Individuals with symptomatic SCADD may show relatively severe phenotype, while the majority of those who are diagnosed through newborn screening by tandem mass spectrometry may remain asymptomatic (PMID:28516284).
SCAD deficiency is an autosomal recessive metabolic disorder of fatty acid beta-oxidation. Clinical features are variable: a severe form of the disorder can cause infantile onset of acidosis and neurologic impairment, whereas some patients develop only myopathy. With the ...SCAD deficiency is an autosomal recessive metabolic disorder of fatty acid beta-oxidation. Clinical features are variable: a severe form of the disorder can cause infantile onset of acidosis and neurologic impairment, whereas some patients develop only myopathy. With the advent of screening for inborn errors of metabolism, patients with putative pathogenic mutations but who remain asymptomatic have also been identified (summary by Shirao et al., 2010)
The definitive diagnostic test for SCAD deficiency is an ETF-linked enzyme assay with butyryl-CoA as a substrate, performed after immunoactivation of MCAD, which has similar activity (Bhala et al., 1995; Tein et al., 1999).
Two distinct clinical phenotypes of hereditary short-chain acyl-CoA dehydrogenase deficiency have been identified. One type has been observed in infants with acute acidosis and muscle weakness; the other has been observed in middle-aged patients with chronic myopathy. SCAD deficiency ...Two distinct clinical phenotypes of hereditary short-chain acyl-CoA dehydrogenase deficiency have been identified. One type has been observed in infants with acute acidosis and muscle weakness; the other has been observed in middle-aged patients with chronic myopathy. SCAD deficiency is generalized in the former type and localized to skeletal muscles in the latter. Cases with neonatal onset have a variable phenotype that includes metabolic acidosis, failure to thrive, developmental delay, and seizures, as well as myopathy (Roe and Ding, 2001). There are no episodes of nonketotic hypoglycemia, which are characteristic of medium-chain (MCAD; 607008) and very long-chain (VLCAD; 201475) acyl dehydrogenase deficiencies. Amendt et al. (1987) described 2 unrelated patients, both of whom presented with neonatal metabolic acidosis and ethylmalonate excretion. Deficiency of short-chain acyl-CoA dehydrogenase was demonstrated in fibroblasts by both an electron-transfer flavoprotein (ETF)-linked dye-reduction assay and a tritium release ADH assay. Coates et al. (1988) demonstrated deficiency of SCAD in a 2-year-old female whose early postnatal life was complicated by poor feeding, emesis, and failure to thrive. She demonstrated progressive skeletal muscle weakness and developmental delay. Her plasma total carnitine level was low-normal, but was esterified to an abnormal degree. The same was true for skeletal muscle carnitine. Fibroblasts from this patient had 50% of control levels of acyl-CoA dehydrogenase activity towards butyryl-CoA as substrate. All of this residual activity was inhibited by an antibody against medium-chain acyl-CoA dehydrogenase. These data demonstrated that medium-chain acyl-CoA dehydrogenase accounted for 50% of the activity towards the short-chain substrate, butyryl-CoA, under these conditions, but that antibody against that enzyme could be used to unmask the specific and virtually complete deficiency of short-chain acyl-CoA dehydrogenase in this patient. Bhala et al. (1995) summarized the clinical and biochemical features of 6 cases of SCAD deficiency, including the only 4 authentic cases that they were able to identify in the literature. In contrast to MCAD and LCAD deficiency, they found no evidence of secondary carnitine deficiency, and further found that hypoglycemia may not be a prominent clinical feature. All patients with SCAD had neurologic deficits: hypotonia/hypertonia, hyperactivity, and/or developmental delay. Ribes et al. (1998) reported mild or absent clinical manifestations in monozygous twin sisters with SCAD deficiency. One twin developed hypotonia and decreased level of consciousness following an upper respiratory infection at 5 months. The other was essentially asymptomatic. Ethylmalonic acid was persistently, although sometimes only slightly, increased in both. SCAD activity was 25% and 16% of control levels. Immunoblot analysis in cultured skin fibroblasts indicated that SCAD protein was of normal size, but was less than 10% of control cell intensity. Tein et al. (1999) described a novel phenotype of multicore myopathy and ophthalmoplegia (see 255320) in a 13.5-year-old Israeli girl in whom there was no detectable SCAD protein on Western blot analysis. Decreased fetal movements as well as facial weakness and a fish mouth were noted at birth. Hypotonia was observed at 3 months of age. She became wheelchair dependent at age 5 years, with proximal weakness with wasting and contractures, arreflexia, ptosis, progressive external ophthalmoplegia, and cataracts. At age 10 she developed transient heart failure. Intelligence, sensation, cerebellar function, and plantar responses were normal. Gregersen et al. (1998) investigated ethylmalonic aciduria in a Spanish girl and an African American male, as well as in 133 patients with elevated ethylmalonic acid excretion. They concluded that ethylmalonic aciduria, a commonly detected biochemical phenotype, is a complex multifactorial/polygenic condition where, in addition to the emerging role of SCAD susceptibility alleles, other genetic and environmental factors are involved. Corydon et al. (2001) came to the same conclusion based on their study of 10 patients with ethylmalonic aciduria. Tein et al. (2008) reported 10 children of Ashkenazi Jewish descent with variable phenotypic expression of SCAD deficiency. Common clinical features included hypotonia, developmental delay, speech delay, myopathy, lethargy, and feeding difficulties. Muscle biopsy was performed in 3 patients and showed 2 with histologic features of multiminicore myopathy and 1 with lipid storage disease. Laboratory abnormalities included ethylmalonic aciduria and methylsuccinic aciduria, as well as increased serum acyl carnitines. - Clinical Variability Baerlocher et al. (1997) stated that up until 1996 about 10 patients in whom SCAD enzyme deficiency could be confirmed in fibroblasts had been described. Both the clinical and the biochemical pattern of the disease was heterogeneous, with all patients showing at least neuromuscular signs. Baerlocher et al. (1997) presented the case of a 16-year-old patient with growth failure, muscular wasting, and hypotonia since birth. Turnbull et al. (1984) reported the case of a 53-year-old woman who presented with a lipid-storage myopathy and low concentrations of carnitine in skeletal muscle. Impaired fatty acid oxidation in muscle was found to be caused by deficiency of short-chain acyl-CoA (butyryl-CoA) dehydrogenase activity in mitochondria. The authors suggested that the muscle carnitine deficiency was secondary to this enzyme deficiency and urged that it be considered in other cases of lipid-storage myopathy with carnitine deficiency (212160). Onset of myopathy was at age 46 years. The patient described by Turnbull et al. (1984) had normal SCADH activity in fibroblasts, which raises the possibility that a distinct SCADH isoenzyme exists in mammalian muscle. However, Amendt et al. (1992) found that in mice SCAD is the same in both muscle and fibroblasts. For that reason, Bhala et al. (1995) proposed that the case of Turnbull et al. (1984) was not a primary case of SCAD deficiency but rather a case of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency, as reported by DiDonato et al. (1989). Pedersen et al. (2008) observed clinical variation among 114 patients with SCAD deficiency ranging in age from 0 to 50 years. Twenty-nine patients (25%) showed some clinical symptoms on the first day of life, 70 (61%) were identified within the first year of life, and only 4 (4%) were more than 10 years of age when diagnosed. The 12 most frequent symptoms were: developmental delay, speech delay, hypotonia, failure to thrive, feeding difficulties, seizures, dysmorphic features, hypoglycemic encephalopathy, microcephaly, optic atrophy, muscular hypertonia, and lethargy. Hierarchical cluster analysis was performed on clinical data from 29 patients presenting with 3 or 4 of the most frequent symptoms and revealed 3 prominent symptom groups: (1) failure to thrive with feeding difficulties and hypotonia as the most characteristic features (23 patients; 20%), (2) developmental delay and seizures (29 patients; 25%), and (3) developmental delay and hypotonia without seizures (34 patients; 30%). A fourth symptom group consisting of 16 patients (14%) showed failure to thrive, developmental delay, and hypotonia. The remaining 8 patients (7%) had a heterogeneous mixture of other symptoms including dysmorphic features, myopathy, cardiomyopathy, hepatic steatosis, respiratory distress, and intrauterine growth retardation, while 4 were reported to have no symptoms. Molecular analysis identified 29 different mutations in the ACADS gene, but there were no clear genotype/phenotype correlations. Pedersen et al. (2008) suggested that pathogenic ACADS protein misfolding is necessary, but not sufficient, for expression of the disease. Shirao et al. (2010) reported unrelated Japanese girls with biochemical evidence of SCAD deficiency detected by newborn screening. However, neither girl had clinical symptoms at age 4 years. Each girl carried compound heterozygous missense mutations in the ACADS gene (606885.0014-606880.0016) that were demonstrated in vitro to have less than 10% residual enzyme activity. Shirao et al. (2010) noted that the genotype/phenotype correlation was unclear
Gregersen et al. (2001) reviewed current understanding of genotype-phenotype relationships in VLCAD (201475), MCAD, and SCAD. They discussed both the structural implications of mutation type and the modulating effect of the mitochondrial protein quality control systems, composed of molecular ...Gregersen et al. (2001) reviewed current understanding of genotype-phenotype relationships in VLCAD (201475), MCAD, and SCAD. They discussed both the structural implications of mutation type and the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. The realization that the effect of the monogene, such as disease-causing mutations in these 3 genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. They stated that the rapid development of mutation detection systems, such as chip technologies, made such profile analyses feasible
Naito et al. (1989) studied the mutant SCAD enzyme and cultured fibroblasts from 3 patients with the deficiency. No difference was observed on Southern or Northern blot analysis, suggesting that the defects in these cell lines were caused by ...Naito et al. (1989) studied the mutant SCAD enzyme and cultured fibroblasts from 3 patients with the deficiency. No difference was observed on Southern or Northern blot analysis, suggesting that the defects in these cell lines were caused by point mutation. In a patient with SCAD deficiency, Naito et al. (1989) found evidence of compound heterozygosity for 2 mutations in the ACADS gene (136C-T; 606885.0001 and 319C-T; 606885.0002). Among 10 children of Ashkenazi Jewish descent with SCAD deficiency, Tein et al. (2008) found that 3 were homozygous for the ACADS 319C-T mutation and 7 were compound heterozygous for the 319C-T mutation and the 625G-A (606885.0007) disease susceptibility polymorphism. The highest concentrations of ethylmalonic aciduria were found in those homozygous for the 319C-T mutation. Five presumably unaffected parents were also compound heterozygous for the 319C-T mutation and 625G-A, indicating that this allelic combination is compatible with a milder or asymptomatic phenotype. Tein et al. (2008) noted the highly variable phenotypic manifestations among patients with similar mutations
In the US, most infants with short-chain acyl CoA dehydrogenase (SCAD) deficiency are identified through newborn screening (NBS) programs. ...
DiagnosisClinical Diagnosis In the US, most infants with short-chain acyl CoA dehydrogenase (SCAD) deficiency are identified through newborn screening (NBS) programs. Older children and adults may be identified with SCAD deficiency after undergoing a biochemical evaluation, typically for hypotonia, dystonia, seizures, metabolic acidosis associated with illness, and/or hypoglycemia [Corydon et al 2001]. TestingSCAD deficiency has been defined by van Maldegem et al [2006] as the presence of:On at least two occasions, increased butyrylcarnitine (C4) concentrations in plasma or bloodspot, and/or increased ethylmalonic acid (EMA) concentrations in urine under non-stressed conditions An alteration of both ACADS alleles by either a mutation or a susceptibility variant. Mutations are typically missense changes that inactivate or impair SCAD enzymatic activity; the susceptibility variants are c.511C>T and c.625G>A (see Molecular Genetics). In the literature, the genotypes of individuals with SCAD deficiency may be generally described as mutation/mutation, mutation/variant, or variant/variant. Relatives are considered affected if they have the same ACADS genotype as the proband and increased C4-C concentrations in plasma and/or increased EMA concentrations in urine [van Maldegem et al 2006].Acylcarnitine profileAcylcarnitine analysis by tandem mass spectrometry is used to detect elevated blood C4 (butyrylcarnitine) on newborn screening. Note: (1) Normal ranges for isolated C4 vary from state to state, necessitating confirmatory testing consistent with the American College of Medical Genetics (ACMG) ACT sheets (see ). Depending on the screening cutoff values used for butyrylcarnitine concentration, most infants with abnormal results are either homozygous for a mutation on both ACADS alleles or compound heterozygous for a mutation on one allele and a common susceptibility variant (c.511C>T or c.625G>A) on the other allele [Lindner et al 2010]; however, butyrylcarnitine concentrations from newborns homozygous for the c.625G>A variant overlap with butyrylcarnitine concentrations in newborns homozygous for a mutation or compound heterozygous for a mutation and a susceptibility variant. Thus, molecular confirmation of the diagnosis of SCAD deficiency is necessary. (2) Isobutyryl-CoA dehydrogenase deficiency (IBDD) that leads to elevation of isobutyrylcarnitine, a C4 species also detectable by NBS, must be distinguished from SCAD deficiency by additional laboratory testing.Plasma acylcarnitines can also be used when age-referenced norms are available to detect C4 elevations in older children and adults suspected of having SCAD deficiency.Urine acylglycines. A random urine sample can be used to differentiate butyrylglycine and isobutyrylglycine and to detect elevated EMA as part of either confirmatory testing after a positive newborn screen or diagnostic testing in older children and adults being evaluated for SCAD deficiency. Urine organic acids. A random urine sample can be collected to detect EMA and dicarboxylic acids, which may be helpful in confirmation of an abnormal newborn screen or during acute illnesses. Urine organic acid screening in symptomatic older children and adults may reveal elevated EMA [Pedersen et al 2008].Carnitine levels. Total and free carnitine levels can be used to detect free carnitine deficiency; however carnitine levels are usually normal in individuals with SCAD deficiency. SCAD enzyme activity is difficult to obtain clinically and probably not helpful. Skin fibroblast, fatty acid oxidation studies. In vitro fatty acid probe analysis, a functional assay that assesses function of the entire beta-oxidation pathway, can reflect residual enzyme levels, which may be useful clinically to confirm SCAD deficiency [Young et al 2003].Molecular Genetic Testing Gene. ACADS is the only gene in which mutations are known to cause short-chain acyl-coA dehydrogenase (SCAD) deficiency. Clinical testingSequence analysis of all ten ACADS exons as well as the intron-exon boundaries is highly sensitive and specific for confirming the diagnosis of SCAD deficiency in an individual who has biochemical findings consistent with the diagnosis of SCAD deficiency.Sequence analysis of select exons. Sequence analysis of exons 5 and 6 only detects the common susceptibility variants c.511C>T and c.625G>A. This test may be useful for follow-up of abnormal newborn screening and/or elevated ethylmalonic acid results. Table 1. Summary of Molecular Genetic Testing Used in SCAD DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityACADSSequence analysisSequence variants 2~100%ClinicalTargeted mutation analysis 3c.319C>T and the susceptibility variants c.511C>T, c.625G>A 461% for these 3 nucleotide changes, but may be higher in certain populations Sequence analysis of select exonsSusceptibility variants c.511C>T and c.625G>A in exons 5 and 6See footnote 5Deletion / duplication analysis 3, 6Exonic or whole-gene deletionsNone reported1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Testing for a specific mutation or panel of mutations4. Mutations in panel may vary by laboratory.5. May be useful for follow-up of abnormal newborn screening and/or elevated ethylmalonic acid results. 6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm the diagnosis in a proband. See .1.Obtain acylcarnitine profile from a dried blood spot (newborn screening) or plasma. If C4-C (butyrylcarnitine) is elevated, then: 2.Analyze urine acylglycines or urine organic acids to confirm that C4 (butyrylcarnitine) is elevated and/or ethylmalonic acid (EMA) concentrations are increased, then:3.Perform molecular genetic testing to confirm the diagnosis of SCAD deficiency using ONE of the following: Sequence analysis of ACADS For some individuals:A panel comprising the ACADS mutation c.319C>T and the susceptibility variants c.511C>T and c.625G>A. If neither or only one mutation/variant is identified:Sequence analysis4.If no ACADS mutation is identified consider ETHE1 sequence analysis to detect EMA encephalopathy [Tiranti et al 2004]. See Differential Diagnosis.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies via molecular analysis require prior identification of the disease-causing mutations in the family. Biochemical genetic testing may be available for at-risk pregnancies when the family-specific mutations are not known. Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in ACADS.
The phenotypic spectrum described in short-chain acyl-coA dehydrogenase (SCAD) deficiency ranges from severe (dysmorphic facial features, feeding difficulties/failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy) to normal, raising questions about the relationship between the biochemical phenotype and clinical manifestations [Gregersen et al 2001, van Maldegem et al 2006, Jethva et al 2008, Pedersen et al 2008, van Maldegem et al 2010c]. ...
Natural History The phenotypic spectrum described in short-chain acyl-coA dehydrogenase (SCAD) deficiency ranges from severe (dysmorphic facial features, feeding difficulties/failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy) to normal, raising questions about the relationship between the biochemical phenotype and clinical manifestations [Gregersen et al 2001, van Maldegem et al 2006, Jethva et al 2008, Pedersen et al 2008, van Maldegem et al 2010c]. SCAD deficiency was first reported in two neonates who had increased urinary ethylmalonic acid (EMA) excretion; the diagnosis was confirmed enzymatically in skin fibroblasts [Amendt et al 1987]. One of these infants died of overwhelming neonatal acidosis as would be typical of an organic acidemia. However, over the last 20 years more experience with the natural history of SCAD deficiency in persons with the biochemical phenotype has identified a much broader phenotypic spectrum than originally anticipated.In the largest series published to date, Pedersen et al [2008] summarized the findings in 114 affected individuals who were mostly children undergoing metabolic evaluation for developmental delay. Among the 114 with developmental delay, three sub-groups were identified: 23 (20%) with failure to thrive, feeding difficulties, and hypotonia25 (22%) with seizures34 (30%) with hypotonia without seizuresFour individuals were asymptomatic, identified either through family studies or newborn screening programs. In a retrospective study from the Netherlands, van Maldegem et al [2006] identified 31 individuals who met the biochemical and molecular diagnostic criteria for SCAD deficiency who also had sufficient information on health and development. The most frequently reported clinical findings were developmental delay (16; designated as “non-severe” in 15), epilepsy (11; non-severe in all), behavioral disorder (8; non-severe in 5), and history of hypoglycemia (6; non-severe in 5). Follow up ranged from one to 18 years: two had progressive clinical deterioration, 12 had no change in clinical findings, 8 improved, and 9 had complete recovery. In addition, three parents and six sibs were found to have ACADS genotypes that were identical to the proband; eight of the nine had increased levels of C4-C and/or EMA and one of the six sibs had transient feeding difficulties in the first year. In a study of ten affected individuals of Ashkenazi Jewish ancestry, eight had developmental delay and four had muscle biopsy-proven mini-multicore myopathy [Tein et al 2008]. It has been noted that persons with SCAD deficiency with a myopathy reported as multiminicore disease had not undergone a full evaluation and may have had another unrelated cause for their muscle disease such as mutation of RYR1 or SEPN1 [van Maldegem et al 2010c]. (See Multiminicore Disease.)As in other fatty acid oxidation disorders, characteristic biochemical findings of SCAD deficiency may be absent in affected individuals except during times of physiologic stress including fasting and illness [Bok et al 2003, Pedersen et al 2008]. In addition, manifestations early in life that could be attributed to SCAD deficiency appear to resolve completely during long-term follow up for most individuals diagnosed with SCAD. Since most infants with SCAD deficiency identified through newborn screening programs have been well at the time of diagnosis, the reported relationship of clinical manifestations to the deficiency of SCAD has come into question [Waisbren et al 2008]. If there is an increased risk for clinical manifestations, it is most likely in those individuals with biallelic mutations that inactivate or impair enzymatic activity. Individuals with biallelic susceptibility variants (c.511C>T and c.625G>A) are so frequent in the general population that this finding cannot represent a significant risk for clinical disease. Individuals with an inactivating mutation on one allele and a variant on the other have enzymatic dysfunction that falls between the other two groups, as may their clinical risk.Since the long-term risk for development of disease is not known, it seems prudent to:Offer individuals diagnosed with SCAD deficiency ongoing follow up in order to monitor them and expand clinical knowledge of the disorder; Consider post-mortem evaluation and testing to determine cause of death in any individual with a diagnosis of SCAD deficiency since the disorder is not usually life threatening;Proceed with further diagnostic evaluation in symptomatic individuals (especially infants and young children) with a presumptive diagnosis of SCAD deficiency [Pedersen et al 2008, Bennett 2010, van Maldegem et al 2010c]. Pregnancy-related issues. Acute fatty liver of pregnancy (AFLP), preeclampsia, and/or HELLP syndrome in mothers of affected fetuses have been described [Matern et al 2001, Bok et al 2003, van Maldegem et al 2010c].
Isobutryl acyl-CoA dehydrogenase deficiency and SCAD deficiency must be differentiated by confirmatory testing of C4-C elevations identified on newborn screen....
Differential DiagnosisIsobutryl acyl-CoA dehydrogenase deficiency and SCAD deficiency must be differentiated by confirmatory testing of C4-C elevations identified on newborn screen.Other disorders to consider in the differential diagnosis:Glutaric acidemia type II (GAII), also known as multiple acyl-CoA dehydrogenase deficiency (MADD)Ethylmalonic encephalopathyMitochondrial respiratory chain defectsJamaican vomiting sicknessNote to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with short-chain acyl-coA dehydrogenase (SCAD) deficiency, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with short-chain acyl-coA dehydrogenase (SCAD) deficiency, the following evaluations are recommended:Carnitine levels. Total and free carnitine levels can be used to detect free carnitine deficiency; however, carnitine levels are usually normal in individuals with SCAD deficiency. Urine organic acids; used to detect ethylmalonic acid (EMA) during acute illnesses Treatment of ManifestationsSince most individuals with SCAD deficiency are asymptomatic, the need for treatment when well is unclear. Given the paucity of research, especially long-term follow up studies, there are no generally accepted recommendations for dietary manipulation or the use of carnitine and/or riboflavin supplementation in SCAD deficiency. However, since the risk for episodes of metabolic decompensation is increased above background risk, increased alertness for dehydration, metabolic acidosis, and/or hypoglycemia during times of otherwise minor illness is prudent. Basic management of acute metabolic acidosis should be similar to that for other fatty acid oxidation disorders: promoting anabolism and providing alternative sources of energy, both of which can be accomplished by administration of intravenous fluids with high dextrose concentrations with or without insulin. Usually 10% dextrose is given at a rate to provide 8-10 mg/kg/min of glucose. This approach is especially important if nausea and vomiting prevent the oral intake of fluids. Hypoglycemia is uncommon but can be treated in the same fashion as acute metabolic acidosis. Flavin adenine dinucleotide (FAD) is an essential cofactor for SCAD function. Thus, riboflavin (vitamin B2) supplementation has been suggested as a possible therapy for SCAD deficiency. In one study, a Dutch cohort of 16 individuals with confirmed SCAD deficiency and at-risk genotypes (homozygous for mutation; compound heterozygous for mutation and a susceptibility variant; homozygous for a susceptibility variant[s]) were treated with riboflavin 10 mg/kg/day for a maximum dose of 150 mg divided three times daily [van Maldegem et al 2010b]. FAD levels were within normal range in all individuals throughout the study, though they were the lowest in the subgroups with genotypes that were either compound heterozygous for mutation and susceptibility variant or homozygous for a susceptibility variant. Plasma levels of C4-C (butrylcarnitine) remained essentially unchanged throughout the study period across all subgroups.Urine EMA levels decreased only in the subgroup of compound heterozygotes for mutation and susceptibility variant. Four of 16 demonstrated biochemical changes and exhibited clinical improvement per parent report. Of note, these four individuals had the lowest baseline FAD levels and maintained biochemical and clinical improvements even after riboflavin supplements were discontinued. No genotype-phenotype correlations for riboflavin responsiveness could be identified.In another retrospective study, 15 individuals with SCAD deficiency ascertained over a period of seven years were challenged with fasting and fat-loading tests [van Maldegem et al 2010a]. Three genotypic subgroups were defined: homozygous for mutation, heterozygous for mutation and a susceptibility variant, and homozygous for a susceptibility variant. Free carnitine levels were normal in all individuals. When fasted, three individuals developed ketotic hypoglycemia associated with decreased insulin levels and increased levels of growth hormone and cortisol. Lactate, pyruvate, and plasma ammonia concentrations were normal and plasma amino acid concentrations were consistent with normal gluconeogenesis and normal proximal urea cycle function [van Maldegem et al 2010a]. Note: In contrast, in disorders of medium- and long-chain fatty acid oxidation fasting has been associated with a Reye-like illness with elevated plasma ammonia concentrations and severe hypoketotic hypoglycemia, suggesting impairment of gluconeogenesis and the proximal urea cycle. Fat-loading elicited a normal ketogenic response without a rise in urine EMA, confirming previous speculation that ketogenesis is likely normal in SCAD deficiency [Bennett 2010, van Maldegem et al 2010a].In the two studies described above as well as previous case reports, hypoglycemia occurred in fewer than 20% of individuals with SCAD deficiency and normal ketogenesis was observed ensuring cellular energy during some physiologic stressors.Prevention of Primary ManifestationsPreventive measures if necessary include avoidance of fasting longer than 12 hours (during childhood) and an age-appropriate heart-healthy diet. Age-appropriate shorter fasting periods would be required in infants and toddlers. No dietary fat restriction or specific supplements are recommended in SCAD deficiency [Bennett 2010, van Maldegem et al 2010a].SurveillanceLongitudinal follow up of persons with SCAD deficiency may be helpful in order to more clearly define the natural history over the life span, including annual visits to a metabolic clinic to assess growth and development as well as nutritional status (protein and iron stores, concentration of RBC or plasma essential fatty acids, and plasma carnitine concentration). For individuals with a history of metabolic acidosis, hypoglycemia, and/or other acutely presenting symptoms, the need for closer follow up and surveillance should be determined by the physician.Agents/Circumstances to AvoidFasting longer than 12 hours especially during a febrile or gastrointestinal illness may predispose an affected individual to dehydration, metabolic acidosis, and/or hypoglycemia. Shorter fasting periods (at least the normal age-appropriate recommendations) should be followed in infants and toddlers. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementMothers of children diagnosed with fatty acid oxidation disorders, including SCAD deficiency, should inform their obstetrician so routine monitoring for pregnancy complications is observed. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Short-Chain Acyl-CoA Dehydrogenase Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDACADS12q24.31Short-chain specific acyl-CoA dehydrogenase, mitochondrialACADS homepage - Mendelian genesACADSData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Short-Chain Acyl-CoA Dehydrogenase Deficiency (View All in OMIM) View in own window 201470ACYL-CoA DEHYDROGENASE, SHORT-CHAIN, DEFICIENCY OF; ACADSD 606885ACYL-CoA DEHYDROGENASE, SHORT-CHAIN; ACADSMolecular Genetic Pathogenesis Possible pathogenic explanations for the observation that most individuals with short-chain acyl-CoA dehydrogenase (SCAD) deficiency do not present with the classic picture of metabolic acidosis and hypoketotic hypoglycemia characteristic of many fatty acid oxidation disorders include the following: SCAD is only needed at the end of the β-oxidation cycle; therefore, gluconeogenesis and ketogenic capacity from the preceding steps of fatty acid oxidation may be sufficient to meet cellular energy needs [van Maldegem et al 2010b]. Overlapping substrate specificity by medium-chain acyl CoA dehydrogenase (MCAD) may partially compensate for deficient SCAD activity [Bennett 2010]. Developmental delay and seizures, findings uncommon in other fatty acid oxidation defects, raise the possibility of a neurotoxic effect in SCAD deficiency directly related to metabolite accumulation [Gregersen et al 2001, Jethva et al 2008, van Maldegem et al 2010c]. Ethylmalonic acid (EMA) inhibits creatine kinase activity, increases lipid peroxidation and protein oxidation, and reduces glutathione levels in the cerebral cortex of Wistar rats [Chen et al 2003, Schuck et al 2010]. EMA inhibits electron transport chain activity in vitro [Barschak et al 2006]. Dicarboxylic acids such as EMA do not cross the blood-brain barrier, and thus sequester in the CNS, another possible explanation of EMA toxicity resulting in neurologic findings [Schuck et al 2010]. EMA toxicity may play a role in the neurologic dysfunction observed in ethylmalonic encephalopathy, characterized by psychomotor delays and progressive pyramidal findings resulting from basal ganglia and white matter damage caused by accumulation of large amounts of butyrylcarnitine and EMA [Barth et al 2010]. However, ethylmalonic encephalopathy is caused by mutations in ETHE1, the gene encoding a mitochondrial protein involved in scavenging reactive oxygen species (ROS); thus, a direct role for EMA in neurotoxicity is not clear. Butyric acid, which accumulates in SCAD deficiency, can modulate gene expression at high levels as a result of its action as a histone deacetylase [Chen et al 2003]. Its volatile nature may also add to its neurotoxic qualities [Chen et al 2003, Pedersen et al 2008, Bennett 2010]. Most mutations identified in persons diagnosed with SCAD deficiency, including the Ashkenazi Jewish ACADS pathologic variant c.319C>T, are missense mutations that lead to intramitochondrial aggregation of misfolded protein, suggesting that this protein aggregation itself could be cytotoxic [Gregersen et al 2001, Pedersen et al 2008, Bennett 2010]. The majority of diseases associated with misfolded proteins exhibit mitochondrial dysmorphology and evidence of increased oxidative stress in cells. In one study, astrocytes transfected with ACADS c.319C>T variant accumulated reactive oxygen species (ROS) and demonstrated mitochondrial dysmorphology consistent with a fission defect that could contribute to cellular apoptosis [Schmidt et al 2010]. Thus, it is possible that the effect on SCAD protein misfolding could be modulated by genetic background, which in turn would lead to variable expressivity of disease [Tein et al 2008, Schmidt et al 2010]. Normal allelic variants. ACADS is approximately 13 kb long, comprises ten exons, and includes 1,236 nucleotides of coding sequence [Jethva et al 2008]. Pathologic allelic variants. At least 70 ACADS mutations, most of which are missense, have been reported.Two nucleotide susceptibility variants have been reported [van Maldegem et al 2010c]. Most individuals who are homozygous for the variants are asymptomatic, although the presence of the variants is thought to represent a susceptibility state that requires one or more other genetic or environmental factors to be present for disease to development [Gregersen et al 2001, van Maldegem et al 2010c]. c.511C>T in exon 5 c. 625G>A variant in exon 6 Both variants are relatively common in the general population. In a study of 694 newborns in the United States, approximately 6% were c.625G>A homozygous, 0.3% were c.511C>T homozygous, and 0.9% were compound heterozygous (one allele with each variation) [van Maldegem et al 2010c]. This provides an allele frequency of 0.22 for the c.625G>A variant and 0.03 for the c.511C>T variant. In the US, 7% of the population is estimated to be either homozygous for one of the variants or compound heterozygous [Lindner et al 2010]. Individuals homozygous for one of the variants have an increased incidence of excretion of EMA [Bennett 2010]. In one European study, 14% of controls were homozygous for one of the variants as compared to 69% of 133 subjects with increased urinary EMA excretion. Table 2. Selected ACADS Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change (Alias 1)Reference SequencesPathologic c.319C>Tp.Arg107Cys 2 (Arg83Cys) 3NM_000017.2Susceptibility variants(i.e., common variants with uncertain pathogenicity)c.511C>Tp.Arg171Trp 2 (Arg147Trp) 3c.625G>Ap.Gly209Ser 2 (Gly185Ser) 3See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Residue in the precursor peptide3. Residue in the mature enzyme, after cleavage of the 24 N-terminal amino acids of the transit peptide that directs the protein to the mitochondriaNormal gene product. Short chain-specific acyl-CoA dehydrogenase, mitochondrial (SCAD) like all of the acyl-CoA dehydrogenases (ACAD), is a flavoprotein synthesized in the cytosol as a precursor protein that is transported to and further processed to a mature form in mitochondria including proteolytic cleavage of a mitochondrial targeting (transit) peptide at the amino terminus [Battaile et al 2002]. Study of the crystal structure of recombinant rat SCAD has revealed a homotetramer arranged as a dimer of dimers that is highly conserved with the other ACAD structures: a glutamic acid residue located at amino acid position 368 of the mature rat SCAD protein (homologous to position 376 in MCAD) acts as the catalytic base to initiate the catalytic reaction [Battaile et al 2002]. In vitro studies show that mutation of this residue in the rat SCAD enzyme to a Gln or Ala inactivates the enzyme. Each enzyme also has amino acid residues specific to its particular function. In vitro studies in rat SCAD also show that Gln-254 and Thr-364 appear to shorten the substrate binding pocket and contribute to its substrate specificity [Kim et al 1993]. Abnormal gene product. Nearly all individuals identified with short-chain acyl-coA dehydrogenase (SCAD) deficiency described to date have missense mutations that lead to protein misfolding, which may provide insight into possible pathologic effects of SCAD [Schmidt et al 2010]. The loss of SCAD enzymatic activity clearly leads to the accumulation of abnormal organic acids; the true risk of this loss of function may be acute metabolic acidosis with physiologic stress [Schuck et al 2010]. Aggregation of abnormally folded SCAD protein in patient cells is distinct and may lead to otherwise unexpected cellular toxicity [Schuck et al 2010]. Moreover, SCAD misfolding is aggravated by environmental factors that may vary person to person, and interact with currently uncharacterized factors to cause disease in some individuals [Gregersen et al 2001, Bennett 2010, Pedersen et al 2008].