Aldh18a1, also known as P5CS (pyrroline-5-carboxylate synthetase), is a gene encoding a bifunctional enzyme involved in the de novo biosynthesis of proline and ornithine. This enzyme participates in arginine and proline metabolism pathways, which are crucial for various biological processes such as maintaining normal connective tissue structure, cell metabolism, and antioxidant responses [3].

Pathogenic variants in Aldh18a1 are associated with a spectrum of human disorders. For instance, a 10-year-old boy with a de novo pathogenic variant in Aldh18a1 had a rare form of metabolic cutis laxa, complicated by atlantoaxial instability and spinal cord compression after a minor fall [1]. In another case, an ALDH18A1-related cutis laxa patient presented with cyclic vomiting and abnormal blood levels of ornithine, citrulline, arginine, and proline [4]. Also, functional assessment of a homozygous Aldh18a1 variant showed broad-based alterations in amino acid and antioxidant metabolism, with reduced levels of glutamate and its derivatives like proline and glutathione, as well as decreased biosynthesis of putrescine [3]. Additionally, in MYCN-amplified neuroblastoma, Aldh18A1 forms a positive feedback loop with MYCN, impacting cell proliferation and tumorigenicity [2].

In conclusion, Aldh18a1 is essential for amino acid biosynthesis and metabolism, which are fundamental to maintaining normal physiological functions. Its dysfunction, as revealed through studies of patients with genetic variants, is associated with various connective tissue disorders, neurological deficits, and metabolic abnormalities, highlighting its significance in understanding the pathogenesis of these diseases.