Eid Alatwi

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder arising predominantly from de novo loss-of-function mutations in MECP2, affecting approximately 1 in 10,000 live female births. MECP2 is a dosage-sensitive epigenetic regulator acting through its methyl-CpG-binding (MBD) and transcriptional-repression (TRD) domains; isoform-specific expression and X-chromosome-inactivation mosaicism drive the wide phenotypic variability, with mutation type broadly correlating with severity. Although historically viewed as neuron-centric, RTT is a multisystem disorder: beyond psychomotor regression, stereotypic hand movements, gait apraxia, and loss of spoken language, MECP2 deficiency contributes to brainstem-mediated breathing dysrhythmia, QTc prolongation, enteric dysmotility, low bone density, and mitochondrial/metabolic deficits, amplified by glial–neuronal crosstalk. Preclinical models, MECP2 rodents, patient iPSC-derived neurons, and cerebral organoids, reveal synaptic and dendritic deficits that improve substantially when MECP2 is reactivated in these systems, indicating that MECP2-deficient neurons remain viable rather than degenerating; whether comparable improvement can be achieved in affected individuals is not yet established. The therapeutic landscape now spans multidisciplinary supportive care, the first approved pharmacotherapy trofinetide, AAV-mediated MECP2 gene replacement (now in pivotal trials, with an important gene-therapy safety signal), antisense oligonucleotides for dosage normalisation, and emerging metabolic agents; validated biomarkers and objective outcome measures remain a major unmet need. Conclusion: RTT is a multisystem monogenic disorder whose management is shifting from symptom control toward disease modification. Phenotypic rescue after MECP2 restoration in rodent models provides the rationale for this shift but does not establish that RTT is reversible in patients; progress now depends on validated biomarkers, dose-controlled disease-modifying therapies, long-term outcome data, and equitable global access. Graphical abstract Integrated overview of Rett syndrome (RTT) from molecular cause to equitable translation. 1 MECP2 as a dosage-sensitive epigenetic reader encoded at Xq28, where a loss-of-function MECP2 variant impairs methylated-DNA binding and chromatin regulation and disrupts transcriptional, splicing, and synaptic gene networks; the MECP2-E1 (492 amino acids) and MECP2-E2 (486 amino acids) isoforms differ in distribution, and severity is modified by mutation type, residual function, and X-chromosome-inactivation mosaicism. Because too little MECP2 causes RTT while too much is also pathogenic, restoration must be dose-controlled, cell-aware, and brain-wide. 2 RTT extends well beyond the central nervous system, direct peripheral effects combining with brainstem autonomic dysfunction to involve brain and glia, breathing, cardiac, gastrointestinal, skeletal and metabolic systems, across the characteristic four-stage clinical trajectory. 3 A therapeutic landscape moving from whole-person supportive care toward controlled gene restoration, spanning trofinetide (modest symptom-level benefit), AAV gene replacement (milestone gains in uncontrolled single-arm programmes, with expression control and immune safety critical after a fatal high-dose event in 2024), and earlier-stage antisense, X-reactivation, editing, and small-molecule approaches. No approach has yet demonstrated reversal of established deficits in humans. 4 Translation, safety, and equitable access as the rate-limiting step, from earlier genetic diagnosis through registry-based natural-history data and biomarker-guided trials to equitable access What is Known: • More than 90–95% of classic Rett syndrome is caused by de novo loss-of-function mutations in MECP2, a dosage-sensitive epigenetic reader whose isoform distribution, residual function and X-chromosome-inactivation mosaicism together account for much of the phenotypic variability. • Reactivating MECP2 in symptomatic adult rodents substantially improves many disease features, establishing that MECP2-deficient neurons are functionally impaired rather than lost and providing the rationale for disease-modifying therapy. What is New: • This review integrates isoform-specific and non-neuronal (glial, respiratory, cardiac, gastrointestinal, skeletal and metabolic) mechanisms with a literature base updated to 15 August 2026, and identifies the continuing absence of any validated biomarker or surrogate endpoint, rather than target identification, as the principal obstacle to efficient trials. • It critically appraises the post-trofinetide landscape — divergent FDA and EMA assessments of the same trial data, a fatal high-dose AAV hyperinflammatory event, and single-arm registrational gene-therapy programmes reported largely outside peer review — and concludes that the demonstrated outcome to date is gain or re-acquisition of developmental milestones, not reversal of established disease.

Background: Dehydroepiandrosterone (DHEA) is considered an endogenous steroid hormone precursor, and 17-ß estradiol (E2) is one of the estrogen steroid hormones. Of the 13 known human cytosolic sulfotransferases (SULTs), SULT2B1a has been shown to be expressed in steroid hormone-responsive tissues such as the prostate, ovary, and placenta, as well as the fetal brain. Previous studies have demonstrated that SULT2B1a is capable of sulfating 3β-hydroxysteroids such as DHEA and pregnenolone. The present study aimed to investigate the effects of human SULT2B1 single-nucleotide polymorphisms (SNPs) on the enzymatic characteristics of SULT2B1a allozymes in mediating the sulfation of DHEA and E2. Methods: To inspect the effects of SNPs of the SULT2B1 gene on the sulfation of DHEA and E2 by SULT2B1a allozymes, 13 recombinant SULT2B1a allozymes were produced, expressed, and purified using established procedures. Thirteen SULT 2B1a nonsynonymous missense coding SNPs (cSNPs) were selected among numerous identified human SULT 2B1a SNPs by a comprehensive database search. The corresponding cDNAs, packaged in pGEX-2TK expression vector, and encoding the selected 13 SULT2B1a allozymes, have been generated by performing site-directed mutagenesis. These were then bacterially expressed in BL21 E. coli cells and purified using glutathione-Sepharose affinity chromatography. The purified allozymes were tested for their ability to sulfonate DHEA and E2. Results: In terms of the kinetic parameters, the wild-type SULT2B1a exhibited higher enzyme affinity toward DHEA than with E2. In comparison with the wild-type SULT2B1a, the purified allozymes displayed differential sulfating activities toward DHEA and E2. Conclusion: Accordingly, these findings indicate an apparent effect of SULT2B1 cSNPs on the sulfating activities of SULT2B1a allozymes toward DHEA and E2, and may provide for a better understanding of the pharmacokinetics of DHEA and E2 in individuals with differing SULT2B1a genotypes.

Background/Objectives: Alopecia areata (AA) is a common autoimmune disorder characterized by non-scarring hair loss. The destruction of hair follicle cells is mediated by cytotoxic T cells, which release cytokines that contribute to tissue damage. Among these, Th17 cells produce key inflammatory mediators, including IL-17, IL-21, IL-6, and TNF-α, which may play a role in disease progression. This study aimed to evaluate the serum levels of IL-17A, IL-21, IL-6, and TNF-α in patients with patchy AA compared with healthy controls and to assess their association with disease severity. Methods: A cross-sectional analytical study was conducted on 50 patients with patchy AA and 50 age- and gender-matched healthy controls. Blood samples were collected, and serum cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA) kits. Results: Of the patients, 70% were female (35 patients) and 30% were male (15 patients). Disease severity distribution showed that 66% had mild AA, 22% had moderate AA, and 12% had severe AA. Compared with controls, AA patients exhibited significantly elevated serum levels of IL-6, TNF-α, IL-17A, and IL-21 (p < 0.001). Additionally, cytokine levels showed a positive correlation with both age and disease duration, suggesting their potential role in disease progression. Conclusions: These findings highlight the involvement of pro-inflammatory cytokines in the pathogenesis of patchy AA and their correlation with disease severity. Understanding these cytokine interactions may provide insights into targeted therapeutic strategies in managing AA.

Pregnenolone is a key intermediate in the biosynthesis of many steroid hormones and neuroprotective steroids. Sulfotransferase family cytosolic 2B member 1 (SULT2B1a) has been reported to be highly selective to sulfate pregnenolone. This study aimed to clarify the effect of missense single nucleotide polymorphisms (SNPs) of the human SULT2B1 gene on the sulfating activity of coded SULT2B1a allozymes toward Pregnenolone. To investigate the effects of single nucleotide polymorphisms of the SULT2B1 gene on the sulfation of pregnenolone by SULT2B1a allozymes, 13 recombinant SULT2B1a allozymes were generated, expressed, and purified using established procedures. Human SULT2B1a SNPs were identified by a comprehensive database search. 13 SULT2B1a nonsynonymous missense coding SNPs (cSNPs) were selected, and site-directed mutagenesis was used to generate the corresponding cDNAs, packaged in pGEX-2TK expression vector, encoding these 13 SULT2B1a allozymes, which were bacterially expressed in BL21 E. coli cells and purified by glutathione-Sepharose affinity chromatography. Purified SULT2B1a allozymes were analyzed for sulfating activities towards pregnenolone. In comparison with the wild-type SULT2B1a, of the 13 allozymes, 11 showed reduced activity toward pregnenolone at 0.1 µM. Specifically, P134L and R259Q allozymes, reported to be involved in autosomal-recessive congenital ichthyosis, displayed low activity (1–10%) toward pregnenolone. The findings of this study may demonstrate the impact of genetic polymorphism on the sulfation of pregnenolone in individuals with different SULT2B1 genotypes.

Pregnenolone is a key intermediate in the biosynthesis of many steroid hormones and neuroprotective steroids. Sulfotransferase family cytosolic 2B member 1 (SULT2B1a) has been reported to be highly selective to sulfate pregnenolone. This study aimed to clarify the effect of missense single nucleotide polymorphisms (SNPs) of the human SULT2B1 gene on the sulfating activity of coded SULT2B1a allozymes toward Pregnenolone. To investigate the effects of single nucleotide polymorphisms of the SULT2B1 gene on the sulfation of pregnenolone by SULT2B1a allozymes, 13 recombinant SULT2B1a allozymes were generated, expressed, and purified using established procedures. Human SULT2B1a SNPs were identified by a comprehensive database search. 13 SULT2B1a nonsynonymous missense coding SNPs (cSNPs) were selected, and site-directed mutagenesis was used to generate the corresponding cDNAs, packaged in pGEX-2TK expression vector, encoding these 13 SULT2B1a allozymes, which were bacterially expressed in BL21 E. coli cells and purified by glutathione-Sepharose affinity chromatography. Purified SULT2B1a allozymes were analyzed for sulfating activities towards pregnenolone. In comparison with the wild-type SULT2B1a, of the 13 allozymes, 11 showed reduced activity toward pregnenolone at 0.1 µM. Specifically, P134L and R259Q allozymes, reported to be involved in autosomal-recessive congenital ichthyosis, displayed low activity (1–10%) toward pregnenolone. The findings of this study may demonstrate the impact of genetic polymorphism on the sulfation of pregnenolone in individuals with different SULT2B1 genotypes.

Non-opioid and opioid analgesics, as over-the-counter or prescribed medications, are widely used for the management of a diverse array of pathophysiological conditions. Previous studies have demonstrated the involvement of human cytosolic sulfotransferase (SULT) SULT1A1 in the sulfation of acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol. The current study was designed to investigate the impact of single nucleotide polymorphisms (SNPs) of the human SULT1A1 gene on the sulfation of these analgesic compounds by SULT1A1 allozymes. Human SULT1A1 genotypes were identified by database search. cDNAs corresponding to nine SULT1A1 nonsynonymous missense coding SNPs (cSNPs) were generated by site-directed mutagenesis. Recombinant wild-type and SULT1A1 allozymes were bacterially expressed and affinity-purified. Purified SULT1A1 allozymes were analyzed for sulfation activity using an established assay procedure. Compared with the wild-type enzyme, SULT1A1 allozymes were shown to display differential sulfating activities toward three analgesic compounds, acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol, as well as the prototype substrate 4NP. Results obtained indicated clearly the impact of genetic polymorphisms on the drug-sulfation activity of SULT1A1 allozymes. Such information may contribute to a better understanding about the differential metabolism of acetaminophen, O-DMN, and tapentadol in individuals with different SULT1A1 genotypes.