Background

• Rett Syndrome, which is typically a rare neurological disorder that primarily affects females and is caused by mutations in the MECP2 gene. It was first described by Dr. Andreas Rett in 1966 and was initially thought to be a variant of autism. 
• The symptoms of Rett Syndrome typically become apparent between the age of 6-18 months after a period of apparently normal development. Affected individuals experience a regression in their abilities and may lose skills they had previously acquired, such as walking, talking, and using their hands. 
• Other common symptoms include hand-wringing, breathing irregularities, seizures, scoliosis, and cognitive impairment. Some individuals with Rett Syndrome may also exhibit autistic-like behaviors, such as social withdrawal and repetitive movements. 
• There is generally no cure for Rett Syndrome, and treatment focuses on managing symptoms and providing supportive care. Physical and occupational therapy, speech therapy, and medication to manage seizures and other symptoms may be helpful. Some individuals with Rett Syndrome may require assistance with daily living activities. 
• Research into the underlying mechanisms of Rett Syndrome is ongoing. Several potential treatments are being investigated, including gene therapy and drugs targeting the underlying molecular pathways involved in the condition. 

Epidemiology

• Frequency: The prevalence of Rett syndrome (RS) is estimated to be around 1 in 23,000 live female births. However, the incidence rates vary significantly across different countries, with some reporting rates as high as 1 in 10,000 live female births. A study conducted in Japan observed a prevalence of 1 in 45,000 girls aged 6 to 14 years. The variations in incidence rates may be partly attributed to including atypical/variant forms of RS, such as congenital RS, milder types with the delayed onset of regression, preserved speech variants. 
• Age: Typically, the clinical manifestation of RS becomes apparent when children are between 2 to 4 years old, but the interruption of normal neurodevelopment likely begins in children aged 6 to 18 months or younger. 
• Sex: Rett syndrome (RS) is mostly diagnosed in females due to its X-linked inheritance. In fact, many males with Rett syndrome-associated mutations are thought to perish in the womb. Nevertheless, a few documented cases of males with mutations in the MECP2 gene and symptoms resembling RS have been documented. While there is no evidence of increased fetal loss among male members in families with RS history, the preponderance of females may be attributed to an alternative explanation. 
• Race: There have been no documented racial disparities in Rett syndrome (RS) incidence. In a Research study that involved individuals of Latin American, Caucasian, and African American descent, no differences in the prevalence or incidence of RS were observed. 

Anatomy

Pathophysiology

• Rett Syndrome is primarily caused by mutations in the MECP2 gene, which provides instructions for making a protein that plays a important role in the development and function of the brain. The MECP2 protein helps regulate the expression of other genes, which is essential for normal brain development and function. 
• In individuals with Rett Syndrome, mutations in the MECP2 gene result in a deficiency or dysfunction of the MECP2 protein. This can lead to problems with neuronal development, function, and connectivity, which underlie the disorder’s symptoms. 
• Studies have shown that the loss of MECP2 function can affect many aspects of neuronal function, including the formation and maintenance of synapses, the communication between neurons, and the regulation of gene expression. The loss of MECP2 function can also lead to abnormalities in the growth, maturation of dendritic spines, which are structures on neurons that play a crucial role in synaptic communication. 
• These changes in neuronal function can result in the characteristic symptoms of Rett Syndrome, including regression of skills, impaired motor function, breathing abnormalities, seizures, and cognitive impairment. The specific mechanisms by which these changes in neuronal function lead to the symptoms of Rett Syndrome are still being studied, and multiple processes likely contribute to the disorder. 

Etiology

• The primary cause of Rett Syndrome is mutations in the MECP2 gene, which provide instructions for making a protein critical for the brain’s normal development and function. 
• The MECP2 gene is generally located on the X chromosome, meaning Rett Syndrome primarily affects females. This is because males who inherit a mutation in the MECP2 gene are typically more severely affected and often do not survive after infancy. In contrast, females have two X chromosomes, and one of these chromosomes can compensate for the mutation on the other X chromosome, resulting in a milder form of the disorder. 
• Most cases of Rett Syndrome are not inherited and occur sporadically due to a new mutation in the MECP2 gene. However, in rare cases, Rett Syndrome can be inherited in an X-linked dominant pattern, meaning the mutation may pass down from parent to child. 
• Other types of genetic mutations have also been associated with Rett Syndrome-like disorders, including mutations in the CDKL5, FOXG1, and MEF2C genes. These conditions share some clinical features with Rett Syndrome but also have distinct clinical and genetic characteristics. 
• Environmental factors generally do not appear to play a significant role in the development of Rett Syndrome, although there is some evidence that environmental stressors may exacerbate symptoms in affected individuals. 

Genetics

Prognostic Factors

The prognosis for individuals with Rett Syndrome can vary widely depending on the severity and specific symptoms of the disorder. However, there is no cure for Rett Syndrome, supportive care and management of symptoms can improve quality of life and functional outcomes. 

Certain factors that may affect the prognosis of Rett Syndrome include: 

• The severity of symptoms: Individuals with milder symptoms may have better functional outcomes and be able to live independently with appropriate support, while those with more severe symptoms may require more intensive support and care throughout their lives. 
• Age of onset: Individuals who experience symptoms earlier in life may have a more severe disease course than those who develop symptoms later. 
• Presence of seizures: Seizures are a common symptom of Rett Syndrome and can be challenging to control. Individuals who experience frequent or severe seizures may have a more challenging disease course. 
• Presence of scoliosis: Scoliosis, or curvature of the spine, is a common complication of Rett Syndrome and can generally affect mobility and quality of life. The severity of scoliosis can impact the prognosis. 
• Respiratory function: Breathing irregularities are a common symptom of Rett Syndrome and can lead to respiratory failure, which can be life-threatening. The severity of breathing problems can affect the prognosis. 

It’s important to note that Rett Syndrome is a highly variable disorder, and it can be challenging to predict the course of the disease in individual cases. Close monitoring and ongoing management of symptoms are essential for improving outcomes and quality of life for individuals with Rett Syndrome. 

Clinical History

• Rett Syndrome is a neurodevelopmental disorder that mainly affects females. The clinical presentation of Rett Syndrome can vary widely, depending on the individual and the stage of the disorder. 
• Age group: Rett Syndrome typically presents in infancy or early childhood, with symptoms becoming more apparent around 6 to 18 months. 

Physical Examination

The physical examination of an individual with Rett Syndrome will depend on their specific symptoms and clinical presentation. However, some common findings that may be observed during a physical examination include: 

• Impaired motor function: Individuals with Rett Syndrome may struggle with balance, coordination, and fine motor skills. They may also exhibit abnormal movements, such as hand-wringing, clapping, or tapping. 
• Breathing abnormalities: Many individuals with Rett Syndrome have irregular breathing patterns, including episodes of hyperventilation, breath holding, and apnea. 
• Scoliosis or also curvature of the spine, is a common complication of Rett Syndrome and can be identified during a physical examination. 
• Growth abnormalities: Some individuals with Rett Syndrome may have growth retardation or other body size or shape abnormalities. 
• Autonomic dysfunction: Autonomic dysfunction, which can cause problems with temperature regulation, heart rate, and blood pressure, is also a common feature of Rett Syndrome and may be observed during a physical examination. 
• Cognitive impairment: Individuals with Rett Syndrome may exhibit cognitive impairment, affecting their communication and interaction abilities. 

In addition to a physical examination, a thorough neurological evaluation, genetic testing, and imaging studies may be necessary to confirm a diagnosis of Rett Syndrome and rule out other potential causes of symptoms. A multidisciplinary approach involving healthcare professionals from various specialties, such as neurology, genetics, physical therapy, and speech therapy, can help manage symptoms and improve outcomes for individuals with Rett Syndrome. 

Age group

Associated comorbidity

• Individuals with Rett Syndrome often have comorbidities, such as epilepsy, scoliosis, and gastrointestinal problems.
• They may also exhibit behavioral abnormalities, such as anxiety, aggression, and stereotypic movements. 

Associated activity

Acuity of presentation

The onset of Rett Syndrome is usually insidious, with a gradual loss of motor and cognitive skills over time. The following are some of the standard clinical features of Rett Syndrome: 

• Regression of skills: Children with Rett Syndrome may experience a regression of skills, including language, social interaction, and motor skills. 
• Motor dysfunction: Impaired motor function is a hallmark feature of Rett Syndrome, and affected individuals may exhibit abnormal movements, such as hand-wringing, clapping, or tapping. They may also need help with coordination, balance, and fine motor skills. 
• Breathing abnormalities: Many individuals with Rett Syndrome have irregular breathing patterns, including episodes of hyperventilation, breath holding, and apnea. 
• Cognitive impairment: Individuals with Rett Syndrome often exhibit cognitive impairment, which can range from mild to severe. They may have difficulty with attention, memory, and executive function. 
• Autonomic dysfunction: Autonomic dysfunction, which can cause problems with temperature regulation, heart rate, and blood pressure, is also a common feature of Rett Syndrome. 
• Scoliosis or also curvature of the spine, is a common complication of Rett Syndrome and can affect mobility and quality of life. 

The clinical presentation of Rett Syndrome can be complex and may require input from specialists in various fields, such as neurology, genetics, and developmental pediatrics. Early diagnosis and intervention may help improve outcomes, quality of life for people with Rett Syndrome. 

Differential Diagnoses

The clinical presentation of Rett Syndrome can overlap with other neurodevelopmental and neurological disorders, making a differential diagnosis important. Some conditions that may be considered in the differential diagnosis of Rett Syndrome include: 

• Angelman syndrome: A genetic disorder that generally affects the nervous system and can cause developmental delays, seizures, and communication difficulties. 
• Autism spectrum disorder is group of neurodevelopmental disorders affecting social interaction, communication, and behavior. 
• Cerebral palsy: A group of disorders that generally affect movement and posture, often due to damage to the developing brain. 
• Dravet syndrome: A genetic disorder that causes seizures and developmental delays. 
• Fragile X syndrome: A genetic disorder that typically cause intellectual disability, behavioral problems, and other symptoms similar to Rett Syndrome. 
• Landau-Kleffner syndrome: A rare neurological disorder that can cause language regression, seizures, and behavioral problems. 
• MECP2 duplication syndrome: It is an infrequent genetic disorder that involves duplication of the MECP2 gene and can cause symptoms similar to Rett Syndrome. 
• Phelan-McDermid syndrome: A rare genetic disorder that can cause intellectual disability, speech and language delays, and autism-like behaviors. 

A thorough medical evaluation, which includes physical exam, neurological exam, genetic testing, and imaging studies, may be necessary to differentiate Rett Syndrome from other conditions. The differential diagnosis process can be complex and may require input from specialists in various fields, such as neurology, genetics, and developmental pediatrics. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

• There is generally no cure for Rett Syndrome, but treatment aims to manage symptoms and improve the quality of life for affected individuals.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

• Altering the environment can help manage the symptoms of Rett Syndrome.
• This can include providing a safe and supportive home environment, adapting the home environment to accommodate the individual’s physical limitations, and using communication aids to assist with language and social interaction. 

• Medications may be used to manage specific symptoms of Rett Syndrome, such as seizures, sleep disturbances, gastrointestinal problems, and behavioral issues.
• Some medications may include anticonvulsants, sedatives, laxatives, and antipsychotics. 

• Various procedures may be used to manage symptoms of Rett Syndrome. These include orthopedic surgery to correct scoliosis, gastrostomy tube placement to provide nutrition, and deep brain stimulation to manage dystonia. 

• Treatment for Rett Syndrome is typically divided into three phases: the early phase, the rapid destructive phase, and the plateau phase. The treatment approach for each phase may vary based on the specific symptoms, needs of the individual. 

In addition to these treatment approaches, supportive care is vital in managing Rett Syndrome. This might include physical therapy, occupational therapy, speech therapy, and psychological counseling to help individuals and families cope with the challenges of the disorder. Early intervention and ongoing support can help improve outcomes, quality of life for individuals with Rett Syndrome. 

Medication

Future Trends

Media Gallary

References

• https://emedicine.medscape.com/article/916377-overview