Very long-chain acyl-coenzyme A dehydrogenase deficiency

Very long-chain acyl-coenzyme A dehydrogenase deficiency
autorecessive.svg
Very long-chain acyl-coenzyme A dehydrogenase deficiency has an autosomal recessive pattern of inheritance.
Synonyms	VLCADD, VLCAD deficiency
Specialty	Genetics, Metabolic disorders, Pediatrics
Symptoms	Hypoglycemia, lethargy, hepatomegaly, cardiomyopathy, muscle pain, hypotonia
Complications	Metabolic crisis, seizure, coma, cardiac arrest
Usual onset	Neonatal to adulthood
Duration	Chronic
Types	Early-onset, childhood-onset, and adult-onset forms
Causes	Mutation in the ACADVL gene
Risk factors	Consanguinity, family history
Diagnosis	Newborn screening, plasma acylcarnitine profile, enzyme assay, genetic testing
Differential diagnosis	Medium-chain acyl-CoA dehydrogenase deficiency, Reye syndrome, sepsis, glycogen storage disease
Prevention	Avoidance of fasting, regular feeding schedules
Treatment	Dietary management, glucose supplementation during illness, emergency protocol
Medication	Medium-chain triglyceride (MCT) oil, L-carnitine (in select cases)
Prognosis	Variable; improved with early detection and treatment
Frequency	~1 in 30,000 to 100,000 births (varies by population)
Deaths	Can be fatal without treatment; mortality reduced with early diagnosis

Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD or VLCAD deficiency) is a rare inborn error of metabolism that affects the body’s ability to break down very long-chain fatty acids into usable forms of energy, especially during times of fasting or increased energy demands.

It is caused by mutations in the ACADVL gene, which provides instructions for making an enzyme necessary for the first step in the mitochondrial beta-oxidation of long-chain fatty acids. This enzyme deficiency leads to the accumulation of unmetabolized fatty acids and a lack of cellular energy, particularly affecting the liver, heart, and skeletal muscles.

Signs and symptoms

The clinical presentation of VLCADD varies widely depending on the age of onset. There are three major forms:

• Neonatal/early-onset form:
  • Hypoketotic hypoglycemia
  • Cardiomyopathy (especially hypertrophic type)
  • Hepatomegaly and liver dysfunction
  • Arrhythmias and risk of sudden cardiac death
  • Hypotonia and poor feeding

• Childhood-onset form:
  • Episodes of metabolic crisis
  • Vomiting, lethargy, muscle weakness
  • Rhabdomyolysis and liver dysfunction
  • Mild to moderate developmental delay

• Late-onset/adult form:
  • Recurrent muscle pain, exercise intolerance, myopathy
  • Rhabdomyolysis triggered by prolonged exercise or fasting

Genetics

VLCADD is inherited in an autosomal recessive pattern. Mutations in the ACADVL gene (located on chromosome 17p13.1) result in defective or deficient activity of the VLCAD enzyme. Over 80 different mutations in the ACADVL gene have been identified. Homozygous or compound heterozygous mutations are required for disease manifestation.

Heterozygous carriers are typically asymptomatic but may show mild biochemical abnormalities.

Pathophysiology

The VLCAD enzyme is responsible for the initial step in the breakdown of very long-chain fatty acids (C14–C20) in the mitochondria. Its absence leads to energy deficits, particularly during fasting or catabolic stress, as the body becomes unable to generate energy from fat stores. Accumulation of toxic intermediates can damage organs, particularly the heart and muscles.

Diagnosis

Diagnosis is often made via newborn screening, which detects abnormal levels of acylcarnitines (especially elevated C14:1) in blood spots. Confirmatory tests include:

• Plasma acylcarnitine profile via tandem mass spectrometry
• Urine organic acid analysis
• Enzyme assay in cultured fibroblasts
• Molecular genetic testing of the ACADVL gene

Treatment

There is no cure for VLCADD, but symptoms can be managed with:

• Avoidance of fasting: frequent meals and overnight feeds in infants
• Dietary modifications:
  • Low-fat, high-carbohydrate diet
  • Use of medium-chain triglyceride (MCT) oil, which bypasses the VLCAD-dependent metabolic pathway
• Emergency care:
  • Prompt treatment of illness or fasting with IV glucose
• Carnitine supplementation: controversial; may be used in select cases under medical supervision
• Monitoring for cardiomyopathy and rhabdomyolysis

Prognosis

With early detection and proper management, many children with VLCADD can lead relatively normal lives. However, the early-onset form is associated with increased risk of mortality, particularly if undiagnosed. Long-term outcomes depend on the severity of the enzyme deficiency and the timing of treatment.

Epidemiology

VLCADD occurs in approximately 1 in 30,000 to 100,000 live births, though the frequency varies among populations. Newborn screening programs have increased the detection rate and improved outcomes through early intervention.

See also

• Fatty-acid metabolism disorder
• Medium-chain acyl-CoA dehydrogenase deficiency
• Inborn errors of metabolism
• Metabolic crisis
• Newborn screening