Short Chain Acyl CoA Dehydrogenase Deficiency (SCAD)

Short Chain Acyl CoA Dehydrogenase Deficiency (SCAD)

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Short Chain Acyl CoA Dehydrogenase Deficiency (SCAD) is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • lipid-storage myopathy associated with SCAD deficiency
  • acyl-CoA dehydrogenase deficiency, short-chain
  • SCAD deficiency
  • SCAD deficiency, adult-onset (localized)
  • SCAD deficiency, congenital (generalized)
  • SCADH deficiency

Disorder Subdivisions

  • None

General Discussion

Short chain acyl-CoA dehydrogenase (SCAD) deficiency 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 well and asymptomatic.



When symptoms are present, they are variable, ranging from severe, neonatal acidosis to mild developmental delay with hypotonia.

Symptoms

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).

Causes

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 40 mutations in the ACADS gene cause SCAD deficiency. 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.

Affected Populations

SCAD deficiency is thought to affect 1 in 40,000 to 100,000 newborns.

Standard Therapies

Diagnosis

Diagnosis of SCAD deficiency in the appropriate clinical setting 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

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.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.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: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



For information about clinical trials conducted in Europe, contact:

https://www.clinicaltrialsregister.eu/

References

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.



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.



Waisbren SE, Levy HL, Noble M, Matern D, Gregersen N, Pasley K, Marsden D. (2008). 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. 1995: 39-45.



INTERNET

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Acyl-Coa Dehydrogenase, Short-Chain; Acads. Entry Number: 606885. Last Update:10/5/11. Available at http://www.omim.org/entry/606885?search=606885&highlight=606885 Accessed June 10, 2013.

Resources

CLIMB (Children Living with Inherited Metabolic Diseases)

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Organic Acidaemias UK

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FOD (Fatty Oxidation Disorders) Family Support Group

PO Box 54

Okemos, MI 48864

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Tel: (517)381-1940

Fax: (866)290-5206

Email: deb@fodsupport.org

Internet: http://www.fodsupport.org



Save Babies Through Screening Foundation

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Genetic and Rare Diseases (GARD) Information Center

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Madisons Foundation

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Childhood Liver Disease Research and Education Network

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Tel: (720)777-2598

Fax: (720)777-7351

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For a Complete Report

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