In this study, nine patients with LC-FAOD received triheptanoin treatment (accounting for 10–34% of the total daily caloric intake) for a mean of 2.2 years after switching from standard therapy with MCT oil (accounting for 8–36% of the total daily caloric intake) for a mean of 7.0 years. The focus of long-term nutritional management in LC-FAOD is to use an energy source other than long-chain fatty acids to provide sufficient daily calories [15]. Dietary management usually involves avoiding prolonged fasting, restriction of LCTs, a modest increase in carbohydrates and MCT supplementation as an alternative form of energy to LCTs [5, 6, 15].

MCTs consist of even-chain fatty acids, are 6–12 carbons long, do not require L-carnitine for mitochondrial transport and do not require oxidation by long-chain acyl-coenzyme A (CoA) hydrogenase enzymes [15], thereby bypassing the metabolic defects in LC-FAOD [6]. The recommended limit for long-chain fatty acid intake ranges from 10% of total daily calories in patients with severe forms of LC-FAOD to 45% in infants with mild disease [15].

Triheptanoin represents an alternative to MCT that has been associated with improved clinical outcomes in patients with LC-FAOD [7, 9, 11, 16, 17]. Triheptanoin consists of odd-chain fatty acids (C7) with anaplerotic properties (different from even-chain variants), which are metabolised through β-oxidation to acetyl-CoA [15]. Since patients with LC-FAOD do not properly oxidise fat to acetyl-CoA, there is an impairment of the tricarboxylic cycle and consequent lack of ketone body formation. Triheptanoin is a source of acetyl-CoA and propionyl-CoA, resulting in increased substrate availability in the tricarboxylic acid cycle [15]. The US prescribing information recommends providing up to 35% of total daily calories from triheptanoin, divided into at least four administrations per day [8]. A retrospective observational study conducted in the US reported that most patients survived the initial trigger event (e.g. severe infection) and demonstrated both short- and long-term improvements in manifestations of LC-FAOD following the initiation of triheptanoin therapy [17].

The current study found a significant reduction in the number of intercurrent catabolic episodes once patients switched from MCT oil to triheptanoin treatment. Enzyme deficiencies in the metabolic pathway that converts LCTs into energy can lead to depleted energy production, resulting in severe acute metabolic crises, such as rhabdomyolysis, hypoglycaemia and cardiomyopathy [18], which may lead to hospitalisation, ICU admission or premature death. In this study, metabolic decompensation episodes requiring hospitalisation were markedly reduced once triheptanoin treatment was started. Similarly, a previous study of three US patients with LC-FAOD reported fewer hospitalisations related to metabolic crises, as well as lower annualised rates and durations of hospitalisation, after the start of triheptanoin treatment [19]. In the current study, we observed a 77.4% reduction in the annualised hospitalisation rate during the triheptanoin treatment period, in line with the final results of a previous open-label extension study, which found an 85% reduction in this outcome measure [16]. In addition, patients with LC-FAOD who received triheptanoin in the previous study had reduced rates of hospitalisation due to rhabdomyolysis, cardiomyopathy and hypoglycaemia; these beneficial effects were sustained with long-term triheptanoin treatment [16].

CK levels, both during metabolic decompensation and steady-state conditions, were lower with triheptanoin versus MCT oil, although these differences did not reach statistical significance. These findings are consistent with those of a similar retrospective observational study of 12 patients with LC-FAOD in Austria, in which the total number of hospitalisation days decreased by 82% and the episodes of elevated CK levels (i.e. > 500 UI/L) decreased by 45% after initiation of triheptanoin (mean treatment duration 5.3 years) compared with the pre-treatment period [13]. Similar to our study, rhabdomyolysis also occurred in one patient during MCT oil therapy, but there were no cases of rhabdomyolysis recorded with triheptanoin treatment in the Austrian study [13]. Another retrospective US study of 52 patients with LC-FAOD reported that episodes of rhabdomyolysis requiring hospital admission were reduced from 85 to 31% after switching from MCT to triheptanoin treatment [20].

Current guideline recommendations specify that patients with severe LC-FAOD should receive their total caloric intake from MCT [15]. However, high-dose administrations of MCT may cause gastrointestinal symptoms (e.g. cramping, diarrhoea and vomiting) [21]. In our study, the only treatment-related adverse effects with triheptanoin were gastrointestinal in nature (i.e. epigastric pain and diarrhoea) and were similar to those observed during MCT treatment. Although triheptanoin is generally well tolerated [17, 22], the documented adverse effects in other studies were also predominantly mild gastrointestinal symptoms (e.g. diarrhoea, abdominal or gastrointestinal pain, nausea and vomiting, abdominal distension and flatulence) [10, 16].

In this study, molecular confirmation was obtained for all patients either diagnosed by NBS or clinically. To this purpose, the use of next generation sequencing can be useful to provide counseling to the family on genetic diseases, establishing the risk of recurrence and advancing potential genotype–phenotype correlations [23, 24].

The limitations of this study include its retrospective, open-label and uncontrolled design, and the relatively small and heterogeneous study population. Since the total daily caloric intake provided by MCT and triheptanoin treatment differed between patients, a dose-dependent effect on clinical outcomes could not be ruled out.