MECP2 – Lubs Type Syndromic X-Linked Intellectual Disability

MECP2 duplication syndrome is an X-linked recessive neurodevelopmental disorder caused by gain of dosage of the MECP2 gene and flanking region at Xq28. Affected males present with infantile hypotonia, severe intellectual disability, absent or minimal speech, progressive spasticity, seizures, and recurrent infections. Female carriers are typically asymptomatic due to skewed X-chromosome inactivation but may manifest variable phenotypes when XCI is random or incomplete.

Extensive case series have established a definitive association between MECP2 dosage gain and Lubs type intellectual disability. Over 129 male patients have been reported with interstitial duplications of Xq28 encompassing MECP2, all exhibiting the core clinical features (PMID:22679399). Familial studies identified at least 16 patients from 10 pedigrees with maternal transmission and skewed XCI in female carriers, confirming segregation (PMID:27180140).

Duplication sizes range from ~209 kb to >14 Mb and invariably include MECP2 and IRAK1; smaller duplications confined to MECP2 have also been described. Triplication events further underscore dosage sensitivity in both male and rare female cases with random XCI (PMID:21934280). No recurrent single-nucleotide variants have been implicated; pathogenic alterations are exclusively copy-number gains.

Mechanistic studies demonstrate that MECP2 overexpression perturbs transcriptional regulation and chromatin architecture. Proximity biotinylation revealed that excess MeCP2 disrupts the MeCP2–TCF20 complex, and reducing Tcf20 in neuronal models partially rescues the overexpression phenotype (PMID:35074918). Patients with MECP2 duplications also exhibit markers of enhanced oxidative stress, mirroring functional assays of altered redox homeostasis (PMID:26930212).

Animal models confirm dosage-dependent neuropathology: Mecp2-null and MeCP2-overexpressing mice develop RTT-like and duplication-like neurological features, respectively, with reduced brain weight and neuronal cell size, validating the dosage-sensitive pathogenic mechanism (PMID:11242118).

Integration of genetic and functional data supports a definitive gene-disease relationship. Clinical testing for Xq28 duplications should be pursued in males with unexplained severe intellectual disability, hypotonia, spasticity, and seizures. Early diagnosis enables tailored multidisciplinary management and informs genetic counseling for carrier females.

References

• Molecular syndromology • 2012 • MECP2 Duplication Syndrome PMID:22679399
• European journal of medical genetics • 2016 • Chromosome Xq28 duplication encompassing MECP2: Clinical and molecular analysis of 16 new patients from 10 families in China PMID:27180140
• Cytogenetic and genome research • 2011 • De novo interstitial triplication of MECP2 in a girl with neurodevelopmental disorder and random X chromosome inactivation. PMID:21934280
• Proceedings of the National Academy of Sciences of the United States of America • 2022 • Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders. PMID:35074918
• PloS one • 2016 • MECP2 Duplication Syndrome: Evidence of Enhanced Oxidative Stress. A Comparison with Rett Syndrome. PMID:26930212
• Nature genetics • 2001 • Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. PMID:11242118

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