Short-Chain Acyl-CoA Dehydrogenase Deficiency

Clinical characteristics.

Most infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria are reported. Thus, SCADD is now viewed as a biochemical phenotype rather than a disease. A broad range of clinical findings was originally reported in those with confirmed SCADD, including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported. In a large series of affected individuals detected on metabolic evaluation for developmental delay, 20% had failure to thrive, feeding difficulties, and hypotonia; 22% had seizures; and 30% had hypotonia without seizures. In contrast, the majority of infants with SCADD have been detected by expanded newborn screening, and the great majority of these infants remain asymptomatic. As with other fatty acid oxidation deficiencies, characteristic biochemical findings of SCADD may be absent except during times of physiologic stress such as fasting and illness. A diagnosis of SCADD based on clinical findings should not preclude additional testing to look for other causes.

Diagnosis/testing.

SCADD has been defined as the presence of:

• Increased butyrylcarnitine (C4) concentrations in plasma and/or increased ethylmalonic acid (EMA) concentrations in urine under non-stressed conditions (on at least two occasions);
  AND
• Biallelic ACADS pathogenic variants.

Management.

Treatment of manifestations: As most individuals with SCADD are asymptomatic, there is no need for treatment. There are no generally accepted recommendations for dietary manipulation or use of carnitine and/or riboflavin supplementation.

Prevention of primary manifestations: No preventive measures are necessary.

Surveillance: Longitudinal follow up of persons with SCADD on a research basis 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).

Genetic counseling.

SCADD is inherited in an autosomal recessive manner. At conception, each sib of an individual with SCADD has a 25% chance of inheriting biallelic ACADS pathogenic or susceptibility variants and possibly developing clinical findings associated with SCADD, a 50% chance of being a carrier of an ACADS pathogenic variant, and a 25% chance of not being a carrier. If the pathogenic variants in the family have been identified, carrier testing for at-risk family members is possible, and prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible but not necessary and not recommended.

Suggestive Findings

Short-chain acyl CoA dehydrogenase deficiency (SCADD) should be suspected in infants with a positive newborn screening result and in symptomatic individuals with supportive clinical and laboratory findings.

Establishing the Diagnosis

The diagnosis of SCADD is established in a proband with typical findings on biochemical testing and confirmed by molecular genetic testing of ACADS with the identification of biallelic pathogenic variants (see Table 1).

Note: Two common variants may lead to the biochemical phenotype, but are not clinically relevant (see Table 1, footnote 4).

Biochemical testing

• Acylcarnitine profile testing is used to confirm C4 elevations.
• Urine acylglycines. A random urine sample can be used to differentiate butyrylglycine and isobutyrylglycine and to detect elevated ethylmalonic acid (EMA) as part of either confirmatory testing after a positive newborn screen or diagnostic testing in older children and adults being evaluated for SCADD.
• 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].

Molecular genetic testing approaches, which depend on the clinical findings, can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (typically exome sequencing and exome array).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Children with the distinctive laboratory findings of SCADD described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas symptomatic individuals with nonspecific supportive clinical and laboratory findings (i.e., who had not undergone NBS or had normal NBS results) in whom the diagnosis of SCADD has not been considered are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Option 2

When the diagnosis of SCADD has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic; however, to date no large deletions or complex rearrangements involving ACADS have been reported for SCADD.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in SCADD

Clinical Description

A broad range of clinical findings was originally reported in those with confirmed short-chain acyl-coA dehydrogenase deficiency (SCADD), including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported.

SCADD 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 SCADD in persons with the biochemical phenotype has identified a much broader phenotypic spectrum than originally anticipated.

Since most infants with SCADD 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]. Most recent publications based on newborn screening identification have suggested that SCADD causes only a biochemical phenotype that is not clinically relevant, although occasional publications demonstrating some cellular phenotype related to SCADD still appear in the literature [van Maldegem et al 2006, Jethva et al 2008, van Maldegem et al 2010c, Gallant et al 2012, Tonin et al 2016, Nochi et al 2017].

The most convincing study on the clinical relevance of SCADD was reported in 76 babies out of 2,632,058 screened in California over a five-year period [Gallant et al 2012]. Clinical follow up was available on 31 infants, none of whom had any findings suggestive of a metabolic disorder. Seven of these babies with available molecular information were homozygous or compound heterozygous for two pathogenic variants, eight had one pathogenic variant and either the c.511C>T or c.625G>A variant (see Table 1), and seven had two alleles that were either c.511C>T or c.625G>A. In an additional study of 12 individuals with biochemical findings suggestive of SCADD, ten were identified before age three weeks; all were either asymptomatic or reported to have mild hypotonia [Tonin et al 2016]. Two older individuals with variable symptoms were shown only to have the common benign polymorphisms.

All older reports on SCADD identified symptomatic individuals retrospectively; many of such reports did not differentiate between true deficiency and the presence of the c.511C>T or c.625G>A variant. Pedersen et al [2008] summarized the findings in 114 individuals, mostly children undergoing metabolic evaluation for developmental delay. Among the 114 with developmental delay, three subgroups were identified:

• 23 (20%) with failure to thrive, feeding difficulties, and hypotonia
• 25 (22%) with seizures
• 34 (30%) with hypotonia without seizures

Four 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 SCADD and 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, eight improved, and nine had complete recovery. In addition, three parents and six sibs were found to have ACADS genotypes identical to the proband; eight of the nine had increased levels of C4 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 multiminicore myopathy [Tein et al 2008]. It has been noted that persons with SCADD 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 pathogenic variants in RYR1 or SELENON (SEPN1) [van Maldegem et al 2010c].

As in other fatty acid oxidation disorders, characteristic biochemical findings of SCADD 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 SCADD appear to resolve completely during long-term follow up for most individuals diagnosed with SCAD.

Individuals with biallelic common variants (c.511C>T and c.625G>A) are so prevalent in the general population that this finding cannot represent a significant risk for clinical disease (see Molecular Genetics). Individuals with an inactivating pathogenic variant on one allele and one of these variants on the other have enzymatic dysfunction that falls between the those with biallelic common variants and those with biallelic inactivating variants. However, California newborn screening data showed that these babies remained asymptomatic [Gallant et al 2012].

Pregnancy-related issues. Acute fatty liver of pregnancy (AFLP), preeclampsia, and/or HELLP syndrome in mothers of affected fetuses have been described, but causation has not been established [Matern et al 2001, Bok et al 2003, van Maldegem et al 2010c].

Genotype-Phenotype Correlations

No consistent clinical phenotype-genotype correlations have been observed. However, data have suggested a correlation between urinary levels of biomarkers (ethylmalonic acid and methylsuccinic acid) and presence of biallelic pathogenic variants versus one pathogenic and either the c.511C>T or c.625G>A variant on each allele [Gallant et al 2012].

Prevalence

Using fairly strict biochemical and molecular criteria, a birth prevalence of at least 1:50,000 has been estimated in the Netherlands [van Maldegem et al 2006]. A prevalence of 1:34,632 or approximately 1:35,000 was calculated from California data for the incidence in the US [Gallant et al 2012].

Evaluations Following Initial Diagnosis

Once a molecular diagnosis of SCAD deficiency is made, there is no need for additional clinical evaluation or further follow up.

Treatment of Manifestations

Since SCADD is now viewed as a biochemical phenotype rather than a disease, there is no need for treatment.

Given the paucity of research, especially long-term follow-up studies, enrollment in a long-term follow-up study with a biochemical geneticist can be offered.

Prevention of Primary Manifestations

Preventive measures if necessary include avoidance of fasting longer than 12 hours (during childhood) and an age-appropriate heart-healthy diet. For infants and toddlers, age-appropriate shorter limits on fasting periods would be required. No dietary fat restriction or specific supplements are recommended in SCADD [Bennett 2010, van Maldegem et al 2010a].

Surveillance

Longitudinal follow up of persons with SCADD on a research basis, 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), may be helpful in order to more clearly define the natural history over the life span.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of a child with SCADD are obligate heterozygotes (i.e., carriers of one ACADS pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical findings related to SCADD.

Sibs of a proband

• At conception, each sib of an individual with SCADD has a 25% chance of inheriting biallelic ACADS pathogenic variants and possibly developing biochemical findings associated with SCADD, a 50% chance of being a carrier of an ACADS pathogenic variant, and a 25% chance of not being a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical findings related to SCADD.

Offspring of a proband. The offspring of an individual with SCADD are obligate heterozygotes (carriers) for an ACADS pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ACADS pathogenic variant.

Carrier Detection

Carrier testing for at-risk family members is possible if the ACADS pathogenic variants in the family have been identified.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have SCADD, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the ACADS pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are both possible but are unnecessary and not recommended.

Molecular 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].
• While developmental delay and seizures (findings uncommon in other fatty acid oxidation defects) raise the possibility of a neurotoxic effect in SCADD directly related to metabolite accumulation [Gregersen et al 2001, Jethva et al 2008, van Maldegem et al 2010c], clinical follow up of individuals identified by newborn screening argues against any pathogenicity.
  • 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 pathogenic variants 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 SCADD, 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 pathogenic variants identified in persons diagnosed with SCADD, including the Ashkenazi Jewish ACADS pathogenic variant c.319C>T, are missense variants 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 in vitro 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].

Gene structure. ACADS is approximately 13 kb long; the transcript NM_000017.2 comprises ten exons and includes 1,238 nucleotides of coding sequence [Jethva et al 2008]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. At least 70 ACADS pathogenic variants, most of which are missense, have been reported.

Common (susceptibility) variants. Two missense variants have been reported (Table 2) [van Maldegem et al 2010c]. Most individuals who are homozygous for either variant are asymptomatic, although the presence of the variants has been proposed to represent a susceptibility state that requires one or more other genetic factors (e.g., a pathogenic ACADS variant in trans) or environmental factors to be present for disease to develop [Gregersen et al 2001, van Maldegem et al 2010c].

• c.511C>T in exon 5
• c.625G>A 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 or compound heterozygous for one of these common variants [Lindner et al 2010]. Individuals homozygous for one of the variants have a higher incidence of increased 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.

ACADS Variants Discussed in This GeneReview

Normal 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. The precursor protein is transported to the mitochondria and further processed into a mature form via proteolytic cleavage of a mitochondrial targeting (transit) peptide at the amino terminus [Battaile et al 2002].

Abnormal gene product. Nearly all individuals identified with SCAD deficiency described to date have pathogenic missense variants that lead to protein misfolding, which has been postulated to cause pathologic cellular effects of SCAD [Schmidt et al 2010]. Although the loss of SCAD enzymatic activity clearly leads to the accumulation of abnormal organic acids, no specific clinical syndrome has been substantiated when unbiased patient populations are assessed. 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 depending on the individual and may interact with currently uncharacterized factors, constituting a possible risk factor for disease [Gregersen et al 2001, Pedersen et al 2008, Bennett 2010, Schuck et al 2010].

Literature Cited

• Amendt BA, Greene C, Sweetman L, Cloherty J, Shih V, Moon A, Teel L, Rhead WJ. Short-chain acyl-coenzyme A dehydrogenase deficiency. Clinical and biochemical studies in two patients. J Clin Invest. 1987;79:1303–9. [PMC free article: PMC424368] [PubMed: 3571488]

• Barschak AG, Ferreira Gda C, André KR, Schuck PF, Viegas CM, Tonin A, Dutra Filho CS, Wyse AT, Wannmacher CM, Vargas CR, Wajner M. Inhibition of the electron transport chain and creatine kinase activity by ethylmalonic acid in human skeletal muscle. Metab Brain Dis. 2006;21:11–9. [PubMed: 16773466]

• Barth M, Ottolenghi C, Hubert L, Chrétien D, Serre V, Gobin S, Romano S, Vassault A, Sefiani A, Ricquier D, Boddaert N, Brivet M, de Keyzer Y, Munnich A, Duran M, Rabier D, Valayannopoulos V, de Lonlay P. Multiple sources of metabolic disturbance in ETHE1-related ethylmalonic encephalopathy. J Inherit Metab Dis. 2010;33 Suppl 3:S443–53. [PubMed: 20978941]

• Battaile KP, Molin-Case J, Paschke R, Wang M, Bennett D, Vockley J, Kim JJ. Crystal structure of rat short chain acyl-CoA dehydrogenase complexed with acetoacetyl-CoA: comparison with other acyl-CoA dehydrogenases. J Biol Chem. 2002;277:12200–7. [PubMed: 11812788]

• Bennett MJ. Pathophysiology of fatty acid oxidation disorders. J Inherit Metab Dis. 2010;33:533–7. [PubMed: 20824345]

• Bok LA, Vreken P, Wijburg FA, Wanders RJ, Gregersen N, Corydon MJ, Waterham HR, Duran M. Short-chain acyl-CoA dehydrogenase deficiency: studies in a large family adding to the complexity of the disorder. Pediatrics. 2003;112:1152–5. [PubMed: 14595061]

• Chen JS, Faller DV, Spanjaard RA. Short-chain fatty acid inhibitors of histone deacetylases: promising anticancer therapeutics? Curr Cancer Drug Targets. 2003;3:219–36. [PubMed: 12769690]

• Corydon MJ, Vockley J, Rinaldo P, Rhead WJ, Kjeldsen M, Winter V, Riggs C, Babovic-Vuksanovic D, Smeitink J, De Jong J, Levy H, Sewell AC, Roe C, Matern D, Dasouki M, Gregersen N. Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res. 2001;49:18–23. [PubMed: 11134486]

• 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. Biochemical, molecular, and clinical characteristics of children with short-chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California. Mol Genet Metab. 2012;106:55–61. [PubMed: 22424739]

• Gregersen N, Andresen BS, Corydon MJ, Corydon TJ, Olsen RK, Bolund L, Bross P. 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. [PubMed: 11524729]

• Jethva R, Bennett MJ, Vockley J. Short-chain acyl-coenzyme A dehydrogenase deficiency. Mol Genet Metab. 2008;95:195–200. [PMC free article: PMC2720545] [PubMed: 18977676]

• Lindner M, Hoffmann GF, Matern D. Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting. J Inherit Metab Dis. 2010;33:521–6. [PubMed: 20373143]

• Matern D, Hart P, Murtha AP, Vockley J, Gregersen N, Millington DS, Treem WR. Acute fatty liver of pregnancy associated with short-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr. 2001;138:585–8. [PubMed: 11295727]

• Nochi Z, Olsen RKJ, Gregersen N. Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms. J Inherit Metab Dis. 2017;40:641–55. [PubMed: 28516284]

• Pedersen CB, Kølvraa S, Kølvraa A, Stenbroen V, Kjeldsen M, Ensenauer R, Tein I, Matern D, Rinaldo P, Vianey-Saban C, Ribes A, Lehnert W, Christensen E, Corydon TJ, Andresen BS, Vang S, Bolund L, Vockley J, Bross P, Gregersen N. The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level. Hum Genet. 2008;124:43–56. [PubMed: 18523805]

• Schmidt SP, Corydon TJ, Pedersen CB, Bross P, Gregersen N. Misfolding of short-chain acyl-CoA dehydrogenase leads to mitochondrial fission and oxidative stress. Mol Genet Metab. 2010;100:155–62. [PubMed: 20371198]

• Schuck PF, Busanello EN, Moura AP, Tonin AM, Grings M, Ritter L, Vargas CR, da Costa Ferreira G, Wajner M. Promotion of lipid and protein oxidative damage in rat brain by ethylmalonic acid. Neurochem Res. 2010;35:298–305. [PubMed: 19757035]

• Tein I, Elpeleg O, Ben-Zeev B, Korman SH, Lossos A, Lev D, Lerman-Sagie T, Leshinsky-Silver E, Vockley J, Berry GT, Lamhonwah AM, Matern D, Roe CR, Gregersen N. Short-chain acyl-CoA dehydrogenase gene mutation (c.319C>T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin. Mol Genet Metab. 2008;93:179–89. [PubMed: 18054510]

• Tonin R, Caciotti A, Funghini S, Pasquini E, Mooney SD, Cai B, Proncopio E, Donati MA, Baronio F, Bettocchi I, Cassio A, Biasucci G, Bordugo A, la Marca G, Guerrini R, Morrone A. Clinical relevance of short-chain acyl-CoA dehydrogenase (SCAD) deficiency: exploring the role of new variants including the first SCAD-disease-causing allele carrying a synonymous mutation. BBA Clin. 2016;5:114–9. [PMC free article: PMC4816031] [PubMed: 27051597]

• van Maldegem BT, Duran M, Wanders RJA, 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. [PubMed: 16926354]

• van Maldegem BT, Duran M, Wanders RJ, Waterham HR, de Koning TJ, Rubio E, Wijburg FA. Fasting and fat-loading tests provide pathophysiological insight into short-chain acyl-coenzyme a dehydrogenase deficiency. J Pediatr. 2010a;156:121–7. [PubMed: 19800078]

• van Maldegem BT, Duran M, Wanders RJ, Waterham HR, Wijburg FA. Flavin adenine dinucleotide status and the effects of high-dose riboflavin treatment in short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res. 2010b;67:304–8. [PubMed: 19952864]

• van Maldegem BT, Wanders JA, Wijburg FA. Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2010c;33:507–11. [PMC free article: PMC2946545] [PubMed: 20429031]

• 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;95:39–45. [PMC free article: PMC4204643] [PubMed: 18676165]

Author Notes

The American College of Medical Genetics has published online an algorithm delineating the appropriate response to an elevated C4 on newborn screening (ACMG-ACT Sheet and ACMG Algorithm [www.acmg.net]).

Revision History

• 9 August 2018 (ha) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 22 September 2011 (me) Review posted live
• 21 March 2011 (lw) Original submission