174 Chapter 6 Next, we assessed the carnitine profile of the organoids to confirm the accumulation of medium-chain acyl-carnitines, characteristic of MCADD patients. Control and MCADD organoids were incubated with palmitate and L-carnitine for 24 hours and the acyl-carnitine profile was assessed both intracellularly and in the supernatant. While no changes were observed in short- and long-chain acyl-carnitines (Suppl Figure 2), MCADD organoids accumulated medium-chain acyl-carnitines with 6 to 10 carbon atoms (C6, C8, and C10 in Figure 2cd). Moreover, intracellularly the C8/C10 ratio, an important diagnostic biomarker of MCADD in clinical practice1, was strongly upregulated in MCADD organoids (from 11 to 20) (Figure 2d). The same pattern was observed in the supernatant where the C8/10 ratio was upregulated from 6 to 8 (Figure 2d). The values are in the same range as those observed in the plasma of severe MCADD patients (median 13.1), whereas mild MCADD patients (≥ 10% residual MCAD activity) had a median C8/10 ratio of 3.10 and healthy controls 0.81.
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