Clinical Guidance

A collaborative retrospective analysis of a cohort of 221 affected individuals identified by NBS in the United States showed that C8 level and genotype were significant predictors of neonatal symptoms. Individuals with neonatal symptoms had significantly higher C8 values . While it appears that residual enzyme activity levels better correlate with phenotype , it is reasonable to assume that environmental factors (e.g., diet, stress, or intercurrent illnesses) are critical in determining the natural history of this condition. Several other genotype-phenotype correlations have been described:

Source: GeneReviews — "Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"

Diagnostic Criteria

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common inherited fatty acid beta-oxidation disorder; it leaves affected individuals unable to break down medium-chain fats for energy. Fatty acid beta-oxidation produces reducing equivalents and tricarboxylic acid cycle intermediates for energy generation in all tissues during times of physiologic stress and fasting. It also fuels hepatic ketogenesis, a major source of energy for peripheral tissues after glycogen stores are depleted during prolonged fasting and periods of higher energy demands.

Suggestive Findings

Scenario 1: Abnormal Newborn Screening (NBS) Result

NBS for MCAD deficiency is primarily based on results of a quantitative acylcarnitine profile on dried blood spots (DBS). It is included in most NBS programs ...

Source: GeneReviews — "Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"

Differential Diagnosis

All causes of a Reye-like syndrome (i.e., acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver) need to be considered in the differential diagnosis of medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency, including other disorders of fatty acid beta-oxidation, defects in ketogenesis, urea cycle disorders, organic acidurias, respiratory chain defects, and inborn errors of carbohydrate metabolism (e.g., hereditary fructose intolerance). Disorders of fatty acid beta-oxidation. Because of the nonspecific clinical presentation of MCAD deficiency, distinguishing it from other mitochondrial fatty acid beta-oxidation disorders requires biochemical and molecular testing. Carnitine transport disorders. The carnitine transport disorders are very closely related to the fatty acid beta-oxidation disorders, as they are involved in long-chain fatty acid transport across the mitochondrial inner membrane. These disorders clinically present with a similar combination of hypoketotic hypoglycemia and liver dysfunction as seen in MCAD deficiency. Recurrent rhabdomyolysis, skeletal myopathy, and cardiomyopathy may also develop. Genes of interest in the differential diagnosis of MCAD deficiency are listed in . Table 2. Genes of Interest in the Differential Diagnosis of Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Management Guidelines

Management guidelines for acute illness in individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency have been published (full text). When MCAD deficiency is suspected during the diagnostic evaluation, including on newborn screening (i.e., due to highly elevated C8-, C6-, C10-, and C10:1-acylcarnitines, elevated C8/C10 ratio, and urine hexanoylglycine elevation), metabolic treatment should be initiated immediately. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (e.g., childhood obesity due to frequent feeding) require a multidisciplinary approach with oversight and expertise from a specialized metabolic center.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MCAD deficiency, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Recommended Evaluations Following Initial Diagnosis

Evaluation | Comment

Consultation w/metabolic physician/ biochemical geneticist specialist metabolic dietitian1 | In a symptomatic individual, consider obtaining the following additional laboratory studies, where clinically appropriate:

Source: GeneReviews — "Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"

Clinical Guidance

Hypoglycemia must be avoided by frequent feedings early in life to avoid catabolism – if necessary, by intravenous administration of glucose. Infant formulas, coconut oil, and other manufactured foods containing medium-chain triglycerides as the primary source of fat are not recommended in MCAD deficiency; however, ingesting small amounts is not contraindicated. Popular high-fat/low-carbohydrate diets are not appropriate for individuals with MCAD deficiency. Alcohol consumption, in particular acute alcohol intoxication (e.g., binge drinking), often elicits metabolic decompensation in individuals with MCAD deficiency . 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 .

Source: GeneReviews — "Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"

Therapies Under Investigation

A Phase II dose-escalating clinical trial examining the use of glycerol phenylbutyrate (Ravicti®) in the prevention of hypoglycemia in affected individuals age ≥16 years is currently ongoing (NCT06067802). A previous Phase I clinical trial for the use of glycerol phenylbutyrate at 2, 4, and 6 g/m2/day in four adults with MCAD deficiency who had at least one copy of the common ACADM c.985AG (p.Lys329Glu) pathogenic variant was completed in 2017 (NCT01881984). The primary outcome was changes in the assessment of metabolic stress pre- and post-dosing with Ravicti®. There were no serious adverse events. Other adverse events included gastrointestinal disorders (e.g., dry mouth, nausea, vomiting), elevated phenylbutyrate level, neck pain, decreased reflexes, and thromboembolic event.

Source: GeneReviews — "Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"

Surveillance Guidelines

Infants should establish care with a biochemical genetics clinic including a metabolic dietitian as soon as possible following a positive newborn screen. A metabolic dietician (see gmdi.org) should be involved to ensure proper nutrition in terms of quality and quantity. After the baseline visit and confirmatory testing, affected infants should be seen in team clinic in two to three months, then every six to 12 months if otherwise clinically well. Affected individuals can be seen more frequently by a metabolic dietitian or in clinic as needed to ensure that families understand and are comfortable with treatment while the infant is otherwise well. The frequency of routine follow-up visits is individualized based on comfort level of the affected persons, their families, and health care providers. In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in are recommended to monitor existing manifestations, the individual's response to care, and the emergence of new manifestations.

Table 8.

Medium-Chain Acyl-Co A Dehydrogenase Deficiency: Recommended Surveillance

Manifestation | Evaluation | Frequency/Comment

Abnormal growth, incl poor growth or excessive weight gain1

| Measurement of growth head circumference | At each visit

Delayed acquisition of developmental milestones2

| Monitoring of developmental progress educational needs

Source: GeneReviews — "Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"