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

Abstract

The methyl-CpG-binding protein 2 gene (MECP2) on the X chromosome encodes an essential epigenetic regulator in human postnatal brain development. Increased dosage of MECP2 causes a severe syndromic form of intellectual disability, the MECP2 duplication syndrome. Males with this syndrome have a progressive neurological disorder, severe to profound intellectual disability, epilepsy and recurrent respiratory infections. We report three cases with copy number gain in Xq28 involving the MECP2 gene. The gains were detected by chromosomal microarray analysis and ranged in size from 300 kb to 4.96 Mb. The three boys were aged between 3 and 16 years old. All three had development delay and no speech. In addition, one patient was diagnosed with Lennox-Gastaut syndrome and another had a Dandy Walker variant. Their clinical features were compared with other reported cases. We concluded that all three patients' clinical features were due to the Xq28 duplication, which confirmed the utility of chromosomal microarray analysis as a first-tier test in patients with unexplained intellectual disability. With a specific genetic diagnosis, we were able to provide appropriate anticipatory guidance for these patients and their families.

Spectrum and time course of epilepsy and the associated cognitive decline in MECP2 duplication syndrome

“…A few reports commented on the use of adjuvant therapy, such as vagus nerve stimulation, deep brain stimulation, ketogenic diet, or corpus callosotomy. 6,9,21,25,27 In our study, parents reported an improvement in seizure frequency and severity in 4/5 patients treated with vagus nerve stimulation and in 5/7 children treated with the ketogenic diet. However, larger collaborative studies are needed for a truly objective assessment of therapeutic efficacies.…”

“…This finding is in contrast to the estimated 10% EE frequency in the published cases (table e-1). [3][4][5][6][7]9,10,[17][18][19][20][21][22][23][24][25] There are several possible reasons underlying the differences in the frequency of epilepsy and EE observed in our case series and that estimated from review of published cases summarized in table e-1. (1) Ascertainment bias-the epileptic phenotype was scrutinized systematically and in detail in this study while published case reports and case series differ in their focus and depth of investigation.…”

“…7 Severe epileptic encephalopathy represented by late-onset spasms, 7 myoclonic-astatic epilepsy, or Lennox-Gastaut syndrome (LGS) has been reported in sporadic cases. 5,[8][9][10] Yet, despite the apparent frequent occurrence, severity, and detrimental effect on cognitive development, epilepsy frequency, types, and treatment responsiveness have not been systematically evaluated.…”

A brief history of MECP2 duplication syndrome: 20-years of clinical understanding

“…Neonatal complications include early infantile hypotonia (388 of 441 individuals from 62 studies [ 1 , 3 , 4 , 7 , 9 – 27 , 29 – 34 , 36 , 38 , 41 – 43 , 46 – 48 , 51 – 53 , 55 , 59 – 61 , 63 , 64 , 67 , 69 – 71 , 73 – 78 , 81 – 86 ]), feeding difficulties with poor sucking [ 16 , 73 , 77 ], bowel obstruction [ 17 , 74 ], malaise and vomiting [ 77 ], respiratory distress [ 77 ], breathing problems [ 84 ], hospitalisation for infections [ 77 , 84 ] and failure to thrive [ 1 , 9 , 12 , 13 , 16 , 17 , 22 , 25 , 27 , 29 , 32 , 38 , 43 , 44 , 51 , 61 , 64 , 67 , 81 , 82 ]. Developmental/psychomotor delay has been reported in most (n = 324) of 343 individuals from 56 studies [ 8 , 11 , 12 , 14 – 16 , 19 – 21 , ...…”

“…Developmental/psychomotor delay has been reported in most (n = 324) of 343 individuals from 56 studies [ 8 , 11 , 12 , 14 – 16 , 19 – 21 , 23 – 27 , 29 , 31 – 33 , 35 – 39 , 41 – 44 , 46 – 48 , 51 – 55 , 57 , 59 – 61 , 63 , 64 , 66 – 70 , 72 – 77 , 79 , 82 , 84 , 86 ], leading to moderate to severe intellectual disability (280 of 286 individuals from 57 studies [ 1 , 2 , 4 , 7 – 9 , 11 – 23 , 25 – 35 , 37 – 40 , 42 , 43 , 46 – 48 , 52 – 56 , 59 , 64 , 68 – 71 , 73 , 75 , 80 , 83 – 85 ]). Most children have impaired communication skills, as more than two-thirds (n = 179) of 261 individuals from 46 studies [ 2 , 3 , 5 , 7 , 9 , 11 , 13 , …”