Clinical Guidance

As a general rule, strong genotype-phenotype correlations exist in VLCAD deficiency :

• Severe disease is associated with no residual enzyme activity, often resulting from null variants. Approximately 81% of pathogenic truncating variants in ACADVL are associated with the severe early-onset form .

• A specific homozygous missense pathogenic variant (c.709TC;) leading to low long-chain fatty acid oxidation flux may also be associated with cardiac disease .

• Milder childhood and adult forms are often associated with residual enzyme activity. The common variant, in both homozygous and compound heterozygous genotypes, is typically associated with the non-cardiac phenotypes .

Source: GeneReviews — "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"

Diagnostic Criteria

Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons.

Suggestive Findings

Scenario 1: Abnormal Newborn Screening (NBS) Result

NBS for VLCAD deficiency is primarily based on quantification of various acylcarnitine levels (C14:1, C14:2, C14, and C12:1) and ratios of acylcarnitine levels (C14:1/C2, C14:1/C16) on dried blood spots. Acylcarnitine values and ratios above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, which typically includes a confirmatory acylcarnitine profile.

Source: GeneReviews — "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"

Differential Diagnosis

Infantile cardiomyopathy with evidence of abnormal fatty acid oxidation may be seen in the autosomal recessive disorders summarized in . Table 2. Disorders in the Differential Diagnosis of Severe Early-Onset VLCAD

Management Guidelines

Clinical guidelines for the nutritional management of very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency at various ages have been published (full text). Guidelines can be accessed from the Genetic Metabolic Dietitians International and Southeast Regional Genetics Network websites. When VLCAD deficiency is suspected during the diagnostic evaluation – for example, as a result of a suggestive acylcarnitine profile – fasting precautions should be implemented immediately. In asymptomatic neonates, maternal breast milk without supplemental medium-chain triglycerides can continue as long as fasting precautions are taken . Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (e.g., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with VLCAD deficiency, the evaluations summarized in or (depending on the age at diagnosis) are recommended, if not previously performed as part of the evaluation that led to the diagnosis.

Table 4.

Recommended Evaluations Following Initial Diagnosis of VLCAD Deficiency in a Neonate or Infant

Evaluation | Comment

Source: GeneReviews — "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"

Clinical Guidance

Avoid the following:

• Fasting, including periods of preparation and recovery from planned surgery or sedation

• Myocardial irritation (e.g., cardiac catheterization)

• Dehydration (risk for acute tubular necrosis)

• High-fat diet (long-chain fats) including ketogenic or carbohydrate-restricted diets for the purpose of weight loss. Careful weight reduction has been accomplished by restricting long-chain fats and calories, supplementing with calories provided through medium-chain triglycerides, and limiting overnight catabolism with uncooked cornstarch .

• Volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate . However, the use of propofol for short-duration procedures has been evaluated in individuals with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency and was not found to cause adverse events .

Source: GeneReviews — "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"

Therapies Under Investigation

Bezafibrates. Small clinical trials have demonstrated controversial results.

• An open-label clinical trial showed continuously improving physical functioning as assessed through quality of life questionnaire scores in all affected individuals who participated .

• An in vitro study found that mitochondrial metabolic capacity and glutathione were affected by benzafibrate treatment .

Dodecanedioic acid. In an in vitro study, dodecanedioic acid supplementation reduced levels of toxic very long-chain acylcarnitines . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"

Surveillance Guidelines

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the surveillance evaluations summarized in are recommended. Table 11. Recommended Surveillance for Individuals with VLCAD Deficiency

Source: GeneReviews — "Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"