Types of Rett Syndrome

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Rett syndrome is a genetic disorder that almost exclusively affects females. Patients typically experience normal growth and development early in life, followed by a slowing or regression in development, abnormal movements, and other problems like seizures.

The two broad types of Rett syndrome — classic and atypical — are based on the specific symptoms and disease-causing genetic mutations.

Classic Rett syndrome

Classic Rett syndrome is the most common form of the disease. It is caused by mutations in the MECP2 gene, which encodes for a protein called methyl-CpG binding protein 2 that is essential for normal brain development. The MECP2 gene is located on the X chromosome, which is one of the sex-determining chromosomes. Females have two X chromosomes, while males have one X and one Y.

Children with classic Rett syndrome usually appear normal in the first months of life, though relatively minor abnormalities like low muscle tone and difficulty feeding are sometimes reported.

At around 6 to 18 months of age, affected children enter a period of developmental stagnation, where they stop acquiring new skills. Then, usually from about ages 1 to 4 years, children begin to lose previously acquired skills like talking and hand skills. Other aspects of physical development are also affected such as, for example, smaller-than-normal head growth.

After this period of rapid deterioration, symptoms generally stabilize or ease slightly, though patients usually still have substantial difficulties with speech and moving their hands. Later in life — after about age 10 — patients typically have more substantial loss of motor function with many unable to walk unassisted. Other symptoms include seizures, uncontrolled muscle contractions, and behavioral abnormalities or autistic traits.

Atypical Rett syndrome

Some people have Rett-like disease, but their symptoms do not meet all the diagnostic criteria for classic Rett syndrome. Such individuals are said to have atypical or variant Rett syndrome. As many as 32% of people with Rett syndrome have an atypical form of the condition which, like the classic form, is more common in females than males.

There are several types of atypical Rett syndrome, and symptoms may be more severe or milder than in classic Rett. Generally, the late-onset, late childhood regression, and preserved speech types are milder, while the congenital (Rolando variant) and early-onset seizure types are more severe.

Late-onset type

The late-onset type is the most common form of atypical Rett syndrome. Symptoms typically are milder than in other forms, with patients retaining some motor skills and communication abilities. As its name suggests, symptoms generally first appear later than in the classic type.

Late-onset Rett syndrome is sometimes called the forme fruste variant. The term “forme fruste” refers to an unusually mild version of a disease, where patients may not meet all the diagnostic criteria typically associated with the condition.

Preserved speech type

Patients with the preserved speech type of Rett syndrome generally experience most symptoms of classic Rett, but their symptoms are milder, and they regain some language and motor skills as they get older. However, patients with this variant may be obese, more aggressive, and show more autistic features.

The preserved speech type is sometimes referred to as the Zappella variant after the psychiatrist who first described it in 1992. Like most classic Rett cases, the preserved speech type is chiefly caused by mutations in the MECP2 gene. Broadly, MECP2 mutations that cause the preserved speech type have less of an impact on the structure and function of the encoded protein than do mutations that cause the classic type, which is thought to underlie the milder symptoms.

Late childhood regression type

The late childhood regression type of Rett syndrome is characterized by symptoms and developmental regression that occur later in childhood — typically in children who are in preschool or early primary school. Individuals with this type usually have a normal head size. A few rare mutations in MECP2 have been linked with this form of the disease.

Early-onset seizure type

Infants with early-onset seizure type Rett syndrome typically begin to experience seizures, usually infantile spasms, before they are 6 months old. Other Rett-like symptoms, like loss of language and abnormal hand movements, have also been reported.

This form is sometimes called the Hanefeld variant after the doctor who first described it in 1985. It is caused by mutations in the gene CDKL5, which is located on the X chromosome.

Congenital type

Congenital Rett syndrome is considered the most severe form of atypical Rett syndrome. Symptoms are generally similar to those seen in classic Rett, with the main difference being age of onset. Whereas children with classic Rett do not show obvious symptoms until 6–18 months of age, those with the congenital type have symptoms that become apparent within three months of birth.

This type of Rett syndrome is commonly caused by a mutation in the gene FOXG1. It is sometimes referred to as the Rolando variant, after the scientist who first described it in 1985.

 

Last updated: Dec. 13, 2021, by Marisa Wexler MS

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