What is it with SCAD?

When talking about fatty acid oxidation disorders, (FAODs, or FOD)s, the conversation generally centers around is it MCAD or one of the long-chain disorders? MCAD is relatively common, FOD-wise, and together, so are the long-chain FODs. Then there’s SCAD – short-chain acyl-CoA dehydrogenase deficiency – the red-headed stepchild in the FOD family.

SCAD is often misunderstood by both families and medical teams unfamiliar with the disorder. There are good reasons for this. Once thought of as extremely rare, expanded newborn screening (NBS) is catching more cases, though some states have declined to add SCAD to their panel because their criteria for testing finds SCAD risk too low to include. Many cases found by the NBS are, in fact, asymptomatic. Individuals identified later are typically symptomatic pre-diagnosis.

Another reason SCAD confounds people is because of the singular way it behaves in the body. Unlike MCAD and long-chain disorders, which react to the ingestion of certain chain-length fats, short-chain fatty acids are produced in the gut in response to the intake of partially and non-digestible carbohydrates and fiber. This writer can find no medical literature that suggests limiting such intake and indeed these carbs and fiber are beneficial to gut health.

Most SCAD patients are also not deficient in carnitine, as are many individuals with other FODs. The most telling test result for SCAD is an accumulation of butyrylcarnitine (C4-C), butyrylglycine, or ethylmalonic acid (EMA) in the blood, urine and cells.

Yet another thing about SCAD that creates confusion is that not only are there many asymptomatic individuals with SCAD, but there are also those who exhibit symptoms of other disorders, such as endocrine imbalances. SCAD is one FOD that requires genetic testing to get a clear picture of the genotype involved. Some mutations are known to cause serious symptoms while others may be susceptibility variants and responsible for other, underlying disorders such as ethylmalonic aciduria, which may be considered a separate inborn error of metabolism. It may seem like medicine is splitting hairs here, but understanding the differences between a pathogenic mutation and a susceptibility variant, can help doctors treat patients with great effectiveness.

Also, keep in mind that SCAD was first described in 1987 and some doctors may not have kept up with the research on the disorder. It is folly to dismiss it as not serious based solely on a NBS or acylcarnitine profile. While most patients with SCAD do not experience hypoketotic hypoglycemia, they may well suffer from hypoglycemia under stressful conditions and may also experience a range of other symptoms common to FODs: acidosis, lethargy, hypotonia, even muscle-wasting. Much depends on the genotype. Also, it is one of the FODs that can produce acute fatty liver of pregnancy (AFLP) or preeclampsia, or HELPP syndrome in the mothers of affected fetuses.

An interesting study from last year, showed that SCAD mice shift their food choice from fat to carbohydrate when offered a choice. This suggests a link between fatty acid oxidation and fat selection. It may also explain why FOD-affected individuals may seem to prefer carbs over fats. [Ghosh 2016] This study also showed that a high fat diet in the SCAD mice increased acylcarnitine levels in the liver as well as reduced ATP (energy) production. This should explain why SCAD patients are typically cautioned against a high-fat diet, even though their mitochondria can handle medium- and long-chain fats.

The bottom line for SCAD families is simply this: the clinical spectrum of SCAD is varied. There are, as of 2016, 59 known ACADS mutations. Of these, 11 are new variants and of those, three are “drastic changes” – two nonsense mutations and one deletion, which, according to the authors, “clearly give rise to deleterious effects on the corresponding SCAD proteins.” [Tonin 2016] So, not all mutations will cause serious effects. Some may cause no effects; some may cause symptoms only under stress, such as fasting or excessive heat; others may well be serious.

This same study appears to conclude that molecular data analysis (genetic tests) should be used to identify those with SCAD who are at risk for such long-term consequences as neurological manifestations. Also, these researchers found that “silent” or “synonymous” mutations do cause disease though these were once believed to have no effect.

Science is learning more about SCAD and other FODs every year. Families and doctors must do the best with the information they have. References for this article are listed below. Both cited articles are open access.

Clinical relevance of short-chain acyl-CoA dehydrogenases (SCAD) deficiency: Exploring the role of new variants including the first SCAD-disease-causing allele carrying a synonymous mutation Rodolfo Tonin et al BBA Clin (2016) June 5 doi: 10.1016/j.bbacli.2016.03.004

Short chain acyl-CoA dehydrogenase deficiency and short-term high-fat diet perturb mitochondrial energy metabolism and transcriptional control of lipid-handling in liver Sujoy Ghosh, et al Nutrition & Metabolism (2016) 13:17 doi: 10.1186/s12986-016-0075-0

Genetic Mistakes Forrest/Baugh 2017

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