The use of L-carnitine, triheptanoin, bezafibrate, riboflavin and coenzyme Q-10 (CoQ10) have all been reported in treatment of individuals with very-long chain acyl-coA dehydrogenase deficiency (VLCAD). The supplements are often used in conjunction with nutritional interventions such as restriction of long-chain fat (LCF) intake and supplementation of medium chain triglycerides (MCT). The use of L-carnitine continues to be controversial in individuals with VLCAD. There are case reports of its successful use in conjunction with other nutritional therapies, and when dosages are reported, the most common range is 25 to100 mg/kg/d to maintain normal free carnitine concentrations. The concern raised by experts is whether supplementation of L-carnitine may increase the production of long-chain acylcarnitines and promote toxic effects, particularly in cardiomyopathy. However, supplementation of L-carnitine alone, without other nutritional interventions, does not provide a clinical benefit.
Triheptanoin (C7), currently only available in clinical trials, is being studied as a substitute for MCT and preliminary studies have shown improvement in cardiac status. Dosages of triheptanoin vary widely - 15-35% of total calories or 2.6-4 g/kg/day are commonly reported. In addition, there have been reports of gastrointestinal (GI) distress.
Bezafibrates have been trialed, often without showing a positive effect, and require further study. Supplementation with CoQ10 and iboflavin have been reported in conjunction with other nutrition interventions, but also need further study to determine efficacy.
In a well individual with VLCAD, L-carnitine supplementation may not be needed, unless free carnitine concentration is <10 µmol/L. If low, consider a starting dose for L-carnitine of 10-25 mg/kg/d and titrate as needed based on lab monitoring.
The Inborn Error of Metabolism Information System (IBEM-IS) followed a cohort of 52 individuals with VLCAD detected by expanded newborn screening (NBS). Twenty-one patients were prescribed L-carnitine but details on dosing or associated clinical outcomes was not provided. Authors noted supplemental L-carnitine may not be needed if it is provided by medical formula (F.4055).
Based on the review of published surveys and Delphi consensus articles, the use of L-carnitine among practitioners is controversial. There was consensus among 18 European centers that L-carnitine should not be routinely recommended for patients with long chain fatty acid oxidation disorders, including VLCAD (F.3), while 17 of 18 metabolic physicians from Canada would prescribe L-carnitine in individuals with VLCAD (F.661). Another Delphi report found that 69% of providers would prescribe L-carnitine to prevent deficiency, but there was no consensus for its use during illness (F.9). Both groups (F.3 and F.9) expressed concern about the potential cardiac risk associated with increased production of long-chain acylcarnitines with L-carnitine. This concern was also expressed in other publications (F.3894, G.97). One additional article suggested that supplementation with L-carnitine (dosages not provided) should be based on the individual's clinical condition and phenotype (F.3859) and a book chapter supported the controversy and lack of consensus for its use (G.128). Despite these concerns, successful carnitine treatment in three children with neonatal hypoglycemia, cardiomyopathy and persistent muscle weakness has been reported (G.141). A book chapter suggested that L-carnitine supplementation may be life-saving in the severe form (cardiomyopathy) of VLCAD (G.28).
L-carnitine use in routine care
A retrospective questionnaire noted L-carnitine supplementation of 30 mg/kg/d for a patient with VLCAD with a plasma carnitine of 3 µmol/L. The same article reported 7 of 9 symptomatic VLCAD patients with decreased plasma carnitine concentrations before the start of treatment (F.2).
In a report of 3 siblings with VLCAD, L-carnitine was prescribed at 100 mg/kg/d for the second child at 10 months of age, in addition to treatment with a low-fat diet, MCT supplementation, fasting restrictions, and riboflavin. He remained stable at 5 years of age. The third child started L-carnitine at birth and required three hospitalizations in the first year, but remained in good health at 2.5 years. The first sibling died at 6 months after intercurrent illness (F.635).
Other case reports include an 18-month-old male with normal growth and development who started an MCT-supplemented medical food in the newborn period. He was prescribed L-carnitine at 7 months of age due to mildly low plasma carnitine concentrations (F.4117). An infant who was hospitalized at 3 months of age was started on L-carnitine at 60 mg/kg/d. Carnitine was discontinued at 5 months of age when he was admitted for a metabolic crisis and hypertrophic cardiomyopathy. The patient remained stable and off carnitine at 12 months of age (F.657).
There was no consensus (69%) for routine supplementation of L-carnitine in an individual with VLCAD who is well. Seven RDs and two MDs stated that supplementation of carnitine depends on the plasma carnitine concentration.
The reference range for plasma concentrations of free carnitine differs with age. Although there is variability between clinical labs, normal free plasma carnitine concentrations typically range from 19-51 µmol/L. Relevant evidence is summarized in topic 3.1.1 above.
There was consensus that there is no evidence to supplement with L-carnitine when plasma free carnitine is >10 µmol/L. One member of the nominal group pointed out that the carnitine in plasma represents only 1/400 of total body carnitine or <1% of the total. The group also stated that there is little/no evidence that long-chain acylcarnitines are harmful.
There was consensus (92% total MD/RD) to supplement with L-carnitine if the plasma free carnitine concentration is <10 µmol/L. One MD commented that L-carnitine supplementation should be initiated if plasma free carnitine falls below the normal range.
In the formal literature, dosing of L-carnitine recommended for individuals with VLCAD is reported primarily in case studies. Reported doses vary widely (25-100 mg/kg or 100-3000 g/d), as did the clinical circumstances and other treatments that were provided. The most frequently reported dose was 25 mg/kg/d. In all cases where repeat laboratory values were reported after initiating supplementation, plasma carnitine normalized or increased above the normal range; however, clinical outcome did not always improve.
A 42-year-old woman with a 2-year history of muscle pain and stiffness (episodes typically occurred 4-8 hours after exercise or during upper respiratory illnesses) reported avoiding rigorous exercise since age 25 years. Supplements of 330 mg carnitine given 3 times a day resulted in normalization of low plasma carnitine; however, clinical improvement was not seen (F.17).
Monozygotic twin sisters were diagnosed with VLCAD in their late 40's during an evaluation for rhabdomyolysis and fatigue (F.6). Starting at 7 years of age, they experienced recurrent muscle pain, nausea, and malaise triggered by prolonged exercise, fasting, and cold temperatures. These episodes worsened during adolescence and were precipitated by mild physical exertion with generalized muscle stiffness, sometimes causing complete immobilization. Treatment after diagnosis included avoidance of fasting, LCF restriction, and MCT supplementation. Initially they were prescribed L-carnitine (100 mg/kg/d), but this was discontinued due to cost. At age 57 years they were reportedly well without signs/symptoms of heart disease. They reported some lack of energy with physical exertion, but no rhabdomyolysis, muscle pain, nausea, or myalgia and they were able to run 3 km daily.
An 11-year-old was diagnosed with VLCAD following a 6-month history of rhabdomyolysis after intense exercise or acute illness requiring 3 admissions (F.636). During his second admission, a low-fat diet was initiated simultaneously with L-carnitine supplementation at 3 gm/day. On his third admission, muscle pain was less severe, creatine kinase (CK) peaked at lower concentrations (3000-5000 U/L), and total plasma carnitine was in the normal range. However, chronic management with L-carnitine did not prevent development of rhabdomyolysis.
Reduced severity of rhabdomyolysis was noted in two females, ages 13 years and 20 years, after supplementation with 1 to 3 g/d of L-carnitine (F.630). Both individuals were on a low-fat, MCT-supplemented diet and took an additional dose of L-carnitine before exercise, although their dietary compliance was reportedly poor.
Another case study followed a female patient from the neonatal period to age 4 years (F.633). She had one episode of hypoglycemia that responded to IV dextrose and at 5 months was hospitalized with acute diarrhea and vomiting. She was shown to have abnormal cardiac function and a low total carnitine of 23 mmol/L (normal 26-67 mmol/L). L-carnitine was initiated at 25 mg/kg/day with gradually increasing doses to 100 mg/kg/day. Dietary modifications were initiated simultaneously with L-carnitine supplements. At 24 months her heart size had normalized and at 4 years, QRS voltage normalized and ventricular hypertrophy resolved.
A male neonate presented with lethargy and apathy at 2 days of age (F.3712). Labs included normal blood glucose, elevated CK (13,445 U/L), and mild elevations of aspartate amino transferase (AST) and alanine aminotransferase (ALT). His initial treatment was not described. He was readmitted at 6 months following a two-day history of vomiting, diarrhea, and decreased intake with mild elevations of liver transaminases and metabolic acidosis. Electrocardiogram (ECG) found a small QRS complex and chest x-ray suggested consolidation or enlarged heart. He was given 50% IV dextrose at 8 mg/kg/min. Normal total carnitine, but low free carnitine was detected; a loading dose of IV carnitine at 100 mg/kg was given followed by a dose of 50 mg/kg three times per day. During admission, cardiac status worsened and despite extracorporeal membrane oxygenation (ECMO) treatment, the patient died.
A neonate (with a family history of sibling death at 2.5 months of age) presented with initial blood sugar instability and elevated CK and was discharged on Pregestimil (50% of total fat as LCF, 50% as MCT) (F.18). She was admitted at 4 months of age with a 4-day history of diarrhea, vomiting, lethargy, and hepatomegaly, but recovered with IV dextrose and fluids. She was readmitted two days later with elevated CK and an echocardiogram detected cardiomyopathy. After the VLCAD diagnosis was confirmed, her formula was changed to Portagen (13% of total fat as LCF, 87% as MCT) and she recovered after 3 days. She was discharged on Portagen and L-carnitine at 100 mg/kg/d.
A 6 year,10-month old boy was admitted with high fever, vomiting, stupor, lethargy, mild hepatomegaly, fatty liver, and elevated AST (831 IU/L), ALT (581 IU/L), and CK (1391 IU/L) (F.14). He had five previous admissions for lethargy with elevated liver transaminases and CK, but recovered rapidly with IV dextrose. Once diagnosed with VLCAD, he was routinely treated with diuretics for heart failure, L-carnitine at 45 mg/kg/day, and "MCT milk" providing 1.5 g MCT/kg/day. On this regimen, the patient's cardiomyopathy improved and transaminases normalized, but he continued to have a slightly elevated CK after prolonged exercise
A male with a severe neonatal presentation of tachypnea was admitted at 32 hours of life with metabolic acidosis (pH 7.24), low blood glucose (2.8 mmol/l), high serum lactate (20.2 mmol/L) and high urinary excretion of saturated dicarboxylic acids (adipic, suberic, and sebacic). An echocardiogram suggested biventricular hypertrophy (F.15). The patient received IV bicarbonate, oral citrate solution, and regular feedings with L-carnitine (250 mg/day) and additional supplements (thiamin 150 mg/day, biotin 7.5 mg/day, and CoQ-10 120 mg/day). Repeat ECG at 1 year of age was normal. At 3 years of age the patient was “good with normal growth and development and without any recurrence of the metabolic acidosis”. His acylcarnitine profile was consistent with VLCAD. Plasma free carnitine was 62.9 umol/L (normal 25-45 umol/L) with L-carnitine supplementation.
There was good consensus (81% MD/RD) to recommend a starting dose of L-carnitine at 10 to 25 mg/kg/d with dose adjustments based on plasma free carnitine concentrations. Two RDs and 1 MD recommended a starting dose of 50 mg/kg/d; one RD recommended starting with 25 mg/kg/d and one MD recommended a starting dose of >25 mg/kg/d.
Triheptanoate (C7) is available only in clinical trials or as an investigational new drug (IND); therefore, recommendations for its general use in VLCAD cannot be made at this time.
Triheptanoate (C7) is a triglyceride composed of three seven-carbon fatty acids. Triheptanoin oil is an investigational product for long-chain fatty acid oxidation disorders (LC-FAOD) and is suggested as an alternative to MCT (fatty acids C8 and C10 in length). Following beta-oxidation of C7, the remaining 3-carbon fatty acid promotes anaplerosis by entering the citric acid cycle as succinyl-CoA to promote continued energy production.
Six formal literature and 7 gray literature articles specifically identified 30 patients with VLCAD who received triheptanoin. (Some studies did not distinguish VLCAD from other LC-FAOD). In the formal literature, use of triheptanoin for treatment of LC-FAOD began in the early 2000's (F.4424, F.4394, F.4395, F.12, F.3859, F.4396). In these studies, doses of triheptanoin are provided, but not all include details about previous MCT dosage or other details about dietary treatment.
One randomized double-blind parallel design study (F.4424) compared C7 and C8 triglyceride in 32 patients with LC-FAOD, 9 of whom had VLCAD; however data from those with VLCAD is not distinguised from those with other LC-FAOD. At entry into the study, all subjects were on a low-fat diet with MCT supplementation. Subjects were randomized to receive either C7 or C8 to provide 20% of total energy for four months. Average consumption of C7 or C8 was 15% of total energy. In the C7 group, left ventricular ejection fraction increased by 7.4% (p=0.046) with a 20% decrease (p=0.041) in left ventricle wall mass compared with the C8 group. The C7 group had a lower heart rate for the same amount of work during a moderate intensity exercise stress test compared to the C8 group. No significant difference was found between groups in reported muscle pain, number of rhabdomyolysis episodes, CK concentrations, phosphocreatine recovery estimating adenosine triphosphate (ATP) synthesis during exercise (suggesting no measurable short-term effect on skeletal muscle energy metabolism), body composition, or energy expenditure. After 4 months of treatment, maximum heart rate during moderate intensity treadmill decreased among subjects on C7, while those on C8 did not see any change. Primary adverse events included GI distress, which was equivalent in both groups (F.4424).
A single arm, open-label, multicenter Phase 2 safety and efficacy study enrolled 29 subjects with severe LC-FAOD (12 with VLCAD), based on severity of musculoskeletal disease with elevated CK concentrations, but without cardiac involvement and normal hepatic ultrasound (F.4394). This study evaluated the acute effects of triheptanoin oil for 24 weeks on musculoskeletal function. Triheptanoin doses were 34% of total energy in patients <1 year, 27% of energy in patients 6 to 18 years, and 31% of energy in adults. Doses were given 4 times per day, orally or via G-tube. Five of 8 subjects with VLCAD showed a 28% increase in baseline endurance in a 12-minute walk test after C7 treatment. Peabody developmental motor scales and Pediatric Evaluation of Disability showed no impairment at baseline and no change after 24 weeks of treatment. Exercise tolerance assessed by cycle ergometry (7 subjects) showed a 60% increase in watts generated after treatment. Adults (disorders not specified) reported significant improvement in physical and mental component scores. Treatment-related adverse events included GI symptoms (55%) and diarrhea (41%). No time frame for these events was given.
Ten patients with moderate/severe LC-FAOD (4 with VLCAD) previously treated with MCT were changed to triheptanoin after an acute decompensation (F.4395). The dose goal for triheptanoin was 25 to 35% of total energy needs, as tolerated, which was equivalent to 2 to 4 g/kg/day in infants and young children, 1 to 3 g/kg/day in older children and adolescents, and 1 g/kg in adults. Improved clinical status was reported for the 4 patients with VLCAD, although 1 died due to septic shock and multi-system organ failure secondary to multiple resuscitations. The primary side effects of C7 were GI distress, usually mild, which resolved with food intake and divided doses throughout the day.
Another study provided detailed dosages, symptoms and clinical course for 3 individuals with VLCAD enrolled in a study with a 9-day admission to change from MCT to triheptanoin, with follow-up visits at 2, 6, 12, and 18 months (F.12). Patient 1 was diagnosed at 3.5 months of age after multiple admissions for hypothermia, hypoglycemia, failure to thrive, respiratory failure, and hypertrophic cardiomyopathy. His baseline diet included Portagen providing 3.3 g MCT/kg/d and L-carnitine, 500 mg four times per day. Triheptanoin was initiated at 5 years 2 months and maintained for 26 months with doses of 3.5 to 4 g/kg/day. Within 5 hours of starting triheptanoin, the patient was able to stand without assistance and open a heavy door. After 6 days, hepatomegaly resolved and after 1 month, cardiac function improved. Patient 2 was diagnosed at 3 months of age after an admission for hypoglycemic seizures, vomiting, hypotonia, metabolic acidosis, hepatomegaly, and cardiorespiratory arrest. Triheptanion was initiated at 7 years, 11 months at 3.2 g/kg/day for 22 months. Within 24 hours of treatment, he had increased activity, no muscle pain or Gowers’ sign and normal liver size. Over the next 3 months, he had brief admissions for elevated CK that improved with IV fluids. During the next 15 months, no admissions were required, attention improved at school, and only one episode of rhabdomyolysis was reported. Patient 3 had hypoglycemia at 12 hours-of-life and an episode of muscle weakness, hypoglycemia, feeding problems, cardiac/respiratory failure, hepatomegaly, and hypertrophic cardiomyopathy/pericardial effusion at age 3 months. Triheptanion was initiated at 2 years of age at a dose of 2.6 g/kg/day for 2 months with clinical improvement in motor skills and weight gain.
Book chapters published from 2009 to 2015 (G.28, G.97, G.141, G.128) provide updates on triheptanoin use as an experimental therapy for LC-FAOD. Doses ranged from 1 to 4 mg/kg/d and improvement in symptoms in treated patients was reported. Additionally, three abstracts were presented at the 2017 International Congress of Inborn Errors of Metabolism (ICIEM) to report on experience with triheptanoin in patients with LC-FAOD (VLCAD patients not differentiated) (G.145, G.146, G.147):
A case study (G.145) described a 4-year-old with severe VLCAD who replaced MCT with triheptanoin at 4 gm/kg/day. Initial clinical improvement was noted; however, after 6 months, the patient was readmitted with left ventricular dysfunction (ejection fraction of 18.1%).
A clinical trial of triheptanoin with 29 pediatric and adult patients with moderate to severe LC-FAOD receiving a mean of 31% of energy as C7 reported a significant reduction in major clinical events (cardiomyopathy, rhabdomyolysis, hypoglycemia) from 1.69 to 0.88 events/year after 18 months of triheptanoin therapy compared to traditional treatment (G.146). Physical activity/strength scales indicated significant improvement in both adults and pediatric subjects. However, other clinical trends that did not reach significance included cardiomyopathy events, hospitalizations due to rhabdomyolysis, hypoglycemia events, and intensive care unit (ICU) care.
A Phase 2 trial of triheptanoin enrolled patients > 6 years of age with LC-FAOD who replaced MCT with C7 for one year. Exercise testing was completed on MCT and repeated after triheptanoin treatment. The authors reported a positive effect on exercise tolerance (measured by mean work load and distance walked in walk test) when C7 was substituted for MCT (G.147).
The nominal group concluded that triheptanoate, as an experimental medicine, remains unproven in clinical trials and at this time, should only be used in a clinical trial or as an IND.
Bezafibrates are an experimental treatment for VLCAD and should not be used outside of a clinical trial.
Bezafibrate is a fibrate drug that increases the catabolism of triglycerides in muscle, fat, and liver tissues. It is being studied in LC-FAOD as a possible treatment for rhabdomyolysis. Case studies have noted improved muscle strength and decreased episodes of rhabdomyolysis in patients with VLCAD treated with this medication (F.4415, F.4379). Bezafibrate increased VLCAD gene expression in fibroblasts from four patients with VLCAD, including one with a severe phenotype (F.4415).
However, a randomized, placebo-controlled, double-blind parallel crossover trial of bezafibrate included 5 subjects with VLCAD and 5 subjects with carnitine palmitoyltransferase II (CPT II) (ages 16 to 70 years) with a history of exercise intolerance, rhabdomyolysis, and myoglobinuria (F.3963). Treatment included 200 mg bezafibrate 3 times per day or placebo. Bezafibrate-induced effects on lipid profiles were measured, but the study did not find a positive effect on exercise tolerance. Palmitate oxidation and total fatty acid oxidation did not improve with bezafibrate in any of the patients compared with placebo. Exercise-induced increases in total fatty acid oxidation and palmitate oxidation rates were only 2-fold in subjects compared with 5-fold increases in healthy subjects. Heart rate response to exercise was identical with placebo and bezafibrate treatments. Additionally, acylcarnitine profiles were abnormal at rest and during exercise in all subjects and bezofibrate treatment did not decrease the concentrations at any sampling time (F.3963). A published commentary questioned these results, noting that the comparison between bezafibrates and placebo was performed in a fed state in subjects with mild VLCAD (F.3964).
A survey of metabolic physicians from Canada regarding LC-FAOD management found that 14 of 18 respondents would prescribe bezafibrates for all or most patients, although VLCAD was not separated from other LC-FAOD (F.661).
The nominal group concluded that bezafibrates are an experimental therapy and, at this time, should only be used in a clinical trial.
There is insufficient evidence on the effectiveness of CoQ10 or other vitamin supplements in VLCAD; therefore, recommendations for their use cannot be made at this time.
In case reports of patients supplemented with CoQ10, treatment included various other modalities as well. In two of 13 adults with VLCAD, subjective improvement was reported with 300 mg/day CoQ10 and 80 mg/day riboflavin. Details of other treatments were not provided (F.617). Twin sisters, diagnosed with VLCAD deficiency at the age of 49 years, were treated with CoQ10 (30 mg/d), folic acid, and vitamin C. Concurrent diet recommendations included fasting avoidance, LCF restriction, and MCT supplementation. After 8 years of treatment, the sisters did not have any evidence of cardiac disease, did not experience further episodes of rhabdomyolysis and were able to run 3 kilometers per day (F.6). An infant with severe VLCAD was started on CoQ10 (dose not specified) along with high dose carnitine, a low LCF, high MCT formula (Portagen), fasting precautions and avoidance of excessive physical activity but continued to have episodes of elevated CK, but cardiac function was normal at 8 years of age (F.4382).
Riboflavin is required for formation of the flavin adenine dinucleotide (FAD) cofactor necessary for very long chain acyl-CoA dehydrogenase activity. Supplemental riboflavin (100 mg/day) has been shown to restore respiratory chain function in some patients with VLCAD (G.141). Six published cases describe riboflavin as part of extensive treatment regimens of patients ranging in age from birth to 11 years (F.617, F.660, F.658, F.3797, F.4098, F.4415). When doses of riboflavin were specified, they ranged from 50 to 80 mg/day (F.617, F.4098, F.3797).
CoQ10 is an experimental supplement with no biological plausible rationale to justify its use, and should only be used in a research setting.