Phenotypic features in MECP2 duplication syndrome: Effects of age

Abstract

Background: MECP2 Duplication syndrome (MDS) is a rare X-linked genomic disorder that is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Although phenotypic features in MDS have been described, there is a limited understanding of the range of severity of these features, and how they evolve with age. Methods:The cross-sectional results of N = 69 participants (ages 6 months-33 years) enrolled in a natural history study of MDS are presented. Clinical severity was assessed using a clinician-report measure as well as a parent-report measure. Data was also gathered related to the top 3 concerns of parents as selected from the most salient symptoms related to MDS. The Child Health Questionnaire was also utilized to obtain parental reports of each child's quality of life to establish disease burden.Results: The results of linear regression from the clinician-reported measure show that overall clinical severity scores, motor dysfunction, and functional skills are significantly worse with increasing age. Top concerns rated by parents included lack of effective communication, abnormal walking/balance issues, constipation, and seizures. Higher levels of clinical severity were also related to lower physical health quality of life scores as reported by parents. Conclusions:The data suggest that increasing levels of clinical severity are noted with older age, and this is primarily attributable to motor dysfunction, and functional skills. The results provide an important foundation for creating an MDS-specific severity scale highlighting the most important domains to target for treatment trials and will help clinicians and researchers define clinically meaningful changes.

Exploring gastrointestinal health in MECP2 duplication syndrome

“…Constipation is common in autism 21,22 and other neurodevelopmental disorders 23–25 including RTT 15 . The frequency of constipation previously reported for MDS ranged from 32% to 81% 2,7,8,10,26 . In the present study, at least three‐fourths of MDS individuals had difficulty pushing out stool and passed large, hard stool and 80% of MDS individuals required laxatives to have a bowel movement.…”

“…15 The frequency of constipation previously reported for MDS ranged from 32% to 81%. 2,7,8,10,26 In the present study, at least three-fourths of MDS individuals had difficulty pushing out stool and passed large, hard stool and 80% of The mechanism of constipation in MDS is unknown. Several studies in RTT, 7,72 as well as other neurodevelopmental disorders, 27 showed dysbiosis of the gut microbiota which may lead to an altered gut metabolome and possible neurotransmitter dysfunction.…”

MECP2 duplication syndrome: The electroclinical features of a case with long-term evolution

“…Unlike what typically happens in epileptic encephalopathies, where BS commonly represents the EEG pattern at disease onset, in our case BS pattern likely reflects a severe cerebral dysfunction secondary to advanced disease progression. As clinical worsening with older age has been suggested, studies on the natural history of epilepsy could potentially point out a progression of EEG findings [11] . Serial EEGs of 9 patients with MDS have been recently reviewed reporting an evolution from normal to abnormal activity within 1–8 years of age in half of the patients [7] .…”

MECP2-Related Disorders in Males

“…As mentioned, some clinical features, such as epilepsy, respiratory tract infections, or constipation, appear or worsen with age. As a result, Peters et al, reported that their older participants have more severe clinical symptoms, specifically regarding motor dysfunction (e.g., dystonia, scoliosis, and/or rigidity) and functional skills (e.g., motor skills, communication skills, chewing, and swallowing) [129]. A longitudinal Japanese study found a similar outcome by comparing the clinical traits of MDS boys at their first medical visit and some years later [130].…”

“…The core phenotype of MDS patients includes hypotonia, developmental delay (DD), mostly moderate-severe intellectual disability, autistic features, epilepsy, progressive lower extremity spasticity, poor speech development, recurrent infections, and gastrointestinal problems. Descriptions of individual cases and, specially, of large cohorts have helped us better understand the main and constant symptoms of MDS and expand its phenotype [53,102,109,113,116,119,121,123,129,130,132]. Even so, there are no publications focused on knowing the natural history of this disorder.…”