Rett Syndrome

Photo courtesy of Vandervilt University Medical CenterOpens in new window Rett syndrome was first described in the 1960s by the Austrian physician Andreas RettOpens in new window. Today Rett syndrome is classified as a pervasive developmental disorderOpens in new window.

In about 1 percent of affected individuals, Rett syndrome arises from an inherited sex-linked defect. The majority of cases, however, arise from sporadic mutations in a gene known as MECP2 (methyl CpG binding protein 2).

In the presence of the mutationOpens in new window, these other genes appear to continue their expression long after the appropriate development period has passed. Because this gene is located on the X chromosome, Rett syndrome almost always affects girls; the disorder is relatively rare, occurring in roughly one in every 15,000 females. However, rare male cases have been found, which are associated with 47XXY karyotype, mosaicism, or a milder form of the MECP2 mutation.

At least 85% of classic Rett’s syndrome cases have shown MECP2 mutations (Amir et al., 2005). However, MECP2 mutations do not appear to be unique to the Rett’s syndrome phenotype, as variations of this gene have been identified in cases of severe encephalopathy, X-linked MR, mild learning disability, and other conditions.

Thus, the presence of an MECP2 mutation by itself is not sufficient to specifically diagnose Rett’s syndrome. Importantly, MECP2 mutations themselves are not generally found in cases of appropriate diagnosed idiopathic autism (Lobo-Menendez et al., 2003). Thus, findings related to MECP2 mutations support the conceptualization of Rett syndrome as a distinct condition from autistic disorder.

Studies of neuropathology in children with Rett syndrome indicate that their brains as a whole weigh less than those of controls matched for age and height (as reviewed by Armstrong, 2005).

Their cortical neurons are underdeveloped with decreased dendritic arboization not accounted for by age; and a variety of their brain features show reductions in size, including the cerebral hemispheres, cerebellar hemispheres, basal ganglia, corpus callosum, inferior olive, and anterior vermis (Casanova et al., 1991). However, the cerebral hemispheres are more affected by this size reduction than the cerebellum (Armstrong, 2005).

Reiss et al. (1993) found reduced cerebral volume, greater reduction in cortical gray matter compared with white (with frontal regions most affected), reduced subcortical gray matter, and increased cerebral spinal fluid in those with Rett syndrome compared with controls. Armstrong (2005) concluded that evidence from cases of Rett syndrome suggests that MECP2 plays an essential role in neuronal maturation.

Rett syndrome causes progressive disabilities in intellectual and motor development, with the initial onset of symptoms usually appearing in infancy, between the 6th and 18th months of life. Symptoms include:

• compulsive hand movements,
• reduced muscle tone,
• difficulties in walking,
• decreased body wight,
• failure of the head to grow with age, and
• increased levels of ammonia in the blood (hyperammonemia).

The DSM-IV-TR (APA, 2000) criteria for Rett syndrome consist of a required sequence of events, beginning with apparently normal prenatal and perinatal development. This includes normal psychomotor development from birth through age 5 months and normal head circumference at birth.

Following the initial period of apparently normal development, substantial regression occurs. This includes:

• a deceleration in head growth (between age 5 months and 4 years),
• loss of previously acquired purposeful hand skills (between ages 5 months and 30 months), [cont.]

• subsequent development of characteristic stereotyped hand movements [hand-wringing or hand washing],
• loss of social engagement early on (though may partially recover later),
• development of poorly coordinated gait and trunk movements,
• severely impaired expressive and receptive language, and
• severe psychomotor retardation.

The condition occurs almost exclusively in females. Associated features include severe to profound MR, seizures, EEG abnormalities, and nonspecific neuroimaging results (adapted from APA, 2000, p. 77).

The updated criteria from the IRSA (adaptd from Hagberg et al., 2002) consist of apparently normal prenatal and perinatal development, largely normal psychomotor development from birth through age 6 months (but may be delayed from birth) and normal head circumference at birth.

This is followed by postnatal head growth deceleration (in most cases), loss of previously acquired purposeful hand skills (between age 6 months and 30 months), development of characteristic stereotyped hand movements [hand-wringing, hand washing, squeezing, tapping, clapping, rubbing, or mouthing]; emergence of social withdrawal, loss of previously acquired words, development of cognitive and language impairment; and impaired or failing locomotion.

Additional, supportive, but nonessential, criteria include breathing disturbances during waking hours; teeth grinding; impaired sleep; muscle tone abnormalities leading to muscle wasting and dystonia; peripheral vascomotor issues; scoliosis; growth retardation; small, cold feet; and small, thin hands.

Exclusionary criteria include enlarged organs or other storage disease signs; retinopathy, optic atrophy, or cataracts; evidence of pre- or postnatal brain damage; presence of a metabolic or other neurological disorder; or an acquired neurological disorder resulting from infection or head trauma.

There is no cure for Rett syndrome. However, some symptoms may be treated through physical therapy, speech therapy, and the administration of medications to control anxiety or to alleviate depression.