Wednesday, March 16, 2016

Monkeys and MECP2 duplication syndrome

Overexpression of methyl CpG binding protein 2 (MECP2) produces inheritable, autism-like behavioral changes in monkeys, according to a study published in the January 25 online edition of Nature. But while the authors suggest the monkeys may provide an important model for understanding MECP2 duplication syndrome (MDS), a common cause of autism in boys, experts not involved in the study have strong reservations that the animals are likely to shed much light on the human disorder, or serve as a model for autism more generally.

“I would caution about making any claims about the use of this model to either understand the pathogenesis of this syndrome, or developing treatment for it,” said Huda Zoghbi, MD, whose work focuses on the MECP2 gene in both Rett syndrome and MDS. Dr. Zoghbi, a professor in the department of neurology at Baylor College of Medicine in Houston, predicted the existence of the duplication syndrome in 2004 based on work in mice.

MECP2 binds to multiple genes, helping to silence them in order to shape brain development. Loss-of-function mutations of the MECP2 gene, which is X-linked, cause Rett syndrome primarily in girls, while duplication causes MDS primarily in boys; girls appear to be spared of MDS because the random inactivation of X chromosomes leaves many cells with the proper dosage of MECP2. Symptoms of MDS include intellectual disability, infantile hypotonia followed by progressive lower limb spasticity, seizures, respiratory infections, and autism...

Compared with wild-type monkeys, transgenic monkeys displayed about twice as much repetitive circular locomotion in their cages, despite no overall increase in activity, a behavior that Dr. Qiu suggested is analogous to the stereotyped movements in autism. Analysis of vocalizations indicated that transgenic animals emitted more sounds associated with anxiety. When paired with wild-type monkeys or other transgenics, transgenic monkeys sat with other monkeys less than did wild-type monkeys, suggesting impaired social interaction.

Using advanced in vitro fertilization techniques, Dr. Qiu created offspring of the transgenic monkeys, and showed they not only inherited the extra MECP2 genes, but exhibited social interaction impairments as well. “The behavior is quite reliable and stable across generations,” he concluded...

But whether the monkeys are a meaningful model of MECP2 duplication syndrome is controversial. The cognition of the transgenic monkeys was largely normal, and none showed seizures. “The model captured a couple of features of the syndrome,” Dr. Zoghbi said, “but I don't think it would be fair to say it captured most of them.

“This is not surprising,” she continued, “because the gene was only expressed in neurons and only using the synapsin promoter, which is quite distinct from the pattern of the endogenous MECP2 promoter.”

The temporal and spatial pattern of normal MECP2 expression, including that of the duplicated gene in MDS, varies over time and among multiple types of brain cells, including non-neuronal cells. “That fine tuning of MECP2 levels was not accomplished in this study, and this probably explains why it doesn't reproduce all the features,” Dr. Zoghbi said.

“I think this is a model to study MECP2 overexpression toxicity in neurons, but I would be really cautious about conclusions from this model that would be relevant to clinical translation.”

One potential value of a truer primate model would be to study the long-term consequences of MECP2 overexpression in a large brain, something that cannot be done in the mouse. “This could be valuable for testing therapies,” she said. Dr. Zoghbi is currently developing antisense oligonucleotide therapy for MDS, and showed in December 2015, that treatment can induce a broad phenotypic rescue in the mouse model of the disease...

The validity of such studies, however, will ultimately depend on whether the observed behaviors model something fundamental about human autism. Can an animal, even a social primate, ever model a disorder of human social interaction? The question is complex, Dr. Muotri said, because the social behavior of a mouse is not the same as that of a monkey, which is not the same as that of a human.
“When we talk about autism, we are talking about the way we look at each other in the eye, the way we interact with people in society. Those behaviors are not the same, and don't mean the same thing, in primate or rodent societies. What is autism in a monkey? You have to go to the primate society to understand that. I would feel shaky using a primate model to understand the human social brain. There may be similarities, but it's a stretch.”


  1. Ramocki MB, Tavyev YJ, Peters SU. The MECP2 duplication syndrome. Am J Med Genet A. 2010 May;152A(5):1079-88.


    In this review, we detail the history, molecular diagnosis, epidemiology, and clinical features of the MECP2 duplication syndrome, including considerations for the care of patients with this X-linked neurodevelopmental disorder. MECP2 duplication syndrome is 100% penetrant in affected males and is associated with infantile hypotonia, severe to profound mental retardation, autism or autistic features, poor speech development, recurrent infections, epilepsy, progressive spasticity, and, in some cases, developmental regression. Most of the reported cases are inherited, however, de novo cases have been documented. While carrier females have been reported to be unaffected, more recent research demonstrates that despite normal intelligence, female carriers display a range of neuropsychiatric phenotypes that pre-date the birth of an affected son. Given what we know of the syndrome to date, we propose that genetic testing is warranted in cases of males with infantile hypotonia and in cases of boys with mental retardation and autistic features with or without recurrent infections, progressive spasticity, epilepsy, or developmental regression. We discuss recommendations for clinical management and surveillance as well as the need for further clinical, genotype-phenotype, and molecular studies to assist the patients and their families who are affected by this syndrome.

  2. Vignoli A, Borgatti R, Peron A, Zucca C, Ballarati L, Bonaglia C, Bellini M,
    Giordano L, Romaniello R, Bedeschi MF, Epifanio R, Russo S, Caselli R, Giardino
    D, Darra F, La Briola F, Banderali G, Canevini MP. Electroclinical pattern in MECP2 duplication syndrome: eight new reported cases and review of literature.
    Epilepsia. 2012 Jul;53(7):1146-55.



    Duplications encompassing the MECP2 gene on the Xq28 region have been described in male patients with moderate to severe mental retardation, absent speech, neonatal hypotonia, progressive spasticity and/or ataxia, recurrent severe respiratory infections, gastrointestinal problems, mild facial dysmorphisms (midface hypoplasia, depressed nasal bridge, large ears) and epilepsy. Epilepsy can occur in >50% of cases, but the types of seizures and the electroclinical findings in affected male individuals have been poorly investigated up to the present. Herein we describe eight patients with MECP2 duplication syndrome and a specific clinical and electroencephalographic pattern.


    Array CGH of genomic DNA from the probands was performed, and an Xq28 duplication ranging from 209 kb to 6.36 Mb was found in each patient. Electroencephalography studies and clinical and seizure features of all the patients were analyzed.


    We found that epilepsy tended to occur between late childhood and adolescence. Episodes of loss of tone of the head and/or the trunk were the most represented seizure types. Generalized tonic-clonic seizures were rarely observed. The typical interictal EEG pattern showed abnormal background activity, with generalized slow spike and wave asynchronous discharge with frontotemporal predominance. Sleep electroencephalography studies also demonstrated abnormal background activity; spindles and K complex were often abnormal in morphology and amplitude. Response to therapy was generally poor and drug resistance was a significant feature.


    Although these cases and a review of the literature indicate that epilepsy associated with MECP2 duplication syndrome cannot be considered a useful marker for early diagnosis, epilepsy is present in >90% of adolescent patients and shows a peculiar electroclinical pattern. Consequently, it should be considered a significant sign of the syndrome, and an EEG follow-up of these patients should be encouraged from early childhood. Moreover, the definition of a more specific epileptic phenotype could be useful in order to suspect MECP2 duplication syndrome in older undiagnosed patients.

  3. El Chehadeh S, Faivre L, Mosca-Boidron AL, Malan V, Amiel J, Nizon M, Touraine R, Prieur F, Pasquier L, Callier P, Lefebvre M, Marle N, Dubourg C, Julia S, Sarret C, Francannet C, Laffargue F, Boespflug-Tanguy O, David A, Isidor B, Le Caignec C, Vigneron J, Leheup B, Lambert L, Philippe C, Cuisset JM, Andrieux J,
    Plessis G, Toutain A, Goldenberg A, Cormier-Daire V, Rio M, Bonnefont JP, Thevenon J, Echenne B, Journel H, Afenjar A, Burglen L, Bienvenu T, Addor MC, Lebon S, Martinet D, Baumann C, Perrin L, Drunat S, Jouk PS, Devillard F, Coutton C, Lacombe D, Delrue MA, Philip N, Moncla A, Badens C, Perreton N, Masurel A, Thauvin-Robinet C, Portes VD, Guibaud L. Large national series of patients with Xq28 duplication involving MECP2: Delineation of brain MRI abnormalities in 30 affected patients. Am J Med Genet A. 2016 Jan;170(1):116-29.

    Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment.