MECP2重複症候群

MECP2 duplication syndrome (MDS) is a rare neurogenetic disorder characterized by neurodevelopmental delay, epilepsy, gastrointestinal dysfunction, and frequent infections. The broader spectrum of immune dysregulation remains poorly understood. We retrospectively reviewed four MDS patients with recurrent sterile polyserositis across multiple centers, analyzing clinical presentation, laboratory findings, treatment responses, and outcomes. All patients developed recurrent pleural and/or pericardial effusions of unclear etiology, with systemic inflammation (leukocytosis, elevated C-reactive protein, hyperferritinemia in some cases). Extensive workups were unrevealing. Patients also demonstrated evidence of immune dysregulation, including hypogammaglobulinemia, altered T- and B-cell populations, and abnormal immunoglobulin profiles. Effusions persisted despite antimicrobials and drainage, but resolved with immune-directed therapies. Earlier immunomodulatory therapy enabled faster recovery and reduced morbidity. One patient achieved sustained remission without recurrence with long-term immunomodulatory treatment. We identify recurrent sterile polyserositis as a previously unrecognized inflammatory manifestation of MDS, suggestive of an autoinflammatory mechanism given the systemic hyperinflammation, absence of infectious or oncogenic causes, and responsiveness to immunomodulatory therapy. Our findings highlight the importance of early immunophenotyping and targeted immunomodulation. Prospective studies are needed to define the prevalence, biology, and optimal management of this emerging inflammatory phenotype.

Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) are disorders caused by decreases and increases in the expression of the transcriptional regulator, Methyl CpG Binding Protein 2 (MeCP2), respectively. We previously performed an mRNA expression profiling study of the temporal cortex region from patients diagnosed with RTT and corresponding age, postmortem interval, and sex-matched controls. These studies identified a significant reduction in the mRNA expression of the histamine H3 receptor (HRH3). In the current manuscript, we expanded receptor profiling to additional RTT patient brain samples representing distinct MECP2 mutations and confirmed significantly reduced levels of HRH3 receptor expression in the majority of patients compared to controls. Using mouse models of RTT and MDS, we observed antiparallel changes in Hrh3 receptor expression across various brain areas, with Hrh3 expression being reduced in RTT model animals and increased in a mouse model of MDS. We then evaluated both a small molecule agonist of the H3 receptor, (R)-α-methylhistamine (RAMH), and the H3 receptor inverse agonist, pitolisant (Wakix®), in RTT and MDS models, respectively, to determine impacts on phenotypes in these disease models. Our results show little to no efficacy of RAMH or pitolisant in modulating behavioral responses in either mouse line.

MECP2 duplication syndrome (MDS) is a rare X-linked neurodevelopmental disorder caused by duplications of the dosage-sensitive methyl-CpG-binding protein 2 (MECP2) gene. Developing therapies for MDS is challenging due to the variability in MECP2 expression among patients and the risk of inducing Rett syndrome through excessive pharmacological intervention. Reducing dosage to optimize silencing often compromises durability and necessitates increased dosing frequency. We present here a series of fully chemically modified small interfering RNAs (siRNAs) designed for isoform-selective and total Mecp2 silencing. Among these, we identify six lead siRNA candidates across two chemical scaffolds, achieving targeted total Mecp2 expression reductions ranging from 25% to 75%, sustained for at least four months following a single administration. The efficacy and safety of human ortholog silencing are evaluated using a mouse model with ~8-fold human Mecp2 transgene expression. In this severe duplication model, a single dose of the total isoform-silencing siRNA rescues early mortality and select behavioral impairments. Overall, this study introduces preclinical candidates for the treatment of MDS. Furthermore, it establishes a target selection strategy applicable to other dosage-sensitive gene imbalances.

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by impairments in social communication and restricted, repetitive behaviors. Increasing evidence suggests that immune dysregulation may be present in a subset of individuals with neurodevelopmental disorders, although its role in ASD remains incompletely understood. We report two male patients with ASD, neurodevelopmental delay, immune dysregulation, and congenital cardiac anomalies. Genetic analysis using chromosomal microarray (CMA) identified distinct copy number variants on the X chromosome in each case. In patient 1, a duplication of the Xq28 region encompassing the MECP2 gene was identified, consistent with MECP2 duplication syndrome, a well-established cause of neurodevelopmental impairment and recurrent infections. In this case, the clinical presentation was comparatively milder than typically described, highlighting phenotypic variability within this condition. In patient 2, a hemizygous deletion at Xp22.12 partially involving the SH3KBP1 gene was detected and classified as a variant of uncertain significance (VUS). The patient presented with recurrent respiratory infections, impaired humoral immune responses, reduced B-cell counts, and neurodevelopmental impairment. This observation broadens the limited clinical spectrum associated with SH3KBP1 variants and may aid future assessment of their clinical relevance, although a causal relationship remains unproven. Together, these observations emphasize the value of comprehensive genetic testing in individuals with complex neurodevelopmental and systemic presentations and support consideration of immunological evaluation in selected patients with ASD who present with recurrent infections, allergic disease, or additional phenotypic features suggestive of inborn errors of immunity.

X-linked intellectual disability (XLID) is a well-recognized group of neurodevelopmental disorders, with pathogenic variants in X-chromosomal genes accounting for approximately 16% of intellectual disability cases in males. Clinical expression in females is variable and depends on patterns of X-chromosome inactivation. We describe three affected individuals from a single family with XLID caused by a confirmed duplication of the Xq28 region, including the genes SLC6A8, L1CAM, MECP2, TKTL1, FLNA, and GDI1. Two male siblings presented with severe phenotypes, including profound intellectual disability, severe speech impairment, behavioral issues, facial dysmorphism, spastic cerebral palsy, epilepsy, and cutaneous abnormalities. Their mother showed mild intellectual disability and skin manifestations. Family history suggested additional affected male relatives with a similar or even more severe clinical presentation. The duplication of multiple dosage-sensitive genes within the Xq28 region likely explains the multisystem involvement and the marked phenotypic variability observed between male and female family members. This report highlights the importance of considering Xq28 duplication, the most common X-linked copy number variation associated with intellectual disability, in the differential diagnosis of families with X-linked intellectual disability, especially if it is accompanied by additional neurological impairment.