Life expectancy and causes of death in classical laminopathic progeroid syndromes: systematic review with individual-patient data synthesis

Classical laminopathic progeroid syndromes link nuclear-envelope defects to accelerated aging, but the specific prognosis for each subtype remains unclear. We conducted a PRISMA-guided systematic review and individual-patient data (IPD) synthesis (PROSPERO CRD420251080312; PubMed/Scopus to 16 July 2025). Genetically confirmed IPD constituted the primary cohort; causes of death were harmonized a priori and survival assessed by Kaplan-Meier with log-rank tests. We included 169 studies and two institutional cases, previously illustrated in the literature but not comprehensively characterized, yielding 158 genetically confirmed IPD (61 deaths, 97 censored). Median survival (years, 95% CI) was: HGPS 16.0 (13.42-19.0; n=60), MAD-B 37.0 (24-44; n=21), RD-LMNA 0.92 (0.096-2.50; n=8), and RD-ZMPSTE24 0.03 (0.014-0.047; n=38); MAD-A had no deaths (n=31). Cause-of-death profiles were subtype-specific: respiratory failure predominated in RD (36/45 deaths), cardiovascular causes in HGPS (6/11), and renal complications in MAD-B (4/5). Findings were robust in sensitivity analyses (including clinical cases, risk-of-bias exclusions, and center-specific checks). In sum, survival and mortality patterns differ markedly across classical laminopathic progeria; genetically confirmed IPD resolved by subtype provides more reliable estimates for clinical counseling and trial design in ultra-rare progeroid disorders.