Última actualización:
2/26/2025
Años publicados: 1996, 1998, 2004, 2009, 2010, 2013, 2016, 2019, 2025
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 genetic abnormality in fatty acid catabolism. SCADD is in a group of diseases known as fatty acid oxidation disorders (FOD). SCADD occurs because of a deficiency of the short-chain acyl-CoA dehydrogenase (SCAD) enzyme and is inherited in an autosomal recessive pattern.
SCADD was initially thought to produce severe problems including progressive muscle weakness, hypotonia, acidemia, developmental delay and even early death, but it is now thought that this deficiency does not lead to health problems. Since the advent of expanded newborn screening programs using tandem mass spectrometry technology, many more infants with SCADD have been identified, all of whom do not have these symptoms.
When symptoms are present, additional diagnostic testing for another condition should be performed as the association is likely coincidental rather than causative.
Essentially all individuals identified with SCADD through newborn screening have been healthy. Therefore, the symptoms reported previously in individuals with SCAD deficiency are all likely coincidental. Importantly, there are two very common variants in the ACADSÂ gene that lead to blood and urine findings suggestive of SCADD but are not sufficiently severe to cause complete SCADD.
SCADD is an autosomal recessive condition caused by variants in the short chain acyl-coenzyme A dehydrogenase (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 mitochondria, the small, well-defined bodies found in all cells in which energy is generated from the breakdown of complex substances into simpler ones (mitochondrial oxidation). Because this enzyme occurs at the very end of the fatty acid oxidation pathway, the compounds that accumulate can be utilized by other enzymes, preventing clinical symptoms from occurring.
More than 100 different variants in the ACADS gene cause SCADD including two common variants. It has been suggested that SCAD deficiency may be a risk factor that can make other neuromuscular disorders worse, but this remains unproven.
SCADD follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
SCAD deficiency is thought to affect 1 in 40,000 to 100,000 newborns. In the US, ~10% of individuals have two copies of one of the common ACADS gene variants leading to potential identification of related metabolites in urine or blood.
Diagnosis of SCADD should be suspected based on elevated ethylmalonic acid (EMA) excretion in urine or butyrylcarnitine (C4 carnitine) in blood. People with this finding should have whole gene sequencing. If a gene variant is not identified and EMA excretion is persistent, additional clinical evaluation is warranted as another diagnosis is likely. The presence of the common ACADS gene variants generally lead to reduction of muscle SCAD activity to 50-67% of normal. Rarely, people with no other identifiable gene variants have had complete loss of enzyme activity. However, there is little or no clinical benefit 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 with SCADD than in the past. Adjustment of the screening results interpretation can usually differentiate between individuals having the common gene variants compared to complete SCADD.
Treatment
There is no need to treat SCADD.
Genetic counseling is recommended for patients and their families.
As of 2025, no clinical trials are underway.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email:Â [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Vockley J, Organic Acidemias and Disorders of Fatty Acid Oxidation. In: Emory and Rimoin Eds. Principles and Practice of Medical Genetics 5th edition. Harcourt Health Sciences Companies. 2006.
Vockley J. Short-Chain Acyl-CoA Dehydrogenase Deficiency. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:438-39.
Roe, CR, Ding J. Mitochondrial Fatty Acid Oxidation Disorders. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:2299-300; 2315-318.
JOURNAL ARTICLES
Gallant NM, Leydiker K, Tang H, Feuchtbaum L, Lorey F, Puckett R, Deignan JL, Neidich J, Dorrani N, Chang E, Barshop BA, Cederbaum SD, Abdenur JE, Wang RY. Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California. Mol Genet Metab. 2012;106(1):55-61.
van Maldegem BT, Wanders RJ, Wijburg FA. Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2010;33(5):507-11.
Jethva R, Bennett MJ, Vockley J. Short-chain acyl-coenzyme A dehydrogenase deficiency. Molecular Genetics & Metabolism. 2008; 95:195-200.
Waisbren SE, Levy HL, Noble M, Matern D, Gregersen N, Pasley K, Marsden D. Short-chain acyl-CoA dehydrogenase (SCAD) deficiency: an examination of the medical and neurodevelopmental characteristics of 14 cases identified through newborn screening or clinical symptoms. Mol Genet Metab. 2008 Sep-Oct;95(1-2):39-45.
van Maldegem BT, Duran M, Wanders RJ, Niezen-Koning KE, Hogeveen M, Ijlst L, Waterham HR, Wijburg FA. Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency. JAMA. 2006; 296: 943-52.
Koeberl DD, Young SP, Gregersen NS, et al. Rare disorders of metabolism with elevated butyryl- and isobutyryl-carnitine detected by tandem mass spectrometry newborn screening. Pediatr Res. 2003;54:219-23.
Van Hove JL, Grunewald S, Jaeken J, et al. D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD). Lancet. 2003;361:1433-435.
Nagan N, Kruckeberg KE, Tauscher AL, et al. The frequency of short-chain acyl-CoA dehydrogenase gene variants in the US population and correlation with the C(4)-acylcarnitine concentration in newborn blood spots. Mol Genet Metab. 2003;78:239-46
Pedersen CB, Bross P, Winter VS, Corydon TJ, Bolund L, Bartlett K, Vockley J, Gregersen N. Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency. Journal of Biological Chemistry. 2003; 278:47449-58.
Seidel J, Streck S, Bellstedt K, et al. Recurrent vomiting and ethylmalonic aciduria associated with rare mutants of short-chain acyl-CoA dehydrogenase gene. J Inherit Metab Dis. 2003;26:37-42.
Leonard JV, Dezateux C. Screening for inherited metabolic disease in newborn infants using tandem mass spectrometry. BMJ. 2002;324:4-5.
Tein I, Role of carnitine and fatty acid oxidation and its defects in infantile epilepsy. J Child Neurol. 2002;17 Suppl 3:3S57-82; discussion 3S82-83.
Gregersen N, Andresen BS, Corydon MJ, et al. Mutation analysis in mitochondrial Fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Hum Mutat. 2001;18:169-89.
Corydon M, Vockley J, Rinaldo R, et al. Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res. 2001;49:18-23.
Marsden D, Nyhan WL, Barshop BA. Creatine kinase and uric acid: early warning for metabolic imbalance resulting from disorders of fatty acid oxidation. Eur J Pediatr. 2001;160:599-602.
Matern D, Hart P, Murtha A, et al. Acute fatty liver of pregnancy associated with short-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr. 2001;xx:585-588.
Gregersen N, Bross P, Jorgensen MM, et al. Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders. J Inherit Metab Dis. 2000;23:441-47.
Gregersen N, Andresen BS, Bross P. Prevalent mutations in fatty acid oxidation disorders: diagnostic considerations. Eur J Pediatr. 2000;159:S213-S218.
Rinaldo P. Mitochondrial fatty acid oxidation disorders and cyclic vomiting syndrome. Dig Dis Sci. 1999;44(8 Suppl):97S-102S.
Gregersen N, Winter VS, Corydon MJ, et al. Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C.T, is present at an unexpectedly high frequency in the general population, as was the case for 625G>A, together conferring susceptibility to ethylmalonic aciduria. Hum Mol Genetics. 1998;7:619-627.
Corydon MJ, Gregersen N, Lehnert W, et al. Ethylmalonic aciduria is associated with an amino acid variant of short chain acyl-coenzyme A dehydrogenase. Pediatr Res. 1996;39:1059-1066.
INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University. Acyl-Coa Dehydrogenase, Short-Chain; ACADS. Entry Number: 606885. Last Update:10/5/11. Available at https://www.omim.org/entry/606885?search=606885&highlight=606885 Accessed Feb 5, 2025.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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