MECP2 duplication syndrome

MECP2 duplication syndrome is a severe neurological and developmental disorder. Signs and symptoms include low muscle tone (hypotonia) in infancy, developmental delay, severe intellectual disability, and progressive spasticity. Other signs and symptoms may include recurrent respiratory infections and seizures. Some people with MECP2 duplication syndrome may have autistic features, gastrointestinal problems, and/or mildly distinctive facial features. The syndrome is caused by having an extra copy (duplication) of the MECP2 gene, and inheritance is X-linked. The syndrome almost always occurs in males (who have one X chromosome), but some females with the duplication on one of their two X chromosomes have some signs or symptoms. Rarely, females may have severe signs and symptoms, similar to those in males with the syndrome.^[1][2][3]

Treatment is individualized and based on the signs and symptoms in each person. Treatment may involve routine management of feeding difficulties, infections, developmental delays, spasticity, and seizures.^[1][2] Respiratory infections are a major cause of death, with only half of people surviving past 25 years of age.^[3]

Signs and symptoms of MECP2 duplication syndrome may include:^[1][2]

• Hypotonia (low muscle tone), which is usually apparent in infancy.
• Delayed development of milestones.
• Moderate to severe intellectual disability.
• Inability to talk, or limited speech ability that may be lost with age.
• Needing assistance to walk or inability to walk.
• Progressive spasticity during childhood, which is generally worse in the legs. This may lead to the development of mild contractures.
• Recurrent respiratory infections (in about 75% of people). Respiratory infections can be life-threatening and are a major cause of death.
• Seizures (in about 50%).
• Feeding difficulties which may require a feeding tube.
• Distinctive head or facial features, such as brachycephaly (abnormally flat back of the head), midface hypoplasia (underdevelopment of the middle of the face), large ears, deep-set eyes, prominent chin, and a depressed nasal bridge.

Other signs and symptoms may include trouble swallowing, gastroesophageal reflux, failure to thrive, excessive drooling, autistic features, and bowel or bladder problems.^[1][2]

Most females with a MECP2 duplication generally do not have symptoms, although depression, anxiety, and autistic features have been described in some women with the duplication.^[1] Very rarely, females have severe signs and symptoms, similar to those in males with the syndrome.^[1][2][3]

The long-term outlook (prognosis) for people with MECP2 duplication syndrome varies. Based on the few documented cases in the medical literature, approximately half of affected people succumb before age 25 years. This shortened life expectancy is largely due to immune system dysfunction and an increased risk for recurrent infections.^[1]

Because MECP2 duplication syndrome affects many different systems of the body, medical management is often provided by a team of doctors and other healthcare professionals. Treatment varies based on the signs and symptoms present in each person. For example, babies who have trouble swallowing and/or feeding difficulties may require a feeding tube. Early developmental interventions may be recommended to help affected children reach their potential. This may include physical therapy, speech therapy and/or occupational therapy. Medications may be prescribed to treat seizures or spasticity. Recurrent infections must be treated with appropriate antibiotics.^[1][2]

Please speak with a doctor if you have any questions about your personal medical management plan or that of a family member.

MECP2 duplication syndrome occurs when there is an extra copy (duplication) of genetic material that includes the MECP2 gene. The size of the duplication can vary (i.e. additional genes around the MECP2 gene may also be duplicated). However, it is unclear whether extra copies of other genes in this location affect the severity of the syndrome.^[3]

The MECP2 gene gives the body instructions for making protein needed for normal brain functioning. One of its most important functions is to regulate the activity other genes in the brain by "switching them on and off." A duplication of the MECP2 gene leads to the production of too much of the MECP2 protein, making it unable to regulate other genes properly. This disrupts normal brain activity, leading to the signs and symptoms of MECP2 duplication syndrome.^[2][3]

MECP2 duplication syndrome is inherited in an X-linked manner.^[3] A condition is considered X-linked if the genetic change that causes the condition is located on the X chromosome, one of the two sex chromosomes (the Y chromosome is the other sex chromosome). In males (who have only one X chromosome), a duplication of the MECP2 gene in each cell is sufficient to cause the condition.

In females (who have two X chromosomes), a duplication of one of the two copies of the gene usually does not cause the disorder. Early in the normal development of females, one of the two X chromosomes is randomly and permanently inactivated in each cell (called X-inactivation). This prevents females from having twice as many active X chromosome genes. Because this process is usually random, the X chromosome inherited from the mother is active in some cells, and the X chromosome inherited from the father is active in other cells. However, when a female has an X chromosome with a duplicated copy of the MECP2 gene, the abnormal chromosome is often the one inactivated in many, or all, cells. This is called "skewed X-inactivation." X-inactivation prevents some females with a MECP2 duplication from developing features of the syndrome.

In most cases, MECP2 duplication syndrome is inherited from a mother who carries the duplication but has no symptoms. Rarely, the condition is not inherited. In these cases it may occur randomly during the formation of the egg or sperm, or shortly after the egg and sperm join together. When this happens, it is called a de novo duplication.^[3][2] The duplication can also arise from an unbalanced translocation involving the X chromosome (and the MECP2 gene).^[1]