The MECP2 duplication syndrome

Abstract

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 Xlinked 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.

Cytogenomic Delineation and Clinical Characterization of Three Cases of MECP2 Duplication Syndrome

“…Developmental regression which usually correlates with seizure onset is evident in Patient 3, possibly also contributed by his post-surgical complications. Abnormal movements mainly involving the upper limbs, observed in Patients 2 and 3, are also typical [5]. Seizures in children with MECP2 duplication syndrome often occur between the ages of 4 to 13 years, but isolated febrile seizures have been reported in younger children [8].…”

“…This is consistent with the clinical presentation of seizures in our cases. Seizure semiology is highly variable -generalized tonic-clonic, atonic, absence and myoclonic seizures have all been previously reported [4,5,8,9].…”

“…Dysmorphic features which may be subtle include brachycephaly, large ears, midface retrusion and depressed nasal bridge. Autistic behaviors and problems with gastrointestinal motility have also been reported [5]. Studies suggest that MECP2 overexpression could have a deleterious effect on brain development and function in mouse models, manifesting as seizures, spasticity, hypoactivity and early death [6].…”

The Impact of MeCP2 Loss- or Gain-of-Function on Synaptic Plasticity

“…A majority of patients diagnosed with MECP2 duplication syndrome are susceptible to severe recurrent respiratory infections, which contributes to a significantly reduced lifespan of 25 years in 50% of affected individuals (Ramocki et al, 2010;Van Esch, 2012). Other hallmark symptoms include autistic-like features, anxiety, stereotypic hand movements, and spontaneous and intermittent writhing of the arms, hands or head (Ramocki et al, 2010). Motor dysfunction is a significant core symptom of MECP2 duplication syndrome; affected patients show delays in basic developmental milestones such as sitting, crawling, and walking (Van Esch, 2012).…”

MECP2 duplications in six patients with complex sex chromosome rearrangements

“…One possible explanation for this phenotype in case 1 is that duplications near but not including the FLNA gene may have an effect on FLNA gene regulation. 30 Alternatively, simple constipation could be attributed to MECP2 alterations as girls with Rett syndrome also have problems with constipation. The presence of constipation in our cases may, therefore, be distinct from the severe intestinal pseudo-obstruction phenotype sometimes observed in patients with FLNA duplications and point mutations.…”