Short-Chain Acyl-Coa Dehydrogenase Deficiency

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2021-01-18
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Summary

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.

Diagnosis

Short-chain acyl-CoA dehydrogenase deficiency (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.

Most infants with 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. Some affected individuals have been identified through metabolic evaluation for developmental delay. 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.

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.

Positive Newborn Screening (NBS) Result

NBS for SCADD is primarily based on acylcarnitine analysis by tandem mass spectrometry to detect elevated blood C4 (butyrylcarnitine).

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 Sheet. (2) Isobutyryl-CoA dehydrogenase deficiency (IBDD) that leads to elevation of isobutyrylcarnitine, a C4 species also detectable by NBS, must be distinguished from SCADD by additional laboratory testing.

C4 values above the cutoff reported by the screening laboratory are considered positive and require additional biochemical testing and in most cases molecular genetic testing to establish the diagnosis (see Establishing the Diagnosis).

Symptomatic Individuals

For symptomatic individuals who were not identified on NBS, the following nonspecific clinical features and preliminary laboratory findings support a diagnosis of SCADD:

  • Clinical findings. Hypotonia, dystonia, seizures, metabolic acidosis associated with illness, and/or hypoglycemia [Corydon et al 2001]
  • Preliminary laboratory findings. Increased C4 concentrations in plasma and/or increased ethylmalonic acid (EMA) concentrations in urine on biochemical evaluation
    Note: Because elevations of these metabolites individually are not entirely specific to SCADD, follow-up testing to establish or rule out the diagnosis of SCADD is required (see Establishing the Diagnosis).

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 1

When NBS results and other laboratory findings suggest the diagnosis of SCADD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Perform sequence analysis first. If clinically necessary and only one or no pathogenic variant is found, gene-targeted deletion/duplication analysis could be considered; however, to date no large deletions or complex rearrangements involving ACADS have been reported for SCADD.
    Note: Two common ACADS variants, c.511C>T and c.625G>A, result in the SCADD biochemical abnormality when in trans with a pathogenic variant. Newborns homozygous for the c.625G>A variant have laboratory test values that overlap with those of affected (i.e., with 2 pathogenic variants) newborns. These variants are not associated with clinical manifestations of SCADD.
  • A multigene panel that includes ACADS and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

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

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
ACADSSequence analysis 3~100% 4
Gene-targeted deletion/duplication analysis 5Unknown6
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

In individuals with biochemical findings consistent with the diagnosis of SCADD [van Maldegem et al 2006, Pedersen et al 2008, Gallant et al 2012]. Most infants with newborn screen results consistent with SCADD are either homozygous for a pathogenic variant on both ACADS alleles or compound heterozygous for a pathogenic variant on one allele and a c.511C>T or c.625G>A variant on the other allele [Lindner et al 2010]; however, newborns homozygous for the c.625G>A variant have laboratory test values that overlap with those of affected (i.e., with 2 pathogenic variants) newborns.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Most studies have performed only sequence analysis; therefore, no data on detection rate of gene-targeted deletion/duplication analysis are available. Given the proposed mechanism of disease, such events are likely to be rare.

Clinical Characteristics

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].

SCADD appears to be pan ethnic.

Differential Diagnosis

Other disorders to consider in the differential diagnosis:

  • Isobutyryl-CoA dehydrogenase deficiency (IBDD) (OMIM 611283). IBDD, also detectable by NBS, leads to elevation of isobutyrylcarnitine, a C4 species indistinguishable from butyrylcarntine without additional separation techniques. IBDD presents with relatively mild and nonspecific hypotonia and is most often asymptomatic at birth. Thus, it is clinically identical to short-chain acyl-CoA dehydrogenase deficiency (SCADD) in newborns. IBDD is caused by biallelic variants in ACAD8.
  • Glutaric acidemia type II (GAII), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), can present with ethylmalonic acid in urine and C4 in blood but has distinguishing biochemical characteristics related to secondary deficiencies of all of the fatty acyl-CoA dehydrogenases. This disorder is caused by biallelic variants in one of three genes: ETFA, ETFB, or ETFDH.
  • Ethylmalonic encephalopathy (OMIM 602473) presents with ethylmalonic acid in urine at much higher levels than in SCADD. C4 may be higher, but as in GAII, other metabolites may be elevated. The clinical characteristics of orthostatic acrocyanosis, petechiae, and severe neurologic symptoms distinguish it from SCADD. This disorder is caused by biallelic variants in ETHE1.
  • Mitochondrial respiratory chain defects are a group of pleotropic disorders that may show mild elevation of ethylmalonic acid in urine and C4 in blood. In practice, these disorders may be the most difficult to distinguish from SCADD, and in minimally symptomatic individuals without lactic acidemia, molecular testing may be necessary to establish a diagnosis.
  • Jamaican vomiting sickness. This condition, characterized by acute hypoglycemia, is caused by eating the unripe ackee fruit, which contains an inhibitor of the acyl-CoA dehydrogenases. The effect is most pronounced for long-chain and medium-chain enzymes, and thus, while small amounts of short-chain organic acids may be seen in urine, the biochemical diagnosis is straightforward.

Management

To establish the extent of disease and needs in an individual diagnosed with short-chain acyl-coA dehydrogenase deficiency (SCADD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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.