Genetics

• Rett syndrome is a rare genetic disorder that is inherited in an X-linked dominant fashion.
• Second most common cause of severe intellectual disability after Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down Syndrome (trisomy 21) 
• Genetic mutations that cause the disease occur sporadically (99% are de novo)
  • 90%–95% of cases are caused by mutations of the MECP2 gene (methyl-CpG binding protein 2).
  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations affects protein production critical for brain development 
  • The mutated copy is often associated with the paternal allele since it occurs during spermatogenesis (only females inherit the paternal X chromosome, as the paternal Y chromosome determines the male sex of the fetus).
• Females are almost exclusively affected.
  • Most males with this mutation are believed to die in utero or during early infancy.
  • Incidence is 1 in 10,000 girls by age 12 in the United States.
• Some boys may have a different mutation, resulting in a less destructive form of Rett syndrome. 
  • Life expectancy is higher.
  • Lower risk for intellectual and developmental problems

Clinical Presentation and Diagnosis

Clinical presentation

• Individuals with Rett syndrome often have normal development until 7–24 months of age.
• Developmental stagnation occurs between 6 and 18 months of age.
• Around the ages of 1–4 years, individuals lose previously acquired skills (regression).

Diagnosis

• Diagnosis is based on clinical presentation, a detailed patient history, and thorough clinical evaluation.
• Genetic testing for MECP2 gene mutations may be used to confirm and/or rule out similar syndromes.

Stages

Stage I: Developmental arrest (6–18 months of age)

• Signs and symptoms are subtle.  
• Lasts for a few months up to a year
• May present with less eye contact and placidity
• The achievement of developmental milestones Developmental milestones Developmental milestones are the skills or abilities that most children are able to perform when they reach a certain age. Understanding the appropriate milestones and at what age they are reached helps clinicians identify symptoms of delayed development. Developmental milestones are divided into 5 important domains: gross motor, fine motor, language, social, and cognitive. Developmental Milestones and Normal Growth becomes slowly and increasingly delayed.

Stage II: Rapid deterioration or regression (1–4 years of age)

• Children lose the ability to perform previously acquired skills.
• Loss can be rapid or more gradual.
• Reduced head growth
• Abnormal hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand movements (“wringing”)
• Hyperventilating
• Screaming or crying for no apparent reason
• Problems with movement and coordination
• Loss of social interaction and communication

Stage III: Plateau or pseudo-stationary (2–10 years)

• Minimal regression may be seen in the symptoms with some improvement of skills.
• Seizures may begin in this stage.

Stage IV: Late motor deterioration (> 10 years)

• Marked by reduced mobility 
• Muscle weakness
• Joint contractures
• Scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis

Complications

• Sleep problems cause significant fatigue and restlessness.
• Difficulty eating leads to malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries.
• Bowel and bladder problems
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease ( GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease)
  • Bowel or urinary incontinence Urinary incontinence Urinary incontinence (UI) is involuntary loss of bladder control or unintentional voiding, which represents a hygienic or social problem to the patient. Urinary incontinence is a symptom, a sign, and a disorder. The 5 types of UI include stress, urge, mixed, overflow, and functional. Urinary Incontinence 
  • Gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract disease
• Pain may accompany other problems, such as gastrointestinal issues or bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones fractures.
• Muscle, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones, and joint problems
• Anxiety and problematic behavior that may hinder social functioning
• Needing lifelong care and assistance with activities of daily life
• Shortened life span (median survival is approximately 45 years of age)

Differential Diagnosis

The following conditions are differential diagnoses for Rett syndrome:

• Angelman syndrome Angelman syndrome Angelman syndrome (AS) is a rare autosomal neurodevelopmental genetic disorders mapped to a specific region of chromosome 15 attributed to genomic imprinting. A maternally derived chromosome 15 with this deletion results in 15q11-13 maternal deletion syndrome, or AS. Prader-Willi Syndrome and Angelman Syndrome: an autosomal neuro-developmental disease resulting from epigenetic sex-specific genomic imprinting and uniparental disomy of paternal chromosome 15 with a simultaneous functional loss of the maternal part. Characterized by inappropriate laughter, seemingly happy demeanor, short attention span, lack of proper speech, use of non-verbal communication skills, ataxia, fine tremors, jerky movements, and severe developmental delay.
• Prader-Willi syndrome Prader-Willi syndrome Prader-Willi syndrome (PWS) is a rare autosomal neurodevelopmental genetic disorders mapped to a specific region of chromosome 15 attributed to genomic imprinting. A paternally derived chromosome 15 with this deletion results in 15q11-13 paternal deletion syndrome, or PWS. Prader-Willi Syndrome and Angelman Syndrome: a rare autosomal neuro-developmental disease resulting from genomic imprinting and uniparental disomy of maternal chromosome 15 with a simultaneous functional loss of the parental part. Characterized by hypotonia, lethargy, feeding difficulties, breathing difficulties, and hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism at birth; with scoliosis, strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus, speech delay, intellectual delays, and behavioral issues during childhood.
• Landau-Kleffner syndrome: a rare neurodevelopmental disorder characterized by the loss of language comprehension, aphasia, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, with severely abnormal electroencephalogram (EEG) findings during sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures.
• Autism spectrum disorder Autism spectrum disorder Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by poor social skills, restricted interests/social interactions, and repetitive/stereotyped behaviors. The condition is termed a "spectrum" because of the wide variability in the severity of symptoms exhibited. Autism Spectrum Disorder: a neurodevelopmental disorder with early-childhood onset, marked by poor social skills, restricted social interaction and communication, and repetitive and stereotyped behaviors. Because it is a spectrum, some patients exhibit impairment in language and intellectual levels, while others may have normal or even advanced levels.
• Cerebral palsy Cerebral palsy Cerebral palsy (CP) refers to a group of conditions resulting in motor impairment affecting tone and posture and limiting physical activity. Cerebral palsy is the most common cause of childhood disability. It is caused by a nonprogressive CNS injury to the fetal or infant brain. Cerebral Palsy: a syndrome of motor impairment caused by a nonprogressive central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System injury. Classified according to muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction, distribution, and the presumed time of injury. May also present with sensory, cognitive, communication, and behavioral disturbances; epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy; and musculoskeletal impairment.
• CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder: a rare genetic disorder that is inherited in an X-linked pattern and characterized by early-onset seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures and severe neurodevelopmental impairment. May also present with scoliosis, visual impairment, sensory issues, and various gastrointestinal difficulties. 
• FOXG1-related disorders or FOXG1 syndrome: a group of disorders caused by a mutation of the FOXG1 gene. Affected individuals develop normally in the perinatal period. This is followed by progressive microcephaly, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, developmental delays, and severe intellectual disability. May also present with constipation, gastroesophageal reflux, scoliosis, foot deformities Foot deformities Foot deformities in children include congenital or acquired malformations of the feet. Two common examples are talipes equinovarus, commonly known as clubfoot, and metatarsus adductus, also called metatarsus varus. Foot Deformities, and stereotypic hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand movements.