Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is a condition that prevents the body from converting certain fats into energy, especially during periods without food (fasting).

Signs and symptoms of SCAD deficiency may appear during infancy or early childhood and can include vomiting, low blood glucose (hypoglycemia), a lack of energy (lethargy), poor feeding, and failure to gain weight and grow at the expected rate (failure to thrive). Other features of this disorder may include poor muscle tone (hypotonia), seizures, developmental delay, and a small head size (microcephaly).

The symptoms of SCAD deficiency may be triggered by fasting or illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe condition that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.

In some people with SCAD deficiency, signs and symptoms do not appear until adulthood. These individuals are more likely to have problems related to muscle weakness and wasting.

The severity of this condition varies widely, even among members of the same family. Some individuals are diagnosed with SCAD deficiency based on laboratory testing but never develop any symptoms of the condition.

Mutations in the ACADS gene cause SCAD deficiency. This gene provides instructions for making an enzyme called short-chain acyl-CoA dehydrogenase, which is required to break down (metabolize) a group of fats called short-chain fatty acids. Fatty acids are a major source of energy for the heart and muscles. During periods of fasting, fatty acids are also an important energy source for the liver and other tissues.

Mutations in the ACADS gene lead to a shortage (deficiency) of the SCAD enzyme within cells. Without sufficient amounts of this enzyme, short-chain fatty acids are not metabolized properly. As a result, these fats are not converted into energy, which can lead to the signs and symptoms of this disorder, such as lethargy, hypoglycemia, and muscle weakness. It remains unclear why some people with SCAD deficiency never develop any symptoms.

Normal Function

The ACADS gene provides instructions for making an enzyme called short-chain acyl-CoA dehydrogenase (SCAD). This enzyme functions within mitochondria, the energy-producing centers within cells. SCAD is essential for fatty acid oxidation, which is the multistep process that breaks down (metabolizes) fats and converts them to energy.

SCAD is required to metabolize a group of fats called short-chain fatty acids. These fatty acids are found in some foods and are also produced when larger fatty acids are metabolized. Fatty acids are a major source of energy for the heart and muscles. During periods without food (fasting), fatty acids are also an important energy source for the liver and other tissues.

Health Conditions Related to Genetic Changes

Short-chain acyl-CoA dehydrogenase deficiency

More than 55 mutations in the ACADS gene have been found to cause short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Almost all of these mutations change single protein building blocks (amino acids) in the SCAD enzyme. These mutations prevent the enzyme from properly metabolizing short-chain fatty acids. As a result, these fats are not converted into energy, which can lead to the characteristic signs and symptoms of this disorder, including lack of energy (lethargy), low blood glucose (hypoglycemia), poor muscle tone (hypotonia), and weakness.

Researchers have also identified two common variations (polymorphisms) in the ACADS gene that each change one amino acid in the SCAD enzyme. Unlike other changes in the ACADS gene, these polymorphisms do not cause SCAD deficiency but may increase a person's risk of developing this disorder. One of these polymorphisms replaces the amino acid arginine with the amino acid tryptophan at protein position 147 (written as Arg147Trp or R147W). The other polymorphism switches the amino acid glycine with the amino acid serine at protein position 185 (written as Gly185Ser or G185S). Other genetic and environmental factors likely influence the risk of developing SCAD deficiency when a person carries either of these polymorphisms.

Other Names for This Gene

• ACAD3
• ACADS_HUMAN
• acyl-CoA dehydrogenase, C-2 to C-3 short chain
• acyl-Coenzyme A dehydrogenase, C-2 to C-3 short chain precursor
• Butyryl dehydrogenase
• Butyryl-CoA dehydrogenase
• SCAD
• Unsaturated acyl-CoA reductase

Genomic Location

SCAD deficiency is a genetic condition. Babies inherit it from their biological (birth) parents.

• SCAD deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking ACADS gene to their baby. Only babies with two nonworking ACADS genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the ACADS gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the ACADS gene, they have a 1 in 4 chance of having a child with SCAD deficiency.
  • Carriers for SCAD deficiency often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with SCAD deficiency.
  • Parents who already have a child with SCAD deficiency still have a 1 in 4 chance of having another child with SCAD deficiency. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Most babies and children with SCAD deficiency have no signs or symptoms. In rare cases, some signs of the condition may be triggered by common illnesses (like a cold or flu) or a long time without food.

For children who do have signs of SCAD deficiency, signs may include the following:

• Low blood sugar (hypoglycemia)
• Small head size (microcephaly)
• Weakness
• Tiredness or lack of energy (lethargy)

Newborn screening for SCAD deficiency is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much of certain substances (called acylcarnitines) are in your baby’s blood. Babies with high levels of these substances might have SCAD deficiency.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for SCAD deficiency is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible.

False-positive newborn screening results for this condition can happen. Babies given carnitine might receive false-positive results.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps.