Development and validation of a clinical severity score for long-chain fatty acid oxidation disorders using...

Mitochondrial long-chain fatty acid oxidation (LC-FAO) disorders (LC-FAOD) are inherited metabolic disorders. Real-World-Data (RWD) contributes to Real-World-Evidence (RWE) for LC-FAOD, as prospective natural history studies are difficult due to their incidence of ∼1:10,000.

We generated a RWD and developed and validated a clinical severity score.

38 patients were included in our RWD (VLCAD n = 7; LCHAD n = 6; CACT n = 3; MAD n = 1; CPT-I n = 14; CPT-II n = 5 and CT n = 2 deficiencies). Our clinical severity score was applied to 14 patients by four independent raters (at the time of diagnosis and on treatment) and compared with an age- and sex-matched control group. Inter-rater reliability was excellent for scores at the time of diagnosis (ICC3k = 0.979 [95% CI: 0.975-0.981]) and on treatment (ICC3k = 0.942 [95% CI: 0.932-0.950]). Using k-means clustering, patients were stratified into mild (0-8), moderate (9- ≤ 14), and severe (≥15) categories. At the time of diagnosis scores were significantly higher compared with control group (p < 0.0001).

Our study provides valuable new RWE with practical clinical applications for LC-FAOD including a RWD and development and validation of a clinical severity score for LC-FAOD. We think that our validated clinical severity score will help for precision therapies to improve patient outcomes in LC-FAOD. Application of our clinical severity score in more patients with LC-FAOD will allow its further validation.