Study population
We retrospectively collected data from 12 patients with LC-FAOD from three Austrian metabolic centers. Nine patients were cared for in Innsbruck, one in Salzburg (Patient 10) and one in Vienna (Patient 11); outcome of one additional patient in Vienna (Patient 12) is reported separately. Data obtained from medical records cover the patients’ history until May 2020. Epidemiological data include sex, age, diagnosis, onset of disease, time to diagnosis, family history, newborn screening results, symptoms, dietary management, and initiation of triheptanoin treatment. Furthermore, number of hospital admissions (in days per year), number of episodes of rhabdomyolysis (defined as peak creatine kinase concentration above 500 U/I), as well as concomitant short- and long-term complications (cardiomyopathy, hepatopathy and retinopathy) were assessed. Total fat intake and quality of fats was obtained from dietary protocols. Additionally, late night feeds and nasogastric or PEG-tube feeding were assessed. Neurological outcome was documented according to self-reported school performance and need for physical support (i.e. wheelchair-bound). Weight, height and BMI percentiles were calculated according to reference data sets (12, 13).
Patients’ characteristics (Table 1)
Two patients have very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) (Patients 6 and 12), one carnitine palmitoyltransferase 2 deficiency (CPT 2 deficiency) (Patient 9), the other nine have long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). Six patients are male, six female. Patients come from ten families, including three siblings from one family of non-consanguineous parents (Patients 3, 7, 8). Median age is 9.1 (range 3.18-32.00) years.
At age 3 years, Patient 12 (currently 32 years old) was diagnosed with VLCADD due to cardiomyopathy. Due to worsening cardiac function, the patient was initiated on triheptanoin at age 29 years.
Diagnosis, symptoms, onset of therapy (Table 1)
In nine patients the diagnosis was established through newborn screening and confirmed by molecular and/or enzymatic testing. Three patients (Patients 1, 10, 12) were detected clinically with metabolic acidosis, hepatopathy, cardiomyopathy and rhabdomyolysis at 23, 6 and 36 months of age, respectively. Patients 1 and 12 were born before the inclusion of LC-FAOD in the Austrian newborn screening panel. Age at diagnosis was between 0 and 36 (median 0.4) months.
Triheptanoin supplementation
The hypothesis on the beneficial anaplerotic effect of triheptanoin was first reported in 2002 by Roe et al (10). After suffering from repeated episodes of rhabdomyolysis, Patient 1 was started on compassionate use triheptanoin at age 4 years in 2004 (14, 15). Initially, triheptanoin was provided as an anticorrosive industrial oil by Company Sasol. After good experience with Patient 1, Patients 2, 3 and 10 were also started on triheptanoin. Since 2013, Ultragenyx Pharmaceuticals has provided triheptanoin in a compassionate use program. Patients 4, 5, 6, 7, 8 and 12 joined the compassionate use program in 2016 and 2017, Patients 9 and 11 followed in 2018 and 2019.
Triheptanoin was started shortly after birth in Patients 6, 7 and 8. The other nine patients were started on triheptanoin between 7.3 and 353.3 (median 44.5, mean 81.1) months of age. Duration between diagnosis and start of triheptanoin was between 6.6 and 317.3 (median 34.8, mean 73.2) months. Median duration of triheptanoin intake was 3.9 (mean 5.3) years, ranging from 1.2 to 15.7 years (Table 2).
Nine patients had an uninterrupted intake of triheptanoin and reported no side-effects (Table 2).
Side-effects of triheptanoin (Table 2)
Patient 9 was started at 1 g/kg/day and after nine months discontinued therapy for 1.5 months because of abdominal pain. Therapy was recommenced at a lower adjusted dosage of 0.55 g/kg/day. He has taken triheptanoin in that dose for six months and reports no further side-effects.
Patient 10 discontinued triheptanoin at a dosage of 1g/kg/day after 1.3 years due to abdominal pain and vomiting. No restart was attempted. Patient 10 was previously reported as Patient 3 in Lotz-Havla et al. (16) and in Karall et al. as Patient 8 (15).
Patient 12 discontinued triheptanoin at a dosage of 1.2 g/kg/d after five months due to abdominal pain. He recommenced therapy after eight months at a lower adjusted dosage of 0.7 g/kg/d. He has been on triheptanoin continuously for 24 months and no further side-effects were reported.
Treatment with triheptanoin was not associated with excessive weight gain. Eleven patients show adequate BMI between percentile 10 and 89 (percentile mean 44, median 50). Patient 9 has a BMI of 22 kg/m2 (percentile 95), probably due to eating habits.
All patients are on a fat-defined, high-carbohydrate diet with an age-appropriate protein and caloric intake (Table 2). Of the total caloric intake, median fat intake was 30% (range 20%-45%), 7.5% (range 0%-30%) thereof is median medium-chain triglyceride (MCT) intake. In addition, for supplementation of long-chain essential fatty acids all patients receive walnut-oil (median 0.27 g/kg/d, range 0.06 – 0.48 g/kg/d). The median amount of triheptanoin intake is 0.58 (range 0.48-2.18) g/kg/d, equaling a median total daily calorie intake of 7.5% (ranging from 7.5 % to 30%).
Statistical analysis
A number of 12 patients constitutes a large cohort for a rare disorder, but is nonetheless a small cohort in absolute terms. Thus, statistics focused on descriptive analyses.
The annualized rate of total days of hospitalization (doht) in pre- and post-treatment with triheptanoin was assessed as follows:
The annualized rate for days in hospital in the one-year pre- and the one-year post-treatment with triheptanoin was calculated as: