The polypharmacy-xerostomia-nutrition triad: the clinical framework for older adults.

Cholesterol is an essential component of mammalian cells that performs diverse structural and regulatory functions beyond its well-established role as a membrane constituent. It serves as the precursor for steroid hormones, bile acids, and vitamin D, while also contributing to the formation of lipid rafts that regulate membrane protein organization, intracellular trafficking, and signal transduction. During embryonic development, cholesterol is particularly critical for the central nervous system, where it supports neural progenitor proliferation, neuronal differentiation, axonal guidance, synaptogenesis, and myelination. Moreover, cholesterol is indispensable for several developmental signaling pathways, including Sonic Hedgehog (Shh), Wnt/β-catenin, and Notch, explaining why disturbances in cholesterol homeostasis result in complex congenital malformations and neurodevelopmental abnormalities [,,]. Inherited disorders of cholesterol biosynthesis comprise a heterogeneous group of rare genetic diseases caused by pathogenic variants in enzymes of the post-lanosterol cholesterol biosynthetic pathway. Among them, Smith–Lemli–Opitz syndrome (SLOS), desmosterolosis, lathosterolosis, and congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome represent the best-characterized disorders associated with pathogenic variants in , , , and , respectively. Despite affecting consecutive enzymatic reactions within the same metabolic pathway, these disorders exhibit remarkable clinical heterogeneity. The severity of clinical manifestations varies considerably even among patients carrying identical pathogenic variants, indicating that disease pathogenesis is influenced by multiple molecular mechanisms extending beyond simple cholesterol deficiency []. Historically, the clinical manifestations of cholesterol biosynthesis disorders were attributed primarily to insufficient cholesterol production. The available evidence now supports a more differentiated interpretation in which cholesterol deficiency and the accumulation of pathway-specific sterols contribute in proportions that depend on the affected enzyme, cell type, and developmental stage. In SLOS, 7-dehydrocholesterol (7-DHC) is exceptionally susceptible to oxidation, and 7-DHC-derived oxysterols have been linked to oxidative stress, altered membrane organization, and disrupted developmental signaling [,,]. By contrast, desmosterol can partially substitute for cholesterol in some membrane contexts, whereas the cellular effects of lathosterol and methylsterols accumulating in lathosterolosis and CHILD syndrome remain less systematically characterized. These differences argue against treating all post-lanosterol disorders as a single mechanistic category and make disease-specific biochemical validation essential when selecting an experimental model.