NORD gratefully acknowledges Jerry Vockley, MD, PhD, Professor of Pediatrics and Human Genetics, University of Pittsburgh and Chief of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, for assistance in the preparation of this report.
Short chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive genetic disorder of fatty acid catabolism belonging to a group of diseases known as fatty acid oxidation disorders (FOD). It occurs because of a deficiency of the short-chain acyl-CoA dehydrogenase (SCAD) enzyme.
Although SCAD was initially thought to produce severe problems including progressive muscle weakness, hypotonia, acidemia, developmental delay, and even early death, it is now believed that this disorder is both more common and less severe in many cases than originally thought at the time of its discovery 20 years ago. Since the advent of expanded newborn screening programs using tandem mass spectrometry technology, many more SCAD infants are being detected, most of whom are asymptomatic.
When symptoms are present, they are variable, ranging from severe, neonatal acidosis to mild developmental delay with hypotonia.
Most individuals identified through newborn screening have been healthy. However, a variety of symptoms have been reported in other individuals with SCAD deficiency. Clinical findings include poor feeding habits, frequent vomiting, failure to thrive, progressive muscle weakness, loss of muscle tone (hypotonia), growth delays, impaired mental development, and/or lethargy. Other symptoms may include abnormally low levels of circulating glucose in the blood (hypoglycemia), accumulation of excessive amounts of fatty acids in muscle and/or liver tissue, and/or abnormally high levels of ammonia in the blood (hyperammonemia). Unusually low levels of carnitine, a substance necessary for mitochondrial fatty acid oxidation, in muscle tissue (secondary carnitine deficiency) may also occur.
Rarely, some infants with congenital SCAD show signs of abnormal fluid accumulation in the brain (cerebral edema), enlargement of the liver and spleen (hepatosplenomegaly), fatty changes in the liver, suppression of the flow of bile from the liver (cholestasis), and/or progressive loss of liver function (focal hepatocellular necrosis).
SCAD deficiency is an autosomal recessive genetic disorder caused by mutations in the acyl-Coenzyme A dehydrogenase, C-2 to C-3 short chain (ACADS) gene leading to deficiency of the SCAD enzyme.
The SCAD enzyme is involved in the breakdown of complex fatty acids into more simple substances. This takes place in the cell’s mitochondria, small, well-defined bodies found in all cells in which energy is generated from the breakdown of complex substances into simpler ones (mitochondrial oxidation). When this enzyme is deficient, excessive amounts of fatty acids accumulate in the liver and muscle tissues, and ammonia and other products accumulate in the blood and body tissues.
More than 100 different mutations in the ACADS gene cause SCADD. Two common variations (polymorphisms) have also been found in the ACADS gene. Most people with one or both of these polymorphisms are clinically well, but hypotonia and developmental delay have been reported. It has been suggested that SCAD deficiency may be a risk factor for neuromuscular disorders rather than a consistent disorder on its own. The full clinical spectrum of this deficiency, and the clinical relevance of the common polymorphisms, remains to be defined.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Diagnosis of SCADD should be suspected on the basis of elevated ethylmalonic acid (EMA) excretion in urine. Patients with this finding should have whole gene sequencing. If a mutation is not identified and EMA excretion is persistent, additional clinical evaluation is warranted as another diagnosis is likely. The presence of the common polymorphisms generally leads to reduction of muscle SCAD activity to 50-67% of normal; rarely, patients with no other identifiable mutations have had complete loss of activity. However, there is little or no clinical utility in measuring enzyme activity and muscle biopsy is not recommended to diagnosis SCAD deficiency.
As noted above, expanded newborn screening with tandem mass spectrometry is identifying more infants affected by SCAD than in the past. There is marked genetic, biochemical and clinical variation in the patients detected in the newborn screening programs.
Treatment for SCAD deficiency has typically been dietary, consisting of reduction of fat intake to 25% of calories from fat, with smaller, more frequent meals to avoid reliance on beta-oxidation. However, these measures are probably unnecessary when an affected individual is otherwise well. In episodes of acute metabolic acidosis, intravenous hydration with a solution containing 10% glucose should be used to reestablish an anabolic state, followed by reintroduction of the patient’s usual diet. Routine supplementation with carnitine is not likely to be of use chronically, though short-term use in acute crises may be warranted.
Genetic counseling is recommended for patients and their families. Other treatment is symptomatic and supportive.
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