Wednesday, November 15, 2023

MECP2 duplication syndrome

Inspired by a patient

Kim TY, Lee SJ, Kim KM, Cho SR. MECP2 duplication syndrome initially misdiagnosed as cerebral palsy: a case report. J Int Med Res. 2023 Mar;51(3):3000605231162452. doi: 10.1177/03000605231162452. PMID: 36988314; PMCID: PMC10064467.


Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene were first described as a cause of Rett syndrome. MECP2 duplication can cause intellectual disability, developmental delay, severe feeding difficulties, and recurrent infections. Here, we report a Korean family with MECP2 duplication syndrome, which was previously misdiagnosed as cerebral palsy. A man in his early 30 s visited our clinic with intellectual disability, speech impairment, epilepsy, and progressive spasticity. He had been previously misdiagnosed with cerebral palsy, and had received orthopedic surgeries such as musculotendinous lengthening and derotational osteotomy. After the surgeries, he received comprehensive rehabilitation. Upon carefully checking his family history, we noted that his younger brother had similar symptoms. Next-generation sequencing revealed whole exon duplication in MECP2 in both the patient and his brother; their mother also had this genetic mutation but was asymptomatic. Early diagnosis is essential for improving the success of MECP2 duplication syndrome treatment. Individuals with MECP2 duplication syndrome should be referred to specialists to manage multidisciplinary symptoms and to regularly check for complications that are common in this syndrome.

Ak M, Suter B, Akturk Z, Harris H, Bowyer K, Mignon L, Pasupuleti S, Glaze DG, Pehlivan D. Exploring the characteristics and most bothersome symptoms in MECP2 duplication syndrome to pave the path toward developing parent-oriented outcome measures. Mol Genet Genomic Med. 2022 Aug;10(8):e1989. doi: 10.1002/mgg3.1989. Epub 2022 Jun 15. PMID: 35702943; PMCID: PMC9356562.


Background: MECP2 Duplication Syndrome (MDS), resulting from the duplication of Xq28 region, including MECP2, is a rare disorder with a nascent understanding in clinical features and severity. Studies using antisense oligonucleotides revealed a broad phenotypic rescue in transgenic mice. With human clinical trials on the horizon, there is a need to develop clinical outcome measures for MDS.

Methods: We surveyed caregivers of MDS individuals to explore the frequency and severity of MDS clinical features, and identify the most meaningful symptoms/domains that need to be included in the outcome measure scales.

Results: A total of 101 responses were eligible for the survey. The top six most meaningful symptoms to caregivers in descending order included epilepsy, gross motor, fine motor, communication, infection, and constipation problems. Epilepsy was present in 58.4% of the subjects and 75% were drug-resistant, Furthermore, ~12% required intensive care unit (ICU) admission. Infections were present in 55% of the subjects, and one-fourth of them required ICU admission. Constipation was present in ~85% of the subjects and one-third required enemas/suppositories.

Conclusion: Our study is one of the largest cohorts conducted on MDS individuals characterizing the frequency and severity of MDS symptoms. Additionally, these study results will contribute to establishing a foundation to develop parent-reported outcomes in MDS.

John Cherian D, Ta D, Smith J, Downs J, Leonard H. How Families Manage the Complex Medical Needs of Their Children with MECP2 Duplication Syndrome. Children (Basel). 2023 Jul 11;10(7):1202. doi: 10.3390/children10071202. PMID: 37508699; PMCID: PMC10377896.


MECP2 duplication syndrome (MDS) is a rare, X-linked, neurodevelopmental disorder resulting from the duplication of the methyl-CpG-binding protein 2 (MECP2) gene. The clinical features of MDS include severe intellectual disability, global developmental delay, seizures, recurrent respiratory infections, and gastrointestinal problems. The aim of this qualitative study was to explore how the parents of children with MDS manage their child's seizures, recurrent respiratory infections, and gastrointestinal symptoms, and the impact on them as parents. The data were coded into three categories: (1) complex care needs in the home, (2) highly skilled caregivers, and (3) impact on caregivers and families. Complex 24 h care was required and parents developed complex skillsets to ensure that this was delivered well to their child. The provision of extensive complex medical care in the home had an impact on parent mental and physical health, family dynamics, and finances. This study captures the management of high-burden comorbidities in MDS at home. Investigations into how best to support caregiver wellbeing to reduce their stresses, whilst maintaining optimal child health and wellbeing, are needed.

Ak M, Akturk Z, Bowyer K, Mignon L, Pasupuleti S, Glaze DG, Suter B, Pehlivan D. Assessing the Burden on Caregivers of MECP2 Duplication Syndrome. Pediatr Neurol. 2022 Aug;133:1-8. doi: 10.1016/j.pediatrneurol.2022.05.008. Epub 2022 May 25. PMID: 35716604.


Background: MECP2 duplication syndrome (MDS) is a rare neurogenetic disorder characterized by severe neurodevelopmental disorder, refractory epilepsy, recurrent infections, and functional gastrointestinal problems. Because of the significant clinical problems and lifelong disability of children with this disorder we hypothesized that the burden on parents/caregivers of these children is significant. However, there are no reports of the impact on caregivers of individuals with MDS.

Methods: We developed and validated a burden scale to investigate the challenges of caregivers of children and adults with MDS and identified factors contributing to the burden on caregivers. We developed a Health Insurance Portability and Accountability Act-compliant patient registry for families with MDS and delivered caregiver burden survey through the registry.

Results: Of 237 completed surveys, 101 were eligible for the study. We identified increased levels of self-perceived anxiety, depression, and emotional exhaustion in caregivers that correlated with higher burden scores. Epilepsy was the only clinical feature that caused a higher burden in caregivers of individuals with MDS. In addition, a higher burden was found in Hispanic caregivers. The duration of care negatively correlated with burden score.

Conclusions: This is the first study to investigate the burden on caregivers of individuals with MDS and identify several factors contributing to increased burden. Addressing these concerns has the potential to improve the health of individuals with MDS and contribute to the well-being of their caretakers.

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