently, there is no cure for Rett syndrome, but certain medications can help manage symptoms. These may include medications to control seizures, improve motor function, and address breathing irregularities. Additionally, drugs such as antipsychotics or antidepressants may be prescribed to manage mood and behavioral issues. It is important to work closely with a healthcare provider to tailor treatments to the individual's specific needs.
- Repurposable Drugs
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There is ongoing research into repurposable drugs for Rett syndrome, although no definitive treatment has been approved specifically for this condition. Some drugs being studied include:
- **IGF-1 (Insulin-like Growth Factor 1):** Initially used for growth disorders, IGF-1 has shown potential in improving symptoms of Rett syndrome.
- **Ketamine:** Traditionally used as an anesthetic and for depression, it has demonstrated benefits in preclinical studies for neurological symptoms.
- **Trofinetide:** Originally developed as a treatment to alleviate neuroinflammation, it’s currently under investigation for its potential to improve cognitive and behavioral symptoms in Rett syndrome patients.
Further clinical trials are necessary to confirm the safety and efficacy of these drugs for Rett syndrome. - Metabolites
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Rett syndrome is a neurodevelopmental disorder primarily affecting girls. One of the critical features regarding metabolites in Rett syndrome is the alteration in neurotransmitter and amino acid profiles. Key findings include:
- Elevated glutamate levels in the cerebrospinal fluid
- Altered biogenic amines such as serotonin and dopamine metabolites
- Changes in levels of glycolytic and tricarboxylic acid (TCA) cycle intermediates, indicating metabolic dysfunction
These metabolic changes are considered significant in understanding the pathophysiology of Rett syndrome and may inform potential therapeutic strategies. - Nutraceuticals
- Currently, there are no specific nutraceuticals (food products that provide health and medical benefits) that have been proven to effectively treat Rett syndrome. Management primarily focuses on symptomatic treatment, physical therapy, and nutritional support to address challenges such as feeding difficulties and gastrointestinal problems. Always consult healthcare professionals for personalized management plans.
- Peptides
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Rett syndrome is a rare neurodevelopmental disorder primarily affecting females and caused by mutations in the MECP2 gene on the X chromosome. Though specific peptides related to Rett syndrome might not form a central part of its pathology or treatment, researchers are exploring peptide-based therapies and MECP2-targeted interventions.
Regarding nanotechnology (nan), it holds potential for advancements in treating Rett syndrome. Nanoparticles could facilitate the delivery of therapeutic agents, such as gene editors or drugs, directly to affected neurons, potentially restoring MECP2 function or compensating for its deficiency. This area of research is still in experimental stages but represents a promising direction for future therapies.