Short-Chain Acyl-CoA Dehydrogenase Deficiency

Clinical characteristics: Most infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria are reported. Thus, SCADD is now viewed as a biochemical phenotype rather than a disease. A broad range of clinical findings was originally reported in those with confirmed SCADD, including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported. In a large series of affected individuals detected on metabolic evaluation for developmental delay, 20% had failure to thrive, feeding difficulties, and hypotonia; 22% had seizures; and 30% had hypotonia without seizures. In contrast, the majority of infants with SCADD have been detected by expanded newborn screening, and the great majority of these infants remain asymptomatic. As with other fatty acid oxidation deficiencies, characteristic biochemical findings of SCADD may be absent except during times of physiologic stress such as fasting and illness. A diagnosis of SCADD based on clinical findings should not preclude additional testing to look for other causes.

Diagnosis/testing: SCADD has been defined as the presence of:

1. Increased butyrylcarnitine (C4) concentrations in plasma and/or increased ethylmalonic acid (EMA) concentrations in urine under non-stressed conditions (on at least two occasions);

   AND

2. Biallelic ACADS pathogenic variants.

Management: Treatment of manifestations: As most individuals with SCADD are asymptomatic, there is no need for treatment. There are no generally accepted recommendations for dietary manipulation or use of carnitine and/or riboflavin supplementation.

Prevention of primary manifestations: No preventive measures are necessary.

Surveillance: Longitudinal follow up of persons with SCADD on a research basis may be helpful in order to more clearly define the natural history over the life span, including annual visits to a metabolic clinic to assess growth and development as well as nutritional status (protein and iron stores, concentration of RBC or plasma essential fatty acids, and plasma carnitine concentration).

Genetic counseling: SCADD is inherited in an autosomal recessive manner. At conception, each sib of an individual with SCADD has a 25% chance of inheriting biallelic ACADS pathogenic or susceptibility variants and possibly developing clinical findings associated with SCADD, a 50% chance of being a carrier of an ACADS pathogenic variant, and a 25% chance of not being a carrier. If the pathogenic variants in the family have been identified, carrier testing for at-risk family members is possible, and prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible but not necessary and not recommended.