Fasting and non-fasting plasma levels of monomethyl branched chain fatty acids: Implications for maple syrup urine disease.

The branched-chain amino acids (BCAA) leucine, valine, and isoleucine provide precursors for monomethyl branched-chain fatty acids (BCFA). Established reference ranges for BCFAs are lacking. In maple syrup urine disease (MSUD), a rare inborn error of BCAA metabolism, the endogen production is impaired and MSUD patients are treated with a low protein (low BCAA) diet. The protein restriction may affect the dietary intake of BCFA, depending on the dietary choices made. Patients with MSUD are prescribed a more or less protein-restricted diet depending on the severity of the disease. The combination of a protein-restricted diet and subsequent impaired endogenous synthesis may render MSUD patients sensitive to BCFA deficiency, with yet unknown implications. To investigate the possibility of lower circulatory BCFA levels in MSUD that favors dietary BCFA supplementation, we first established fasting-state reference ranges for selected BCFAs and saturated/unsaturated fatty acids in plasma. Then, the effect of fasting on BCFA levels was evaluated by comparing the distribution in a fasting versus a non-fasting cohort. To test the hypothesis that BCFA deficiency could contribute to MSUD pathophysiology, we recruited patients with intermittent, intermediate, and classical form of MSUD and analyzed the corresponding BCFA z-scores. None of the BCFA species had |z-scores| > 2 relative to the reference range. Our findings do not support the requirement of BCFA supplementation in MSUD patients. The origin of BCFAs is discussed. Impaired capacity to synthesize BCFA do not manifest as reduced plasma levels in MSUD, suggesting that endogenous synthesis is dispensable for plasma levels.

A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction.

COX16 is involved in the biogenesis of cytochrome-c-oxidase (complex IV), the terminal complex of the mitochondrial respiratory chain. We present the first report of two unrelated patients with the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16 with hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis, and isolated complex IV deficiency. The absence of COX16 protein expression leads to a complete loss of the holo-complex IV, as detected by Western blot in patient fibroblasts. Lentiviral transduction of patient fibroblasts with wild-type COX16 complementary DNA rescued complex IV biosynthesis. We hypothesize that COX16 could play a role in the copper delivery route of the COX2 module as part of the complex IV assembly. Our data provide clear evidence for the pathogenicity of the COX16 variant as a cause for the observed clinical features and the isolated complex IV deficiency in these two patients and that COX16 deficiency is a cause for mitochondrial disease.