MRPS22 encodes a structural component of the mitochondrial small ribosomal subunit, essential for mitochondrial translation and protein synthesis 1. As a nuclear-encoded mitochondrial ribosomal protein, MRPS22 is critical for oxidative phosphorylation system biogenesis and ATP production 2. During development, MRPS22 is required to initiate gastrulation, with loss resulting in severe developmental delay and failure to progress past the egg-cylinder stage due to compromised mitochondrial function 3. MRPS22 mutations cause two distinct phenotypic spectra. Biallelic missense mutations (p.R135Q, p.R202H) cause primary ovarian insufficiency (POI) in adolescent females through a germ cell-autonomous mechanism, where mitochondrial defects appear tissue-specific rather than affecting overall bioenergetic capacity 4. Conversely, other MRPS22 mutations cause severe mitochondrial disease presenting in infancy with developmental delay, hypotonia, and distinctive brainstem/thalamic lesions 5. Recently, adult-onset neurological disorders associated with MRPS22 mutations have been characterized by leukoencephalopathy, cerebellar ataxia, motor neuropathy, and profound cerebral folate deficiency, responding to folinic acid supplementation 2. MRPS22 mutations account for approximately 10-20% of genetic POI cases and represent a rare but important cause of combined oxidative phosphorylation deficiency 6. Therapeutic approaches remain personalized and mutation-specific 7.