Background Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency is a disorder of fatty acid ß-oxidation. The defect involves short-chain (butyryl) acyl-CoA dehydrogenase, one of four mitochondrial acyl-CoA dehydrogenases that carry out the initial dehydrogenation step in the ß-oxidation cycle. SCAD deficiency impairs oxidation of fatty acids of short-chain length (4 carbons).
Clinical
SCAD deficiency usually has clinical onset between the second month and second year of life, although presentations as early as two days and as late as adulthood have been reported. Clinical presentation is highly variable with patients having constant symptoms marked by episodic deterioration. Patients have hypotonia, progressive muscle weakness, developmental delay and, possibly seizures. Failure to thrive, vomiting, and hypoglycemia may be seen. Symptoms may be worsened by a seemingly innocuous illness (a cold or otitis media) that is associated with prolonged fasting, which may lead to lethargy, coma, apnea, cardiopulmonary arrest, or sudden unexplained death. Physical examination of the acutely ill child may reveal mild to moderate hepatomegaly. Symptoms often precede the onset of hypoglycemia, which occurs from an inability to meet gluconeogenic requirements during fasting despite activation of an alternate pathway of substrate production - proteolysis. Cerebral edema and fatty liver and muscle are noted at autopsy, often leading to a misdiagnosis of Reye’s Syndrome or Sudden Infant Death Syndrome (SIDS). SCAD deficiency accounts for about one of every 100 SIDS deaths. Older patients who present chiefly with progressive muscle involvement may respond to riboflavin (Vitamin B2) supplementation and have a generalized multiple acyl-CoA dehydrogenase deficiency. SCAD enzyme is the most vulnerable dehydrogenase to low riboflavin levels.
Testing
Newborn screening by tandem mass spectrometry of a dried blood spot identifies elevated levels of butyrylcarnitine (C4 acylcarnitine), usually with an elevated C4/C2 ratio. These results can be seen with another metabolic genetic defect (Isobutyryl-CoA Dehydrogenase Deficiency - IBDH) and therefore require further testing. Laboratory examination of blood may reveal hypoglycemia, mild metabolic acidosis, mild lactic acidosis, hyperammonemia, elevated BUN, and high uric acid levels. Liver function tests are often abnormal. Examination of the urine may show ketones, and urine organic acids often have elevated ethylmalonic acid. Plasma carnitine may be normal or low. Analysis of fibroblasts for the activity of SCAD identifies affected individuals, while heterozygous carriers for the defect usually have intermediate levels of activity, but are otherwise clinically and biochemically unaffected. SCAD activity should be assayed after antibody precipitation of MCAD activity, due to the overlap of substrate recognition. Detection of mutations in the SCAD gene on chromosome 12 in affected individuals allows for confirmation of biochemical testing and detection of asymptomatic carriers in other family members. In addition to disease-causing mutations, the gene has two common polymorphisms, which may interact to cause reductions in SCAD activity and complicate the genetic analysis. DNA analysis of postmortem tissue is possible when plasma and urine samples are not available. Prenatal diagnosis is possible from cultured amniocytes using direct enzyme assay. DNA analysis in amniocytes or chorionic villi can also be helpful in the diagnosis of affected fetuses in pregnancies at risk where both parents carry a known mutation.
Treatment
Fundamental to the medical management of SCAD deficiency is to avoid fasting, particularly during periods of high metabolic stress, such as illness. Overnight fasts should be managed with nighttime or late evening feedings where appropriate. The addition of food-grade uncooked cornstarch mixed in liquid for a bedtime feeding has helped to decrease the frequency of morning hypoglycemic episodes in several patients. High carbohydrate intake should be encouraged during illness, with initiation of intravenous glucose supplementation if the child is unsuccessful in keeping down fluids, or unable to take adequate oral feedings. The preventive efficacy of a low fat diet versus a normal fat diet is unclear, but high intake of long and medium chain fatty acids should be avoided. Supplementation with oral L-carnitine may be indicated during acute illness. For individuals with SCAD deficiency, it is imperative that the lethargic patient receives parenteral dextrose to avoid hypoglycemia during evaluation. Because the diagnosis and therapy of SCAD deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.
Inheritance
This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder. As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.
References Amendt, B.A., Greene, C., Sweetman, L., et al. Short-chain acyl-coenzyme A dehydrogenase deficiency: Clinical and biochemical studies in two patients. J Clinical Investigation 79:1303, 1987. Coates, P.M., Hale, D.E., Finocchiaro, G., et al. Genetic deficiency of short-chain acyl-coenzyme A dehydrogenase in cultured fibroblasts from a patient with muscle carnitine deficiency and severe skeletal muscle weakness. J Clinical Investigation 81:171, 1988. Corydon, M.J., Vockley, J., Rinaldo, P., et al. Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 49:18, 2001. Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Oxidation Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg. 2297-2326.
Web Sites SaveBabies.org
Site established and maintained by parents of newborns affected with a rare genetic defect, with information for parents and professionals and links to other informative sites. National Newborn Screening and Genetics Resource Center
Provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.
Disclaimers
The analyses conducted by PerkinElmer Genetics produce results that can be used by qualified physicians in the diagnosis of disorders described herein. Evidence of these conditions will be detected in the vast majority of affected individuals; however, due to genetic variability, age of the patient at the time of specimen collection, quality of the specimen, health status of the patient, and other variables, such conditions may not be detected in all affected patients. PerkinElmer Genetics makes no warranty whatsoever, express or implied, including any warranty as to accuracy, completeness or timeliness, concerning the information contained herein, and you should not assume that such information is complete or the most up-to-date information available. PerkinElmer Genetics shall not be liable for any loss, claim or damages caused in whole or in part by our provision of, or your use of, any of the information contained herein. As a general statement, this information was drawn from published literature and is not drawn from our patient population or screening experience. The information contained herein is not intended to be a substitute for professional medical advice and should not be used for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions.
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