Clinical 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].

Testing

SCAD 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 profile

• Acylcarnitine 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].

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 analysis

4.

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.

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 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 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].

Genotype-Phenotype Correlations

No consistent phenotype-genotype correlations have been observed.

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].

SCAD deficiency appears to be pan ethnic with the first cases among Japanese recently reported [Shirao et al 2010].

Evaluations 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 Manifestations

Since 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 Manifestations

Preventive 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].

Surveillance

Longitudinal 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 Avoid

Fasting 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 Risk

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

Pregnancy Management

Mothers 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 Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with SCAD deficiency are obligate heterozygotes (carriers) for a disease-causing ACADS mutation.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations 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 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 are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations or susceptibility variants in the family have been identified, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Biochemical genetic testing. Quantification of butyrylcarnitine or butyrylglycine in amniotic fluid can identify affected fetuses, but the sensitivity and specificity are unknown.

Requests for prenatal testing for conditions which (like SCAD deficiency) do not affect intellect and have a high likelihood of normal clinical outcome are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations or susceptibility variants have been identified.

Molecular 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.

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 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].

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Author Notes

The American College of Medical Genetics has published online an algorithm delineating the appropriate response to an elevated C4 on newborn screening (Newborn Screening ACT Sheets and Confirmatory Algorithms [www.acmg.net]).

Revision History

• 22 September 2011 (me) Review posted live
• 21 March 2011 (lw) Original submission