Medium-chain acyl coenzyme A dehydrogenase deficiency

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: ACADM (HGNC:89)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 08/03/2020
• Curation Status: Released (1.0.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
ACADM	medium chain acyl-CoA dehydrogenase deficiency (0008721)	201450	Strong Actionability

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity associated with metabolic decompensation / Metabolic management (dietary management and illness protocols)	2	3N	3B	3	11NB
Morbidity associated with metabolic decompensation / Carnitine therapy when carnitine levels are insufficient	2	3N	0D	3	8ND
Mortality associated with metabolic decompensation / Metabolic management (dietary management and illness protocols)	3	2C	3B	3	11CB
Mortality associated with metabolic decompensation / Carnitine therapy when carnitine levels are insufficient	3	2C	0D	3	8CD

Severity of Outcome

Prevalence of the Genetic Condition

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common inborn error of metabolism and occurs in an estimated 5.3 (99% CI: 4.1-6.7) per 100,000 births. MCAD deficiency is prevalent in individuals of (especially northern) European descent. In the US, prevalence ranges from 1/13,000 to 1/19,000 live births. Native Americans may have a prevalence similar to northern Europeans (1/7500 live births). Prevalence is similar among newborns of Hispanic, Black, and Middle Eastern origin (1/23,000 live births). Estimates for incidence across the world are 1/51,000 in Japan, 1/18,000 in Saudi Arabia, 1/263,500 in Taiwan, 1/19,000 in New South Wales of Australia, 1/4900 in northern Germany, 1/24,900 in Austria, 1/23,000 in central Italy, and 1/23,400 in Canada.

Clinical Features (Signs / symptoms)

MCAD is an enzyme involved in fatty acid-β oxidation. An individual with MCAD deficiency is at risk of metabolic decompensation when their energy needs are not met with exogenous sources and have to rely on stored fat, such as during prolonged fasting or periods of higher energy demand. Clinical symptoms in a previously apparently healthy individual with MCAD deficiency include hypoketotic hypoglycemia and nausea or vomiting that may progress to lethargy, seizures, coma, and even sudden death. Symptoms may be triggered by a common illness, fasting, excessive drug or alcohol intake, diarrhea, or vomiting and can progress to seizures or coma within 1-2 hours of onset; on occasion, seizures or coma may be the presenting sign. Hepatomegaly and liver disease are often present during an acute episode. Uncontrolled metabolic decompensation can increase the risk of neurological findings secondary to brain injury (e.g. loss of developmental milestones) and chronic muscular weakness.

Natural History (Important subgroups & survival / recovery)

Children with MCAD deficiency appear normal at birth and, if not identified through newborn screening, typically have the first acute episode between age 3 and 24 months, although presentation as late as adulthood is possible. Late-onset presentations have been described in adults after prolonged fasting, including after fasting for surgery, or with alcohol intoxication, often with fatal results. Infants and young children with MCAD deficiency are at a greater risk of metabolic decompensation than older children and adults. Prognosis in infants and young children is excellent once the diagnosis is established and frequent feedings are instituted to avoid prolonged periods of fasting. MCAD deficiency can manifest with sudden and unexpected death, even as late as in adulthood.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

>1-2 in 100

The carrier frequency of c.985A>G, the most common variant, is between 1/40 and 1/100 in northern Europeans, suggestive of a founder effect. A similar prevalence has been observed among Portuguese with Roma ancestry and Native Americans of California.

Tier 3

1-2 in 500

A recent newborn screening study in Denmark estimated the carrier frequency of c.985A>G as 1/105.

Tier 5

Unknown

More than 98% of cases of MCAD deficiency have a pathogenic variant in ACADM, with the c.985A>G variant accounting for between 56-91% of cases.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

5-39 %

If the diagnosis of MCAD deficiency has not been previously established, at least 18% and up to 25% of affected individuals die during their first metabolic crisis.

Tier 3

>= 40 %

Newborn screening followed by confirmatory variant analysis of 519,350 newborns in Denmark estimates the incidence of MCAD deficiency as 1/8954. This estimate is four times higher than the incidence of 1/39,691 of clinically presenting cases during the 10-year period prior to initiation of newborn screening. The discrepancy was explained by both a difference in variant spectrum, with the screened population having high numbers of variants associated with a milder biochemical phenotype, as well as a reduced penetrance of 50% of the common c.985A>G variant.

Tier 5

>= 40 %

A case series of 14 individuals affected with MCAD deficiency who presented in adulthood (age range 16 to 45 years) reported a 50% mortality rate in acutely presenting cases and a 29% mortality rate overall. Mortality in the infantile cases is approximately 25%.

Tier 5

Expressivity

Some individuals with MCAD deficiency may remain asymptomatic, and some individuals with a “milder” biochemical phenotype can still develop life-threatening symptoms.

Tier 3

Intervention Effectiveness

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening: https://www.acmg.net/PDFLibrary/C8-C6-C10.pdf

To establish the extent of disease in an asymptomatic individual with a diagnosis of MCAD deficiency, the following evaluations are recommended:

• Plasma acylcarnitine, and free and total carnitine analyses

• Urine acylglycine and organic acid analyses

• Consultation with a biochemical geneticist, clinical geneticist, and/or genetic counselor.

Tier 4

The mainstay for prevention of primary manifestations in asymptomatic patients with MCAD deficiency is avoidance of prolonged fasting. Infants and children require frequent feedings, with maximum “safe fasting times” of 4-12 hours depending on age. The times are based on the few single patient reports of controlled fasting studies in infants and the feeding practices that have proven successful in avoiding symptomatic episodes in screened populations elsewhere in the world. Older children and teenagers should continue to eat regularly and avoid prolonged overnight fasts by having a starchy bedtime snack and not to miss or have a late breakfast. Adults should continue to avoid fasting and eat a heart-healthy, age appropriate diet. Prolonged and/or intense exercise should be "covered" with adequate carbohydrate intake and hydration.

Tier 2

There is a risk of metabolic decompensation during surgery, particularly if catabolism is precipitated by fasting and surgery. It is important to minimize catabolism by providing adequate amounts of carbohydrate (orally or intravenously) prior to and during surgery. Operations should be postponed, if possible, in children who are unwell.

Tier 2

Careful monitoring during trauma and injury is important given increased caloric needs and the risk of decreased intake due to pain and possible alteration in mental state.

Tier 2

Immediate attention and therapy during an acute crisis are key to preventing sudden death. Patients should be assessed and treated aggressively for the precipitant of the metabolic decompensation (e.g., dehydration, fever, infection). Treatment is aimed at reversal of catabolism and prevention of hypoglycemia by giving simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or intravenous fluids.

Tier 2

Low-dose L-carnitine supplementation is recommended when carnitine levels are below the normal range. Individuals with MCAD deficiency may develop a secondary carnitine deficiency as excess medium chain fatty acids bind to free carnitine and are excreted.

Tier 2

Exercise studies in individuals with MCAD deficiency have had mixed results on the effects of supplementation, with some showing improved exercise tolerance and increased carnitine concentrations in muscle and plasma while others have shown no improvement in exercise tolerance or reduction of fatty acid oxidation rates. Carnitine supplementation has also shown no improvement in detoxification of medium-chain fatty acids or response to fasting.

Tier 3

Individuals should be provided with an emergency protocol/letter to carry at all times. They should be strongly advised to seek medical attention if the individual with MCAD deficiency has an acute illness accompanied by poor intake, vomiting, and/or lethargy. The letter should contain patient identifiers, description of the disorder, emergency treatment protocol, and contact information for the metabolic specialist.

Tier 2

Pregnant women should receive supplemental carnitine to account for reduced plasma free carnitine levels during pregnancy, though free carnitine may still not reach pre-pregnancy levels. Intravenous glucose should be started as soon as labor begins and continued until the patient has adequate oral intake and can maintain normoglycemia.

Tier 2

Surveillance

Regular surveillance should include assessment of anthropometrics, blood carnitine, and diet.

Tier 2

Circumstances to Avoid

Individuals need to be informed that drinking large amounts of alcohol is dangerous. Alcohol intake needs to be limited and must always be taken in combination with food.

Tier 2

Individuals should avoid infant formulas, coconut oil, and other manufactured foods that contain medium-chain triglycerides as the primary source of fat.

Tier 4

Popular high-fat/low-carbohydrate diets and weight loss diets that recommend fasting are not appropriate in MCAD deficiency.

Tier 2

Aspirin has been demonstrated to exacerbate MCAD deficiency by increasing mitochondrial fatty acid oxidation and long-chain fatty acid flux, and inhibiting peroxisomal fatty acid oxidation, which normally serves as a lipitoxic buffer.

Tier 3

Artificial sweeteners should be avoided.

Tier 4

Nature of Intervention

Nature of Intervention

Interventions identified for MCAD deficiency include avoidance of fasting, carnitine supplementation, and regular monitoring. Children with MCAD deficiency are at risk for obesity after initiation of treatment, likely due to the frequency of feeding. The cost of long-term supplementation with carnitine could be significant. Furthermore, while no severe untoward effects of L-carnitine have been reported in individuals with MCAD deficiency, some individuals have complained about nausea, diarrhea, abdominal pain, and a fishy odor at higher doses.

Context: Adult Pediatric

Chance to Escape Clinical Detection

Most children with MCAD deficiency are diagnosed through newborn screening. However, affected children have often been misdiagnosed as having Reye syndrome or episodic hypoglycemic coma.

Context: Adult Pediatric

Tier 4

Sudden and unexpected death can be the first manifestation and may occur as late as adulthood.

Context: Adult Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			ACADM			201450	0008721

References List

ACYL-CoA DEHYDROGENASE, MEDIUM-CHAIN, DEFICIENCY OF; ACADMD. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 201450, (2014) World Wide Web URL: http://omim.org/

Andresen BS, Lund AM, Hougaard DM, Christensen E, Gahrn B, Christensen M, Bross P, Vested A, Simonsen H, Skogstrand K, Olpin S, Brandt NJ, Skovby F, Nørgaard-Pedersen B, Gregersen N. (2012) MCAD deficiency in Denmark. Molecular genetics and metabolism. 106(1096-7206):175-88.

British Inherited Metabolic Diseases Group. Adult emergency management; Medium chain fat oxidation disorders. (2018) URL: http://www.bimdg.org.uk/store/guidelines/ADULT_MCAD-rev_2015_566641_09012016.pdf

British Inherited Metabolic Diseases Group. Management of surgery in children with MCAD deficiency. (2017) URL: http://www.bimdg.org.uk/store/guidelines/Management_of_surgery_in_children_with_MCADD_2017_234496_15042017.pdf

British Inherited Metabolic Diseases Group. Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) - Acute Illness/Decomposition (standard version). (2020) URL: http://www.bimdg.org.uk/store/guidelines/ER-MCADD-v5_232766_05042017.pdf

Dixon, M. Champion, M. British Inherited Metabolic Diseases Group - Dietitians' Group. Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) - Dietary management guidelines for dietitians. (2007) URL: http://www.bimdg.org.uk/store/guidelines/ER-MCADD-v5_232766_05042017.pdf

Frazier, D.M.. Medium chain acyl CoA dehydrogenase deficiency (MCADD). Genetic Metabolic Dietitians International: Nutrition Guidelines (2008) URL: http://gmdi.org/Resources/Nutrition-Guidelines/MCAD

Lang TF. (2009) Adult presentations of medium-chain acyl-CoA dehydrogenase deficiency (MCADD). Journal of inherited metabolic disease. 32(1573-2665):675-683.

Medium chain acyl-CoA dehydrogenase deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=42

Merritt JL, Chang IJ. (1993) Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. GeneReviews^®.

New England Consortium of Metabolic Programs. Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD). (2013) URL: https://newenglandconsortium.org/for-professionals/acute-illness-materials/fatty-acid-oxidation-disorders/medium-chain-acyl-coa-dehydrogenase-deficiency-mcadd/