CMH Lahore Medical College and Institute of Dentistry

Rett syndrome (RTT) is a devastating X-linked neurodevelopmental disorder, primarily affecting females, caused by mutations in the MECP2 gene. After a brief period of normal development, affected children experience rapid regression, losing motor and communication skills. Core features include microcephaly, seizures, stereotypic hand movements, and breathing abnormalities. While rooted in neurological dysfunction, growing evidence reveals RTT's widespread impact extends beyond the brain, implicating MECP2 in multisystem disruption. This review provides a comprehensive overview of RTT's genetic and neuropathological basis and highlights the significant advances in gene therapy to restore MECP2 function. Notably, adeno-associated virus (AAV)-based approaches have shown promise in preclinical models by improving survival and motor function in RTT mouse models. Recent advancements in AAV vector design have optimized targeted delivery to neurons and enhanced the regulation of MECP2 expression to prevent overexpression-related toxicity. Additionally, nanoparticle-based delivery systems are being explored as non-viral alternatives, offering the potential for improved targeting and safety. These advancements in gene therapy hold promise for RTT, bringing the possibility of effective targeted treatments closer to clinical application. As research continues to unravel RTT's complex pathophysiology, emerging therapies may offer new hope for improving patient outcomes and quality of life.

Transcatheter aortic valve replacement (TAVR) is a first-line therapy for severe aortic stenosis (AS). In patients with contraindications to immediate TAVR, temporizing balloon aortic valvuloplasty (BAV) may be performed to stabilize patients prior to TAVR. The relative efficacy and safety of TAVR with or without temporizing BAV remains inadequately described.

We searched PubMed, Embase, and Cochrane databases for studies comparing TAVR with and without temporizing BAV in patients with severe AS. Random-effects models were used to calculate pooled odds, risk ratios (RRs) and mean differences with 95 % confidence intervals (CIs).

Nine studies (59,205 patients: 95.7 % immediate TAVR, 4.3 % BAV + TAVR) met inclusion criteria. Mean age was 82.9 ± 6.6 years old, and 45.9 % were males. Patients in the TAVR group were a mean difference of 1 year younger with no difference in gender distribution between groups. Direct TAVR was associated with a lower risk of 30-day all-cause mortality than BAV + TAVR (RR = 0.62; 95 % CI 0.41 to 0.93; p = 0.02). There were no significant differences in risks of post-procedural pacemaker implantation, myocardial infarction, cardiac tamponade, major vascular complications, ischemic stroke, major bleeding, 2+ or greater aortic regurgitation grade or acute kidney injury.

While immediate TAVR was associated with slightly lower short-term mortality compared to BAV + TAVR in patients with severe AS, other binary endpoints were equivalent. This potential mortality difference should be considered when offering BAV + TAVR in patients with contraindications to immediate TAVR. Randomized studies are required to confirm these results.