ALPL encodes tissue-nonspecific alkaline phosphatase (TNSALP), a critical enzyme for skeletal and dental mineralization that hydrolyzes phosphate compounds including inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP), and N-phosphocreatine. In bone mineralization, ALPL hydrolyzes extracellular PPi, a potent mineralization inhibitor, thereby promoting hydroxyapatite crystal formation and increasing inorganic phosphate concentration 1. ALPL also dephosphorylates PLP to its transportable form pyridoxal, providing essential vitamin B6 cofactors for neurotransmitter synthesis in the brain 2. Additionally, ALPL mediates adaptive thermogenesis through futile creatine cycling in thermogenic fat cells and can dephosphorylate microbial products and immune ligands 3. Loss-of-function mutations in ALPL cause hypophosphatasia (HPP), characterized by persistently low serum alkaline phosphatase activity and elevated substrate levels 4. HPP presents as a heterogeneous spectrum from perinatal lethal forms with skeletal hypomineralization and seizures to mild adult-onset disease with musculoskeletal pain, dental problems, and stress fractures 2. Clinical severity correlates with residual TNSALP activity and variant-specific dominant-negative effects 5. Asfotase alfa enzyme replacement therapy has improved outcomes in severely affected children, though comprehensive multidisciplinary management addressing skeletal, neurological, and dental complications remains essential 2.