ABCA7-80 moderates vascular stiffness-p-tau217 association in older African Americans.

Inborn errors of metabolism (IEMs) are individually rare but collectively important monogenic disorders in which a defective enzyme or transporter disrupts a metabolic pathway. The most severe forms declare themselves in the neonatal period, when the newborn, no longer buffered by placental clearance, accumulates toxic metabolites within hours to days of birth. Urea cycle disorders (UCDs), which impair the hepatic detoxification of ammonia, and the classic organic acidemias are archetypal examples: affected neonates present with encephalopathy, feeding intolerance, and rapidly progressive metabolic crisis that can be fatal or leave survivors with permanent neurologic injury [,]. Carbamoyl phosphate synthetase 1 (CPS1) deficiency, a proximal and among the most severe UCDs, illustrates the therapeutic gap. Even with prompt recognition and intensive management, protein restriction, nitrogen-scavenger drugs, hemodialysis for acute hyperammonemia, and eventually liver transplantation, neonatal-onset disease carries an estimated 50% mortality in early infancy, and the standard of care is lifelong, burdensome, and only partially protective [,]. Because such disorders typically result from specific, identifiable point mutations in a single gene, they are conceptually ideal candidates for a durable, one-time genetic correction that restores the missing enzymatic function rather than managing its consequences. The tools to attempt such a correction have matured rapidly. Base editing enables the precise conversion of one DNA base pair to another without introducing the double-strand breaks that limit the safety of first-generation nuclease editing, and it can be delivered to the liver in vivo using lipid nanoparticles (LNPs) or viral vectors [-]. In 2025, these advances converged in the first report of a bespoke in vivo base-editing therapy designed, manufactured, and administered for a single infant with CPS1 deficiency []. For readers new to the field, the practical difference between the two leading precision tools is straightforward: a base editor chemically converts one DNA letter into another within a small target window and is therefore best suited to correcting single-nucleotide substitutions, whereas a prime editor uses a short RNA template to write in a specified new sequence and can additionally make small insertions and deletions [-]. The liver is a particularly favorable target for both approaches. It receives a large share of cardiac output and takes up systemically infused lipid nanoparticles efficiently, and the enzymes deficient in urea cycle disorders and the classic organic acidemias are normally expressed in hepatocytes, so that correcting a fraction of those cells can restore enough metabolic flux to alter the clinical phenotype [-]. This review surveys the clinical problem, the enabling technology and delivery systems, the preclinical and single-patient evidence, and the ethical and regulatory questions raised by individualized 'N-of-1' genetic medicine. Throughout, we distinguish carefully between what has been demonstrated and what remains aspirational.