NORD gratefully acknowledges the Rett Syndrome Research Trust; Huda Zoghbi, MD, Professor, Pediatrics, Molecular and Human Genetics, Neuroscience, and Neurology, Baylor College of Medicine, Director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital; and Bernhard Suter, MD, Assistant Professor, Pediatrics & Neurology, Associate Medical Director of the MECP2 Duplication Clinic at the Blue Bird Circle Rett Center, Baylor College of Medicine & Texas Children’s Hospital, for assistance in the preparation of this report.
MECP2 duplication syndrome is a rare genetic neurodevelopmental disorder characterized by a wide variety of symptoms including low muscle tone (hypotonia), potentially severe intellectual disability, developmental delays, recurrent respiratory infections, speech abnormalities, seizures, and progressive spasticity, a condition characterized by muscle stiffness that is worsened with movement and can be associated with involuntary muscle spasms. Additional symptoms can occur. MECP2 duplication syndrome is caused by the duplication of genetic material on a specific region on the X chromosome (Xq28). This region includes the MECP2 gene and typically several adjacent genes. In most affected individuals, the MECP2 duplication is inherited in an X-linked manner; in rare cases, the duplication may occur randomly for no apparent reason (de novo duplication). The disorder predominantly affects males, but females who carry the duplication on one X chromosome (heterozygotes) may exhibit some signs of the disorder. Rarely, females can develop a severe form of the disorder similar to males
One of the first descriptions in the medical literature of this disorder as a distinct neurological entity was by Lubs et al. in 1999. The discovery that microduplications involving the MECP2 gene on the X chromosome cause a distinct neurological disorder (now known as MECP2 duplication syndrome) was first reported in the medical literature in 2005. Mutations of the MECP2 gene are known to cause Rett syndrome, a neurological disorder that primarily affects females. These disorders are sometimes grouped together as MECP2-related disorders.
MECP2 duplication syndrome is characterized by a wide variety of symptoms. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes influencing the disorder hamper physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
One of the initial signs of MECP2 duplication syndrome may be feeding difficulties during the first few weeks of life likely resulting from diminished muscle tone (hypotonia). Affected children may also experience difficulty swallowing, gastroesophageal reflux and excessive drooling. Affected children will often fail to gain weight or grow at the expected rate for age and gender (failure to thrive) and may be at risk of aspiration, however, some infants experience no recognized problems in the newborn (neonatal) period and concern is not raised until other developmental milestones are missed.
Children with MECP2 duplication have moderate to severe intellectual disability and experience delays in attaining developmental milestones including sitting and crawling. Consequently, walking is also delayed and, in some cases, individuals develop an unsteady, uncoordinated gait. This abnormal gait can result in the development of exaggerated inward curvature of the lower spine (lumbar hyperlordosis). As affected individuals grow older, about half may experience neurological regression that ultimately results in the loss of previously acquired skills such as the ability to walk. In many cases the onset of regression is linked to onset of epilepsy.
The majority of affected individuals do not develop the ability to talk. Some individuals may be able to speak a few words during early childhood or have a limited use of speech, but frequently this ability is progressively lost during adolescence. Most affected individuals have better receptive language skills (i.e. understanding what is said to them). Rarely, some boys do retain the use of speech into adulthood.
In many affected children, hypotonia may progress to spasticity, a condition that is generally defined in the medical literature as an abnormal increase in muscle tone or stiffness of affected muscles. Spasticity can be associated with muscle spasms, increased deep tendon reflexes, and fixed joints (contractures). Spasticity affects the legs more severely and, over time, mild to severe contractures of the hips, knees and ankles may develop. A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint.
Up to half of individuals develop recurrent seizures (epilepsy) in childhood or adolescence. However, the true prevalence of seizures by adulthood may be higher. In some individuals, seizures may not respond to treatment (refractory) and the onset and severity of seizures may correlate with neurological deterioration (e.g. loss of speech, hand use, and ambulation). Seizure types that have been reported in individuals with MECP2 duplication syndrome include head/neck and trunk drop attacks, absence seizures, myoclonic seizures, and generalized or secondarily generalized tonic-clonic or simply tonic seizures (once known as grand mal seizures).
Some individuals with MECP2 duplication syndrome experience dysfunction of the immune system, which causes them to be prone to recurrent infections such as respiratory tract infections. Affected individuals may develop recurrent pneumonia that is sometimes severe requiring mechanical ventilation. Middle ear infections (otitis media) and sinusitis are also common. Additional infections have been reported including meningitis or urinary tract infections. Recurrent infections can cause life-threatening complications, and are a major contributing factor for reduced life-expectancy.
Many individuals with MECP2 duplication syndrome meet formal criteria for diagnosis with an autism spectrum disorder due to poor expressive language skills, abnormal social affect, and restricted/repetitive behaviors. Mood disorders such as anxiety sometimes occur.
Affected individuals often have clinically significant constipation. Bladder dysfunction has also been seen. According to some reports, affected individuals may have chronic intestinal pseudo-obstruction (CIP), a condition characterized by abnormalities affecting the involuntary, coordinated muscular contractions (peristalsis) that propels food and other material through the digestive system. Symptoms may develop due to obstruction of the small bowel and can include nausea, vomiting, abdominal pain, abdominal swelling and constipation. Ultimately, normal nutritional requirements cannot be met leading to unintended weight loss and malnourishment. The acute onset of GI symptoms such as abdominal pain, unusual distension, or vomiting warrants urgent medical evaluation as it can precede life-threatening complications.
Individuals with MECP2 duplication may have distinctive facial features including an abnormally flat back of the head (brachycephaly), underdevelopment of the middle of the face (midface hypoplasia), ear anomalies, large ears, deep-set eyes, prominent chin, pointed nose, and an abnormally flat bridge of the nose.
Additional findings have been reported in some children with MECP2 duplication syndrome including some degree of growth retardation. Early in life, head size appears to be normal, but as the boys get older, some might develop abnormally small head circumference (microcephaly). However, large head circumference (macrocephaly) has also been observed, and overall these are not consistent features of the syndrome.
Some boys have underdeveloped (hypoplastic) genitalia. Affected males may experience failure of the testes to descend (cryptorchidism) and have the urinary opening located on the underside of the penis (hypospadias) rather than at the end.
Although MECP2 duplication syndrome is primarily associated with males, females can develop mild symptoms of the disorder or, rarely, a severe form of the disorder. Some researchers have noted that women who have a MECP2 duplication on one of their X chromosomes (heterozygote or carrier females) may be prone to developing neuropsychiatric features including depression, anxiety, and specific personality traits. In addition, recent reports have identified women (i.e., women with unfavorable X-linked inactivation) who developed some symptoms of the disorder including recurrent infections, poor speech development, or seizures.Rarely, females may have a genetic abnormality, known as a translocation, which involves the X chromosome and a non-sex chromosome (autosome). Females with this specific underlying genetic abnormality may develop a severe form of the disorder similar to that seen in males. For more information, on X-linked inactivation and translocations, see the Causes section below.
MECP2 duplication syndrome is caused by a genetic abnormality in which a portion of the X chromosome appears two times on one of the X chromosomes (duplication) instead of once. By definition, the affected region always contains the methyl-CpG-binding protein 2 (MECP2) gene. Most affected children have very small duplications called microduplications, but larger, more complex rearrangements (e.g. translocations) can also cause the disorder. Depending upon the exact size and location of the duplicated area, additional genes are also duplicated. The duplication size is unique to each affected family or individual.
The MECP2 gene contains instructions for producing (encoding) a protein called MeCP2. This protein is essential for normal brain function and most likely has several different functions in the body. Researchers believe that the protein may regulate other genes in the brain by fine tuning the levels of those genes. The presence of an extra copy of the MECP2 gene leads to overproduction (overexpression) of the MeCP2 protein. This overexpression is believed to increase the activity of the protein. Researchers believe that the more excess protein produced, the worse the associated symptoms. Rarely, affected males have MECP2 triplication, in which there are two extra copies of the MECP2 gene for a total of three. In these cases, MeCP2 overexpression is greater and the associated symptoms have been more severe.
Researchers have recently discovered that MeCP2 overexpression can impair the function of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e. invading microscopic life-forms [microorganisms]). One specific part of the immune system affected in this disorder is the T cell system, which helps to fight several viruses, some bacteria and yeast and fungi. Researchers believe that MeCP2 overexpression suppresses the secretion of a protein known as interferon-gamma from certain T cells, as well as lower levels of immunoglobulins IgA, IgG and IgM, leading to a partially immunodeficient state. Low tone, gastrointestinal reflux and swallowing dysfunction may additionally predispose to recurrent respiratory tract infections and pneumonias. More research is necessary to determine the specific pathogens that affect individuals with MECP2 duplication syndrome and how to best treat the abnormal immune system.
Most affected males inherit the disorder from a carrier mother who has favorable survival of the X-chromosome carrying the one normal copy of MECP2 as the active X chromosome. Such carrier females either have no symptoms or extremely mild symptoms such as anxiety or mild symptoms of the disorder. When a mother is a known carrier of the MECP2 mutation, there is a 50% chance of passing that mutation on to her children. In extremely rare cases, the duplication that causes the disorder occurs randomly for no apparent reason (de novo duplication). Affected males can also develop the disorder due to a translocation involving the X chromosome and a non-sex chromosome (autosome). In such cases, the parent’s chromosomes are unaffected and the disorder is not inherited.
Random X-chromosome inactivation is a normal process in females. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, certain disease traits on the X chromosome such as a mutated gene may be “masked” by the normal gene on the other X chromosome (random X-chromosome inactivation). Basically, in each cell of the body one X chromosome is active and one is turned off or “silenced”. This occurs randomly and generally happens as a 50-50 split. However, some females may have favorable X-inactivation, in which the affected X chromosome is silenced in most of the cells and these females may only have mild symptoms of the disorder. Other females may have unfavorable X-inactivation, in which the unaffected X chromosome is silenced in most of the cells and these females usually have a severe expression of the disorder.
In the initial reports, most women with a MECP2 duplication have had preferentially favorable X-inactivation (near 100% inactivation of the duplication-bearing X chromosome). As previously discussed, these women generally have no symptoms or only mild symptoms of the disorder. However, recent reports have identified women in whom the percentage of cells with the duplication-bearing X chromosome is more numerous. Consequently, these women have developed symptoms of the disorder.
Rarely, females with a MECP2 duplication have developed a severe form of the disorder similar to that seen in affected males. This occurs when an additional (concomitant) abnormality involving the X chromosome occurs, such as an unbalanced translocation. An unbalanced translocation occurs when a region of one chromosome breaks off and is attached to another chromosome, causing a shifting of genetic material. In these specific cases, the Xq28 region breaks off and attaches to an autosome (non-sex chromosome). Because the duplicated material on the X chromosome has been translocated to an autosome, this prevents the normal X-inactivation of the duplicated segment. An unbalanced translocation occurs randomly (de novo).
Unbalanced translocation involving the Xq segment can also cause MECP2 duplication syndrome in males. Translocation between the Xq segment and short arm (p) of the X chromosome, the Y chromosome, or an autosome has been reported.
As mentioned above, additional genes can be involved in the duplicated area on the X chromosome. These genes include IRAK1, L1CAM, FLNA and many others. It is possible that these genes contribute to the overall spectrum of disease associated with MECP2 duplication syndrome. The IRAK1 gene, which is involved in the immune system, is typically duplicated as well, even in individuals with very small duplications. Many individuals with very small duplications, involving only the MECP2 and IRAK1 genes, have developed the core symptoms associated with the disorder. However, larger duplications that contain additional genes may be associated with other symptoms. For example, the FLNA gene is associated with gastrointestinal problems such as pseudo-obstruction and may be associated with a distinct clinical phenotype involving this condition. The exact role that these adjacent genes play in the development of MECP2 duplication syndrome is not fully understood.
Though plausible, no clear indication has so far been found that involvement of additional genes modifies the expression of MECP2 duplication syndrome, despite several studies having looked at a potential association.
More research is necessary to determine to what extent additional genes influence the development of MECP2 duplication syndrome.
The exact incidence and prevalence of MECP2 duplication syndrome in the general population is unknown. Because affected individuals may go undiagnosed or misdiagnosed, determining the disorder’s true frequency in the general population is difficult. Well over 200 individuals have been reported in the medical literature. It has been estimated that approximately 1-2% of unexplained cases of X-linked intellectual disability may be due to MECP2 duplication syndrome.
A diagnosis of MECP2 duplication syndrome is based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. It should be included in the differential diagnosis of male infants with hypotonia.
Clinical Testing and Workup
There are a variety of tests that can be used to diagnose MECP2 duplication syndrome including array comparative genomic hybridization (array-CGH). This test can detect the gain or loss of chromosomal material including microduplications. In rare instances, when a current array-CGH does not detect a change in genetic material, whole exome or even whole genome sequencing can be utilized, a sophisticated technique that determines the complete DNA sequence (or, in the case of whole exome, the sequence of the expressed part of the DNA) of an individual.
Additional tests that can confirm CGH results or for direct clinical testing include polymerase chain reaction (PCR), fluorescent is situ hybridization (FISH) analysis, chromosome microarray SNP analysis, and multiplex ligation-dependent probe amplification (MLPA).
PCR is a laboratory technique that has been described as “photocopying”. It enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes.
A FISH test can be used to determine a person’s karyotype. A karyotype is a visual representation of a person’s chromosomal makeup (i.e. the 46 chromosomes in a cell). The FISH test can detect chromosomal abnormalities such as duplications or translocation.
Chromosome microarray SNP analysis uses probes that can detect chromosomal abnormalities including microduplications, including those that are the underlying cause of many cases of MECP2 duplication syndrome.
The MLPA test is a relatively new method for assessing chromosomes and can detect certain chromosomal abnormalities including those associated with MECP2 duplication syndrome. Pre-implantation genetic diagnosis (PGD) may be an option when a parent has a known genetic abnormality (i.e. carrier mother). PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested such an option should seek the counsel of a certified genetics professional.
The treatment of MECP2 duplication syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, pediatric neurologists, gastroenterologists, psychiatrists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.
Treatment options that may be used to treat individuals with MECP2 duplication syndrome are complex and varied. The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Inclusion of novel augmentative communication devices, such as eye-tracking technology based communication devices, in the therapy regimen are encouraged. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Some children who lose skills are able to re-learn them with intensive therapy. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.
Other treatment is symptomatic and supportive. Additional therapies for MECP2 duplication syndrome depend upon the specific abnormalities present and generally follow standard guidelines.
Some general therapies common for infants or children include monitoring feeding and swallowing difficulties. Insertion of a feeding tube through a surgical opening in the stomach (gastrostomy) may be necessary to ensure proper nutritional support and to prevent aspiration.
Drugs may be used to treat a variety of symptoms associated with MECP2 duplication syndrome. Anti-seizure medications (anti-convulsants) are usually effective in treating seizures; however, in a significant subset of cases these medications do not completely control seizures (refractory seizures) and complementary approaches such as some implementation of the ketogenic diet, or implantation of a vagus nerve stimulator may be sought. Drugs may be used to improve spasticity and muscle rigidity, but can also be ineffective or even potentially worsen the condition. Working with a physical medicine and rehabilitation specialist to treat spasticity is recommended. Prompt treatment of spasticity may prevent the development of contractures.
Because of the susceptibility to infections, when affected individuals develop an infection, they should be treated immediately and aggressively with appropriate antibiotics. Recurrent infections, especially respiratory infections, can be severe enough to necessitate hospitalization and require assisted (mechanical) ventilation. Individuals who develop recurrent pneumonia should be evaluated by an immunology specialist since medical interventions including the use of prophylactic antibiotics and/or immunoglobulin therapy are indicated in some cases.
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Contact for additional information about MECP2 duplication syndrome:
Bernhard Suter, MD
Assistant Professor, Department of Pediatrics
Section of Pediatric Neurology and Developmental Neuroscience
Baylor College of Medicine and Texas Children’s Hospital
6701 Fannin St. Suite 1250
Houston, Texas 77030
Email: [email protected]
Huda Y. Zoghbi, MD
Professor, Baylor College of Medicine
Investigator, Howard Hughes Medical Institute
Director, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
1250 Moursund Ave, Suite 1350
Houston, TX 77030
Email: [email protected]
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