Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 2.0.0
• Status (Pediatric): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: ACADVL
• Condition: Very Long Chain Actyl-CoA Dehydrogenase Deficiency (VLCAD)
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• ACADVL ⇔ 0008723 (very long chain acyl-coa dehydrogenase deficiency): Limited Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric. While this condition has been well studied in newborn screen populations, the experts discussed uncertainty about the ability to predict the likelihood of specific outcomes in adults when ascertained on the basis of genetic variants.

Final Consensus Scores

Gene Condition Pairs: ACADVL ⇔ 0008723 (OMIM:201475)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality due to VLCAD deficiency / Surveillance by specialists to guide management, including diet, emergency planning, triheptanoin therapy, and prevention of secondary complications	2	0D	2C	2	6DC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Based on newborn screening (NBS) data, the incidence of the deficiency of very long-chain acyl-coA dehydrogenase (ACADVLD) has been estimated from 1/30,000 to 1/95,000. Prevalence estimates range from 1/100,000 to 9/100,000. [1, 2, 3, 4]

Clinical Features

VLCAD deficiency is an inborn error of mitochondrial long-chain fatty acid (LCFA) oxidation, which results in impaired energy production from exogenous and endogenous fatty acids. VLCAD deficiency is associated with three phenotypes. The severe, early-onset form has high mortality and typically presents with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent rhabdomyolysis. The intermediate or moderate form typically presents with hypoketotic hypoglycemia and hepatomegaly associated with a catabolic stress, but without cardiomyopathy, and is associated with a lower mortality than the severe form. The later-onset mild form, probably the most common phenotype, presents with intermittent rhabdomyolysis, muscle cramps and/or pain, and/or exercise intolerance.
In pediatric patients, early signs of decompensation may be subtle, including lethargy and/or floppiness. In adult patients, early signs of metabolic decompensation are predominated by muscle symptoms, but also can be subtle including lethargy, muscle aches and pain or feeling ‘not right.’
Hypoglycemia typically is not present at the time of symptoms (GR), though some patients may have a previous history of hypoglycemia. Patients can be seriously ill without hypoglycemia or hypoglycemia only occurs at a relatively late stage. [2, 4, 5, 6, 7, 8, 9]

Natural History

Most affected individuals identified by NBS are asymptomatic at the time of diagnosis.
The severe form typically presents within the first 3-12 months of life and as early as the neonatal period. The hepatic or hypoketotic form typically presents during early childhood. The later-onset myopathic form typically presents in later childhood or adulthood, usually >10 years of age.
Episodes are usually triggered by exercise, fasting, cold/heat and/or stress but viral infection can also precipitate/exacerbate this presentation. In rare cases it can lead to renal failure and can be fatal.
NBS allows for early detection of individuals with milder forms of VLCAD deficiency. The outcome for all phenotypes is improving due to early identification via NBS. In individuals with VLCAD deficiency identified by NBS and treated from infancy, a presentation of rhabdomyolysis is more common than cardiomyopathy and the first episode often appears in the toddler years with elevations in creatine kinase. [1, 4, 7, 8, 10]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening: https://www.acmg.net/PDFLibrary/C14.pdf [11]

To establish the extent of disease and needs in an individual diagnosed with VLCAD deficiency, the following evaluations are recommended for all individuals:
•Consultation with a metabolic physician, biochemical geneticist, and specialist metabolic dietician
•Measurement of baseline laboratory studies, including serum creatine kinase concentration, liver transaminases
•Consultation with psychologist and/or social worker
•Genetic counseling.
Specific to neonates/infants:
•Measurement of baseline blood glucose concentrations
•Electrocardiogram and echocardiogram
•Nutrition and feeding team evaluation
Specific to older child or adult
•Developmental assessment (Tier 4) [2]

LONG TERM MANAGEMENT
Nutrition intake recommendations when the patient is well include the following:
•Consider age, disease severity and clinical history when establishing nutrition prescriptions for dietary fat composition Provide total dietary protein at or above the age-appropriate dietary reference intake for protein intake. In 9 individuals with VLCAD, a significant negative correlation between protein intake and percent body fat was found in those consuming diets with a higher protein to energy ratio.
•Use standard equations to determine fluid requirements for an asymptomatic individual
•Advise all individuals with VLCAD to avoid excessive fasting, taking into consideration the severity of disease.
•Consider an individual's age, dietary LCF restriction, and plasma or RBC fatty acid profiles to determine if additional sources of EFA are required. (Tier 1) [7]

Additional nutrition recommendations when the patient is well include the following:
•Individuals with late-onset VLCAD deficiency older than 12 months are also recommended to have some sort of dietary modification. Specifically, an age-appropriate ‘‘heart-healthy” diet supplemented with medium chain triglycerides (MCT) has been recommended. For those patients who have symptomatic myopathy, a diet with more stringent LCFA restriction may be considered. However, for asymptomatic patients, the role of LCFA consumption in the development of later-onset myopathy is not known and there is some concern that a highly restricted or less palatable diet could contribute to catabolism or essential fatty acid deficiency. (Tier 2) [1, 12]

•Support breastfeeding of infants, taking into consideration the following: (1) For asymptomatic infant with a MILD form, allow breastfeeding without MCT, as long as breast milk supply remains adequate, age appropriate weight gain is maintained, and fasting recommendations are followed; (2) For asymptomatic infant with a MODERATE form, allow breastfeeding but consider supplementing breast milk with low LCF, high MCT medical food; (3) For asymptomatic infant with SEVERE form, primary source of nutrition should be a low LCF, high MCT medical food; (4) for symptomatic infant, depending on the severity of symptoms and lab monitoring, consider allowing some breast milk while using a low, LCF, high MCT medical food to meet energy needs; (5) if breast feeding was discontinued during metabolic decompensation, consider reintroduction partial breast feeding after the infant returns to an asymptomatic clinical state, if the mother's breast milk supply remains adequate.•To meet fasting guidelines and prevent catabolism in children and adults, consider adding a bedtime snack emphasizing complex carbohydrates. For those with a severe phenotype who do not tolerate extended fasting times, an overnight enteral feeding should be considered when a bedtime snack is not sufficient. (Tier 2) [7]

In a retrospective analysis of 75 patients with long-chain fatty acid oxidation (FAO) disorders evaluated dietary treatment and disease outcome. In the cohort, 25/27 of patients with enzymatically and/or molecularly confirmed VLCAD deficiency were on a long-chain triglyceride-restricted diet and most (21/27) received supplementation with MCT. In 9/22 patients with VLCAD deficiency, additional carbohydrates were supplemented, resulting in a hypercaloric diet. Optimal adherence to treatment was reported in 20/27 (74%) of patients with VLCADD. Despite high compliance, 38% of patients with VLCADD had intermittent muscle weakness and pain despite adhering to therapy. Five of the 13 patients with VLCADD and myopathy had symptoms during intercurrent illnesses and following exercise. (Tier 2) [7]

In a well individual with VLCAD deficiency, 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 use of L-carnitine continues to be controversial in the treatment of LC-FAOD since L-carnitine may increase the production of long chain acylcarnitines and promote toxic effects, particularly in cardiac tissue. (Tier 1) [7]

Triheptanoin supplementation (to provide 30% of daily caloric intake) is an alternative to daily treatment of MCT oil supplementation (Tier 3) [2]

•Benefits include decreased in total days of hospitalization per year and reduction in episodes of rhabdomyolysis. Improvement in cardiomyopathy, hepatomegaly, and hypoglycemia was reported in those treated with triheptanoin compared to pretreatment, although most studies included individuals with a range of long-chain FOA disorders. In June 2020, the FDA approved DOJOLVI (triheptanoin) for the treatment of pediatric and adult patients with molecularly confirmed long-chain FAO disorders. A double-blind randomized controlled trial of 32 patients (age range 7-64 years) with long-chain FAO disorders (9 patients with VLCAD deficiency) were assigned a diet containing 20% of their total daily energy from either C7 (triheptanoin) or C8 (trioctanoin) for four months. Patients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% (p=0.046) while experiencing a 20% (p.0.041) decrease in LV wall mass on resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test, when compared to patients taking C8. There was no significant difference between treatment groups in musculoskeletal symptoms (e.g., intermittent muscle pain, acute rhabdomyolysis) or any other secondary outcome measures over the 4‐month treatment period. Another study reported the safety and efficacy of 78 weeks of triheptanoin treatment versus a retrospective 78-week period (when patients were optimally managed under published dietary guidelines) in 29 patients (mean age 12.06 years, range 0.87-58.78 years) with symptomatic long chain FAO disorders (12 patients with VLCAD). Following treatment, mean annualized major clinical event (MCE) rate decreased by 48.1% (p = 0.021) and mean annualized MCE event-day rate decreased by 50.3% (p = 0.028) independently from other dietary changes (Tier 5) [13, 14, 15]

Additional routine treatments may include:
•Management for cardiomyopathy manifestations, including standard treatment per cardiologist. With appropriate dietary modifications and cardiac support, cardiac dysfunction may be reversable.
•For increased energy and calorie demands, a nasogastric tube feeding may be necessary.
•For speech or gross motor delay, speech therapy, physical therapy and rehab can be considered (Tier 4) [2]

ACUTE MANAGEMENT
Most of the evidence on nutrition management during illness comes from case studies of individuals presenting cardiomyopathy, rhabdomyolysis, and/or hypoglycemia. There are no published studies on managing mild illness in VLCAD deficiency. The following recommendations are for nutrition management during illness:
•During illness, adjust the composition of the diet according to the severity of current symptoms: (1) For individuals with VLCAD deficiency who were previously asymptomatic but develop complications, restrict LCF according to the severity of the individual's current symptoms (2) When treating individuals with acute rhabdomyolysis, emphasize carbohydrate (oral or IV) as an energy source.
•For an individual with VLCAD deficiency who has mild illness managed at home, in consultation with the medical team: (1) Counsel individuals and their caregivers to provide frequent, high carbohydrate feedings (glucose polymers, or simple or complex carbohydrates) and strive to achieve usual energy intake to prevent catabolism (2) Decrease fasting duration as compared to when well.
•For individuals with VLCAD deficiency who are hospitalized for illness (regardless of cause), in consultation with the medical team: (1) Provide a minimum of 10% IV dextrose with electrolytes at a rate of at least 1.5 times maintenance fluids (equivalent to a glucose infusion rate of 8 mg/kg/min) if the individual is unable to consume adequate energy (2) Avoid use of L-carnitine in acute illness (3) Consider central line placement for improved access in individuals with severe VLCAD/cardiomyopathy who require frequent hospitalizations (4) Avoid the administration of IV lipids; however, after 7 days a source of essential fatty acids should be provided. (Tier 1) [7]

For all individuals with VLCAD deficiency , employ strategies to prevent conditions that may lead to metabolic decompensation: (1) Counsel individuals with VLCAD and/or their caregivers to space meals and snacks to avoid prolonged fasting and meet energy needs (2) Encourage asymptomatic individuals with VLCAD deficiency to be physically active, as tolerated, and to increase energy intake prior to and during exercise (3) Consider gastrostomy-tube placement for individuals with severe VLCAD deficiency who have feeding difficulties and are prone to frequent hospitalizations due to inadequate energy intake (4) Discourage the use of home blood glucose meters to monitor the severity of clinical symptoms, as hypoglycemia is not likely to be the presenting symptom during illness (5) Provide caregivers with an emergency letter to use when seeking urgent medical care. (Tier 2) [7]

Emergency treatment for individuals with VLCAD deficiency aims to prevent mobilization of fat by providing ample glucose, enterally or intravenously. The aim of emergency treatment should always be to intervene while blood glucose is normal.
•It is important to listen to parents’ insight into their child’s illness. Patients unable to tolerate their “oral emergency regimen” or are increasingly unwell should contact their doctor or be admitted. Management decisions should be based primarily on clinical status. If the patient is relatively well, they may be treated orally using their “oral emergency regimen,” but assess very carefully.
•If patient is obviously unwell, they must be treated with intravenous fluids. Complete initial investigatory labs, correct dehydration, start IV dextrose, treat any underlying infection or other clinical problem, if cardiac signs arrange echocardiography, and if significant renal impairment (due to rhabdomyolysis) consider dialysis. (Tier 2) [6, 8, 9, 10, 16, 17, 18]

The following is recommended specific to physical activity:
•Provide MCT as an energy source 20 min prior to exercise, and adjust dose (range 0.1–0.3 g/kg total body weight or 0.25–0.5 g/kg based on LBM) to improve exercise tolerance for those not tolerating physical activity. Experimental and observational studies indicate that consumption of MCT 20 min prior to exercise can improve exercise tolerance (Fair)
•Counsel individuals with VLCAD regarding appropriate fluid needs for physical activity. (Tier 1) [7]

Administration of MCT prior to exercise has demonstrated benefit in older individuals with LCFA defects who have exercise intolerance. However, one report of 2 adult men with VLCAD deficiency with exercise intolerance did not respond to intravenous glucose or MCT (Tier 3) [5]

Surgical procedures in patients with metabolic disorders require specific perioperative and anesthetic measures based on the nature of the disorder. During surgery, prolonged fasting, perioperative stress, and certain anesthetics can lead to metabolic derangements (Tier 3) [2]

Menstruation and pregnancy-related recommendations include the following:
•Monitor young women for rhabdomyolysis events during the premenarchal period and provide supportive care
•Develop a plan with the metabolic and obstetric team for pregnancy planning, precautions, and monitoring. The plan should include delivery method, pain management, and emergency protocols. There are few cases of VLCAD deficiency with reported pregnancy-related outcomes. One study reported nine pregnancies in five women. Three women experienced delayed myalgias after their first delivery, with concomitant elevation of CK levels or myoglobinuria, but renal function remained normal.
•Provide nutrition guidance and encourage diet adherence throughout the pregnancy to support a healthy pregnancy and prevent complications such as rhabdomyolysis. Nutrition recommendations should include a high carbohydrate, low LCF diet with MCT supplementation, replenishment of carnitine deficits and avoidance of fasting. Follow other normal pregnancy recommendations for energy and protein needs, vitamin/mineral supplementation and weight gain
•Monitor for and aggressively treat pregnancy-related illness and rhabdomyolysis
•Develop a plan with the metabolic and obstetric team to minimize catabolism during labor and delivery. This includes preventing fasting, providing continuous IV support (10% dextrose with appropriate electrolytes at 1 to 1.5 times maintenance), managing medications and monitoring laboratory values
•Provide additional calorie support during the postpartum period, especially if the mother is breastfeeding. Provide close monitoring for signs of decompensation, rhabdomyolysis, and cardiac complications for up to 8 weeks postpartum and as long as the woman is breastfeeding (Tier 1) [7]

Surveillance

Recommendations for VLCAD deficiency include ongoing assessment of clinical and nutritional status:
•Conduct nutrition assessments (dietary history, nutrient analysis, feeding skills and schedule, anthropometrics/growth, activity level and nutrition-related physical findings) to determine adherence and nutritional adequacy of a dietary prescription
•Evaluate confirmatory testing (plasma acylcarnitine profile, genetic testing, enzyme testing) as it may suggest the severity of the disorder and can be helpful in guiding early nutrition management
•Monitor creatine kinase and plasma carnitine profile (total, free, esters) for routine management of VLCAD
•Consider additional monitoring, when indicated by special circumstances, which may include comprehensive metabolic panel, acylcarnitine profile, essential fatty acids, fat-soluble vitamins, cardiac monitoring and other biochemical markers. (Tier 1) [7]

Recommended surveillance for individuals include:
•Growth (including head circumference through 36 mo) and assessment of nutritional deficiencies and feeding issues at each visit
•Biochemical laboratory parameters, including plasma carnitine panel, acylcarnitine profile, and creatine kinase level every three months for the first year of life, every three to six months for those between age one and seven years, and every six to 12 months for those older than age seven years; red blood cell or plasma essential fatty acids every six months for those on long-chain fat restriction; measurement of vitamins A, D, and E annually or as clinically indicated for those on long-chain fat restriction; measurement of complete blood count, ferritin level, comprehensive metabolic panel, troponin, and B-type natriuretic protein as clinically indicated (Tier 4, GR)
•Cardiomyopathy, including echocardiogram at least annually or as clinically indicated; measurement of troponin and BNP as clinically indicated
•DXA scan every five years in adults (Tier 1) [7]

Ongoing care recommendations for pregnant and lactating women include:
•Nutritional deficiencies, including formal visit with nutritionist familiar with VLCAD deficiency, monthly or at least in each trimester
•Biochemical laboratory parameters, including plasma carnitine panel and creatine kinase level at each visit; plasma acylcarnitine profile weekly to monthly in pregnant women and every clinic visit in lactating women; RBC or plasma essential fatty acids (for persons on long-chain fat restriction) at least once during pregnancy; Vitamins A, D, and E as baseline during pregnancy or as clinically indicated
•Cardiomyopathy, including an echocardiogram as baseline either prior to conception or as soon as pregnancy is recognized; assessment by cardiologist and maternal fetal medicine specialists regulatory, if affected person has known cardiac issue (Tier 1) [7]

Circumstances to Avoid

Individuals with VLCAD deficiency should limit fasting times. The fasting time should be determined by the specialist service and is assessed regulatory as a function of age and individual tolerance of the child (Tier 2) [16]

Individuals may need to limit exercise duration and intensity, specifically avoiding strenuous exercise. (Tier 2) [7, 16]

Contraindicated drugs include acetylsalicylic acid (aspirin), valproic acid. Need for corticosteroid therapy should be assessed carefully. (Tier 2) [16]

Do not administer any long chain fat, such as IV intralipid, and avoid medications containing lipids, such as propofol. (Tier 2) [6, 7]

Patients should avoid a high-fat diet, including ketogenic or carbohydrate-restricted diets, for the purpose of weight loss. (Tier 3) [2]

Patients should avoid myocardial irritation (e.g., cardiac catheterization). (Tier 4) [2]

Patients should avoid dehydration due to risk for acute tubular necrosis. (Tier 4) [2]

Patients should limit cold/heat exposure. (Tier 4) [4]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive [2, 4, 5]

Prevalence of Genetic Variants

Information on the prevalence of genetic variants associated with VLCAD deficiency was not available.

The prevalence of homozygotes should be similar to the prevalence of VLCAD deficiency detected during newborn screening, which can identify asymptomatic individuals. Based on newborn screening data, the incidence of VLCAD deficiency has been estimated from 1/100,000 to 1/30,000 (Tier 3) [1, 2, 3]

Using the VLCAD deficiency prevalence estimate of 1/31,000 based on newborn screening data, the carrier frequency has been estimated as 1/90 (Tier 5) [19]

Between 95-97% of probands have pathogenic variants in the ACADVL gene, while large deletions or duplications are rare (Tier 3) [2]

Penetrance

No information on penetrance of signs and symptoms in adults identified based on genetic status was identified.

Severe forms are suspected to be fully penetrant. However, since the later-onset forms may have vague or intermittent symptoms, it is possible that some individuals will have no symptoms during their lifetime. (Tier 4) [2]

A retrospective analysis of outcomes of 52 individuals diagnosed with VLCAD deficiency by newborn screening in the US aged 1-18 years found that most individuals remained asymptomatic during the observed periods. Of the 52 individuals, cardiomyopathy was diagnosed in 2 (4%), 14 (27%) had elevated serum kinase (usually diagnosed between ages 1-3), and 11 (21%) developed rhabdomyolysis. A report of 22 patients identified by newborn screening in Australia followed for a median of 104 months on a low fat diet found no episodes of encephalopathy or hypoglycemia, but 3 (14%) cases had muscle pain with or without rhabdomyolysis. (Tier 3) [5]

Among 13 clinically diagnosed patients (age of onset: birth to 13 years; median age at examination: 30.5 years) all patients were found to have exercise intolerance and recurrent rhabdomyolysis episodes generally triggered by strenuous exercise, fasting, cold, or fever (median age at onset: 10 years). (Tier 3) [2]

In a sample of 30 individuals with VLCAD deficiency (in a study from 2009), the following clinical presentations were reported (variable denominator reflects patients with available data:
For those identified by NBS (n=20):
•Symptomatic: 3/20
•Cardiomyopathy: 0/3
•Arrhythmias: 2/3
•Reye syndrome: 0/3
•Hypoglycemia: 1/3
•Hepatopathy/-megaly 1/3
•Hypotonia/myopathy: 1/3
•Deceased: 0/20
For those clinically diagnosed (n=10):
•Age at diagnosis (1 day - 36 years; median 2.5 months)
•Cardiomyopathy: 6/10
•Arrhythmias: 3/10
•Reye syndrome: 1/10
•Hypoglycemia: 6/10
•Hypotonia/myopathy: 4/10
•Deceased: 2/10 (at ages 2 months, 3 months) (Tier 5) [20]

Relative Risk

Information on relative risk was not available for the Adult context.

Expressivity

There is a strong genotype-phenotype correlation in VLCAD deficiency, with severe disease associated with no residual enzyme activity (often resulting from null variants) and milder childhood and adult forms are often associated with residual enzyme activity (often resulting from pathogenic missense variants). (Tier 3) [1, 2, 5]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions for individuals with VLCAD deficiency include regular monitoring and emergency management, dietary modifications and adherence, MCT or triheptanoin supplementation (adjustment to exercise regimens, and avoidance of fasting. Individuals should also have extra precautions during surgical procedures.
Adverse events with triheptanoin in the clinical trials were similar for triheptanoin or trioctanoin treatment and predominantly consisted of gastrointestinal symptoms. Gastrointestinal upset included diarrhea (55%) and vomiting (48%). [2, 7, 12, 15]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Patients with VLCAD deficiency were traditionally diagnosed after developing symptoms of the disorder. NBS has demonstrated that VLCAD deficiency is more prevalent than previously suspected. The majority of children ascertained by NBS are asymptomatic during the first few years of observation, suggesting that these individuals may have gone undiagnosed prior to the advent of population-based screening. Importantly, complete ascertainment by NBS is not assured. (Tier 4) [2]

Date of Search: 03.08.2017 (updated 03.08.2025)

Reference List

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