About the MECP2 Duplication Syndrome
MECP2 Duplication syndrome has been well described since 2005. It is an X-linked condition, and therefore it almost always is seen in boys and only very very rarely in girls. The condition is caused by microduplication of a section of the X-Chromosme that results in at least one extra copies of MECP2 gene. Usually, additional genes in the same area are also duplicated, but it is unclear whether these other extra genes have clinically significant effects. Normally, the condition is inherited by sons from their mothers who are carriers of the duplication but do not exhibit severe effects. As of 2011, the number of known cases remains very small, but now exceeds 1,000 cases. With the increased availability of diagnostic testing (Chromosomal Microarray Analysis) the number of identified cases is rapidly rising. At this time, it appears that the condition is not extremely rare, but up until this time it is rarely diagnosed. There is inadequate information to make any reasonable estimate of incidence, but it may affect as many as 1 in 10,000 to 1 in 20,000 live births of boys and probably is about 50 times less common in girls.
This is an X-linked disorder that results from an extra copy of the MECP2 gene located near the end of the long arm of the X chromosome (xq28). In most cases, other adjacent genes are also duplicated, but there is no conclusive evidence that extra copies of these other genes affect the nature or severity of the syndrome. In some cases there is more than one extra copy resulting in MECP2 triplication, which generally results in more severe expression of the same symptoms as duplication. In most cases the extra copies of the MECP2 gene remain on the X chromosome. Girls with this form of the duplication are typically asymptomatic carriers because they selectively inactivate the X-chromosome with the extra copy of the gene in each pair. In a smaller number of cases the extra copy of the MECP2 gene is attached to another chromosome, resulting in similar symptoms. Since this from cannot be compensated by skewed inactivation, both boys and girls are affected similarly by this form of duplication.
Description of MECP2 Syndrome
A number of descriptive reports have described clinical findings among individuals with MECP2 Duplication Syndrome. In addition parents have sometimes described additional features. The following list of features must be considered to be tentative at this time, since the number of cases observe remains small and there is considerable individual variability as well as variation in the clinical reports.
Frequently Reported Findings
Infantile hypotonia At birth or during the first weeks or months of life these infants are typically hypotonic (have low muscle tone). In most cases, low muscle tone persists in the face and trunk throughout childhood and into adult life. This is often the first noted atypicality.
Increasing limb spasticity Over time the low muscle tone in the limbs typically is replaced by excessive muscle tone, particularly in the legs. In some cases, the progression from hypotonia to is apparent in childhood. In other cases, it has been described as occurring in adolescence or even adulthood. This has been observed in most cases and appears to be almost universal among individuals who live into adolescence or adulthood.
Gastroesophageal Reflux Reflux has been noted in about 80% of cases.
Significantly Delayed Developmental Milestones Rolling over, sitting, and other motor milestones are significantly delayed. Some individuals never walk independently others begin walking at 3-5 years of age or older. Lugtenberg and colleagues record the age of first walking for 12 individuals as ranging from ages 2 to 6 with a mean age of 3. Those who do walk typically have a wide unsteady gait
Severe or profound intellectual disabilities Severe or profound intellectual disabilities have been reported in almost all cases.
Limited language Some individuals develop limited use of speech others never use speech. Most individuals are described as having more receptive language and understanding much of what is said to them. Ramocki and colleagues describe 8 individuals ( mean age 10 years 5 months) with an average of receptive language level of 11.4 months and average expressive language level of 6.1 months. Many individuals are described as losing language language skills as they get older. Lugtenberg and colleagues report no speech in 82% of 55 cases.
Developmental regression The loss of motor and language skills over time has been reported in many but not all individuals. This loss of skills has been described as starting at wide variety of ages. Regression is frequently occurs around the same time as the unset of seizures, but the relationship between these symptoms remains unclear.
Autistic behaviors Some autistic behaviors, such as hand-flapping and spinning objects, are described among many individuals with MECP2 Duplication Syndrome. Ramocki and colleagues reported that six of nine patients had prior diagnoses of autism, nine of nine tested as autistic on one test, while eight of nine met the criteria of autism on a second test and the ninth met the broader criteria for autism spectrum disorder. Some who have developed the use of speech exhibit echolalia.
Severe and recurrent infections Infectious disease and pneumonia are major health challenges and the most frequently reported cause of death for individuals with MECP2 Duplication Syndrome. The underlying cause for this is not entirely clear, and may be multifactorial. Some individuals have been reported to have deficiencies in Immunoglobulin A or other immune factors, such as toll-like receptors, but these specific findings do not correlate well with the finding of frequent severe infections. Functional immune system weakness does appear to be present in many, reflux, swallowing problems, axial hypotonia, and other factors may contribute to the frequency and severity of lower respiratory infections.
Multiple types of seizures Seizures are very common, and become more common as children get older. As a result, they are less frequent among younger children, but very frequent by the second decade of life. Many different categories of seizures have been reported among individuals with MECP2 Duplication Syndrome, and frequently many different forms are reported in the same individual with the nature of the seizures changing over time. Astatic and myoclonic seizures are much more common among these individuals than among others with seizure disorders. Some parents report that seizures are particularly frequent upon awaking or between waking and sleep states. A variety of anticonvulsants have been used with varying degrees of success in individuals but no method of seizure control has emerged to date as particularly well suited to individuals with MECP2 Duplication Syndrome. Echenne and colleagues have suggested that the EEG and seizure findings in these individuals is somewhat unique and makes up one of the characteristic findings in MECP2 Duplication Syndrome.
Drooling Excessive drooling has been reported in about 2/3 of individuals with MECP2 Duplication syndrome.
Constipation Constipation has been reported in many individuals and is often severe. Bowel pseudo-obstruction has also been reported in many cases.
Other Possible Findings
Late dentition Very late eruption of teeth has been reported by some parents.
Atypical Fingers and Toes Long thin fingers and toes have been reported in some cases.
Temperature regulation dysfunction Some individuals have been described as having chronic hypothermia or labile body temperature.
Peripheral circulatory problems A number of individuals have been described as having Reynaud phenomena or similar persistent purplish engorgement of hands or feet when exposed to cold temperatures.
Bruxism Grinding of the teeth has been frequently reported among older children, adolescents, and adults.
Sleep disorders Sleep disorders are described in some individuals, particularly later in childhood and beyond.
Prenatal growth retardation Some parents report incomplete development of gums, earlobes, etc at birth in spite of full-term pregnancies.
Postnatal growth retardation Some are described as small for their age.
Low bone density and fractures Fractures and poor bone density have been reported frequently. These effects may be associated with diet, anticonvulsant therapy, combined with frequent seizure related falls.
Atypical Facial Features Although atypical facial features have been reported, they have been inconsistent across individuals. For example, about 1/3 have been reported as microcephalic but macrocephaly has also been reported. Large ears are among the most frequently reported feature.