Clinical Guidance

Genotype-phenotype correlation is seen in the three known genes that lead to MADD (ETFA, ETFB, and ETFDH) . The information provided here applies to pathogenic variants in all three genes.

Source: GeneReviews — "Multiple Acyl-CoA Dehydrogenase Deficiency"

Diagnostic Criteria

Formal clinical diagnostic criteria for multiple acyl-CoA dehydrogenase deficiency (MADD) have not been established.

Suggestive Findings

Scenario 1. Abnormal Newborn Screening (NBS) Result

NBS for MADD is primarily based on quantification of the analytes C4, C5, and C8 with or without other higher acylcarnitine species on dried blood spots. Multiple acylcarnitine species (C4, C5, C8, and other higher acylcarnitine) values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, including plasma acylcarnitine and urine organic acid profiles (see , Specific findings). If follow-up biochemical testing supports the likelihood of MADD, additional testing is required to establish the diagnosis .

Source: GeneReviews — "Multiple Acyl-CoA Dehydrogenase Deficiency"

Differential Diagnosis

Disorders of Riboflavin Metabolism Disorders of riboflavin metabolism can mimic multiple acyl-CoA dehydrogenase deficiency (MADD) (both biochemically and clinically) or have overlapping phenotypic features with MADD and should be considered as the primary differential diagnoses. With frequent use of exome sequencing, it is postulated that many individuals diagnosed with MADD of unknown genetic etiology will be identified as having a genetic alteration associated with a disorder of riboflavin metabolism. Cellular uptake of riboflavin is mediated by the transmembrane proteins hRFVT1, hRFVT2, and hRFVT3 (encoded by SLC52A1, SLC52A2, and SLC52A3, respectively). Riboflavin is then converted to the coenzyme flavin mononucleotide by riboflavin kinase and then to flavin adenine dinucleotide (FAD) by FAD synthase (encoded by FLAD1). FAD is a cofactor for electron transfer by the ETF/ETFDH complex from oxidations of fatty acids and some amino acids to the electron transport chain in the inner mitochondrial membrane . If FAD biogenesis is deficient, electron transfer by the ETF/ETFDH complex is compromised, which can result in a clinical presentation mimicking that of MADD (as MADD is caused by impairment of the ETF-ETFDH complex itself; see ). summarizes disorders of riboflavin metabolism presenting as MADD or with overlapping phenotypic features with MADD that should be considered in the differential diagnosis. Table 2. Riboflavin Metabolism Disorders to Consider in the Differential Diagnosis of MADD

Management Guidelines

When multiple acyl-CoA dehydrogenase deficiency (MADD) is suspected during the diagnostic evaluation (i.e., due to abnormal acylcarnitine profile and urine organic acids profile following a positive newborn screening, or evaluation of exercise intolerance and/or muscle weakness in adults), 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 (i.e., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, 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 MADD, the evaluations in and (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6.

Recommended Evaluations Following Initial Diagnosis of MADD in a Neonate

System/Concern | Evaluation | Comment

Metabolic

decompensation | Consult w/metabolic physician / biochemical geneticist specialist metabolic dietitian.1 | Transfer to specialist center w/experience in management of inherited metabolic diseases strongly recommended

• STAT blood gas (arterial or venous), ammonia lactic acid

• Glucose, liver transaminases (AST, ALT)

• Electrolytes w/bicarbonate, BUN, creatinine

Clinical Guidance

Avoid the following:

• Fasting, including periods of preparation and recovery from planned surgery or anesthesia

• Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)

• Inadequate calories following vaccination. Vaccination is safe.

• Dehydration (risk for rhabdomyolysis and acute renal failure)

• High-fat, high-protein diet, including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet

• Volatile anesthetics and those that contain high doses of long-chain fatty acids such as propofol and etomidate. However, a combination of low-dose propofol, fentanyl, and nitrous oxide was used successfully in an individual with MADD .

• Administration of intravenous intralipids during an acute metabolic crisis

Source: GeneReviews — "Multiple Acyl-CoA Dehydrogenase Deficiency"

Therapies Under Investigation

There are few experimental therapies for MADD. Only a few case reports are available to support their utility:

• Sodium D,L-3 hydroxybutyrate (NaHB). Favorable outcome after ketone body treatment has been reported . Ketone bodies not only replace the missing endogenous energy supply but also provide building blocks for myelin synthesis in the brain. Hence, it may be helpful in re-myelination as well as cardiomyopathy .

• Bezafibrate. Bezafibrate is a hypolipidemic drug and an agonist of peroxisome proliferating activator receptor. It increases expression of several enzymes involved in mitochondrial fatty acid oxidation. Bezafibrate was reported to have favorable outcome on acylcarnitine profile in one affected individual and on skin fibroblasts from 12 people with MADD .

Source: GeneReviews — "Multiple Acyl-CoA Dehydrogenase Deficiency"

Surveillance Guidelines

Published guidelines for surveillance are not currently available. In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations in are recommended.

Table 12.

Recommended Surveillance for Individuals with MADD

Manifestation/Concern | Evaluation | Frequency/Comment

Metabolic control

| Plasma free total carnitine, acylcarnitine profile, CK, urine organic acid | At each visit

Poor growth

| Measurement of head circumference1 growth

Delayed acquisition

of developmental

milestones | Monitor developmental milestones.

Neuropsychological testing using age-appropriate standardized assessment batteries | As needed

Standardized quality-of-life assessment tools for affected persons parents/caregivers

Cardiomyopathy

| EKG, echocardiography | Annually for severe forms; less frequently for milder presentations

CK = creatine kinase

1. In infants and children

Source: GeneReviews — "Multiple Acyl-CoA Dehydrogenase Deficiency"