Rett's syndrome (RS) is a neurodevelopmental disorder of infancy almost exclusively affecting females. RS is characterized by severe regression of cognitive, motor, language, and social abilities between the age of 4 and 18 months, following a seemingly normal period of development. Hallmark features include stereotypic hand movements (hand wringing), microencephaly, and autistic-like behaviors. Prevalence ranges from 1:10,000 to 1:22,000 with diverse representation among the world population. The syndrome is named after Andreas Rett who, in 1966, first described its clinical features.
RS is a genetic disorder caused by mutation on the X-linked MECP2 gene, and subsequent MeCP2 protein deficiency (Amir et al., 1999; Hagberg, 2002). The majority of cases occur sporadically; inherited cases are rare. Genotype–phenotype studies have identified different clinical abnormalities associated with different MECP2 mutations (Percy, 2008a; Zhang & Minassian, 2008).
Studies to determine the specific neuropathology/neurophysiology of RS have found decelerated head growth starting at 3–6 months leading to microencephaly, decreased size of the dendrites of pyramidal neurons in the frontal and temporal lobes, and abnormalities in the substantia nigra. Neuropathology also involves the precentral gyrus, frontal cortex, superior temporal area, and parietal cortex (Brodmann areas 4, 45, 22 and 40). MRI findings have revealed atrophy in selective regions of gray and white matter in the prefrontal, frontal, and anterior temporal regions (Ibrahim & Khan, 2008; Pizzamiglio et al., 2008). EEG findings are characterized by the appearance of focal, multifocal, and generalized epileptiform abnormalities and the occurrence of theta activity in the frontal-central regions. Frequent seizure activity is reported; however, video EEG monitoring is critical because many apparent seizures are not correlated with EEG activity (Glaze, 2002).
There are four clinical stages of RS (Hagberg, 2002): (1) early onset stage, between the age of 6 and 18 months, which involves subtle hypotonia with decreased sitting or crawling, beginning loss of eye contact, disinterest in toys, subtle hand wringing, and decreased head growth; (2) rapid destruction stage, between the age of 1 and 4 years, involving loss of purposeful hand movement; emergence of the characteristic hand wringing, clasping, or clapping; repetitive hand movements to the mouth; loss of communication; autistic-like, repetitive and stereotyped behaviors; irritability; emotional outbursts; and disturbed sleep; gait apraxia; and breathing abnormalities; (3) plateau or pseudo stationary stage, between the age of 2 and 10 years, involving epileptic seizures, with improvements in awareness, attention, communication skills, and emotional state; and (4) late motor deterioration stage, involving loss of ambulation in previous walkers, spasticity, muscle weakness, rigidity and stiffness, dystonia, and scoliosis, with improvements in eye gaze and hand wringing.
Overall cognitive and functional abilities are profoundly impaired. Most persons with RS communicate through eye gaze and hand gestures rather than language. Global cognitive skills are generally developed to an age level equivalent to 9 months. Daily living abilities generally correspond with age of 12–14 months. Psychological and behavioral health features of RS include anxiety and panic, lack of interest in play, and self-injury that is mostly in the form of hand-biting and face-hitting (Pizzamiglio et al., 2008). Survival through 10 years of age is typical, with at least 80% survival to the age of 20 years and 50% survival for those over the age of 50 years (Percy, 2008b). Sudden death has been described in RS. Although the specific cause of death is often unclear, it may well involve autonomic dysfunction or a cardiac conduction system abnormality.
Specific guidelines are used in the clinical diagnosis of RS (Ben Zeev Ghdoni, 2007; Hagberg, Aicardi, Dias, & Ramos, 1983; Hagberg et al., 1985; Hagberg & Witt-Engerstrom, 1986; Hagberg & Skjeldal, 1994). Essential criteria include normal head circumference at birth and apparently normal development, followed by deceleration of head growth, loss of purposeful hand skills with repetitive hand movements, severely impaired expressive language, gait apraxia, and torso apraxia/ataxia between the age of 1 and 4 years. Supportive evidence is present in some RS cases, but is not necessary for the diagnosis. Such evidence includes seizures, EEG changes, epileptiform discharges, scoliosis, teeth grinding, breathing difficulties, muscle rigidity, spasticity, abnormal sleep patterns, chewing and swallowing difficulties, growth retardation, and poor circulation of the lower extremities with cold feet or hands.
The presence of any one of the following exclusion criteria rules out a diagnosis of classic RS: microcephaly at birth, loss of vision due to retinal disorder or optic atrophy, acquired brain damage after birth, evidence of growth retardation in utero, metabolic disorders or acquired neurological disorder from severe infection or head trauma, or any other degenerative disorder. Differential diagnosis with autism is important (Mount, Charman, Hastings, Reilly, & Cass, 2003). Genetic testing can confirm a clinical diagnosis in 70% to 80% of RS cases.
Treatment interventions have focused on the alleviation of core medical symptoms through medication management of breathing difficulties, sleep problems, seizure disorder, and motor difficulties. Occupational therapy, physiotherapy, and hydrotherapy are used to assist individuals with self-directed activities and mobility (Ben Zeev Ghidoni, 2008). Music therapy has been shown to interrupt hand movements and sooth individuals, but only while treatment is in progress. Therapeutic horseback riding has promoted balance and created positive emotional states (Pizzamiglio et al., 2008). Cognitive rehabilitation has focused on improving visual-motor and communication skills.
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