MECP2重複症候群

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.

The overexpression of MECP2 leads to severe neurological deficits in MECP2 duplication syndrome, and its dosage is considered a risk factor in gene therapy for Rett syndrome. However, in MECP2 duplication syndrome patients, MECP2 dysregulation arises at the embryonic stage while in Rett syndrome gene therapy, MECP2 is delivered into the mature brain. Here, we show that MeCP2 overexpression induces transcriptional alterations in neural progenitor cells, but has minimal effects in neurons in both mouse and human contexts. Consequently, MeCP2 overexpression in neural progenitor cells, but not mature neurons, leads to functional changes. Mechanistically, we observe that both endogenous and overexpressed Mecp2 bind to the same CpG island repertoire. In neurons, where endogenous Mecp2 is highly expressed, ectopic protein expression leads to reduced CpG island binding and accelerated protein degradation. In contrast, in neural progenitor cells, lower endogenous Mecp2 levels facilitate stronger deposition of the ectopic protein onto CpG islands, driving the transcriptional activation of many developmental bivalent genes. We show that this activation is mediated by the interaction with the SWI/SNF chromatin remodeling complex. Our findings establish that increased gene dosage-dependent effects are highly influenced by cell type, levels of proteins and their mechanisms of action.

OBJECTIVE: Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator essential for synaptic development, plasticity, and neuronal maturation. Altered MeCP2 dosage, such as its decrease in Rett syndrome (RTT) or increase in MECP2 duplication syndrome (MDS), has been associated with altered pain sensitivity and progression. This systematic review integrates preclinical and clinical studies to synthesise evidence on MeCP2's role in pain and identify mechanistic and translational limitations. METHODS: We followed PRISMA guidelines to systematically search three major databases (PubMed, Web of Science, and Scopus) followed by quality appraisal. We extracted models, modalities, tissues, MeCP2 manipulations and molecular readouts, and performed an exploratory Gene Ontology (GO) enrichment analysis. RESULTS: Preclinical models report context-dependent MeCP2-associated transcriptional changes including activity-dependent phosphorylation in dorsal horn neurons and peripheral nociceptors, and alterations in neurotransmission and signalling programmes (including opioid-related genes), alongside selective chromatin-associated changes. Loss-of-function studies report modality- and circuit-specific deficits from peripheral afferents to cortex, whereas overexpression models report nociception and neuropathic hypersensitivity. Clinically, proxy-based studies often report apparent hyposensitivity in RTT and MDS, particularly to external pain. However, pain may still be under-recognised, as caregivers also report that pain is common and frequently related to internal/visceral comorbidities. INTERPRETATION: MeCP2 dysregulation is associated with altered nociceptive processing, but conclusions are tempered by heterogeneity and a predominance of proxy-based and often correlative evidence. Future work should combine objective biomarkers with harmonised preclinical and clinical designs to strengthen mechanistic inference.

BACKGROUND: People with Rett syndrome (RTT) have abnormal psychomotor skill development manifested by delay or failure to acquire skills, loss of skills, and potential regain of lost skills. This study aimed to provide detailed characterization of the frequency, timing, and trajectory of gain, loss, and regain of developmental skills in RTT. METHODS: The occurrence and time of gain, loss, and regain of 51 developmental skills was collected during in-person visits in the RTT Natural History Study from 1228 females with Classic RTT and a pathogenic loss-of-function variant in MECP2. The percentage of participants experiencing gain, loss, or regain events, mean and median age of event and time to event with confidence intervals, and the cumulative incidence curves were calculated and compared to normative data. One-year incidence of either gain or regain of each skill from 0 to 20 years old and one-year incidence of either gain or regain of any of 51 developmental skills was calculated. RESULTS: Across skill domains, acquisition occurred more frequently for lower-level skills than more advanced skills, with a median age of gain before 2 years old and rarely after 6 years old. Loss of previously gained skills occurred in all skill domains, with highest frequency in fine motor and expressive language domains. For most skills, loss occurred early in life and within 2 years of gain, except for loss of gross motor skills which occurred at older ages and further from age of gain. Regain of lost skills was infrequent for most skills, occurred mainly before 6 years old, and within 2 years of loss. After 6 years old, the incidence of either gaining or regaining skills was low. CONCLUSION: These results reveal that most skill gain, loss, and regain in RTT occurs early in life and stabilizes after 6 years old, except for the continued loss of gross motor skills beyond 6 years. The lack of gain or regain of skills beyond 6 years old suggest that any functional gains in these skills after a clinical intervention would represent an important indicator of efficacy as a clinical trial endpoint in RTT.