Triheptanoin administration
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 0.6 and 29.4 (median 3.7, mean 6.7) years of age. Duration between diagnosis and start of triheptanoin was between 0.6 and 26.4 (median 2.9, mean 6.1) years. 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, 11/12 patients have an ongoing intake of triheptanoin on study date (Table 2).
Adverse events 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 adverse events.
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 adverse events 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 0.48-1.30) g/kg/d, equaling a median total daily calorie intake of 7.5% (ranging from 7.5 % to 30%).
Triheptanoin treatment decreases hospitalizations per year (Figure 2)
As a parameter of metabolic stability, we compared total days of hospitalization (doht) pre- and post triheptanoin as well as days of hospitalization (doh1y) one year prior to one year after start of therapy with triheptanoin. We excluded four patients from these calculations: In Patients 6, 7 and 8 time interval between birth and commencement of triheptanoin intake was less than six months, and in Patient 12, in whom triheptanoin was started at age 29 years to treat cardiac disease, the retrieved data were incomplete.
For the 8/12 included patients, the total days of hospitalization per year (doht) decreased by 82.3% from mean 27.1 (median 23.1, range 11-65) days/year during the pre-triheptanoin period (mean 3.9, median 2.3, range 0.61-11.64 years) to mean 4.8 (median 3.1, range 0-13) days/year during the post-triheptanoin period (mean 7, median 5.9, range 1.18 – 15.72 years) (Figure 2, Panels 1a and 1b).
Days of hospitalization in the year pre-triheptanoin (doh1y) as compared to the year post-triheptanoin decreased by 69.75% from mean 27.1 (median 20, range 4-74) days/year to mean 8.2 (median 3, range 0-25) days/year (Figure 2, Panels 2a and 2b).
Clinical signs, short- and long-term symptoms and complications
All patients are in stable clinical condition to date with BMI percentiles between P10 and P95 (Table 2).
Hypoglycemia was present in Patients 1, 2, 5, 10, 11 and 12 at the time of diagnosis. Only in Patient 5 episodes of hypoglycemia occurred thereafter until the age of 3 years, but resolved after frequency of meals was adapted to be adequate to age.
In summary seven patients developed hepatopathy between 0.2 and 31.3 (mean 6.3, median 0.7) years of age, defined as elevated liver enzymes (GOT, GPT, GGT) and sonographic findings (Table 1). At date, all patients have normal liver function.
Eight patients developed cardiomyopathy, defined as fraction shortening (FS) < 25% and/or ejection fraction (EF) <50% in at least one echocardiographic screening between 0.3 and 11.6 (mean 2.4, median 0.8) years of age (Table 1). Five patients showed a dilative, three a hypertrophic cardiomyopathy, seven were on medication. At last echocardiography, six showed normal cardiac function; in Patients 11 and 12, cardiomyopathy had not completely resolved (Table 1).
Retinopathy has been reported in 6/9 LCHADD patients, first diagnosed between 2.0 and 8.2 (mean 4.7, median 4.4) years of age. Patients 1 and 10 show impaired vision due to myopia and wear glasses (Table 1). Patient 11 developed polyneuropathy, firstly diagnosed around age 10 years, and slowly progressed over time. In his apartment he does not need a walking aid but for longer distances he is dependent on a wheelchair (Table 1). Triheptanoin, which was started at age 11.6 years, has not had an obvious impact on the polyneuropathy, but observation time is still short.
As part of clinical follow-up checks, patients were continuously clinically and neurologically examined and any restrictions in daily life activities were raised. Collectively, our patients report adequate to good school performance, except Patient 11 who has needed school support since the age of 12 years. Patient 12 is employed and lives independently. All 12 patients lead an independent life and report no subjective restrictions in daily life.
Triheptanoin decreases episodes with elevated CK followed by hospitalization
Elevated creatine kinase (CK), the marker of rhabdomyolysis/muscle involvement (defined as CK over 500 U/l followed by hospitalization), was recorded in 75 episodes in 8/12 patients. Three patients never showed CK concentrations >500 U/l. For Patient 12 no data are available.
CK concentrations ranged from 500 U/l to 142.700 U/l (median 4.360 U/l; mean 12.630 U/l). The range of episodes with a CK > 500 U/l is one to 18 (median 10) episodes per patient.
Comparing CK concentrations >500 U/l pre- and post-triheptanoin, we calculated a mean reduction of 45% in total episodes pre- vs post triheptanoin treatment. We recorded a total of 13 episodes per patient year (44 episodes in 3.4 patient years) before triheptanoin (mean 5.5, median 2.5, ranging from 0 to 17 episodes/patient) and a total of 3.5 episodes per patient year (24 episodes in 6.7 patient years) after commencement of triheptanoin (mean 3, median 1.5, ranging from 1 – 13 episodes/patient) (Figure 2, Panels 3a and 3b).
Dietary long-term management
In our patient cohort, 11 patients eat self-sufficiently. Patient 10 is regularly fed via PEG. Since age 3 months he has suffered frequent vomiting and refused to eat. At age 1 year, he received a PEG tube. At date, he increasingly shows interest in food, feeding via PEG is performed only during the night. Seven (Patients 1, 2, 4, 5, 6, 9, 12) have a late evening meal around 22:00 pm (Table 2), three (Patients 3, 7, 8) have no late meals or night feeds. Patients 10 and 11 have night feeds (around 02:00 – 03:00 am), Patient 10 via PEG and Patient 11 orally (Table 2).