Development and validation of the modified-comprehensive Kumamoto Score: a multi-organ assessment tool for hereditary...

Disease-modifying therapies for hereditary transthyretin (ATTRv) amyloidosis necessitate sensitive, multi-organ assessment tools capturing early disease manifestations across heterogeneous phenotypes. We developed and validated the modified-comprehensive Kumamoto Score (mKS).

This prospective validation study enrolled 76 genetically confirmed ATTRv amyloidosis patients. The mKS comprises four organ-specific subscales: peripheral neuropathy (mKS-PN, 0-258), cardiomyopathy (mKS-CM, 0-195), eye (mKS-E, 0-60) and central nervous system (CNS) involvement (mKS-CNS, 0-45); total range 0-558. Construct validity was primarily assessed through Spearman's correlations with established clinical scores, objective biomarkers and patient-reported quality of life.

The median patient age was 56.2 years; 60.5% had Val30Met (p.Val50Met) mutations. The mKS demonstrated strong validity with established scores (Kumamoto Score (KS): ρ = 0.798; Neuropathy Impairment Score (NIS): ρ = 0.791; both p < .001) and quality of life (EuroQol 5-Dimension 5-Level (EQ-5D-5L): ρ = -0.731, p < .001). Organ-specific subscales demonstrated strong construct validity: mKS-PN correlated strongly with NIS (ρ = 0.906) and neurophysiological parameters (peroneal CMAP (compound muscle action potential): ρ = -0.819; tibial CMAP: ρ = -0.801); mKS-CM correlated strongly with cardiac biomarkers (B-type natriuretic peptide, BNP: ρ = 0.776; high-sensitivity troponin T (hs-TnT): ρ = 0.712) and imaging parameters (extracellular volume fraction (ECV): ρ = 0.743; interventricular septum thickness in diastole (IVSTd): ρ = 0.716). Subscale intercorrelations were weak (ρ = 0.155-0.381), confirming independent organ assessment.

The mKS provides a validated comprehensive assessment tool for ATTRv amyloidosis with enhanced early-stage sensitivity and independent organ-specific subscales, addressing critical unmet needs in the era of disease-modifying therapies.