Types of Rett Syndrome: Classic, Atypical, and More

Rett syndrome is a genetic neurodevelopmental condition, but not all cases are the same. The different types of Rett syndrome vary in when they’re most often diagnosed, what symptoms they cause, and which gene changes are involved.

In this article, we describe classic Rett syndrome and compare it with several atypical Rett syndrome variants.

Classic Rett Syndrome

Classic Rett syndrome is the most common form. Symptoms usually start between 6 and 18 months of age. This type is caused by mutations (changes) in the MECP2 gene, which affect brain development and often lead to developmental delays in the first stage.

Classic Rett syndrome has four stages, but not everyone experiences them at the same time or in the same way. The first stage includes subtle developmental delays. For example, a child with stage 1 classic Rett syndrome may learn to crawl later than other children.

In the second stage, usually between ages 1 and 4, children begin to lose their language and motor skills.

In stage 3, symptoms stop getting worse and reach a plateau, sometimes even improving.

Many people with Rett syndrome enter a fourth stage, when muscle strength and some motor skills decline, while most communication and thinking abilities remain.

Symptoms of Classic Rett Syndrome

In addition to developmental delays, a wide range of symptoms that affect motor skills and communication can occur. A person may keep some abilities while losing others.

Common symptoms and key features of Rett syndrome include:

• Repeated hand movements, such as hand wringing or clapping
• Difficulty speaking
• Trouble with balance and walking
• Sleep disturbances
• Scoliosis (abnormal curvature of the spine), which can worsen balance and coordination
• Seizures
• Breathing problems
• Behaviors similar to those seen in autism spectrum disorder, such as avoiding social interactions.

Some children also develop related health conditions, including epilepsy, breathing problems, gastrointestinal problems (including acid reflux and constipation), and aspiration pneumonia. Doctors can help manage these complications as part of a person’s overall Rett syndrome care plan.

Atypical Rett Syndrome

Researchers have identified several variants called atypical Rett syndrome. Some stem from the same gene change as classic Rett syndrome, and others are linked to changes in different genes.

Zappella Variant

Zappella variant Rett syndrome, also called the preserved speech variant, is considered a milder form. Like classic Rett syndrome, the Zappella variant mostly affects girls, according to the journal Brain & Development, and progresses through the four stages. In most cases, it’s also linked to MECP2 gene changes.

Girls with Zappella variant Rett syndrome often show improvements in speech and motor skills, usually between ages 5 and 10. Many can speak in full sentences and walk without help. Children with this variant usually don’t have microcephaly (smaller head size), which is often seen in classic Rett syndrome.

Although many symptoms of the Zappella variant are milder than those in classic Rett syndrome, behaviors similar to those seen in autism spectrum disorder are common. According to StatPearls, epilepsy affects around 60 percent of girls with classic Rett syndrome. Another study estimates the rate at about 30 percent in girls with the Zappella variant.

Hanefeld Variant

The Hanefeld variant of Rett syndrome is known for early-onset seizures. With this type, seizures begin before a child is 6 months old. These seizures are often challenging to treat.

Most other symptoms are similar to those of the classic type but may be more severe. Although girls with classic Rett syndrome may experience different breathing problems, forceful breathing is the most common breathing issue in the Hanefeld variant. Other severe symptoms commonly seen in the Hanefeld variant include:

• Inability to walk
• Inability to talk
• Inability to feed oneself
• Scoliosis
• Vision problems
• Sensory issues
• Gastrointestinal problems

Hanefeld variant Rett syndrome is usually linked to changes in the CDKL5 gene rather than the MECP2 gene.

Rolando Variant

The Rolando variant is also called the congenital variant. This type is often associated with changes in the FOXG1 gene but is rarely linked to MECP2.

Children with this type show major developmental delays within the first few months of life, earlier than symptoms typically appear in children with the classic type. The Rolando variant is also characterized by a distinctive loss of muscle tone and severe symptoms, including:

• Microcephaly (small head size)
• Developmental delays
• Intellectual disability (learning disability)
• Gastrointestinal problems
• Scoliosis
• Foot problems

Forme Fruste Variant

The forme fruste variant of Rett syndrome is usually milder than the classic type. The term “forme fruste” means the condition is incomplete or less severe and may not meet all the typical diagnostic criteria.

People with this type can usually use their hands purposefully and have fewer problems with abnormal hand movements. Stage 2 of this form often appears later than in the classic type, and the loss of motor and speech skills may be less noticeable.

Rett Syndrome in Boys

In rare cases, Rett syndrome can affect boys, according to StatPearls. Boys with Rett syndrome can develop symptoms similar to those seen in girls with classic or atypical types of Rett syndrome, including movement problems, seizures, and learning disabilities.

Many boys with MECP2 gene changes die before birth or shortly after. This happens because the genes linked to Rett syndrome and its variants are on the X chromosome. Typically, males have just one X chromosome, whereas females typically have two, which is why Rett syndrome is so rare in boys and often causes severe symptoms early in life. However, boys who survive may have milder symptoms than girls with the same gene change.

Disorders Similar to Rett Syndrome

Some conditions can look similar to Rett syndrome and may even be mistaken for Rett syndrome variants. One example is Angelman syndrome, which causes similar speech and developmental delays, as well as seizures.

Other conditions that may be mistaken for Rett syndrome include:

• Autism spectrum disorder
• Cerebral palsy
• Brain injuries before or after birth
• Other neurodevelopmental disorders

Rett syndrome can be difficult to diagnose. Doctors may perform tests to rule out conditions like these before confirming a diagnosis.

Talk to Your Doctor

People who notice signs of developmental delays in their babies or children should talk with a doctor or pediatrician. A healthcare provider can review the symptoms and may use diagnostic tests to rule out other possible causes of developmental delays.

Changes in the MECP2 gene can often be identified with a simple genetic blood test, which may confirm a Rett syndrome diagnosis. Once Rett syndrome is diagnosed, the child’s healthcare team can recommend an individualized care plan. Rett syndrome requires lifelong care, and treatment may change over time, depending on the stage of the condition.

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