Causes / typical injury mechanism: Rett syndrome is an X-linked dominant neurological disorder causing a regression in motor, verbal, and cognitive abilities. The most common mutation that attributes to this is a de novo mutation of MECP2 on the X chromosome. MECP2 is responsible for transcriptional regulation and DNA methylation. The mutations are almost exclusively of paternal origin.

Classic history and presentation: After a short period of normal development, classic presentation of the regression symptoms typically follow, including partial or complete loss of acquired hand skills, delayed acquisition of higher-level fine motor skills, spoken language, gait abnormalities, postnatal deceleration of head growth, ataxia, seizures, and stereotypic hand-wringing. Many individuals with Rett syndrome have random X-inactivation, allowing normal allele expression in some cells, causing a spectrum of clinical presentations.

Patients can be classified into 3 distinct syndromes based on their clinical presentation and specific mutations in their loci.

• Preserved speech / Zappella variant, associated with the majority of inherited MECP2 mutations, are the least compromised.
• Congenital / Rolando variant, more closely associated with mutations in FOXG1
• Early seizure / Hanefeld variant, more closely associated with mutations in CDKL5

Prevalence:

• Age – Symptoms of Rett syndrome appear between the ages of 1-4 years
• Sex / gender – The disorder is almost exclusively seen in girls. Boys that inherit Rett syndrome typically die in utero or shortly after birth.
• The prevalence of Rett syndrome is estimated at 1 /10 000 females at an age of 32 years.

Pathophysiology: Rett syndrome is characterized by inactivating mutations of MECP2 resulting in neurotransmitter system abnormalities, manifesting in dysfunctions of breathing, feeding, and alteration of cardiorespiratory coupling.

Grade / classification system: Prior to the discovery of MECP2 and its known mutation to cause the syndrome, a staging system was created to better track the clinical course.

• Stage I: Onset between ages 6-18 months, consists of developmental arrest; includes less eye contact, reduced play, gross motor delays, nonspecific hand-wringing.
• Stage II: Onset between ages 1-4 years, consists of rapid deterioration / regression; includes loss of acquired hand use and spoken language, periodic breathing irregularities, hand-wringing, sleep disturbance, autistic behavioral patterns.
• Stage III: Onset between ages 2-10 years, follows period of rapid deterioration; includes behavioral improvement and some communication and dexterity improvement by using "eye pointing."
• Stage IV: Onset after 10 years, consists of late motor deterioration; includes increased rigidity, reduced mobility, dystonia, hypomimia, and bradykinesia.